My Multiple Myeloma Cancer Log
broken neck: 9/14/14 (sun)
hospital stay: 9/15/14 (mon)  - 9/22/14 (mon)
cancer diagnosis: 9/15/14
neck (fusion) operation (Dr. Wh........): 9/18/14 (thur) Follow up:12/24/14, 3/18/15, 9/18/15
radiation (neck and back) (Dr. Hu....., Dr. Ni): 10/7/14 - 10/31/14, 11/17
 hematological oncologist (Dr. .......): 10/14/14, 28/14, 11/17, 12/4, 1/2/15, 2/6, 3/9 - continuing (11/7/14 Dr. ........)
Lahey consulting hematological oncologist (Dr. W.........)
Dana Farber consulting MM specialist (Dr. L.........) (2/16)
Celgene Revlimid purchase (cycle #1) (10,167, no insurance) 11/24/2014
GP (Dr. An...) 10/9/14, 12/3/15
Dr. Ab...& Dr. He... (blood analysis): 10/14/14, 11/17, 12/24, 1/30, 3/2
zometa & carfilzomib infusions: (M.Y. infusion nurse) 10/31/14
(zometa continuing monthly, carfilzomib 3wk on/1wk off)
Dr. Ma..........: 12/9/14, 2/10/15 (bone man)
P.Su.... (physical therapy, neck)
Dr. Ta... and Dr At... 8/16/16 (eye team)
Dr V (4/24/17) (lung man)
       created: 4/6/15

Go to homepage
My related essay 'Medicare Part D and Medigap: What cancer patients on super expensive chemo need to know' is here
My related essay 'Drug Discount Cards Provide Big Savings for Drugs not Covered by Insurance' -- Tutorial into the murky world of buying
                                    erectile dysfunction drugs and other expensive drugs not covered by insurance is here

MM drugs organized by class
      Ninlaro update (4/5/2016)
        Drugs to counter chemo 'side effects' (9/21/17)
      Drugs to increase hemoglobin and RBC (red blood count)

Tracking my cancer
** My key numbers in a table
Introduction (update 7/27/15) (8/11/15) (10/28/15)
Overview (May 2015)
MM tracking numbers
Overview of my numbers (cycles 1 - 17.5)
         My numbers start to rise (10/26/15)
* Plot of my numbers (1 - 9 months)
         Plot of my M-spike numbers for 12 months of 2016
         Plot of my M-spike and lambda free light chain for much of 2017
         Equivalent Freelite plot
Change in my numbers  (4/15/16)
Change in my numbers  (4/4/16)
Change in my numbers  (12/1/15)
Thresholds to trigger chemo change
Cycle 9.5 confirms (9/4/15)
Cycle 8.5  results --- Too good to be true? (8/10/15)
Cycle 7.5

My cancer diagnosis story
Can't get my head off pillow for 30 min!
Cancer diagnosis and neck fusion operation
Treatments -- Radiation of C2 (neck) and T12 (back)
Staging my multiple myeloma
Did I want a stem cell replacement?
Did I want to join a chemo clinical trial for new oral botzezomib added to rev/dex?
Choosing a chemo regimen
         Chemo cost and insurance
         500 dollar a day chemo pill!
Signing up for medicare Part D drug plan
DNA variations -- cytogetics
         My cytogenetics test results (from Mayo clinic)
Free light chains --- supplement to M-spike
         Leading indicator?
         Free light chains are a true leading indicator
         Is kappa or lambda free light chain a leading indicator?
         Excess free light chains damage the kidneys

Living with cancer

Run down (4/2/17)
Chemo transition to maintenance (7/13/15)
         An advantage of cycled revlimid
           Advantages of no streoids (11/20/15)
Daily pills (1/16/16) (4/15/16)
Driving a car with limited neck mobility
         Key neck trick
Bone pain
Kidney damage
Anemia -- Low blood oxygen capacity
       Really bad anemia -- very low hemoglobin (9/20/17)
           Hemoglobin raising hormones ---Brand names: Epogen, Procrit and Aranesp
       New hospital schedule to address my anemia (9/26/17)
       EPO vs blood transfusions
Vision issues
* How MM patients die
2nd look at stem cell replacement option
Clinical trial time lag
Accessing my hospital records
Lahey new online patient 'portal' (4/15)
Dana Farber portal (2/16)

End of 1st Remission -- switch to new pom/carfilzomib/dex chemo (6/27/16)
4.5 month overview --  2nd remission (11/18/16)
  ** Plot of my M-spike(s) numbers for 2016
       Update on new pom/carfilzomib/dex chemo
       Relapsed and refractory
       New agressive chemo for 2nd round --  pom/carfilzomib/dex (7/11/16)
       Carfilzomib risk breakdown
    * Aspire phase 3 clinical trial results for carfilzomib (2015)
Dana Farber update on my cancer (jan 2017)
Two cancers? -- surprising & discouraging new result(10/3/16) 10/17/16)

End of my 2nd remission -- New Test Results   (mar 2017)
        Pom/carfilzomib/dex chemo started off strongly with a big drop in free light chain in the first cycle,
but after 8.5 months my lambda free light chain was rising strongly as was M-spike and worse a little later
a pet scan showed my 9th rib plasmacytoma had also brightened substantially in just the last 9 weeks,
so clearly the cancer has evolved around this chemo. My 2nd remission has ended.
        High cost of carfilzomib and daratumumab infusions! (10/23/16) (10/14/17)
           44.2k/yr out of pocket cost of new chemo! (pom/carfilzomib/dex) (10/23/16)
        Photos from last day of carfilzomib infusion   (3/21/17)

Begin pom/Ninlaro/dex chemo (4/3/17)
        Searching for a 3rd remission
        Low platelets --- known Ninlaro side effect

Begin pom/daratumumab/dex chemo (8/1/17)
        Searching for a 4th remission -- failure
        Castor vs Pollux clinical trials
        My first dose infusion reactions
        Infusion times summary
    *  Blood type baseline (prior to first daratumumab infusion)

End Game (10/8/17)
       Health update (10/8/17)
       New marrow needle biopsy
          ** MDS a 2nd cancer --- "myelodysplastic syndrome" (10/4/17)
       Health update (10/14/17)
       Health update (10/21/17)

Pet scans
      1st PET scan results   (5/19/16)
      2nd PET scan images     (9/6/16)
      3rd PET scan images     (1/11/17)
      4th PET scan images     (3/22/17)
      5th PET scan images     (7/10/17)
      6th PET scan images     (10/20/17)

Big picture of MM treatment options

Special topics in detail
My Pictures
Inventory of my MM bone tumors (12/17/15)
Details of cancer in my bones from MRI and CT scans during my hospital stay (Aug 30, 2015)
        One year follow up cervical CT scan (9/16/15)
        Failing or failed C1,C2 fusion

History and info on the thalidomide class of drugs
Lahey Hospital and Medical Center
Details of my neck C1,C2 fusion operation
Lahey online patient 'portal'
About the Lahey MM clinical trial I was offered
Protein Electrophoresis test
        Nice description of M-spike
Cytogenetics and deletion 13
         My cytogenetics test results (from Mayo clinic)
       Variability of patient response to chemo
       Spectrum of MM patients
What bones are affected by MM?
Antibody proteins
More on 'Complete Response'
         'Complete response' discussion
Tom Brokaw perspective
Multiple Myeloma spectrum
'The Role of CR  (complete response) in MM' --- excellent 2009 French paper
MM cure vs control debate
Criteria for my MM progression (Aug 2015)
       What are the clinical implications of CR?
       What about 'Very Good Partial Response'?
  ** I achieve CR (based on M-spike) (2/16)
'Understanding Protein Electrophoresis' notes
M-spike to total protein ratio (7/15)
Value of kappa/lamda ratio in monotoring MM patients for relapse
       MM marker without a measurement of M-spike?
History of myeloma
Bone remodeling
Multiple myeloma drugs
Documentation with little concern for patients
Clincial indicators of disease progression
Clincial indecators of disease relapse
Experiences of others with MM chemo
Other blood cancers
Excerpts from 'Multiple Myeloma Patient Handbook' Myeloma Canda
Blood test machines
Drugs used in Multiple Myeloma
       MM drugs organized by class
       Ninlaro update(4/5/2016)
       Compassionate Use (1/10/16)
MM treatment history
       FDA approval 'zoo'
Options for relapsed muliple myeloma
Will Medicare pay?
Vertebrae terminology and anatomy
       Cervical anatomy
       Fracture of dens
       How the C1,C2 dens joint really work
Reviewing my scans
Protein electrophoresis equipment

New test results (aug 2016)
Heart tests (6/14/16)
Updated view of the plasmacytoma behind my left eye (8/9/16)
Radiologist report on my 8/9/16 brain MRI
Retinal tomography -- 3d images of my retina
Arteries and veins of the neck
       What to do if this (mini-stroke) happens again?

New test results (feb 2017)
Heart tests (2/14/17)
        Heart echocardiogram test

Lung tests
     Pulmonary function  tests   (2/22/17)
         DLCO test result
        COPD -- Pink Puffer and Blue Bloaters
     Lung CT scan
     My strange collection of lung symptoms
     Pulmonary ventilation/perfusion scan   (4/28/17)
         Perfusion images   (4/28/17)
       Spiriva HandiHaler powder inhaler  (4/24/17)
     Incruse Ellipta  --- another once daily powder inhaler (5/4/17)
Red blood cell tutorial
Hemoglobin into the normal range   (3/6/17)
Iron blood tests   (3/6/17)
Carfilzomib Reference

Appendix 2
Sphenoid bone
Proteasome and 'proteasome inhibitor' drugs
Daratumumab discussion

My key numbers in a table
        Multiple myeloma (MM) being a blood cancer a simple blood can reveal a lot about general level of cancer in the body. Here is a table with all my key blood numbers since I was diagnosed. The two most important blood cancer terms are on the left side of the table: M-spike and (lambda) free light chain. M-spike is direct measure of the quantity of clonal (cancer) anti-body cells in the blood and is zero in a healthy person. Free light chain on the other hand has a baseline value (0.57 to 2.63 mg/dL) in healthy individuals because it is a by-product of how disease fighting immunoglobulin blood proteins are made. The virtue of free light chain is that it is a 'leading indicator'. It is the signal to watch when chemo is changed. Clinical trials use thresholds of these two blood components as indicators of disease progression, [10 mg/dL for (lambda) free light chain and 0.5 g/dL for M-spike], so this provides reference points to interpret the numbers.

rev/dex chemo
(21 of 28
day cycle)
(begun 11/24/14)
IgG lambda 
monoclonal peak
(fractional decrease
during cycle)
cancer ratio

monoclonal proteins/total protein

free light
(0.57 - 2.63)
free light
chain ratio
(0.26 - 1.65)
(involved -  uninvolved)
free light
(>10 mg/dL
indicates disease progression)
(13.8 - 17.4)
(white blood
(4.4 - 11.3)
(1.4 - 6.6)
platelet count
(150 - 450)
 (0.75 - 1.4)
protein) ratio
(liver), (g/dL)
(0.52 - 0.58)
(0.6 - 1.3)

(calculated from creatinine)

(8.4 - 10.4)
(very high)
(super high)
(super low)

(8.60 10/14/14)


(5.96 10/14/14)

(2.4/10.6 )
(very low)
(> 60)

(1.4 earlier)
(1.7 hospital)


(11.0 11/7/14)

cycle 1
(.05 IgG kappa)
(0.7% kappa)
(> 60)
cycle 2
(.06 IgG kappa)
(0.8% kappa)
(nearly normal)
cycle 3
(IgG kappa monoclonal band detected, but too small to quantitate)
(> 60)
cycle 4
(> 60)
cycle 5
cycle 6.25
Chemo transition to maintenance (began 5/24/15):   revlimid: 25 mg/day => 10 mg/day (21 of 28 day cycle);  dexamethasone: 40 mg/wk => 0
                                                 aspirin (blood thinner): 325 mg/day => 162 mg/day; zometa (biphosphate) infusion (bone strengthening) monthly => unchanged
cycle 7.5
(3.5/6.0 )
(> 60)
cycle 8.5
"No monoclonal
(< 0.05)?
No bands detected
(< 0.015)?
< 1%?
(3.7/6.4 )
cycle 9.5
Weak oligoclonal IgG bands present
Band(s) present
but not quantifable
< 1%?
(3.7/6.6 )
(> 60)
cycle 10.5
Weak monoclonal IgG lambda band detected, other weak oligoclonal bands present.
Band(s) present
 but not quantifable
< 1%?
(little high)
(little low)
(little low)
Monoclonal IgG lambda
Band(s) present
(bad cold)
(> 60)
Monoclonal IgG lambda. Additional weak oligoclonal IgG bands.
Band(s) present
Monoclonal IgG lambda. Additional weak oligoclonal IgG bands.
no change from previous
cycle 14.25
Monoclonal IgG lambda. Additional weak oligoclonal IgG bands.
no change from previous
(two weeks)
(> 60)
cycle 14.75
Monoclonal IgG lambda. Additional weak oligoclonal IgG bands.
no change from previous
(two weeks)

(no change in last month)

cycle 15.25

(Dana labs)

in the beta region, of insufficient quantity to be quantified.
<0.1 g/dL?
(.17 g/dL est from IgG)
(two weeks)
cycle 15.75
Monoclonal IgG lambda. Additional weak oligoclonal IgG bands.
Increase in maintenance dose (began 2/29/16): revlimid: 10 mg/day => 20 mg/day (28 of 28 day cycle initially),  dexamethasone: none (unchanged)
                                                 aspirin (blood thinner): 162 mg/day => unchanged; zometa (biphosphate) infusion (bone strengthening) monthly => unchanged
cycle 16.00
Monoclonal IgG lambda. Additional weak oligoclonal IgG bands.
(one  week)
cycle 16.75
Monoclonal IgG lambda.
Monoclonal lambda light chains.
Additional weak oligoclonal IgG bands present
(3 weeks)

(> 10 mg/dL
diff limit)

( 60)
Revlimid maintenance ended, original rev/dex reestablished (began 3/25/16): revlimid: 20 mg/day => 25 mg/day (cont Revlimd for first 7 wks, change to 21 of 28 days pending), 
                               dexamethasone: 40 mg/wk,  aspirin (blood thinner): 162 mg/day => unchanged; zometa (biphosphate) infusion (bone strengthening) monthly => unchanged
cycle 17.5
Monoclonal IgG lambda.
Weak Oligoclonal IgG bands present.
(3 weeks)

(3 wk Revlimid)

cycle 18.25
Monoclonal IgG lambda.
Normal immunoglobins decreased
(3 weeks)

(2 of 3 wk Revlimid)

cycle 19
Monoclonal IgG lambda.
Normal immunoglobins decreased

(1st PET scan 5/19/16)

cycle 19.75

(Dana labs)


The beta M-spike concentration includes both the M-spike and physiologic beta proteins,
and is thus an overestimate.

(3 weeks)
cycle 19.75
Monoclonal IgG lambda.
Normal immunoglobins decreased
cycle 20
Monoclonal IgG lambda.
Normal immunoglobins decreased
cycle 20.25
Monoclonal IgG lambda.
Normal immunoglobulins decreased
(5/16/16) With lambda free light chain hovering for months near 10 mg/dL and M-spike at .25 g/dL an MRI found a plasmacytoma growing behind left eye and a Pet scan (5/19/16) later found other metabolically active bone lesions, indicating my cancer was outrunning my rev/dex chemo. Clearly my first remission has ended and a new chemo regimen is needed.

Chemo change (6/27/16)
Switched chemo rev/dex => pom/carfilzomib/dex (begun (6/27/16): pomalyst: 4 mg, 21 of 28 days, carfilzomib (infusion) six times/cycle with first cycle 20mg x (body area index), dexamethasone 20 mg on days of carfilzomib (continued during 4th week), aspirin (blood thinner): 162 mg/day => unchanged; zometa (biphosphate) infusion (bone strengthening) monthly => unchanged. (Carfilzomib for first cycle at 75% of its final strength.) 

28 day cyele
IgG lambda 
monoclonal peak
(fractional decrease
during cycle)
cancer ratio

monoclonal proteins/total protein

free light
(0.57 - 2.63)
free light
chain ratio
(0.26 - 1.65)

free light chain
(0.33 -
1.94) mg/dL)

(involved -  uninvolved)
free light
(>10 mg/dL
indicates disease progression)
(13.8 - 17.4)
(white blood
(4.4 - 11.3)
(1.4 - 6.6)
platelet count
(150 - 450)
 (0.75 - 1.4)
protein) ratio
(liver), (g/dL)
(0.52 - 0.58)
(0.6 - 1.3)

(calculated from creatinine)

(8.4 - 10.4)
cycle 20.75
Monoclonal IgG lambda.
Normal immunoglobulins decreased
(2 weeks)
cycle 21.25
Monoclonal IgG lambda.
Normal immunoglobulins decreased
(2 weeks)
(7/25/16) Carfilzomib dose increased 35% [20 mg x (body area index)] => [27 mg x (body area index)] at beginning of 2nd pom/carfilzomib/dex cycle    (my body area index = 2.074)
cycle 21.75
Monoclonal IgG lambda.
Normal immunoglobulins decreased
(2 weeks)
cycle 22.25
Monoclonal IgG lambda.
Normal immunoglobulins decreased
(2 weeks)
(cycle 22.50
(one week later)
cycle 22.75
Monoclonal IgG lambda.
Normal immunoglobulins decreased
(2 weeks)

(2nd PET scan 9/6/16)

cycle 23.00

(Dana Labs)

Monoclonal gammopathy with faint IgG Lambda paraprotein.

Immunofixation shows a faint M-spike that is not apparent on the
electropherogram and, therefore, cannot be quantitated

cycle 23.25
(.24 total)

Monoclonal IgG lambda.

Monoclonal IgG kappa

Normal immunoglobulins decreased

(2 weeks)
4.44% total
cycle 23.50
cycle 24.00
(.26 total)

Monoclonal IgG lambda

Monoclonal IgG kappa

Normal immunoglobulins decreased

IgG lambda unchanged

IgG kappa

(2 weeks)

 (not applicable, both free light chains are involved)
cycle 24.50
(.17 total)

Monoclonal IgG lambda

Monoclonal IgG kappa

Other weak oligoclonal IgG and IgM bands present

Normal immunoglobulins decreased

IgG lambda 

IgG kappa

(2 weeks)

(not applicable, both free light chains are involved)
(start 4 Tums/day)
cycle 24.75
cycle 25.00
(.18 total)

Monoclonal IgG lambda

Monoclonal IgG kappa

Other weak oligoclonal IgG and IgM bands

IgG lambda 

IgG kappa

(2 weeks)

(not applicable,
both free light chains are involved)
cycle 25.25
Monoclonal IgG lambda

A weak monoclonal IgG kappa band detected, but too small to quantitate

cycle 25.50
Monoclonal IgG lambda

A weak monoclonal IgG kappa band detected, but too small to quantitate. 



cycle 25.75


cycle 26.00
Monoclonal IgG lambda

Other faint oligoclonal IgG bands present..

IgG lambda 


Monoclonal IgG lambda

Other weak IgG bands also present



cycle 27.50
Monoclonal IgG lambda

(3rrd PET scan 1/11/17)



cycle 27.75

(Dana Labs)

Immunofixation shows a faint M-spike that is not apparent on the
electropherogram and, therefore, cannot be quantitated.
Monoclonal gammopathy with IgG Lambda paraprotein.


(antibodies low)
cycle 28.50
Monoclonal IgG lambda

Decreased gamma globulins


(residual cold)





cycle 29.50
Monoclonal IgG lambda

Additional oigoclonal IgG bands present


(4th PET scan 3/22/17)


(65 mg iron pill  added 2/15/17



cycle 30.50
Monoclonal IgG lambda

Additional oligoclonal IgG bands.


(fatigued, run down)



Chemo change (4/3/17)
Swarped proteasome inhibitors today: pom/carfilzomib/dex => pom/Ninlaro/dex. Began first cycle of new pom/Ninlaro/dex chemo on 4/3/17.  For about 6-7 months (since 6/27/16)  pom/carfilzomib/dex chemo has been effective, but in the last 1-2 months that is no long the case with a rising free light chain (4.55 mg/dL) and M-spike (.17 g/dL) plus importantly a recent pet scan showing significant growth in my 9th rib plasmacytoma. Furthermore carfilzomib appears to have done significant damage to my lungs in recent months (DLCO = 13.98). As an experiment this change in chemo swaps out the proteasome inhibitor in my current chemo for a different proteasome inhibitor with a somewhat different target (carfilzomib => Ninlaro), Ninlaro being the pill equivalent of Velcade, which has had a good ten year track record and which my cancer has never seen.
28 day cyele
IgG lambda
monoclonal peak
(fractional decrease
during cycle)
cancer ratio

monoclonal proteins/total protein

free light
(0.57 - 2.63)
free light
chain ratio
(0.26 - 1.65)

free light chain
(0.33 -
1.94) mg/dL)

(involved -  uninvolved)
free light
(>10 mg/dL
indicates disease progression)
(13.8 - 17.4)
(white blood
(4.4 - 11.3)
(1.4 - 6.6)
platelet count
(150 - 450)
 (0.75 - 1.4)
protein) ratio
(liver), (g/dL)
(0.52 - 0.58)
(0.6 - 1.3)

(calculated from creatinine)

(8.4 - 10.4)
cycle 31.25
Monoclonal IgG lambda
Weak monoclonal
IgG kappa band detected, but too small
to quantitate. 

(3 weeks)



cycle 32.25

(5/30/17 recheck)

Monoclonal IgG lambda
Weak monoclonal
IgG kappa band detected, but too small
to quantitate.




(early in off week)


(first week of Ninlaro cycle)



(at Dana
cycle 33.25
Monoclonal IgG lambda
Weak monoclonal
IgG kappa band detected, but too small
to quantitate.






(early in off week)




cycle 34.25

Monoclonal IgG lambda.
Normal immunoglobulins decreased


(above disease progression

(early in off week)


Ninlaro review (6/20/17)
About three months ago (4/3/17) a (new) pill proteasome inhibitor (Ninlaro) was swapped in for my old infused proteasome inhibitor (carfilzomib). This change was prompted because my lambda free light chain was beginning to rise (4.55) and after 9 months on carfilzomib it was continuing to damage my lungs. Unfortunately the new (pom/Ninlaro/dex) chemo was relatively ineffective and in ten weeks (6/20/17) my lambda free light chain was up strongly (8.42) indicating another change in chemo was needed. This was confirmed by a 5th pet scan (7/10/17) showing substantial growth in two existing plasmacytomas in my ribs. By 7/18/17 lambda free light chain was up to 11.3 mg/dL  and M-spike up to .26 g/dL.
Chemo change (8/1/17)
Switched chemo (pom/Ninlaro/dex)  => (pom/daratumumab/dex) with first daratumumab infusion (8/1/17 and 8/2/17) coordinated with starting a new cycle of Pomalyst (pills). This is my 5th change in chemo. If successful, daratumumab infusions will be once a week for 9 weeks. Pomalyst will continue on a four week cycle (21 of 28 days with a week off). The pairing of daratumumab with Pomalyst was only approved by the FDA weeks earlier (6/17/17).  Due to the delay in scheduling daratumumab infusions, I essentially had two weeks off with no chemo. Prior to every daratumumab infusion limited blood parameters will be measured to assess whether each infusion can be done. (update --- inclusion of the free light chain test initially has allowed some weekly cancer monitoring.)

Daratumumab is very different from my previous chemo. This is a very large molecule. It is fully formed 'Y' antibodies that are all the same. The manufacturer says daratumumab is not chemotherapy, describing it as a CD38 targeted monoclonal antibody. Daratumumab decreases WBC (white blood count) and platelets.



.49 IgG lambda
.05 IgG kappa

Pattern also suggests inflammation.


(three weeks)


(11.30 => 5.04) nice drop in first week)


(residual cold)



.49 IgG lambda
.05 IgG kappa
x 1,00

(one week)


(residual cold)



.51 IgG lambda
.06 IgG kappa

Small monoclonal IgG kappa band may be an interference by the drug daatumumab.


(one week)


(2.80 two days later)


(50 two days later)




1st cycle

.37 IgG lambda
.06 IgG kappa

Small monoclonal IgG kappa may be an interference by the drug daratumumab.


(one week)




2nd cycle

.37 IgG lambda
.06 IgG kappa

location of the small monoclonal IgG Kappa suggests that the band is the drug daratumumab.

Normal immunoglobulins decreased.



.36 IgG lambda
.06 IgG kappa

The location of the small monoclonal IgG Kappa suggests that the band is

Normal immunoglobulins decreased.


Pomalyst suspended due to low platelets)



Chemo change (9/14/17)
Pomalyst (and 162 mg daily aspirin) suspended because platelets are extremely low (11). In the interim daratumumab (with dex) is my only chemo drug. Pomalyst may return at lower dose if (or when) platelets exceed 50.
 .35 IgG lambda
.06 IgG kappa

The location of the small monoclonal IgG Kappa suggests that the band is


(22 after platelet infusion)



.53 IgG lambda
.06 IgG kappa

The location of the small monoclonal IgG Kappa suggests that the band is


(hemocrit 20.7)



.54 IgG lambda
.06 IgG kappa

The location of the small monoclonal IgG Kappa suggests that the band is

.71 IgG lambda




(hemocrit 25.6)

(after two red blood cell transfusions)



6.01 (10/6/17)


(10/3/17) after two platelet transfusions






Chemo change --- new cancer (10/10/17)
       Chemo (pom/daratumumab/dex) has been discontinued because a marrow biopsy (of pelvis) 10/4/17 showed NO multiply myeloma, even though blood data shows an M-spike of .5 g/dL. The proposed explanation is that the marrow in some (smaller) bones still has MM cancer. The marrow biopsy shows a systematic failure of  the marrow to make red blood cells and platelets. My new diagnosis based on the 10/4/17 marrow biopsy is 'Myelodysplastic syndrome (bone marrow failure disorder), refractory cytopenia (low blood cell counts) with multi-lineage dysplasia (abnormal shape). It is only repeated transfusions of red blood cells and platelets (2 and 3 times a week) that has been keeping me alive in recent weeks.
.71 IgG lambda
.05 IgG kappa






























.99 IgG lambda
.05 IgG kappa












1.02 IgG lambda
.05 IgG kappa


































* A month after my diagnosis my monoclonal M-spike was first measured at 5.17 g/dL (10/14/14),
and in the following month just before beginning chemo it increased to 5.31 g/dL (11/17/14) becoming the baseline.
Beta2-Microglobulin (10/14/14) = 6.9 mg/L  (1.1 - 2.4 normal),  (> 5.5 mg/L indicates stage 3 MM)
VGPR = Very Good Partial Response (> 90% reduction)
CR = Complete Response (no detectable M-spike, no detection on immunofixation, < 5% clonal cells in marrow aspiration)
GFR - glomerular filtration rate is the best test to measure your level of kidney function and determine your stage of kidney disease.
(light blue: Lahey lab;   darker blue: Dana Farber lab)
M-spike plot number table, my numbers, my response to rev/dex chemo, my numbers table in image format(base - cycle 9.5)
M-spike plot number table, my numbers, my response to rev/dex chemo, my numbers table in image format2 (cycle 10.5 - cycle 14.75)
Comments on white blood cells, platelets, red blood cells
        The Celgene Revlimid web site says, "Revlimid causes low white blood cells and low platelets in most people', and my numbers (above) show this. Pomalyst side effects are basically similar to Revlimid, low white blood cells (neutropenia), low platelets (thrombocytopenia), and low red blood cells (anemia). The 6/27/16 transition from Revlimid to Pomalyst (rev/dex=> pom/carfilzomib/dex) was initially correlated to a substantial drop in my WBC (3-4 => 2.5), but after a couple of months it recovered. Platlets too shows an initial drop, but soon recovered and after six months are normal. Hemoglobin was relatively unchanged, running a little below normal.
        My breathless on the new carfilzomib chemo maybe be related not so much to the hemoglobin/red blood cell count, but that red blood cells do not look normal under a microscope (morphology): variations in size and appearance (teardrops, oval, polychromasia (abnormally high number of immature red blood cells)).
        I have a fatal blood cancer, multiple myeloma. I started this essay seven months after my diagnosis to document my disease, so in this respect it's part blog, but it's also a general essay on multiple myeloma, on my interactions with the medical community, on available MM chemo options, on my cancer genetics, on my broken neck, on how decisions about my treatment get made.

Introduction (update 7/27/15) (8/11/15) (10/28/15) (4/30/16) (4/30/16) (5/9/16)
        I am still doing pretty well at 20 months into my diagnosis, but a little more jittery and sleep deprived since now I'm again taking a corticosteroid paired with my chemo drug and have somewhat less energy. My numbers started to rise about six months ago (from a low level about 99% down) and for four months we just watched. As my numbers began to get within striking distance of my target of .5 g/dL (M-spike) that I did not want to exceed, plans were made to change chemo, i.e. change from 10 mg Revlimid (only) maintenance. First change was suggested by a Dana Farber consultant to just double Revlimid dose to 20 mg. A three week test showed it didn't work, both M-spike and free light chain continued to rise as before. Next change was to go back to original rev/dex chemo that I was originally on for first six months (25 mg Revlimid (21 of 28 days) + 40 mg/wk dexamethasone) and surprisingly in a 6 week test both numbers stopped rising and turned down a little: free light chain (a leading indicator) dropping about 33% and M-spike down 20%.

(update 5/7/16)
        The 6 week test was actually two 3 week tests of rev/dex. Obviously the best news for the second 3 weeks would have been that both tracking numbers drifted lower, and the worst news would have been they both drifted higher. What happened is that M-spike was unchanged (.25 g/dL) and lambda free light chain drifted a little higher (7.89 => 10.2 mg/dL). (A complication in comparing these two 3 week tests is that in the first 3 weeks Revlimid was taken every day. In the second 3 weeks cycled Revlimid was started (to help platelets down to 88) so Revlimid was only taken two of the three weeks.) I think the best way to look at these two short (sub-cycle) tests is as the two combined, a cycle and half.

        What this shows is that the rising pattern has been stopped (or at least been interrupted). M-spike dropped 20% (.31 => .25 g/dL) and lambda free light chain dropped 33% (15.3 => 10.2 mg/dL). I think this says we should now continue to a full cycle on rev/dex and take another look. Of course lower numbers would be welcome, but I won't be unhappy if rev/dex is able to hold  M-spike (.25 g/dL) for a while at half of my .5 g/dL target and 5% of my cancer level at diagnosis (5.31 g/dL).

        When people ask me how I am, the short answer is, I am in the 'sweet spot' getting back to normal. Chemo (so far) has been effective at beating back my cancer. At 13 months the story I tell people is that 12 months ago I was diagnosed with stage 3 of 3 fatal blood cancer and given 12 months to live, but I'm still here. This is completely true, but also misleading since the numbers in the literature are historical. Even today Wikipedia (beta2microglobin), which is used to stage MM, says for values > 4 mg/L median survival is 12 months, and my value at diagnosis was far above this at 6.9 mg/L. Indeed at 17 months in my beta2microglobin is still high at 4.1 mg/L. A 2011 french reference lists median suvivial time with beta2microglobin >5.5 mg/L as 29 months (2.5 yrs).

        Some cancer patients opt for aggressive treatment, I did the opposite. At three critical decision points I made the more conservative choice for treatment of my stage 3 of 3 cancer, saying no a stem cell transplant, no to a clinical trial, and no to aggressive three drug chemo. Luckily I responded well to my conservative regimen. In six months my pill based chemo reduced the high levels of cancer in my body by 96%. Then I transitioned to maintenance dropping one of my two chemo drugs and reducing the dose of the other by 60%. [(update) My latest blood work two months into maintenance shows a further drop in cancer levels to about 99% down, below the threshold of the test.] Many multiple myeloma patients have all kinds of problems, but except for a few months recovering from my cancer caused broken neck and neck fusion operation, I have had no serious problems. The neck fusion operation did leave me with a permanent loss of half of my head rotation and some occasional neck pain, but all in all I feel pretty good, and once my neck healed up I was able to resume driving.

4th conservative decision (nov 2015)
        I recently had to make a 4th semi-critical decision. Again I made the more conservative choice, putting quality of life first. My neck fusion to repair a pathological fracture of C2 is failing or failed. At a one year review my surgeon was hoping to see that bone had grown into my C1,C2 hardware and C1 and C2 were fusing, but bone has grown into only one of the four screws, and there are gaps in the C1,C2 fusion. Unhappy with what he saw on a CT scan my surgeon suggested I might want to try a bone growth stimulator. There is one brand approved by the FDA for the neck and the manufacturer recommends that it be worn 4 hours/day. Wearing this thing for six months (my next scheduled appointment with surgeon) would be a real pain. I'm probably not going to do it, knowing that it's a long shot it would help, and there a chance that the bone growth will continue since my body is getting back closer to normal after going on chemo maintenance (discontinuing dexamethasone, a corticosteroid) and my bones have probably been strengthened by monthly bisphosphonate (zometa) injections.
        The question is how long this will last? No one can say, patients differ a lot in how they respond to treatment. My (cancer) genetics are pretty good (but not the best), which is probably why I have responded well to chemo, so statistically there's a reasonable chance I will have 2-3 years before my cancer comes back, but if I'm unlucky maybe six months to a year. When the cancer comes back, and with multiple myeloma it always comes back, I will then have maybe another year or two, but this is a bad period as things begin to fail and more aggressive chemo drugs are used.

Overview (May 2015)
        In Sept 16, 2014 at age 72 I was diagnosed with multiple myeloma after my neck broke in my sleep, so overnight I went from being active and healthy, or so I thought, to having cancer and a broken neck. Multiple myeloma (MM) is a fairly rare cancer (1% of all cancers) that doctors will tell you is incurable, but treatable. It only been in the last decade or so that reasonably effective chemo for this disease has become available, meaning chemo that can extend the (average) lifetime by a few years and is fairly well tolerated. However, how an individual MM patient will respond to the currently available chemo varies widely, depending strongly on what DNA variations his cancer cells display, so personalized medicine comes into play here. Survival times can vary four to one depending on whether a patient has good or bad DNA with half to two thirds of patients falling into the good category.

        A week in the hospital for a neck fusion operation and lots of tests was followed by two months of wearing a neck collar, two weeks of radiation to kill the cancer cells in the neck and in a large bone lesion in my mid-back. Initially my blood numbers were bad and x-rays showed a lot of bone tumors, diagnosis was multiple myeloma stage 3 of 3 with the literature showing a median survival of 12 months (!), but then DNA analysis of my cancerous bone marrow came in and was positive, not the very best but pretty good. I have the hyperdiploidy variation (extra copies of chromosomes), and that lowered my risk from 'high' to 'standard'. I said no to a clinical trial, no to a stem cell transplant (a horrendous procedure requiring weeks in the hospital), and began targeted chemo for multiple myeloma taking the widely used, but super expensive, patented revlimid (slightly modified thalidomide) plus the inexpensive corticosteroid dexamethasone. In five months this conservative, but commonly used, pill based rev/dex chemo lowered the cancer in my blood by 95.5%, which is considered a 'very good partial response' and is correlated with longer survival.

        The chemo side effects were small at first but have lately begun to give me some jittery days, affecting my sleep, and giving me anemia making me tire easily, but hopefully these side effects will subside when I transition to a lower dose maintenance regimen. Even though I have three large bone lesions (holes) and many smaller ones, I have no bone pain, probably because my holes (really hollows)  remain inside the bones where there are no pain sensors. My neck fusion operation has left me with some occasional neck pain and a permanent loss of of about half my head rotation, but by trial and error I have learned I can compensate for this by changing my driving style, reorienting my car at intersections to lower the angle through which I need to look to see oncoming traffic and twisting my back. In short after a few bad months I am now doing pretty well.

MM tracking numbers
        Multiple myeloma is very unusual cancer in that being a blood cancer the amount of cancer in the body, specifically how many cancerous blood plasma cells exist in the bone marrow, can be accurately measured with a simple blood test. Amazingly there is not just one, but two components of the blood that are useful for tracking the amount of cancer in multiple myeloma patients.

M-spike and free light chain MM cancer indicators
        The reason MM has tracking indicators in the blood is that MM is a cancer of the marrow cells (plasma cells) that make disease fighting antibody proteins in the blood. Antibodies in the blood are normally all different with different molecular weights to fight a wide range of invaders, but the cancerous plasma cells in the marrow are clones that are genetically identical, so they make identical blood antibodies. Therefore the area under any spike of blood proteins with identical weights is taken as a (linear) measure of the total amount of cancerous marrow cells in the body that created them. This indicator is called the monoclonal spike or (for short) M-spike.
Caveat -- delayed fall
        There's a caveat to M-spike as an good indicator of marrow cancer cells. When chemo is started or changed and M-spike is falling it may read falsely high for months. The argument of the people who make the free light chain measuring equipment (Binding Site, UK) is that there is a recycling mechanism that reconstitutes anti-bodies slowing their clearance from the blood. The result is M-spike has a downside lag, it tends to fall more slowly than the actual fall in marrow cancer cells. There would be no comparable lag on the upside.
        The anti-body protein is Y shaped, made of two joined double strands, each of which is composed of a longer (heavy) chain bonded to a shorter (light) chain. With this shape it can't be made in one go like a classic textbook protein, it has to be made in four pieces, which are later joined to form the complete Y shaped antibody. There can never be perfect balance between the amount of light and heavy chains that are made and one reference says, "for unknown reasons, the plasma cells typically produce more light chains (40% more says Wikipedia) than are required to create the whole immuno-globulins or monoclonal proteins." A sensitive test is able to measure these partial antibodies in the blood, which are the excess light and heavy chains that never joined up to form a complete Y shaped antibody. There is an established test for the light chains, called 'free light chain', and this is the second MM cancer indicator in the blood. (There is also a test for the heavy chains in the blood, but it much less accepted and standardized.)

        It's not at all clear how linearly the amount of free light chains in the blood track the cancerous MM cells in the marrow. The above reference says only, "the amount of free light chain production is linked to the activity of myeloma or plasma cell growth." Wikipedia (serum free light chain measurement) describes a process where the kidneys rapidly (hours) and efficiently remove free light chains from the blood, and the levels in the blood only rise when the kidneys get overwhelmed.  In my case when my M-spike was very high pre-chemo (5.31 g/dL) my lambda free light chain was also very high (379 mg/dL).

        Free light chains have an advantage over the M-spike as a MM cancer indicator in that their survival time in the blood is hours not weeks or months as with the M-spike, hence they track the amount of marrow cancer with much less lag. In the parlance of the control engineer it is a leading indicator. This is very useful in patient care to to evaluate chemo for its effectiveness, to see more quickly when existing chemo stops working or if a new chemo is working.

        Doctors tend to focus on the 'M-spike', which is the amount (g/dL) of identical (monoclonal) Y shaped antibody proteins in the blood. For a healthy person the amount of this indicator is zero. The other indicator, 'free light chains', is the amount (mg/dL) of pieces of the antibody Y proteins found in the blood (in my case 'lambda free light chain'). This indicator is found at a concentration orders of magnitude lower than the M-spike and has a non-zero residual value in healthy people, so it is not useful when cancer levels are low. The virtue of free light chain is that when cancer levels are high it responds much more quickly (and accurately says a manufacturer of test instruments) to chemo. My numbers, plotted up below, show I had a 98% decrease in my lambda free light chain (from a very high value) in just my first month of chemo, whereas it took 8-9 months for my M-spike to show the same proportional decline.
 M-spike in beta region (feb 2016)
      When considering how much weight to put on M-spike vs free light chain, another consideration recently came to light. I have an IgG plasma cancer so my M-spike consists of identical IgG antibody proteins. IgG antibodies are large so they don't diffuse far, putting them at the end of a serum electrophoresis distribution in a region known as gamma. Normal IgG antibodies have a range of weights so form a smooth broad lobe in the gamma region. An IgG M-spike is typically seen as a narrow spike on top of this broad peak. This is considered fortunate from an M-spike testing point of view because the M-spike is easily measured above the smooth background.

        When Dana Farber recently did an electrophoresis of my serum proteins, they reported my M-spike is not in the gamma region, but in the adjacent beta region. I think this means my cancerous plasma clones are producing an IgG antibody that is smaller than the average IgG antibody, so it diffuses better and makes into the beta region. The consensus seems to be that it is more difficult to get a quantitative reading of an M-spike when it is in the beta region. I suspect this means the normal beta region proteins form a series of peaks such that an M-spike does not stand out and can be partially obscured.

        Dana lab was unable to assign a numerical value to my beta region IgG M-spike (.1 g/dL threshold??), yet in the preceding months Lahey lab had reported five smoothly varying and slowly increasing M-spike values ranging from .07 to .18 g/dL, slightly decreasing to .16 g/dL two weeks before the Dana collection. As I write, this apparent disparity is not yet resolved, but it argues that maybe my M-spike should be somewhat discounted because of testing difficulties.

M-spike in beta region (june 2016)
        In june 2016 while Lahey was reporting M-spike at .24 g/dL, Dana Labs at about the same time reported .46 g/dL, but noted its value was an "overestimate" since my lambda M-spike is in the (noisy) beta protein region and includes some other normal proteins found in the this region.

Overview of my numbers (cycles 1 - 17.5)
        I began chemo with standard rev/dex and responded well, transitioning to a lower maintenance dose of Revlimid after six months. Rev/dex caused my M-spike to decline about 99% to the point where after 8 months (10 months after diagnosis) no numerical value could be assigned, and my M-spike stayed unmeasurable for the next three months. This is a good response, a CR (complete response) based on M-spike. I was told by my Dana specialist that only 10-15% of patients on rev/dex respond this well.

My numbers start to rise (10/26/15)
        After about a year, my M-spike became measurable again (10/28/15), and for the next several months both it and my free light chain showed a steady upward creep. Although in absolute terms they were still low, this steady rise caused me concern as I didn't want to wait until my body started deteriorating before changing chemo, so I planned a consultation with a MM specialist at Dana Farber to get his opinion. At our meeting he said if the pending free light chain hit a target (10 mg/dL), which it did, then regardless of the M-spike he thought a tweak now in my Revlimid maintenance dose was called for [10 mg => 20 mg]. However, when a few days later when the Dana labs were unable to get a numerical reading of my M-spike, he then suggested perhaps it was better to wait another month or two before changing course. When two weeks later Lahey reported yet another increase in M-spike (.22 g/dL) and free light chain (12.00 mg/dL), my oncologist and I agreed this was the time (2/29/16) to increase my maintenance dose of  Revlimid to 20 mg. I am comfortable with this as this as I see it as the smallest possible stepup in chemo possible.

        I was hoping to get 2-3 years out of my first remission and this change is happening 15 months into chemo (17 months after diagnosis) and less than a year into maintenance. Of course, I am hoping it will be effective in arresting the rise in the numbers. If it does and if side effects don't noticably change, then I think it's fair to say the first remission continues, that this was just a 'tweak' to the maintenance dose.  We will see in another couple of months.

Didn't work
       ** Well the data is in (3/22/16). A three week test showed clearly that increasing the maintenance dose of Revlimid [10 mg => 20 mg] didn't work at all, both free light chain and M-spike continued to rise strongly just as before [.22 => .31 M-spike and 12 => 15.3 free light chain]. It looks like my cancer is no longer responding to Revlimid. (bummer)
        Before abandoning Revlimid my oncologist is suggesting a we try a few weeks of the (original) rev/dex. While this is probably the smallest step and ordinarily I would like it because it fits with my philosophy of taking small steps, the problem is that my M-spike is rapidly approaching my personal max target (.5 g/dL) that I don't want to exceed, and my lambda free light chain at 15.3 is well above the 10 mg/dL target. At the current rate of increase (x1.41/three wks) my M-spike will hit .43 in one more month if it doesn't work, and I'm betting it won't. We need to plan now for a bigger step up in chemo (to 2nd line drugs) for use soon. Not good news.
       ** Well the data is in (4/11/16). A pleasant surprise, adding back the corticosteroid 'booster' seems to be making Revlimid work again. In a three week test back to the original rev/dex both numbers stopped rising and began to drop [.31 => .25 M-spike and 15.3 => 7.89 free light chain]), bringing the free light chain below the 10 mg/dL target. This chemo change was mostly just adding back the original dex (40 mg/wk of  dexamethaone), which is considered a 'booster' for Revlimid, plus a minor tweak in the Revlimid dose (20 mg => 25 mg) (not cycled initially).
        My particular monoclonal antibody is of type: IgG lambda, which means it is composed of the G heavy chains (most common of five heavy types) and lambda light chains (less common of the two light types, about 1/3rd of light chains are lambda).

Plot of my numbers (1 - 9 months)

m-spike chart, multiple myeloma M-spike plot,  monoclonal protein, response to chemo.  Free light chain reduction with rev/dex chemo.
My first 9 months of (rev/dex) chemo.
Multiple myeloma is a very unusual cancer in that being a blood cancer the level of cancer cells in the body
can be accurately measured with a simple blood test.
find this plot online: 'M-spike plot' (Google image search)

Plot of my M-spike numbers for 12 months of 2016

my M-spike numbers for all of 2016
Notice the big shift in this graph'a vertical scale from the plot above
(5 g/dL vs 0.3 g/dL max)

        On the left side of the table are the two markers (proteins) in my blood that tracks the cancer. Free light chain (with a lifetime in the blood of hours) responds rapidly to changes in marrow cancer levels. The M-spike (with a lifetime in the blood of weeks) responds more slowly. The doctors focus on the slow responding M-spike, because it can go deeper and is a direct measure of amount of cancerous (anti-body) proteins in the blood. Notice the fast responding marker (free light chain) shows 98% of my cancerous marrow cells were (likely) wiped out in the very first month of rev/dex chemo. [Well, maybe. How linearly the free light chain marker correlates to the amount of cancer in the marrow is murky.] My M-spike cancer levels in Aug 2015 (cycle 8.5) were reported as undetectable, below the threshold of the test (probably .05 g/dL or a little less).

        The transition to maintenance coincided with an increase in hemoglobin to the lower end of the normal range where it has remainded ever since (10 months). The transistion to maintanence, however, has caused platelets to drop below normal (minor issue, which could be treated by adding back some dexamethasone).
Plot of my M-spike and lambda free light chain for much of 2017
        Includes three different chemo regimes: pom/carfilzomib/dex, pom/Ninlaro/dex, and pom/daratumumab/dex, which produced only a one month dip.

Equivalent Freelite plot
m-spike plot2, m-spike chart2, free light chain vs M-spike, multple myeloma tracking, Freelite
red: IgG production by cancerous plasma
blue: IgG serum concentration
SPE =  serum protein electrophoresis
(source --

        Later I discovered a nearly identical plot (above). This is from the Freelite (Wikilite) people ( and who advocate for use of free light chain to (rapidly) track MM cancer levels. They explain that the long tail of IgG anti-bodies [= (M-spike + 0.1 g/dL (nom) residual)] is due to a cellular recycling mechanism and argue that it can give a false indication of residual disease for months. It's uncanny how alike the two plots are, yet I never saw the Freelite plot until after I done my plot!

        The objective of chemo in my case is to eliminate as much as possible of the cancer from my body, which clinically means driving the amplitude of the M-spike (shorthand for 'Monoclonal protein SPIKE') as low as possible, then switching to a lower doses of chemo to attempt to hold the number low for as long as possible. A reduction of greater than 90% (VGPR -- Very Good Partial Response), or better still cancer levels below the threshold of the test (loosely speaking, a CR -- Complete Response), is the target as these levels are associated with longer survival (really longer disease free progression).

        As the cancer cells in the marrow decline, there is more room for the normal blood making marrow cells to expand, hence this should allow blood number to tend toward the normal range, but at the same time rev/dex can affect hemoglobin and WBC (white blood count). A lower chemo dose in maintenance should hopefully reduce the chemo side effects, important since my chemo (revlimid) has a record of killing a few percent of patients with a 2nd cancer or a deep vein blood clot. Thus entering maintenance I will be tracking so see if my blood numbers improve.

        Another criteria clinical trials use for disease progression are new (or growing) bone lesions. This is one of the black holes as cancer levels rise. My experience with my femur tumor is (small) changes would be difficult to see on x-ray, and my bone doctor seemed to focus on whether or not it hurt. Luckily so far, except for my neck, I have been free of bone pain. The problem with relying on bone pain as an indicator is that pain doesn't start until the lesion has progressed significantly, penetrating to the surface of the bone. This makes it a crappy indicator. I don't want my many bone lesions to begin growing again, but I have no information as to what cancer level this begins. In lieu of bone pain only a whole series of body x-rays (or spot x-rays on my known large tumors) might be able to pick up changes in my bones before pains begins,  but I suspect this is a very insensitive test. One problem is my x-ray baseline is old, the last series of full body x-rays I had was more than a year ago. My doctor has had no serious discussion with me about getting a new x-ray baseline.  It might soon be useful to seek out a 2nd (and 3rd) opinion at a major MM cancer center, to get some perspective on these issues from an outside expert.

My numbers
Change in my numbers  (4/15/16)
        At a meeting with my doctor of 4/11/16 there was no new data to review because blood was taken that day. We planned for the next step in chemo if the current test of original rev/dex failed, which I, and I think my doctor, expected because the previous three weeks of doubling the dose of Revlimid [10 mg => 20 mg] had done nothing to arrest the rise in both numbers. The next chemo step planned was to add a 3rd drug to rev/dex, a proteasome inhibitor either Ninlaro (pill) or Velcade (injection). The plan was to try for Ninlaro and if blocked by my Part D insurer, a fall back would be month on Velcade then try again to get the Part D insurer to approve payment.

        If rev/dex in the short three week test appeared to be working, meaning it caused the numbers to fall (or maybe just arrested the rise), then we would hold course and stay with it. (If the two tracking number had split, one going up and one down, it would have been a tough call, but that didn't happen.)

        When the data came in a few days later, a pleasant surprise, three wks on the old rev/dex arrested the rise and caused both numbers to fall [.31 => .25 M-spike and 15.3 => 7.89 free light chain]). I put more emphasis here on the free light chain drop of  50%, because M-spike falling  tends to lag and also the lambda free light chain had fallen under its 10 mg/dL threshold, though the kappa/lamda ratio showed no improvement coming in slightly below normal.

        After seeing the free light chain drop in half, I was less concerned about how much the M-spike would drop, just that it would show a drop, and two days later the data came in with a 20% drop, so both numbers had turned around. We would hold course on rev/dex and would have another set of data in three more weeks (5/2/16) from appointments previously set up. At this point I had been on Revlimid 7 wks straight, but my platlets were getting quite low (88), so my doctor wanted to start cycling rev/dex. The first off week to start when my current Revlimid pills ran out (first off day tues 4/19). Thus the 2nd three week test of rev/dex I am just beginnng will be Revlimid (25 mg, one week off and two weeks on) with (40 mg) dex continuing every fri. It will be interesting to see if the decline continues and for how long it will hold.

Am I still in my first remission?
        So an interesting question now arises. Am I still in my first remission? I had declared my first remission had ended, but now back at the original rev/dex after my M-spike had risen to [.31 g/dL] or 6% of my pre-chemo (5.31 g/dL) and both numbers are falling. No 3rd drug added or new drug swap in. If I taken the original clinical trial offered me [(Ninlaro + rev/dex) vs rev/dex], I would have remained on original rev/dex continuously, and this would clearly be treated as still in first remission. Maybe the answer is yes.
Change in my numbers  (4/4/16)
        For the last four months (dec thru march) the upward trend in my numbers has continued: (M-spike .16,  .16,  .22,  .31 g/dL) (lambda free light chain 6.41, 8.41, 12.00, 15.30 mg/dL). When M-spike reached .22 and free light chain 12.00 (2/23/16), on the recommendation of a Dana Farber MM specialist the dose of my maintenance Revlimid was increased from 10 mg to 20 mg. But three weeks on the higher Revlimid dose gave no improvement at all. The rise in both numbers continued just as before: (M-spike .22 to .31) and (lambda free light chain 12.00 to 15.30).

        The 20 mg Revlimid maintenance dose was not working, so about ten days ago a quick decision was made to put me me back on the original rev/dex. This is a small step up and chemo and worth a couple of weeks or so to see if it is effective. The end of my 1st remission can be dated to 3/25/16, the day I began to add back the dexamethasone (at first paired with 20 mg Revlimid, in a few days was changed to 25 mg) to the same rev/dex I took for 6 months when I first started chemo in late 2014: (25 mg Revlimid (21 of 28 days) and dexamethasone (40 mg/wk)). The corticosteroid (dexamethasone), considered a 'booster' for Revlimid, that I happily stopped ten months ago came back. (And two days/wk of almost no sleep due to the corticosteroid came back too.)

        This rev/dex test will be a short one (about threeweeks) since I am closing in fast on my M-spike target (.5 g/dL). Personally I will be surprised if going back on rev/dex works, since my cancer just did not respond at all to a doubling of the Revlimid dose. It acts like it has become resistant to Revlimid, but who knows, maybe the 'booster' will help, the data will tell the tale. If it doesn't work and the rise continues as before, my next blood sample (due 4/11/16)  will probably show an M-spike above .4 g/dL. The next change in chemo will be important and is not decided yet.

First remission ended (3/25/16)
        My first remission 'officially' ended with my recent chemo change back to rev/dex. (or did it?  see above) I only got ten months on Revlimid maintenance before my M-spike numbers rising from a very low level (99% down) began to approach .5 g/dL, which clinical trials usually use as the threshold (as applied to me) for disease progression. And even more worrying (to me) my lambda free light chain has continued to climb, up about 50% in the last two months. It passed 10 mg/dL, used as a threshold to join some clinical trials, around (2/1/16) and as of (3/22/16) it reached 15.30 mg/dL.

        I was hoping for 2-3 years in my first remission, but I only got 1.5 yrs. My 2-3 yr expectation was based on data showing the 50% point was about 2 yrs, and I had good cancer genetics. Good genetics tend to 'predict' how well one responds to chemo, and consistent with my genetics I did respond quite well, achieving a depth of response that only about 10-15% of patients on rev/dex achieve. Rev/dex dropped my M-spike levels about 99% (5.31 to <.05 g/dL) and my lambda free light chain dropped from an initial 379 to 1.50, well centered in the normal range. A good deep response tends to be correlated with a longer time to disease progression, but in my case after three months of being unreadable my M-spike began to climb. So bottom line 18 months after diagnosis, a chemo change is needed to get into a 2nd remission.

Thresholds to trigger chemo change
        What should be the M-spike and free light chain thresholds that trigger changes in chemo? I slowly began to realize that clinical trials provide guidance here. The most common end point used in MM clinical trials is disease progression. Every clinical trial I have looked at uses a standard's committee guideline, which (applied to me) is M-spike of .5 g/dL (technically it is an increase of .5 g/dL from <0.05 g/dL). So this is a good hard number.

        But there is additional threshold guidance in clinical trials. Clinical trials for relapse MM patients have both M-spike and free light chain thresholds, one of which must be exceeded just to join the trial. In other words clinical trials on relapse MM patients use these numbers verify you have a moderate level of cancer in your body, that you are not in remission. Importantly the trial joining requirement includes a free light chain threshold. This is useful, because there is no free light chain threshold in the disease progression definition. However, a (backup) free light chain threshold may be provided to define disease progression for a class of MM patients who have no measurable M-spike (or its urine equivalent).

        I found the join criteria for one trial (Ninlaro) to be thresholds M-spike >.5 g/dL and free light chain >10 mg/dL (kappa/lambda ratio must also be abnormal). This M-spike level is the same for disease progression, so at .5 g/dL you go from one category to the other. Ninlaro's backup free light chain criteria for disease progression was 10 mg /dL. Dana Farber doctor said to me his threshold to trigger the doubling of Revlimid maintenance dose was lambda free light chain exceeding 10 mg/dL. My latest free light chain reading is right on the edge of meeting this first criteria. While my free light chain at 15.30 mg/dL is well above 10 mg/dL, my kappa to lambda ratio is still normal, but just barely at .26 (0.26 - 1.65 normal). However, the backup progression criteria (Ninlaro) defines the free light chain threshold differently as follows: "Difference between involved and uninvolved free light chain (FLC) levels (absolute increase > 10 mg/dl)". In other words it's not the ratio, but the difference that is being used. I am now above this theshold: [15.30 (lambda) - 3.96 (kappa) = 11.34 mg/dL > 10 mg/dL].

        Another trial had  M-spike >1 g/dL and free light chain  >?? mg/dL.

Thresholds bottom line: M-spike .5 g/dL,   lambda free light chain 10 mg/dL

Change in my numbers  (12/1/15)
        The initial decline in my cancer numbers has ended. For the last two months my numbers have begun to tick upward [M-spike <.05, .07, .12], but since the beginning base was low, my latest number is still low. The big question now is how long to watch this trend without 'doing something', which realistically means changing chemo. Of course, I am hoping it plateaus soon, but what if it doesn't? A MM patient has few resources here. I asked my oncologist and got only 'look for a trend'. One source of information is the definition clinical trials use for MM disease 'progression', typically a major milestone in the trials. The trials use as a threshold an M-spike increaseof .5 g/dL from minimum, which since my minimum was <.05 g/dL is is pretty much an absolute level of .5 g/dL.  Another source of information is MM forums where MM patients detail their experiences, useful but numbers here are all over the place.

        On the one hand at .12 g/dL I am now 25% of the way to the .5 g/dL clinical threshold with an increasing trend. This is worrying. On the other hand .12 g/dL is still less than at the end of my six months rev/dex chemo (.23 to .19 g/dL). Lambda free light chain has crept up a little (4.08), but this is only about 1% of my 379 pre-chemo. The kappa/lambda free light chain ratio has moved down a little (1.17 > .95), but is still in the center of the normal range. My albumin/(total protein) ratio is fine, my calcium level is fine, and my IgG hasn't moved. My M-spike cancer level while up a little is still nearly 98% down from my pre-chemo baseline (5.31 g/dL).

        It's useful to extrapolate the existing trend to make a prediction for my next number. There are only two uptick intervals, but they both showed a x1.75 increase in the monoclonal protein, a proxy for the plasma blood cancer in my marrow. This is a little less than doubling in one cycle, so if this trend holds, my .12 g/dL in early Dec would be expect to increase to .20 g/dL in early Jan 2016. I could potentially be getting up into the .5 g/dL range by Feb/March so I need to get busy with planning and research.

Cycle 9.5 confirms (9/4/15)
         I'm a natural skeptic, partly my engineering training, but I wasn't going to accept cycle 8.5 good tracking result at face value [no detection of M-spike or on immunofixation] until I could see another reading the following month. Well the 2nd results are in, and they basically confirms cycle 8.5 results. In cycle 9.5 cancer is detected both in the M-spike and on immunofixation, but it was small enough that it could not be quantified and that's the point. Taken together it looks like my cancer levels are just about at the threshold of the tests, probably a reduction of 98% to 99% in M-spike from my baseline value. Now what exactly the test thresholds are remain to be determined. Also two different doctors signed off of the results in the last two months and that may make a difference.

        The weak bands in cycle 9.5 are described as 'oligoclonal'. I can't find a good definition of this term, but it seems to refer to several smaller spikes close together rather a single large spike (monoclonal). What the clinical significance of this is I don't know. The spikes are described as type IgG, which is the type of cancer I have. I suppose oligoclonal might mean I have two spikes, one with a lambda light chain and one with a kappa, which was reported in my results many months ago.
Cycle 8.5  results --- Too good to be true? (8/10/15)
       My latest M-spike (cycle 8.5) looks a little too good to be true, which means it might not be. Previous monthly values were 0.24, 0.23, 0.19 (g/dL), a slowly declining value that appears to be approaching an assymptote a little below 0.20 g/dL, so what is the probability that a month later that it has suddenly dropped to undetectable levels (probably <0.05 g/dL)? I'd say there's a significant chance there's a test error here. I did see that corticosteroids can affect the serum protein phosphoresis test, so maybe going onto maintenance with the dropping of dexamethasone is having an effect.

       Notice the sloppy blood work reporting, there are no M-spike numbers, it just says "No monoclonal immunoglobulin detected" and the "immunofixation: no bands detected", which translated means the monoclonal density is below the threshold of the tests. While I believe this type of reporting is common, it begs the question: What is the threshold of the tests? It should be reported as < xxx g/dL. I read in one european paper the test threshold is normally around 0.03 to 0.05 g/dL, but this information is hard to come by. Multiple references say the threshold of monoclonal protein detection by immunofixation is lower still. One reference lists the thresholds as 0.05 g/dL for protein electrophoresis and 0.015 g/dL for immunofixation.

        When I asked my doctor about the M-spike test threshold, she said she has seen levels as low as 0.1 (g/dL). Well I have seen levels as low as 0.05 (g/dL) in my own blood work (small kappa monoclonal spike).  I suspect the best way to really understand this test would be to talk to the doctors at the hospital that do the test and analysis, and I am pursuing this.

        ** I found (below) an interesting tidbit on the excellent web site of Amerian Association for Clinical Chemistry. Could this be the reason why after entering maintenance and stopping dexamethasone a big change in M-spike was found this cycle? (My doctor made a vague reference that sometimes she has seen this happen.)

        -- Aspirin, bicarbonates, and corticosteroids can affect protein electrophoresis results.
Cycle 7.5
        My numbers are in the table above. The sketch shows my 96.4% reduction in M-spike over 7.5 month of chemo, and hemoglobin, which improved for three months then rolled off as chemo continued. My doctor appeared pleased with the first few months of my M-spike reduction. In the first four 28 days cycles (about four months) of rev/dex chemo my cancer levels dropped by a factor 15 (from 5.31 pre-chemo to 0.34) into the VGPR range. One way to look at these numbers is to say (on average) each 28 day cycle of rev/dex has cut the cancer level about in half [geometric mean of the four fractional decreases is 0.47].

        In later months the relative declines have slowed, and there's some evidence I may be approaching a plateau, but still each reading continues to be lower than the previous reading. The first reading in maintenance showing an additional 17% decline.
        As I begin to write this, it has been about seven months since I was diagnosed with cancer (multiple myeloma) and a broken neck caused by the cancer on the same day. Before my memories of those turbulent early months slip out of brain and random notes get lost, I want to write them up in a personal cancer essay that I plan to put online on my home page.

        On Sept 15, 2014, age 72, I was diagnosed with multiple myeloma, often called a 'blood' cancer, but technically it is a cancer of the bone marrow plasma cells, considered incurable but treatable. Marrow within bones make four types of blood cells: red blood cells to carry oxygen, white blood cells to fight infection, platelets to clot blood and plasma cells that produce a range of antibodies that provide an immune response. An antibody is a large protein (string of amino acids) made and exported by plasma cells at a rate of thousands/sec for each cell. Multiple myeloma is a cancer of the bone marrow cells that make blood plasma cells. A specific plasma cell can only turn out one type of antibody, so when a marrow plasma making cell goes cancerous and makes lots of clones of itself, the result is a huge excess of identical antibodies in the blood. The concentration of identical antibodies in the blood, called the M-spike (or monoclonal spike), is a marker for this cancer. This is an usual feature for a cancer and useful as it allows the amount of cancer in the body to be tracked using blood tests. My diagnosis that day was triggered by multiple myeloma having so weakened some of my bones that a bone near the top of my neck (C2) broke during sleep. This occurred totally without warning, no previous symptoms or pain, all while I was leading an active life and thinking I was in good health. But in reality I probably had had multiple myeloma (or its precursor) for some time, possibly years.

        Multiple myeloma is a sneaky disease that can, and often does, develop and metastasize throughout the body without producing any symptoms. Multiple myeloma, screws up your blood and can affect your kidneys, but primarily this cancer targets bones not vital organs. And a key reason this cancer can fly under the radar is that bones don't have pain sensors. Multiple myeloma can be hollowing out bones from the inside without causing any pain. Often it is only when the 'holes' the cancer is making in the bones reach the surface of the bone and disrupt the membrane around the bone, called the periosteum which does have pain sensors, or a bone breaks, is it that disease get discovered.

Can't get my head off pillow for 30 min!
       One Sun in Sept 2014 at age 72 I had gone to bed the previous night feeling fine. I thought I was in good health, I was active, I had even taken a ballet class that day as I did several times a week, only to find upon waking that I could not get my head off the pillow! I live alone and after 30 min I was wondering if I was ever going to be able to get out of bed. I finally was able to slide out of the bed onto the floor holding my head and taking some pain. Having no idea what was wrong and as a matter of principle avoiding doctors, I wrapped a towel around my neck to support it, toughed out the pain and hoped it was a neck spasm which I read about online, but when after 24 hours the pain began getting worse, I finally called 911. I visited two emergency rooms that night. The first ambulance took me to my local hospital (Winchester Hospital, Winchester MA), where I was told my x-ray showed I had a broken neck and needed neck surgery. They said they couldn't do that there I was to be transferred to their sister hospital, so in an hour or two I was strapped into a full body carrier usually used for auto accident victims and moved to Lahey Hospital (Burlington MA), where I was admitted and was soon told that not only did I have a broken neck, but I also had cancer, multiple myeloma.

        Multiple myeloma, often called a 'blood' cancer, is considered to be 100% fatal. According to the American Society of Hematolgy blood cancers affect the "production and function of your blood cells". The three main types of blood cancer affect different types of white blood cells: Leukemia (abnormal white blood cells), Lymphoma (abnormal lymphocytes which collect in the lymphatic system), Myeloma (abnormal plasma cells that don't mature into disease fighting antibodies). In other words 'blood' cancers are really bone marrow cancers. Blood cells don't live long (3-4 days for white blood cells, 120 days for red blood cells), so the bone marrow is continually cranking out new blood cells. Because the volume inside bones for making blood cells is fixed, uncontrolled growth, characteristic of all cancers, of one aspect of the blood making marrow squeezes the normal marrow. More (abnormal) white blood cells being made means fewer oxygen carrying red blood cells can be made. (Not sure how accurate this is, but it's my tidy little picture.) A nice feature diagnostically of this type of cancer is that analysis of your blood gives a good indication of the extent of the cancer in your system.

        Besides screwing up your blood, multiple myeloma metastases widely to bone marrow throughout the body, capable of softening bones to the point of breakage. It is not that uncommon for people to first find out they have multiple myeloma only when a bone breaks. However, my transition from seeming good health to finding out I had both a (fatal) cancer and a broken neck all in one evening is more extreme that any case I have come across. More commonly I find people report they found out they have multiple myeloma from routine blood tests or when they they go to the doctor complaining about persistent bone pain (like Tom Brokaw). When lying flat on my back and being wheeled through the corridor of the hospital a few days later, a resident leaned over to me and simply said, you have to consider that you have cancer "from head to toe". And that turned out to be right. X-rays showed bone lesions inside my skull, down my neck and back and in my legs. Many were small, but I had three big ones, 'holes' my doctor called them, in my neck (C2, which broke), in my back (T12 with 30-40% bone loss), and discovered later in my left femur (1.5" top-bot, spanning about 30% of the dia).

Cancer diagnosis and neck fusion operation
        To stabilize my broken neck within days of entering the hospital I had a three hour C1,C2 neck fusion operation. The bone that broke in my neck was C2, which is near the top of the neck just below the skull. Much of the rotation of the neck comes from the top vertebrae C1 sliding on C2. To keep the C2 vertebrae aligned with C1 C2 has a vertical projection (called a dens or odontoid process), shown below, that sticks up into the main donut hole of C1 where the spinal column goes. What broke in my neck my surgeon explained to me, was that the vertical projection of C2 had snapped off. (I remember him at a follow up meeting pointing to white blob on an MRI saying see this bone is totally separate.)

        I was told by the same resident who said I had cancer from head to toe, prior to my neck operation that a C1,C2,C3,C4 fusion was being considered, which luckily was scaled back to only two vertebrae (C1, C2) being fused instead of four. However much of the rotation of the neck occurs between C1 and C2, so screwing C1 to C2 with hardware has left me with a permanent loss of about half my neck rotation. I can now rotate my head only about +/- 45 degrees, which somewhat affects my ability to drive. For two months after the operation my surgeon required me to wear a neck collar 24 hours a day for the first month (sleeping in that thing was next to impossible) and during the day for a second month. And the whole broken neck/fusion thing has left me with a reoccuring semi-permanent pain in the neck. (See appendix for details of the C1, C2 fusion operation.)

xray of C2 vertebrae with broken dens
vertical projection of C2 vertebrae (dens or odontoid process) snapped off while I was sleeping!
(right) C2 (dens) projection clearly shows in this x-ray of my neck

How does the neck provide lateral support to the head? (update)
       It has slowly dawned on me that I don't really understand after my C2 vertebra broke what in my neck needed to be stabilized. The reason for this is two fold: one I don't have a good understanding of how the neck structurally supports the head, and two my surgeon, who I have had very few minutes of face time with over 9 months, has not explained it to me.

        This much is clear to me. When I awoke in bed that fateful day in Sept 14, I found my neck was suddenly providing no lateral support, none, that's why I couldn't lift my head off the pillow for 30 min. When I did manage to get out of bed, it was by first sliding my lower body off the bed onto the floor such that my neck & head were more like 45 degrees with respect to gravity. So how does the cervical (neck) vertebral column transmit force from the thoracic (chest) spine to hold the (heavy) head when the body is not vertical?  Frankly at this point I have no idea. In textbook sketches the spinal column is nearly always shown vertical. This puts the spine in compression, and it is easy to see how the spine works in compression, one vertebrae sitting on top of another with disks in between to provide some movement and cushioning. But what happens structurally when the body is not vertical? Do the spinal and cervical vertebrae directly provide any lateral support, or must the muscles hold the vertebrae column in compression to transmit lateral force?

        If the dens on C2 did break, why did I feel I had no lateral support for my head? Does the dens itself provide lateral support, transmitting force from C2 to C1, or was it that with no dens C1 was just free to slide around, so when the neck muscles tightened the head + C1 slipped sideways causing pain? I am going to have to research this.

Neck anatomy
        There are some nice youtube videos showing the anatomy of the neck. Below are some scn captures. There are a LOT of muscles in the neck, including the big trapezius muscle in the back, and nearly all these muscles run vertically. The center image shows there are specific muscles that attach C2 to C7 to the rib cage. Just from looking at the video you can see the muscles are arranged to 'pull down' on the vertebrae (and skull) allowing the cervical column to be in compression. There are also ligaments between C1 and C2. I think this is the answer to the lateral stability question.
        The long (downward pointing) projections of the neck verterbrae in the back are called the 'spinous process'. Wikipedia says they serve as an attachment point for ligaments and muscles.
        Notice there is no disk between C1-C2. It is replaced by two sliding joints that allow C1 (and the skull) to rotate 45 degrees or so with respect to C2. The right image is a top down view (with the skull removed) showing C1 and the dens projecting upward from C2. From this we can visualize how C1 rotates on C2. (The video lecturer says the modelling is not entirely accurate here in that there is really no space between the dens and the front rounded arch of C1. They actually touch he says.)  The purpose of the C2 dens is that it is a pivot point around which the rounded (front) arch of C2 rotates. As I look at the right figure, the C2 dens provides a hard stop preventing the C1/skull from sliding backwards, but there doesn't seem to be any bone structure to prevent C1/skull from sliding forwards and potentially compressng the spinal column. It must be the muscles and legaments job to hold the head centered or sliding forward, perhaps the big trapezius muscle which runs up from the back to the back of the head is key. So is this the answer to why I couldn't get my head off the pillow? Maybe.
        Looking at the bone structure of the neck it does seem to me that to lift the head off the pillow (face up) some of the lifting force transmitted to C1/skull probably comes via C2 dens pushing on the rounded front (anterior) arch of C1. It might be that with the C2 dens broken off there was insufficient force from the muscles and ligaments alone to lift the head. Or maybe with C2 dens gone my head tended to slide backward a little and that triggered pain (by pushing on the spinal cord?).
 .  .
(left) muscles attach C2 - C7 in neck to rib cage (front view)
(middle) more neck muscles (front view)
(right) top down view of C1 and C2 (top is front)
Crap neck video
        There's crap about the neck on Youtube too. Here's one by a doctor (Dr. Ross Hauser) pushing some sort of injection to fix the ligaments between C1 and C2. His animation is absurd. It shows as normal that C1 and C2 move as a unit when the head rotates. C1 rotating more than C2 he calls that an instability saying it pulls on the blood vessels going through C1 and C2 affecting the flow. I presume there must be some slack in the blood vessels to allow C1 to C2 rotation, which I hadn't thought about before.  Of course he ignores the fact that the anatomy of C1 and C2, with a sliding joint between them, shows C1/skull are designed to rotate a lot with respect to C2, about 45 degrees most references and my surgeon say. (If this guy isn't a quack, he is pretty close to it. He's a shameless self promoter with books by him and his wife on Amazon about curing back pain (Prolo Your Pain Away! Curing Chronic Pain with Prolotherapy), cancer ('Treating Cancer with Insulin Potentiation Therapy') and even a diet book.

Treatments -- Radiation of C2 (neck) and T12 (back)
        I was in the hospital for seven days, the first days filled with extensive diagnostic tests and waiting for a cervical (neck) surgeon to become available. Two weeks after my release from the hospital two weeks of daily radiation began in Oct 2014 to kill then cancer cells in my two big bone lesions then known, in my neck (C2 that had broken) and T12 in my lower back. Radiation was pain free and turned out to be nearly free of side effects as my radiation oncologist explained to me that blood marrow cancer cells are more sensitive to radiation than most cells, so a lower dose of radiation (about half) can be used.

        The irradiation was done with one of three multi-million dollar linear accelerators Lahey owns. One semi-grusome aspect of the radiation procedure was since neck vertebrae C2 high up near the skull was to be irradiated, my head could not move. This was accomplished by making a form fitting mask of my face so my head could be bolted to the table. A flat sheet with holes in a frame was softened by wetting it, and then it was stretched (hard) over my face and the frame bolted to the table. (You can see this mask below in the pictures.) I had to stay bolted down quite a while (20-25 min) while it dried and hardened. Then on each daily visit my mask would be pulled from the mask shelf, my face again mashed down to the table as the frame was snapped down. Pretty claustrophobic, stayed on for 10-15 min each day while the neck was irradiated, during which time I have to breath through holes in the mask, but after a day or so I got used to it and it was no big deal. In contrast the radiation for the back, which immediately followed, was a breeze. The body was lined up with tattoo marks that had been applied the first day, and I was just told not to move for 10 min.

        I was initially concerned that radiation of C2, since it is near the top of the spinal column and near the brain, would expose my brain to radiation. But my radiation oncologist explained to me how the targeting is done (and the frequencies chosen) giving sharp margins, and she assured me that my brain would be safe. I think that was true as I noticed no mental effects at all from the radiation.

        My C1,C2 neck fusion operation failed, meaning the two vertebrae did not fuse. The bone only grew into one of the four screws. My surgeon points to the neck radiation I got 18 months earlier to fight the cancer as the reason, saying that radiation affects the ability of bone to grow. I haven't researched this, but that is what he tells me.
Staging my multiple myeloma
        After the neck operation and radiation treatments, my cancer was worked up following a full body set of x-rays and blood work specific for multiple myeloma to asses the severity of my cancer and to plan for chemo. My numbers and prognosis were not good. I was told I had stage 3 (of 3) multiple myeloma cancer. This was based on extensive number of bone lesions found including my pathologic neck fracture plus my high level of beta2microglobulin, a key blood molecule used for staging MM. I did a literature search, and it showed median survival for levels of beta2microglobin above 4.5 mg/L of only 12 months, and my number was 6.9! A sample of my bone marrow (taken later) showed 70% of the cells were plasma cells, grossly high since normally only 2-3% of marrow cells are plasma cells. One of my blood proteins, lambda free light chain, had a density x150 higher than normal! I was consider 'high risk' and was being steered into an aggressive three drug regimen of chemo drugs.
        I told everyone my goal at that time was to live long enough (about a year) to see Billy Elliot again when it came to the Boston area in the fall (early Oct) of 2015. Responding to chemo pretty well, so I make it, so I have added a new goal a little further out: To live long enough to see one of my favorite shows again, the romantic musical 'She Loves Me', returning to Broadway after 22 years. It's on the Roundabout Theater Company schedule for sometime in early 2016 (no dates yet).

        I now understand that the very short survival times in the literature associated with high levels of beta2microglobulin levels reflects (by necessity) historical data, and this can be misleading where treatments options and survival rates have improved a lot in the last 10-15 years as been the case with MM.

        I resisted starting chemo until I heard back on how my DNA tests, which take weeks because they are done on my DNA sent to the Mayo Clinic came in, even though I was told by one of the hospital's hematology oncologists one time to 'forget the DNA tests'. Wrong!! I had done the right thing. When the DNA results came in, my doctor was singing a different tune. Finally I had a little luck, I had the one DNA mutation (of seven) that on average leads to a better response to chemo, so overnight my risk dropped from 'high' to 'standard', and I was now being steered to the most common multiple myeloma chemo combo of recent years consisting of two drugs in pill form: revlimid and dexamethasone. The staging process after the radiation took about a month so was not until the last week of nov, about nine weeks after my diagnosis, that chemo began.
Chemo options
      At this point in the narrative my memory failed me a little. Reviewing my doctor(s) contemporaneous notes, I find that before my DNA (cytogenic) results came in a substitute hematologist (my regular oncologist was out sick that day) did indeed recommend I start an aggressive chemo regimen called CyBorD: cyclophosphamide,  bortezomib (Velcade), and dexamethasone. But, but later when my favorable (hyperdiploidy) DNA results came in dropping my risk to 'standard', my regular oncologist notes show she gave me the the option of choosing between the three drug CyBorD regimen (one of them injected) or the two drug dex/revlimid (both pills) regimen. I asked for 48 hours to think about it. I opted for quality of life over aggressive and chose dex/rev. I follow the philosophy KISS (keep it simple stupid). Also I knew dex/rev had a good track record, was the regimen that 50% of the patients would get in the clinical trial I was offered, and at the time had been described by my doctor as 'standard' chemo for multiple myeloma. With hindsite I am surprised that the option of adding velcade to dex/rev wasn't mentioned, since I now find that RVD (revlimid, velcade, dexamethasone) is the chomo regimen being used in a phase 3 clinical trial for newly diagnosed MM patients.
FDA approval restrictions (update)
        I may have discovered why RVD was not recommended (or mentioned) to me as a chemo option. Reading one of the ongoing phase 3 clinical trial description comparing RVD vs [RVD + transplant] it says that while all three drugs are approved by the FDA to treat MM, this particular combination has not approved for treating newly diagnosed MM patients. The corollary being one of the goals of the study is to obtain the FDA approval.

        This drives home an issue I have noticed, but probably not fully appreciated. The various treatment drugs for MM that are approved by the FDA come with various restrictions. They may be for MM patients who have had some prior other treatment, or for MM patients whose disease has come back (refractory MM). For example (according to a Celgene press announcement) dex/rev was FDA approved in 2006 for MM patients who have had at least one other therapy. Well that very likely included me because I had radiation prior to beginning chemo. Only recently, in Feb 2015 which is after I started chemo, was FDA dex/rev approval expanded to cover newly diagnosed MM patients. It's a good bet that doctors, while they don't say so, are in some way obligated or under pressure (fear?) to recommend FDA approved chemo regimens. In fact the Celgene announcement includes this quote:

        "The approval of REVLIMID as an option for use in all patients with multiple myeloma represents a new paradigm in the management of this disease," said Kenneth Anderson, M.D., Director, Jerome Lipper Multiple Myeloma Center, Dana-Farber/Brigham and Women's Cancer Center. "We now have clinical evidence demonstrating that starting and keeping newly diagnosed multiple myeloma patients on REVLIMID significantly improves progression-free survival."
        Unlike other cancers where say after a tumor is removed a person might have chemo for a month or two, chemo for multiple myeloma (without a stem cell transplant) means essentially staying on chemo forever, meaning I will likely be on chemo until it stops working, which it invariably will. Thus side effects of the chemo, as well of course as its effectiveness, are an important consideration, it's a balancing act.
        "The recommended starting dose of REVLIMID is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with
dexamethasone. Dexamethasone dosing is typically 40 mg (ten 4 mg pills on single day!) taken on days 1,8,15,22 of the cycle. For patients > 75 years old, the starting dose of dexamethasone may be reduced. Treatment should be continued until disease progression or unacceptable toxicity." (Celgene revlimid proscribing sheet)

        For historical reasons the (obviously) high dose (10 x 4 mg/pill) of 40 mg/wk dexamethasone is referred to as 'low dose'. The historical reason is that in years prior dexamethasone as part of MM treatment was given in much higher doses! (The description of 40 mg/wk (10 pills to be taken in a single day) as 'low dose' I found to be absurd when I first came across it in the MM clinical trial I was offered.)

        Why revlimid or dexamethasone works, or any of the chemo drugs for multiple myeloma, does not appear to be well understood. These drugs mess around with the immune system changing several pathways. Twenty-five years ago it was discovered clinically, and essentially by accident, that thalidomide had anti-inflammatory properties that was effective against some diseases, and later work showed it had anti-angiogenic and anti-tumor activities properties too, so that prompted work to develop variants like lenalidomide (revlimid) which would be better tolerated and more effective. I know from reading some papers that the reason that the chemo drugs stop working in multiple myeloma is also not well understood and is an area of active research.

Revlimid risks
        Revlimid (lenalidomide) made by Celgene is a variant of an old drug, thalidomide. Celgene calls revlimid a "thalidomide analogue" and as given for multiple myeloma has real risks. The odds of it killing you are something like 3%-4%/year! There are two big risk. One, it can cause a deep blood clot, which if it travels to the heart is a heart attack or to the brain a stroke. To combat this risk I am taking a full dose (375 mg) of aspirin every day a 'blood thinner' meaning it makes platelets less likely to stick together. In one clincal study 18 of 145 surviving patients (12.5%) got a secondary cancer in four years on revlimid maintenance (10 mg).

        "REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as
risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with REVLIMID and dexamethasone
therapy." (Celgene revlimid proscribing sheet)
        Two, revlimid can give you another cancer! Some clinical trials involving revlimid have been stopped because the data showed those getting revlimid had an excess of new cancers, which was attributed to the revlimid. Presumably both of these risks are (to some extent) dose and length dependent, but data on this is hard to come by. I have been able to pry little about these risks from my doctors.

Decisions I had to make before chemo began
       There were three clinical decisions up front that I had to make. Decisions which due to the complexity of multiple myeloma and all the various treatment options are difficult to get your arms around in the short time in which you are asked to decide.

Did I want a stem cell replacement?
        One, was whether I might at some point want a total stem cell replacement. I was told this was important to decide up front because it affected the types of chemo that could be used. At that point I had had enough of hospitals, and when I found out a stem cell replacement meant a three week stay in the hospital, a long recovery period and was fraught with risk, and was not a cure only a possible life extension, I said no. Reinforcing that was I was told that until recently people my age didn't qualify for a stem cell replacement, but people older than me were now getting them. Keep it simple stupid is my motto. I preferred a less aggressive treatment, perhaps not living as long, but hopefully with a higher quality of life. If I was younger, I might have looked at this differently, but at my age I found this an easy decision to make, and have not wavered since, though I will reassess if facts change.

Revlimid does not exclude stem cell transplant
       "The other reason it is important to have a discussion at the beginning about the possibility an autologous stem cell transplant is that it determines which chemotherapy drugs will make up the initial treatment. Alkeran (melphalan) damages stem cells making collection difficult or impossible. Thus, patients who elect to have stem cells collected and stored are frequently treated with a Thalomid (thalidomide)-based regimen that does not include Alkeran. "
Did I want to join a chemo clinical trial for new oral botzezomib added to rev/dex?
        The second decision I had to make up front was whether I wanted to join a multiple myeloma clinical trial I qualified for that the hospital was offering. Lahey is a teaching hospital for Tuft medical school. I read the multi-page paperwork on the clinical trial I was given. This was a phase 3, double blind, placebo study comparing a new triple multiple myeloma chemo combo against a standard double multiple myeloma chemo treatment, which was in fact revlimid and dexamethasone both in pill form taken daily at home. The study was evaluating the effectiveness of adding a 3rd pill, a newly developed pill form of an older injectable drug (velcade), generic name Ixazomib, by the manuf of velcade, Millennium Pharmaceuticals. (update --- In Nov 2015 the proteasome inhibitor pill that was the subject of this trial, now called Ninlaro, was approved for sale by FDA.)

        I really didn't like the idea that I wouldn't know whether my side effects would be due to two or three drugs, that the protocol was rigid (could be changed only by dropping out of the trial) and various other restrictions. After some thought, I found this also an easy decision to make, and I said no to the trial, even though its expensive chemo drugs might have been provided free? Nope, I rechecked the trial documents and only the new pill is provided free. The cost of the revlimid "will be billed to you or your insurance carrier". Yikes! Nice guys. Of course they omit that the cost of the revlimid is 10k/month! How do they ever get people to sign up for these clinical trials? (I later found out that Lahey withdrew from the clinical trial I was offered. What they couldn't get anyone to sign up?)

        ** I now see another issue, which is finessed in the clinical trial paperwork. There's aparently no maintanence. The dose of revlimid remains at 25 mg for years (7 years says the paperwork), or until the discease progresses. This has got to increase the risk of secondary cancers. My doctor never mentioned this issue to me!

Choosing a chemo regimen
       The 3rd decision, which I discussed above, was choosing between an aggressive three drug chemo regimen that included a general anti-cancer drug (cyclophosphamide) and an injectable drug (velcade) or to opt for a two drug regimen in pill form (dex/rev -- dexamethasone and revlimid). I liked the idea of two drugs over three for fewer side effects, and pills over hospital trips ever few days for injections, so I chose dex/rev.

Chemo cost and insurance
        The first shock about the chemo was that Celgene's patented Revlimid is an extremely expensive tier 5 drug that costs about 500 dollars a pill! That's a 500 dollars a day for 21 day of a 28 day cycle, or about 10k per month, about 120k/yr. In contrast the other chemo pill, dexamethasone, a drug that mimics the function of natural corticosteroid hormones regulated by the adrenal gland, was cheap about 14 dollars bought 40 pills for the 28 day cycle. The weird thing about dexamethasone is that largest dose made is 4 mg, but the usual rev/dex multiple myeloma protocol is for 40 mg to taken on single day every week, that's ten pills on that day. I read there were lots of options here, so I asked my doctor if I could take five pills on two consecutive days instead and she said OK.

500 dollar a day chemo pill!
        The huge cost of my chemo immediately became an issue. Revlimid pills cost about 500 dollars each, over 10k/month, over 120k/yr. I was a basic medicare patient with medicare A (hospital) and B (physician and outpatient) coverage. Due to a quirk in the law the standard form of chemo under consideration was not covered by part A or B since it was available in pill only form. Injectable chemo, because they occur in the hospital are covered under part B. The pills would be covered under optional part D of medicare available only from insurance companies, but I assumed that because I was already diagnosed with cancer that buying part D coverage now would be impossible. This turned out to be wrong, an insurance company has to accept you at standard rates, regardless of your health status, but it took me a while to find this out.

        I really fault my haematology oncologist for no support here. In spite of several extended discussions of the cost of revlimid with my doctor and her knowing that I only had medicare part A and B coverage (no supplemental coverage), and my telling her that my income was too high to qualify for any supplemental programs to help pay for the cost of the drug, she refused to discuss cost insurance. All she had to do was drop a hint, a single sentence like 'looking into buying part D drug coverage, they have to accept you', but nothing. On top of this by luck these these drug decisions were being made during the end of the calendar year, which is the short open enrolment period of part D.

Signing up for medicare Part D drug plan
       Doing online research I eventually found out that if I applied for part D, the insurance company had to accept me, and that the cost of the part D was for me negligible since I was facing drug costs over a hundred thousands of dollars a year! (I don't think this has anything to do with Obamacare, I think it was built into Part D when it was established under Bush 2.) So I did my homework to pick an insurance company and signed up with Cigna for part D drug coverage for 2015 (beginning Jan 1, 2015). My chemo had began mid Nov 2014, about eight weeks after my diagnosis (plus neck operation and radiation), and sure enough I found it costs me out of pocket over ten thousand dollars for that first 28 day cycle of revlimid. The insurance company's pharmacy (Cigna Speciality Pharmacy) was a real bastard about payment (surprise!) demanding payment in full before they would deliver the pills, even though as sole supplier they had me totally over a barrel. I had the 10k in my checking account, but (hidden) daily card limits got tripped, and it turned out to be a real hassle trying to get the 10k delivered to them quickly so I could start my chemo on schedule. After hours on the phone with the bank and Cigna, Cigna eventually agreed to ship the pills after charging my debit card 8,999, just under its 9k daily limit, later adding a second charge to the card for the balance. Nice guys....

You have got to be freaking kidding me
        Some background, ever since I started chemo in late 2014 I have been getting my 500/pill Revlimid chemo pills home delivered from Cigna Speciality Pharmacy. I didn't actively chose this pharmacy, like much in medicine the selection occurred by default. I told my doctor and hospital that Cigna was my Part D insurer so every month they forward my prescription there, and Cigna Speciality Pharmacy calls me to arrange home delivery (I need to be home to sign for the pills) and payment. I have been satisfied with this Cigna pharmacy as they reliably deliver (by air) overnight, and with drugs like Revlimid that are patent protected with a single supplier there's no incentive to dp price shopping.

        It's a year later and I get a letter from Cigna that says, "In 2016 Cigna Home Delivery Pharmacy will not be a preferred network pharmacy".  Say what!! The insurance company Cigna has their own in-house pharmacy, yet as of 2016 when you buy Part D coverage from Cigna their own pharmacy is not in the preferred network. You have got to be kidding me. They advise switching to Walmart Home Delivery, which they say is in the preferred network for my plan. (And note letter about higher 2016 costs if you buy stick with them arrived Jan 22, 2016!) Yikes, insurance companies... Luckily the letter has a caveat that applies to me, saying if you take a tier 5 drug (Revlimid as a super expensive cancer drug is a tier 5 drug), then you pay the same percentage of the cost regardless of the pharmacy you chose.

        (update --- What I didn't recognize at the time was I had lucked out by starting (pill based) chemo during the seven week Part D open enrollment period (oct 7 to dec 15). That's why I was able to get in when I called.)

Delaying 2nd chemo cycle for Part D insurance to cut in
       My second 28 day chemo cycle was scheduled to start about ten days before Jan 1 when my part D drug coverage would cut in, so my doctor suggested the start of cycle two be delayed for a few days (turned out to be 10 days) until it cut in, thus saving me from another 10k drug charge.

Part D coverage
        Part D covers only a portion of drugs costs and has a very complicated three part coverage formula with a donut hole. My jan chemo out of pocket costs were about 4k, but because revlimid is so freaking expensive, I was through the donut hole before the month was over. For the next 11 months of 2015 I am in what is called the 'catastrophic' phase of Part D where I pay only 5% of the retail cost, or about 500/month, or 5.5k for the remaining 11 months of the year. Bottom line by joining part D (drug coverage) I will cut my total out of pocket drug costs in 2015 by something like a factor of twelve. My out of pocket costs for the entire 2015 year, including that of plan D itself, will be less than 10k I paid Cigna for revlimid in Nov 2014 without part D coverage.

DNA variations -- cytogetics
        There are about eight known variations in DNA that have an influence on the agressiveness of multiple myeloma and the responsiveness to chemo. Only one is really positive (hyperdiploidy), and here I had a little luck. I have the hyperdiploidy variation in my DNA.  I also have the negative factor Deletion 13, but my oncologist says clinical practice shows the positive result overrides the negative one. This test (FISH -- fluorescence in situ hybridization)) takes 2-3 weeks,  and I think it was done by sending my marrow to the Mayo clinic. The Mayo clinic has a cytogenetics laboratory, which (they say) is a 'leader in the field of cytogenetics'. In the FISH analysis DNA probes are labeled with different colored fluorescent tags to visualize one or more specific regions of the genome.

        From the table below I first thought the hyperdiploid (not hypodiploid) variation was rare, but the estimate is about half of multiple myeloma patients have this variation, but of course nothing is ever simple. One paper I read says they see four sub-populations in the hyperdiploid category with a 4:1 difference between them in median survival (2.5 years to 10 years).

List of DNA abnormalities that affect severity of multiple myeloma
I have the hyperdiploidy variation (and deletion 13)
(Notice the 'poor' outcome for deletion 13 is when measured not with Fish, but with the less sensitive conventional test.)
(my Mayo clinic cytogenetics results on my marrow are here)

         Prior to my cytogenetics test results becoming available (test takes several weeks) I was considered 'high risk' and in early Nov 2014 was being steered by my doctors toward an agressive chemo regimen with standard anti-cancer drugs, but I resisted starting chemo until the test results became available. When they did arrive and I was found to be hyperdiploidy, there was a dramatic turn around. My risk dropped to 'standard risk', and the recommended chemo was now the standard mulitple myeloma targeted chemo of revlimid and dexamethasone. I agreed and in late Nov 2014 I began by first cycle of dex/rev chemo.

        (update, May 2015) I finally pried the written report from the Mayo Clinic done on my extracted bone from my doctor and have posted its key section in the Appendix. It details which chromosones I have extra copies of (my good hyperdiploidy variation) and maybe not so good chromosone 13 deletion where I have only one copy instead of the usual two. The Mayo clinic used the Fish test.

M-spike blood test
        To assess how well the dex/rev chemo is working my doctors focus on one number in my blood, the mono-clonal spike (or M-spike). Blood plasma cells turn into a wide range of antibody cells, whose atomic weights that when plotted form a smooth curve. Because one particular marrow cell that makes plasma cells has gone cancerous and wildly clones itself, there is in my blood a huge excess of anti-bodies (proteins) of one particular atomic weight, which shows up as a large spike riding on top of the normal smooth curve of anti-body weights. A special blood test is needed to spread out (spacially) the anti-bodies by atomic weight. This test, called electrophoresis test, forces charged anti-bodies to diffuse through an agarose gel by driving them with an E field (voltage). The smaller the molecule the faster it can diffuse, so this test spreads out the anti-bodies by atomic weight. [The force driving the diffusion (F = qE) is also depends on the charge of the anti-bodies, but the net charge on biological molecules is affected by the surrounding medium's ph and can become more positively or negatively charged due to the gain or loss, respectively, of protons (H+) from the molecules' double H+/OH- charge.]

Free light chains --- supplement to M-spike
        When reading the postings of other MM patients, I found some never mentioned an M-spike. This initially confused me, but then I found out that about 20% (one reference) of MM patients don't have a significant M-spike, so in these patients to track the cancer doctors look to the free light chains. The difference between them is the M-spike is the full monoclonal anti-body, whereas a monoclonal light chain is only a portion of the anti-body.

Leading indicator?
       I have included this marker (kappa/lambda ratio) on the left side of my numbers table. One virtue it may have over the M-spike is that it appears to respond more rapidly to cancer levels. As such it might be a leading indicator for changes in cancer levels. Notice in my numbers my lambda free light chain value dropped 98% [379 => 8] with my first rev/dex chemo cycle vs a 66% reduction in M-spike! And the kappa/lamda free light chain ratio dropped into the normal range at the end of two cyles of rev/dex, while the M-spike was still high (0.99 g/dL).
        My numbers shows the strength and weakness of this free light chain marker. It moves fast, but it likely loses it's usefullness when cancer levels are low because it doesn't go to zero. It has a residual normal value with a wide range (0.26 - 1.65). In contrast with a known time lag of months the M-spike will eventually (maybe in 6 months or so) settle toward zero if all clonal cells are killed off, so it looks to me that it should be much better than the free light chains for measuring the depth of response to chemo. My guess is that this is why it is the preferred MM tracker, not to mention that it has a much longer track record, free light chain measurements, which use a new laser scatter instrument, and only got approved within the last ten years.

        I found a 2009 Mayo Clinic paper that says the recent introduction of quanitative assays of free light chains has made it a useful cancer tracking indication, saying "Surprisingly, free light chain quantification has also proved to be prognostic ... for survival in MM". The paper also says that M-spike is preferred over free light chain, and it cautions there are some (2009) concerns that lambda coverage may not be complete. The paper says several studies have shown that adding serum free light chain assays to M-spike testing eliminates the need to screen urine for free light chains, which because they are small pass through the kidneys readily. This point is relevant to me because my monthly blood screening have routinely included free light chain assays, but my doctors have never tested my urine.

       -- Free light chain quantification has also proved to be prognostic ... for survival in MM

       -- Increased skewing of the ratio between kappa and lambda light chains after a MM patient has been treated is an indication of disease recurrence (Wikipedia -- nephelometry)

       -- FLCs (free light chains) are thought to be associated with imbalances in heavy and light chain production in monoclonal plasma cell populations

       -- Although several disorders lead to abnormal concentrations of kappa and lambda FLC, the FLC Kappa/Lambda ratio appears to remain within the reference range except in the monoclonal plasma cell proliferative disorders. (translation: only plama cancers appear to affect the kappa/lambda ratio, so it is a good test to identify blood plasma cancers)

       -- The use of capillary electrophoresis for SPEP (serum protein electrophoresis) and nephelometry for FLC (free light chain) quantification would essentially automate screening for monoclonal gammopathies. (In contrast "immunofixation electrophoresis" is described as being costly because it must be done manually.)

    ** -- With treatment induced plasma cell kill, free light chain concentrations (which have a lifetime measured in hours) decrease rapidly and precipitously. In contrast the longer half live of intact immunoglobins (measurable in weeks) leads to a long lag-time in the assessment of treatment response.  (From LabCorp a manufacturer of blood test equipment)

        -- In a 2005 report from Sloan Kettering normalization of the free light chain ratio after one or two cycle of chemo in MM patients was found to be significantly associated with subsequent complete or near complete response as assessed many cycles later using measurment of intact immunoglobins (M-spike). (This is consistent with my response.)

**Free light chains are a true leading indicator
       Above is the key to why free light chains are indeed a true leading indicator. It's due to the difference in the lifetimes in the blood of the light chains (hours) vs the intact monoclonal proteins (weeks). This long lifetime of weeks for monoclonal protein explains why even if the plasma cells are rapidly killed off by chemo, the concentrations in the blood of intact clonal cells will fall slowly over several monthly cycles. Whereas free light chains, with the caveat that they are clearly abnormal, respond so quickly (hours) that they accurately track the concentrations of clonal cells. So looking at my numbers rev/dex killed off most (98%) of the marrow cancer cells in the 1st cycle and polished off most of the remaining cancer cells by the end of cycle #2! (Well, this is if the response is linear and it may not be.)

        This allows the lifetime of M-spike proteins in my blood to be estimated from the shape of my M-spike curve and is probably 3-4 weeks, which is consistent with what I read.

        At a 2015 Binding site MM symposia a talk says, "Mark Drayson demonstrated that the half-life of free light chains is measured in hours, whereas the half-life of intact immunoglobulins is approximately 20-30 days. This means that free light chain detection is able to give a much faster indication of response to treatment than measurement of intact immunoglobulins." (video of the 15 min talk here) A half-life of a month for M-spike would mean it would take 5 months for a factor of x32 reduction and 7 months for a factor of x128 reduction. These are times roughly comperable with what my data shows. However, viewing the talk I think he said this M-spike lifetime is without dexamethasone. With dexamethasone the M-spike time constant is reducted to 7 to 10 days, which is totally inconsistent with my plotted data.

**Excess free light chains damage the kidneys
        Wikipedia has a page on 'serum free light chain measurement'. It discusses that discusses ''myeloma kidney' (or Cast Nephropathy), where a component of urine binds to the free light chains forming a precipitate that blocks the small tubes of the kidneys. The referenced paper says, however, this is is a "potentially reversible cause of chronic renal failure." This condition is also discussed on the Binding site, which makes instruments to measure free light chains. They show that levels of 'clonal' free light chains  > 50 mg/dL (500 mg/L) are potentially dangerous to the kidneys and require treatment. (My pre-chemo free light chain was far in excess of this threshold at 379 mg/dL.)

My rising kidney numbers (update 2/24/16) (10/24/16)
            My cretinine bounces around between 1.1 to 1.3. Excluding the time just after diagnosis it had hit 1.4 only once in feb, but today (10/24/16) eight months ago, but today (10/24/16) it hit 1.4 again.
        As I see my pattern of rising (but still low) numbers of the last few months, I am beginning to be concerned about my kidneys. About two weeks ago my Dana Farber doctor said my kidneys were not too bad, but not the best, and yesterday my infusion nurse looking at my latest numbers said pretty much the same thing. Over the past 16 months of chemo my creatinine has bounced around, but alway remaining in the normal range (.6 to 1.3 mg/dL). Two weeks ago (at Dana labs) for the first time it was (barely) out of the normal range at 1.34 mg/dL. My latest value from Lahey labs this week is 1.4. mg/dL. The last time I was 1.4 mg/dL was before I started chemo, and my GP referred to this level as 'renal insufficiency'. Wikipedia (kidney disease), says "The process of most kidney diseases is renal Insufficiency, renal failure, and then uremia." My highest creatinine was when I was first diagnosed in the hospital at 1.7 mg/dL.

        Another blood monitor of kidney function the doctors call creatine clearance, but it appears in blood work as GFR (see below), and it has gone from normal (> 60) to 55 a month ago, to 52 two weeks ago to 50 this week.

Creatinine clearance vs GFR
        With regard to the to blood parameters that track the health of the kidney I'm (or was) a little confused. There are two kidney related parameters, 'creatinine' and 'creatinine clearance'. Creatinine is a density in the blood of a waste product from the muscles that the kidneys clear. 'Creatinine clearance' (CrCl) is defined as a measure of the rate that the kidneys are able to clear creatinine. (How this is measured I don't have a clue.) Both my Dana doctor and nurse mentioned "creatinine" and "creatinine clearance" while talking about the health of my kidneys. Creatinine in included in my blood work, but there is no parameter in blood work given to patients called 'creatinine clearance', or ''CrCl' (I see 'ClCr' used in literature), which is the abbreviation I saw looking over a nurse shoulder at her screen.

        I am now beginning to suspect that 'creatinine clearance' is in my blood work (or a related value), but under a different name. In Lahey blood work it's called GFR (EGFR on Dana blood work). Wikipedia (renal function) says "Glomerular filtration rate (GFR) describes the flow rate of filtered fluid (blood) through the kidneys. Creatinine clearance rate (CCr or CrCl) is the volume of blood plasma that is cleared of creatinine per unit time (mL/min) and is a useful measure for approximating the GFR."  According to Wikipedia 'eGFR', which Dana uses, is a an estimated (or calculated) value, but what's actually being measured is not clear. How can a single blood test measure a rate? (It can't, see below.) Lahey's GFR must be the same as Dana's eGFR because it has got the same normal range.

GFR is 'calulated' from creatinine
      OK, got it. 'GFR' (mL/min) in blood work is not a real measured value. It is just measured 'creatinine' scaled (engineers would say 'normalized') for race, sex, age, and weight. The higher the measured creatinine, then the lower will be the calculated creatinine clearance. (There is a precise test for creatinine clearance which requires urinating into a jug for 24 hours, and then testing the urine for creatinine. This works because almost no creatinine is broken down and recycled by the kidneys, all the creatinine it extracts from the blood is excreted into the urine. )
        The time I waste with trying to understand confusion like this, which is due to a lack of standards and because doctors use different names from those used on blood work, is a testament to the medical community basically not giving a shit about informing patients.
Stages of chronic kidney disease
       The National Kidney Foundation gives the following interpretation of GFR, which they describe as "best test to measure your level of kidney function and determine your stage of kidney disease". (But of course it's not a test. When determined from blood work, GFR is just creatinine normalized for age, race, etc.)  In my case for creatinine 1.2 and lower Lahey labs just reports GFR >60. When after 15 months of chemo, my creatinine broke out of the range of 1.1 to 1.3 hitting 1.4, the reported GFR was 50 (mild to moderate loss of kidney function).

        Diagnostic criteria for chronic kidney disease is GFR < 60 for three months or (if GFR > 60) high levels of albumin in urine. A urine test for kidney disease is standard. They give another table showing that with GFR between 30 to 60 risk can be moderate, high or very high depending on the level of albumin in urine.  I have never had my urine tested. (ask about this test)

stage of chronic kidney disease
Kidney damage with normal kidney function
Kidney damage with mild loss of kidney function
89 to 60
Mild to moderate loss of kidney function
59 to 44
Moderate to severe loss of kidney functionModerate to severe loss of kidney function
44 to 30
Severe loss of kidney function
29 to 15
Kidney failure
pretty sure 'renal function' (mL/min) in literature is same as GFR

        Their site has the formula for converting from creatinine to GFR. Playing with it I can see the big variables are race and gender, with age secondary. They give several standards, and I see that of of late feb 2016 Lahey has just changed their standard from CKD-EPI to MDRD. When I plug in my numbers, here the what their (MDRD) formula translates creatinine to GFR:

                                        1.0 creatinine        GFR = 73
                                        1.1 creatinine        GFR = 65
                                        1.2 creatinine        GFR = 59
                                        1.3 creatinine        GFR = 54
                                        1.4 creatinine        GFR = 50       (agrees with Lahey)
                                        1.5 creatinine        GFR = 46
                                        1.6 creatinine        GFR = 43
                                        1.7 creatinine        GFR = 40
                                        1.8 creatinine        GFR = 37
                                        1.9 creatinine        GFR = 35
                                        2.0 creatinine        GFR = 33
                                        2.1 creatinine        GFR = 31
                                        2.2 creatinine        GFR = 29

       Almost everyone has seen how a shaft of sunlight in a dark room can show tiny dust particles suspended in the air. Nephelometry is an automated version of this. It allows the density of small suspended particles in a fluid to be measured by shining a laser though the fluid and looking for reflected light to the side. The brightness of the reflected light is a measure of the particle density. This is a relatively new technique and is now widely used to measure pollutants in air. It can be considered a measure of turbidity of a fluid. (Nephel is derived from greek and means cloud.)

        In blood analysis nephelometry is used to measure of the concentration of proteins in blood plasma. Plasma is blood with all the cells removed. This technique is exquisitely sensitive. Whereas full immuglobins, like the M-spike, are given in units of g/dL, free light chains are given in units of mg/dL. I read the threshold is around 0.3 mg/dL. Calibration is used to compensate for shape, color and reflectivity of various particles. The type of protein (M, G, or A) seem to be detected by adding various anti-bodies as reagents. (Don't know the details, but even large protein molecules are tiny, so prior to the test some reactant may be added to react with the proteins.)

Protein electrophoresis
        Most MM patients show a tight high concentration (bar) in an abnormal location when proteins are spread out by diffusion in a protein serum electrophoresis test The amount material in this bar is measured (my guess is by measuring its brightness in reflected ultraviolet light) is taken as a proxy for the amount of cancer cells in the body's bone marrow. The total material of this bar is the 'monoclonal peak quant' (or M-spike) value in blood work. Here's a picture I found online showing a multiple myeloma patient's anti-bodies spread out, and the monoclonal M-spike is clearly visible. There's a bar (at the other end) to which consists of albumin that makes up a little more than half of normal blood protein.

Multiple myeloma monoclomal peak quant band (left)
in output of protein electrophoresis test done on blood serum.
(protein migration here is right to left,
so the spike on right is probably albumin, yup)

 Protein electrophoresis
        -- "Protein electrophoresis separates proteins based on their size and electrical charge. This forms a characteristic pattern of bands of different widths and intensities on a test media and reflects the mixture of proteins present in the body fluid evaluated. The pattern is divided into five fractions, called albumin, alpha 1, alpha 2, beta, and gamma. When a health practitioner is investigating symptoms that suggest multiple myeloma, such as bone pain, anemia, fatigue, unexplained fractures, or recurrent infections, to look for the presence of a characteristic band (monoclonal immunoglobulin) in the beta or gamma region; if a sharp band is seen, its identity as a monoclonal immunoglobulin is typically confirmed by immunofixation electrophoresis, which by use of anti-bodies determines which type of antibody (immunoglobulin) is present."
        A review of my blood work (Monoclonal profile serum panel) for the last seven months shows 'immunofixation' as a follow up to protein electrophoresis was done only one time (end of 1st cycle). Most monthly blood tests note "Immunofixation not performed" and "No change in electrophoretic pattern since previous". This test uses antigens to identify which anti-bodies make up the M-spike.

Dual M-spikes
        When I reviewed my blood work, I was surprised to find that in the early months of chemo I had two measurable M-spikes: IgG lamda (initially 5.31 g/dL) and IgG kappa (0.05 g/dL). The meaning of this I don't know, because my doctors never mentioned it, and I haven't researched it. It probably means nothing but who knows. The IgG kapp spike is tiny, only about 1% of the IgG lamda spike. Curiously there is no mention of a kappa M-spike in my baseline blood work, but after the first cycle it is identified with a reading of 0.05 g/dL, 0.06 g/dL after second cycle, and after third cycle it is identifed but marked 'too small to quantitate'. It doesn't show up in subsequent cycles.

M-spike test threshold
        One useful thing this small M-spike does is show the threshold of the M-spike test (as done at Lahey) is at least 0.05 g/dL. This is pretty consistent with what I have read is the limit of the test. 0.05 g/dl is about four times less than my current 0.19 g/dL of my lamda IgG M-spike. All my oncologist had to say about the M-spike test threshold is she has seen levels as low as 0.1 g/dl, but of course my own blood record shows (kappa) monocloonal readings at one half of this level.

How much increase in M-spike would be a problem?
        Now I am in the decreasing phase of my monoclonal M-spike, but as time goes on the cancer is going to come back and it's going to rise. The obvious question is, how much increase in  M-spike would signify that the cancer is returning and how much variation should be considered noise? A reference point is what MM clinical trial use to define 'progression' of the cancer. That number is an increase of 0.5 g/dl in the M-spike from the minimum level achieved (see appendix for details). Say 0.24 is as low as my M-spike gets, then an M-spike 0.5 g/dl higher, which is 0.74 g/dl, would trip a threshold in a clinical trial and signal an end to TTP (time to progression) of the disease.

        To put this in perspective my blood cancer level at the end of the fifth cycle has been driven down by the chemo to 95.5% from my initial baseline (5.31 g/dl), but if, or when, the level rises to (just) 14% (0.74/5.31 = 0.14) of my baseline that is a clinical indication that the cancer is "progressing", i.e. coming back. Or from another point of view if my blood cancer levels increase from 96.5% down to (still) 86% down below pre-chemo that is a clinical indication that my cancer is 'progressing', it is becoming immune to the maintenance chemo.

Is kappa or lambda free light chain a leading indicator?
        The table of my numbers above shows something interesting. Prior to chemo there were two markers in my blood for my cancer: M-spike and lambda (or kappa) free light chain blood. The M-spike a clonal immunoglobulin, a large Y shaped protein with dual heavy and light chains. Normally it is not present at all, so its ''normal range' is effectively zero. Lambda and kappa free light chains in blood are just fragments of immuglobins and both are always present in small quantities with a normal range of [0.33 - 1.94 mg/dL (kappa)] and [0.57 - 2.63 mg/dL (lambda)], and their ratio, which being a ratio is less sensitive to test errors and variability, has a normal range of [kappa/lamda 0.26 - 1.65].  A MM patient at diagnosis will typically have both a large M-spike and one highly elevated free light chain. Since the elevated free light chain can be either kappa or lambda type, a marker for MM is a kappa/lamda free light chain ratio that is either sky high (kappa clones) or nearly zero (lambda clones). I have a lambda cancer, so my ratio prior to chemo was super low, nearly zero.

        My baseline numbers were M-spike = 5.31 g/dL and lambda 379 mg/dL. The sky high lambda free light chain making my kappa/lamda ratio < 0.01. (The lambda blood free light value of 379 value is so off the charts that I doubled checked that its units are mg/dL in the lab reports.)

        Here's what's interesting. After just two cycles, while my M-spike had dropped about a factor of five (5.31 => 0.99), my lambda free light chain had dropped by more than a factor of 100 (379 => 2.74)! This brought my lambda free light chain to very close to its normal range (0.57 - 2.63 mg/dL), and my kappa/lamda ratio of 0.52 after two cycles was well within the normal range (0.26 - 1.65). In fact after just one rev/dex cycle my lambda free light chain had declined 98%  (379 => 8.17) giving me a kappa/lamda ratio of 0.21 pretty close to the normal range [0.26 - 1.65].

        This is a very fast and deep response to rev/dex chemo (at least in my case), so free light chains might be a good leading indicator going forward looking for signs of relapse. In fact I saw one poster on the Myeloma Beacon forum recommending just that.

        (update -- I later learned that the reason for rapid response of free light chains is well understood. Free light chains have a lifetime in the blood of hours vs weeks for the M-spike, so a measured 98% reduction in free light chains in the first cycle probably means about a 98% reduction in clonal cells during the cycle, because it is the clonal cells that are outputting the free light chains. The rapid response of free light chains is touted as a clinical advantage for assessing the effectiveness of chemo by the companies that make insturments for measuring free light chains.)

        This may not true for everyone. A MM patient (K_Shash), whose chemo is almost concurrent with mine, has been posting frequently on Myeloma Beacon forum during his 8 months of RVD chemo. He has a kappa cancer and began with a kappa free light chain value of 853 mg/dL. (I suspect he messed up his units, it's more likely 85.3 mg/dL, because he had a kappa/lamda ratio of 127 (0.26 - 1.65 normal). He had a reduction in his kappa free light chain of a factor of 98% in three cycles, whereas I had the same 98% reduction in my first cycle. It took him 8 months for his kappa free light chain to get into the normal range, and his kappa/lamda ratio of 1.74, while close, was still not quite normal (0.26 -  1.65).

        Curiously he never mentions his M-spike and calls the kappa free light chain value his 'main marker'. In other words instead of focusing on this M-spike value, as my oncologist does, it appears his oncologist is focusing on the kappa free light chain value! (research this) One likely explanation may be that some MM patients don't have an M-spike, so their cancer marker becomes the high free light chain value. (Other MM patients have the reverse, an abnormal M-spike, but normal free light chain values. It all depends on the nature of the chomasoidal damage.)

        A company that makes protein measuring equipment (Freelite) says 82% of MM patients have a (measurable) M-spike and 96% of MM patients have abnormal free light chain value.

        Another poster reports these numbers: M-spike 2.16 g/dL, lambda 21 mg/dL, kappa 0.78 mg/dL, kappa/lamda ratio 0.04. When my M-spike was in the 2 g/dL range (after one cycle), my kappa/lamda ratio was 0.21, pretty close to the lower end of the normal range.

Oxygen blood numbers and white blood cells
        Prior to chemo my red and white blood counts were quite a bit below normal. For the first three cycles of chemo as the cancer decreased my red and white blood counts improved. Heoglobin went from 30% below normal to well centered in the normal range. This made sense to me because normal marrow cells should have room to expand as the number of cancerous marrow cells decreased. But in the 4th cycle and continuing in the 5th cycle the improvments of my red and white counts reversed, dropping to the low end of normal at the 4th cycle and 5% below normal at the 5th cycle. This disturbs me, and I can feel a low red blood count, my blood has less oxygen carrying capacity. It doesn't take much of a walk to get me breating hard. My doctors suggests that it's probably a side effect of the chemo, and a well known side effect of revimid is anemia, which is a low red blood count.

        My initial dose of revlimid (25 mg) has been maintained through the 5th cycle, and there is a good chance it will be maintained for a 6th cycle (yup). I now have the OK from my doctor to experiment with the dose of dexamethasone. If I want, I can cut its dose from 40 mg/week to 20 mg/week to see if it will take the edge off its well known side effects that are bothering me, loss of sleep and a jittery feeling for 2-3 days. Beginning midway through the 5th cycle I experimented with cutting the dose of dexamethasone in half, 20 mg/wk (on a single day), and I did feel better, sleeping better and less jittery, so I plan to continue at 20 mg/wk though the remaining half of the 5th cycle and (probably) through the 6th cycle. My doctor is suggesting that dexamethasone will probably not be part of maintenance (just revlimid), so tapering off the dose now makes sense as the transition to maintenance is coming up fast, probably
beginning with the 7th cycle.

Living with cancer
Run down (4/2/17)
        My quality of life has degraded a lot in the last couple of months. Nothing hurts, but I am getting completely run down with episodes of diarrhea and vague belly pain, and most critically a complete lack of energy and fatigue. Some days I feel OK, but had a run of bad days. Some days I can hardly keep my eyes open. It's hard to say what the cause is, but the likely prospect is the pom/carfilzomib/dex chemo I have been on for the last 8 months which appears to have (or may have, assessment of my lungs continues) damaged my lungs. This chemo has just ended and begging next week carfilzomib will be swapped out for another proteasome inhibitor Ninlaro (Velcade in pill form).

        I changed chemo three times in 2016. Pom/carfilzomib/dex chemo begun at the end of June 2016 worked well for six months, but in early months of 2017 I began to be more and more limited in my activity by shortness of breath, and the last couple of months I have felt quiet run down. How I feel varies from day to day. Some days I feel pretty chipper, but just a few days ago after going out to lunch I was so exhausted I pretty much napped for the entire day. Diarrhea and vague admominal distresss comes and goes, which must be handledd with Immodium and is a pain in the neck. A recent lung functional test (DLCO) showed my oxygen intake was is half what it should be. A recent pet scan picked up indicates some unexplained opacities in my right lung. A CT scan of the lungs next week will hopefully clarify the situation.

        For perspective I have an aggressive cancer. Newly diagnosed MM patients are told you can reasonably be expected to live 5-6 years. This doesn't apply to me. I am only 2.5 years into my MM treatment (diagnosed in Sept 2014) yet I have been racing through the chemo options. I get plasmacytomas, soft tumors composed of plasma cells, that only 5% to 10% of MM get, an indication of the aggressive nature of my disease. My remissions tend to be less than the median. A long standing on in my 9th rib and another one behind my left eye that which has been beaten back with radiation and gives some residual double vision.

        My 1st remission (rev/dex) is over and lasted about 18 months, My 2nd remission (pom/carfilzomib/dex) is over and lasted 8 months. My free light chain values are rising (4.55 mg/dL), my M-spike is rising (0.17 g/dL) and a new pet scan should my rib plasmacytoma has grown 50% (2 cm => 3 cm) in the last 11 weeks. With an upcoming chemo change next week (pom/Ninlaro/dex) I will be looking for a 3rd remission. If this doesn't work, and it's sort of a short term experiment swapping out the proteasome inhibitor carfilzomib for the proteasome inhibitor Ninlaro,  chemo will probably be changed to (pom/daratumumab/dex). This chemo is built around a new humanized monoclonal antibody drug.

Chemo transition to maintenance (7/13/15)
        About two months ago there was a key change in my treatment. My chemo transitioned to what is called 'maintenance', meaning (some combination of) fewer cancer drugs and/or lower doses. In my case the change was from [25 mg revlimid (21 of 28 day cycle) + 40 mg/wk dexamethasone], which I have been on for six cycles (about six months), to revlimid only at a lower dose [10 mg revlimid (21 of 28 day cycle)].

        At the end of six cycles of 'standard' chemo the key indicator of cancer in my body, monoclonal spike, which is a measure of the amount of cancerous identical IgG clone cells in my blood plasma, measured 0.23 g/dl, or about x20 times lower than the value prior to beginning rev/dex chemo (5.31 g/dl). My chemo induced 95.7% decline is classified as a VGPR (very good partial response), the threshold of which is > 90% decline. However, my monoclonal spike of 0.23 g/dl was still measurable with the standard electrophoresis test, which has a threshold somewhere in the range of  [0.05 to 0.1 g/dl], so I did not qualify as having a CR (complete response).

        This chemo transition raises several important questions. One, does continuing to stay on a lower dose of revlimid chemo indefinitely (maybe years) make sense? Two, what form should maintenance take? Three, was the transition done at the right time?

        In 2015 the first question is easy to answer. Enough clinical trials have been held over the last decade to make it relatively clear that continuing to take (some) revlimid, which is fairly well tolerated, leads to a substantial improvement in 'time to progression', though the evidence is less clear that it leads to longer survival time. The clinical trials (as far as I know) provide less than clear guidelines on the details of the maintenance, so I think there is clinical judgement (guesswork) here. 10 mg of revlimid appears to be the preferred maintenance does, though I think at least one clinical trials from a decade ago may have kept the dose at 25 mg. (I need to spring for $35 dollars to read this paper and find the details), because they reported 80 of 100 patients on revlimid for several years had a serious reaction. It is certainly my expectation that a lower dose of revlimid would lead to a (much) lower probability of its nasty, potentially fatal, 'side effects (stroke, heart attacks and 2nd cancers!) which at 25 mg affect a few percent of patients (per year).

        My primary hemotological oncologist originally suggested that maintenance should be 10 mg of revlimid taken every day (not 21 out of 28 days). She seemed to say that when she discussed this with colleague(s) they recommended the revlimid be 'cycled', meaning given 21 days out of 28. To get a 2nd opinion (prior to the transition) I had a meeting with another hemotological oncologist at Lahey and his (firm) suggestion was take it cycled (21 days out of 28). So this is what I I told my primary oncologist this is what I preferred, and she gave me no argument. There was no discussion at all (from either oncologist) as to the rationale for their recommendation, and I (foolishly) asked few questions. For example, why drop dexamethasone?

Does dexamethasone increase platelet count?
        My Zemeta (biphosphate) infusion nurse recently told me something interesting about dexamethasone. With my recent transition to maintenance (lowering revlimid dose from 25 mg to 10 mg and dropping dexamethasone) the oxygen carrying components of my blood (hemoglobin, red blood cell count, etc) which lately have been quite a bit below normal have started to improve. However, the tranistion to maintenance seems to have made one blood component, platelets, which are responsible for blood clotting, worse. During my six months of regular chemo platelets drifted lower but remained within the normal range (150 - 450). But one month into maintenance and platelets are only 122, quite a bit below the normal range.  I had no idea why this one blood components seems to have gong into reverse, so it has been bothering me (have had no chance to discuss this yet with my oncologist).

        My infusion nurse today suggested a possible reason why my platelet count might have gone lower and that is with the transition to maintenance dexamethasone has been discontinued. The nurse said some patients with platelet disease take only dexamethasone as treatment. Very interesting. (I need to research this. Find out if dexamethasone is sometimes used with 10 mg of revlimid.) If research confirms this, then perhaps adding a little dexamethasone (5 to 10 mg/wk) to 10 mg of revlimid for maintenance might be worth a test. The tradeoff being (at least in my mind) improved platelet count vs loss of sleep, a well known side effect of dexamethasone that at 40 mg/wk (and 20 mg/wk) bothered me. I was never given any reason for it to be discontinued by my doctor. In fact I have never been given any explanation by my doctor of the role dexamethaone serverd, nor have I found any good explanation online.

update (4/29/16) (5/2/16) --- My recent experience doesn't bear this out. On 3/22/16 I returned to rev/dex, at this time my platelets were down to 94. After three weeks taking dexamethasone (40 mg/wk as before), platelets did not rise, but drifted still lower to 88. At that point my oncologist suggested that because platelets were pretty low (88), it was better to cycle Revlimid. Maybe this was right, because three weeks later, with one of them being the Revlimid off week, platelets rose to 113.

        What would have been helpful, and both doctors know I am interested in the papers and details, would have been a brief summary of the clinical trials on maintenance. I have yet to come across a good summary, though I am aware that the New England Journal of Medicine, a couple of years ago reported in one issue on three clinical trials on revlimid maintenance, all of which showed it very beneficial, and there was an editorial in that issue reinforcing this conclusion.
An advantage of cycled revlimid
       Now nearly two months into maintenance I see an advantage of cycled revlimid that I had not anticipated. I always try and start my cycles on Mon, so that means I should have run out of revlimid on a Sun, which was yesterday, but I still had three pills left in the bottle. That means I missed taking my revlimid on three days in the last month, two of which I am pretty sure was when I was rushing around in a ME hotel trying to make checkout time after a late breakfast. Since it was originally proposed that I take 10 mg of revlimid continuously, there can be little harm in just continuing to take the three, reducing my 'off time' from 7 days to 4 days, so that is what I am doing. If the prescriptions were written for continuous usage, forgotten days would result in a pile up of $500/day pills.
Advantages of no steroids (11/20/15)
        I'm now six months off steroids after having taken 40mg/wk of dexamethasone for six months while my M-spike was being driven down. Here the improvements I have seen in my body since stopping steroids.

        * Vision --- My eye doctor was amazed at the improvement in my left eye in the eight months since my last exam. In Mar 2015 on steroids for four months for the first time no vision correction worked for my left eye, and a scan of its retina shows some macular degeneration in the center. Eight months later, six months after stopping steroids, the vision in my left eye is greatly improved, pretty close to my sharp right eye.

        * Gums --- My dentist was amazed at the improvement in my gums after stopping steroids. Comparison photos shows my lower front gum went from raw and rough while on steroids to pink and firm after being off steroids for about four months.

        * Fingernails --- While on steroids my fingernails were weak and always breaking. Off steroids for a few months they began to strengthen and grow normally.

       * Dark growths on the skin --- During my induction chemo various raised dark crusted 'things' grew on my skin. One that particularly annoyed me was on my forehead. After being off steroids for a while, I found I could peal some of these dark crusty surface layers off. Now six months off steroids the raised dark crusted things are gone and the dark thing on my forehead has faded to nothing but a slight discoloration on flat skin.

      * Bone growth? ---- The jury is still out on this one, but I am hoping my bone will improve and grow, in particular that the fusion of C1,C2 vertebrae in my neck will be substantially better with no steroids. At the one year review of my neck fusion operation (Sept 2015) bone growth into the hardware and between C1 and C2 was relatively poor. But of that 12 months I didn't start chemo for two months, which included two weeks of neck radiation, and then six months of steroids. So that's 8 of 12 months where bone weakening cancer, radiation, and steroids could very well have impeded the bone growth/fusion process. I am hoping that with six months of no steroids between my one year review (sept 15) and my 18 month review (march 16) will show improvements in bone health comparable to other improvements in my body I have seen since stopping steroids.

        There are other changes that may have influenced the outcome, but I suspect the steroids are the key change. On my gums I switched to an automatic rotary toothbrush from a manual one at my dentist suggestion. On the eye I began to take a dietary supplement at my eye doctors suggestion which provides two quasi-vitamines known to be present in the eye and for which this is some clinical evidence that they may help macular degeneration. In the case of my bones I have been getting a bone strengthening injection (zometa, monthly) since the beginning of the year. This drug is given to elderly women with osteoporosis (annually), and there is good clinical evidence that it strengthens bones by altering balance between bone growth and bone disolving enzymes.

Less side effects (8/26/15)
         About three months into maintenance I see three changes in my body that indicates it's getting back to normal. One is minor just cosmetic, some long existing 'things' on my skin grew black crusts during chemo. On my forehead there has always been a spot that was a little weird, but since it was always the same color as the forehead skin it was not noticeable, but during my six months of rev/dex chemo it became quite noticeable growing a raised black crust, and the same thing happened on lots of spots on my neck and upper chest. But now about three months into maintenance some of the crusts have come off and the forehead thing is noticeably lighter in color. Is this due to lots of sunlight and saltwater swimming this summer or going into maintenance?

        Another improvement is my fingernails now can grow long. This is a big change from my time on rev/dex chemo where my fingernails easily splintered.

        More importantly four months ago (april 15) my dentist was upset with the look of my gums and a closeup picture of my two lower front teeth and gums scared even me. The gum was red and raw looking and the boundary to the teeth was ragged. The dentist suggested I change to a automatic rotary toothbrush, which I did, but also three months ago I went into maintenance dropping the corticosteroid dexamethasone and reducing the dose of revlimid by 60%. Now four months later at my most recent dental appointment the look of my gums is hugely improved. Side-by-side pictures of the two lower front teeth area show a dramatic improvement. The dentist describes the gums now as firm and pink like they should be, and boundary to the teeth is smooth and clean looking. Is this due to the rotary toothbrush, which I ran over the gums for four months, or the dropping of dexamethasone three months ago?

        I'm betting all of these external issues were more likely than not a side effect of the chemo. Steroids are very powerful. A few micrograms of dexamethasone on the skin will heal breakouts overnight, and for six months I was ingesting 40 mg of the stuff weekly! With the transition to maintenance and the dropping of the corticosteroid my body is getting back (closer) to normal.

Was six months the right time to transition chemo to maintenance?
        With a more recent perspective that I gained from reading about free light chains, yes, six months was not too soon to transition to maintenance, and maybe a quicker transition could have been justified. The Freelite people, who make instruments that measure free light chains, argue free light chains give a much truer indication of cancer levels in the body than M-spike, at least for abnormal values or big moves where the free light chain is outside its normal baseline. The reason is M-spike has an inherent lag of months since once created the monoclonal anti-bodies in the blood are cleared so slowly. My lambda free light chain dropped 98% in my first chemo cycle and in 2-3 cycles free light chain values were in (or close to) the normal range. The last three months of the six months of the chemo was probably just waiting for the M-spike to catch up.
        There was little discussion by my doctor as to why six months was the right time to make the transition, and I didn't press the point. A major reason I didn't ask questions was I was all for switching to maintenance soon since the side effects (particularly loss of sleep from the dexamethasone) were beginning to get to me in the last couple of months. I got the impression from reading multiple myeloma blogs that six months was sort of a 'formula' that was widely used, though some in the blog said you should flee an oncologist who does this without taking your status into account. My primary haematological oncologist a few months earlier had mumbled that some clinicians don't use a rigid time table, but keep the revlimid dose at 25 mg until the monoclonal spike plateaus and then go one more cycle. But when the time came to do the transition nothing more was said of this option. However, after five months I had achieved more than a 95% reduction in cancer levels, and my monoclonal spike was close to plateauing since it barely dropped from cycle 5 to 6 (0.24 => 0.23 g/dl), though my doctor didn't know this because the decision was made before the cycle 6 results were in. So all this seemed to add up to making the transition in six months reasonable. Also my prreference is always to opt for the most conservative treatment option that is reasonable, and it qualified on this score.

        Additional details: Besides the 10 mg revlimid (21 days out of 28) I am taking daily aspirin as an anti-coagulent (to counter the possibility of a blod clot since the disease and revlimid thicken the blood). I was taking a full aspirin dose of 325 mg/daily, but (on my own) going into maintenance I decided to scale down the aspirin dose. (I was aware that 1/4 aspirin dose is used in some countries and clinical trials.) Only full and 1/4 doses are sold (even on Amazon!), so I have gone over to taking two 81 mg (coated) aspirin/day for a half (full) dose of 162 mg. My engineering judgement is that scaling down the aspirin dose to (roughly) match the dose reduction of revlimid makes sense. These 1/4 dose pills are tiny pill, so I can easily take the two with one swallow. Also I am continuing to get a biphosphate (Zometa) infusion every month, which strengthens bone, but is not technically a chemo drug.

        One discordant note is Tom Brokaw's treatment and his chemo transition. He's two years older than me, but was diagnosed with multiple myeloma a year earlier than me. Within days of his diagnosis he had a bone break (in his back). He's being treated by one of the big guns in the field (Ken Anderson at Dana Farber in Boston) and was put on rev/dex, and as he tells it they didn't recommend a stem cell transplant. This is all pretty close to me, except in my case I made the decision not to have a stem cell transplant not my doctors. However, as best as I can tell (from the tidbits he drops) his transition to maintenance was something like 16 months after his diagnosis, far longer than my six months. Just prior to his transition to maintenance he announced his cancer was in "remission", whatever the hell that means. So did his doctors treat him to achieve a CR before going to maintenance?  Probably. What I am missing is all his details, his monoclonal spike, tumor load, etc. Whether or not it is in his book I don't know, the reviews say the book has little medical detail and is mostly stories about his life. This is an open issue I am still working.

         While I have read elsewhere Brokaw was on rev/dex, the authoritive sounding posting below from a MM forum says he was on RVD: Revlimid, Velcade and dex. [However, a more recent posting on a MM forum splits the difference, saying it "looks like" Brokaw started off on rev/dex and then graduated to RVD.] The addition of Velcade (in infusion) is another standard option. [I am wondering if Brokaw with his big name doctors got access to the pill form of Velcade which was the option being tested in th clinical trial offered to me.] The author assumes Brokaw means by remission is that he achieved a CR (complete response) after 15 months or so of treatment. However, even he doesn't know the details of Brokaw"s CR or his maintenance regime. [Brokaw after 12 months of treatment said his cancer was undetectable (probably meaning his monoclonal spike was below the test threshold), but that he had one other marker to get down.]

        And according to this posting I am in much better shape than Brokaw. Brokaw has had several vertebrae in his back collapse. He has had kyphoplasty to help repair them. He admits to being in constant pain. He has been plagued by infections. He went out hunting, but reports he got very tired and couldn't really function. (Kyphoplasty surgery is done through a small incision where a balloon is inflated to make a cavity in a collapsed vertebrae, then the cavity is filled with a quick drying cement.)
Rev without dex in maintenance
        From www.myelomabeacon.comforum, by Dr. Adam Cohen on Thu Apr 18, 2013 11:07 pm
        Yes, Revlimid maintenance (without dex) would be considered standard, and has been tested in 3 large randomized trials, 2 done after stem cell transplant and 1 after non-transplant induction. In all 3 trials, the use of Revlimid prolonged the time in remission compared to no maintenance, though only 1 of the 3 has shown an improvement in overall survival with maintenance. In these trials, Revlimid was given continuously at a dose of 10-15 mg per day, though in practice, many oncologists use the 3 weeks on/1 week off schedule to reduce the side effects such as low blood counts.
Daily pills (1/16/16) (4/15/16)
        One sign of being old and sick is how many pills you take. Below is the pile of pills I take every morning. I am not a big believer in (food) supplements. I take only two, each recommended to me by my doctors.

My daily pills on revlimd maintenance (Jan 16, 2016)

My friday pills back on rev/dex (April 15, 2016)
Once a week I add 40 mg of a corticosteroid in the form of ten 4 mg dexamethasone (green) pills on a single day.
Doctors refer to this as 'pulse' and a 'booster' for my chemo pill Revlimid.

        Top (left to right): two sildenafil (Revatio generic used off label), Revlimid (10 mg, 500/pill) chemo, two 81 mg aspirin (blood thinning to counter side effect of Revlimd), vitamin D pill (important for bones in MM , my vitamin D is at the bottom of the normal range), lutein & zeaxanthin pill (for vision, I have the beginnings of macular degeneration in left eye). I can do each row in one swallow. The while pills and the transparent vitamin D pill are quite small.

        Bot: I am back on rev/dex by April 2016. Revlimid dose incrased 25 mg. Once a week (shown) ten 4 mg dexamethasone pills. The total weekly dose of 40 mg is taken on one day (or spread over two) of a week, referred to as a 'pulse'. It is ten pills because the largest dexamethasone pill made is 4 mg. Doctor's laughingly refer to these ten pills as 'low dose" dexamethasone.

Neck pain
        One of my biggest issues since the C1,C2 fusion neck operation is a reoccurring stiff neck. It comes and goes, but it's not unusual for me to need to adjust the angle of an easy chair to find an angle that doesn't hurt, and sometimes this is hard. Affects the positions I can comfortable sleep in too. Head left is reliably OK, head right more problematic since it sometimes starts to hurt after a while. I have no feelings in the back of my skull, because I assume the nerves were cut during the operation, and it make sleeping on my back a little weird, but the nerve issue is really just a minor issue. This 'stiff neck' issue has been about the same since the collar came off and my neck strengthened over the next month or two, hence I expect this issue to remain, maybe forever.

Driving a car with limited neck mobility
        The biggest issue (by far) with my fused neck has been learning how to safely drive a car. Normally about half the rotation of the head uses the two large sliding joints between C1 and C2, but I have lost this rotation term since hardware (and pending bone fusion) holds C2 fixed to C1. The rotation of my head now is about +/- 45 degrees (vs 90 degrees normally). I didn't drive my car for two and half months after my neck operation. It was simply impossible to drive with the neck collar as I could not turn my head at all, and it took a month or two for my neck to strengthen when the collar came off after two months. When I went to start my car after it sat for that long time, of course the battery went dead, but AAA came and for a very reasonable price tested the old battery and installed a new one. While I had been fearful to drive again, that afternoon after the AAA guy left I took a little trip a few hundred yards just driving around my local parking lots and it felt OK.

        My main worry was seeing far enough leftward to safely cut into busy traffic. The problem occurs right where I live. My apartment complex driveway angles rightward joining a busy downhill, divided two lane road (rt 28) at an angle of 135 degrees. I soon found that I could see 90 degrees left by adding a 45 degree back twist to my 45 degree head twist. I couldn't hold the back twist for more than a second or two, but that was OK leaving home as the car normally needs to stop at the bottom of the driveway to wait for a break in the traffic. At the beginning I thought leaving at night would be safer because I could more easily see headlights, but I soon learned a trick to do it safely during the day.

Key neck trick
       The trick, the key trick I have found to driving safely with limited neck rotation, is to avoid (whenever possible) 135 degree lane mergers by angling the car leftward by 45 degrees. In other words use the car to reduce the angle of lane merger, change a merger which may be lined at 135 degrees to 90 degrees, which my back/head rotation can manage. Leaving my apartment complex this is easy as the road down the hill to rt 28 is very wide and normally the car needs to stop anyway to wait for an opening in traffic. It may look to an observer a little strange as the car cuts perpendicularly into traffic and then quickly makes a sharp 90 degree turn into the right lane of a two lane road. But this is a safe manuver. I can see the oncoming traffic and if the opening is reasonable making the right hand turn is no problem.

        For several months I drove locally, first just a mile or two around town and then more and more, but still all local, I stayed off the highway for quite a few weeks. My main concern with the highways was the sharply angled entrances and exits (some of them probably more than 135 degrees). They scared me and the problem was made worse (much worse) at the time because it was winter and we had record snowfall this year, so after a while the snow banks were so high that coming down a highway off ramp you could not see the traffic on the merge road at all. You had to go to the actual merge, stop and peer around the snow banks.

        For months I took taxis back and forth to the hospital. I watched carefully how the (many different) taxi drivers did highway entrances and exits. I then got on Google Earth and looked closely at local entrances and exits near where I live. I found some highway exits are no problem. These are exits that join the local road at 90 degrees and/or a light. This is my local 128 exit (from north) and also the 128 exit to the Lehay hospital.

        Entrances are generally not too bad. Entering onto busy 128 in rush hour can be tough. Many a time I heard my taxi drivers curse as tightly packed cars and trucks would not let them merge, but still I never saw them look back, they did it all with the outside mirror. While there is going to be the odd merge which is risky, I have come to believe that entering a highway is generally going to be low risk, because it is normally done with using the outside mirror, and I can see rearward using the outside mirror perfectly fine as it only takes a a 45 degree (or less) twist. As a further twist at a clover leaf of two crossing roads the entrace ramps before the overpass are to be preferred as they will tend to be cleaner and longer, mainly because they don't have exiting traffic crossing over in front of you. I went on Google Earth and using its ruler feature took a real close look at my local highway (128) cloverleaf entrances and exits, which look pretty typical. My local highway entrance going north, which is before the overpass, has a long acceleration lane, should be no problem here using only the outside mirror.

update (May 2015)
        On the ride home from the hospital I had often observed my taxi drivers having problem with the merge into highway traffic. They used the normal ramp to go north on 128, which approaching from the hospital is the ramp after the overpass. This is a ramp with tougher, shorter merge lane and crossing traffic. So when I drive to the hospital I avoid this potentially tough merge by simply making a left turn (after the going under the same overpass) into a little mall where I can easily reverse direction. At the expense of an extra minute or two of travel time, I am able to enter the highway north using a ramp before the highway giving me a safer merge, because it is longer and without crossing traffic.
        More worrying was my local exit off the highway (128) close to where I live. This is the typical 135 degree ('yield') merge that is often taken at high speed when traffic is light, and requires a stop if traffic was busy. But Google Earth shows, and I confirmed this on a walk, that while its lined for a 135 degree merge, near the end it flares open enough so that a car can stop (or nearly stop) and angle left to make it a 90 merge just like with my driveway. I have only taken this exit a couple of times, so I have not yet had the opportunity to try this out. Sometime in middling traffic I worry it it going to be a little tricky, because if I slow down quickly and unexpected and angle the car strangely, I worry I could surprise the driver behind me and be rear ended. It's all in the technique, probably the right approach is to come in slow so I have the option to stop (and the driver behind me has time to stop too). In general route planning is important. Circles are tricky. I have only done one to date. In a parking lot if possible I always take a spot I can drive forward out of, but realistically about half the time backing out is required, and here I pull out my towing mirror to take a look (from inside the car).

        For a little added safely I added (glued) a two inch 'blind spot' mirror to my built-in outside mirror, but realistically this little mirror is so convex, that cars can't be seen until they are about up to my bumper. It really is nothing more than a blind spot mirror, so it doesn't provide any real help when merging. I spent a lot of time looking for mirror on Amazon at my local auto parts store. I bought a universal towing mirror ($25 bucks or so) that seems to have some promise. It's quite large, adjustable as it is on a ball swivel, but the universal mount, wrapping rubber bands around my outside mirror so it sits outside my main outside mirror, I can see are just not going to be reliable. With some added (cludgy) spacers top and bottom I can get it on, but there is no way to properly tighten the rubber straps, and I bet on my first trip to ME its going to fall off on the highway within a few miles. Not only will it be gone, but its big enough to be a serious road hazard, so I will need to stop an retrieve it, which will be dangerous.

        There are (much) more expensive towing mirrors. I saw a video of one with ratchets to tighten the straps, and that's a step forward. Maybe I can find one with adjustment in the hooks to the outside mirror frame, so the (unreliable) spacers can be eliminated.  A trip to my local auto body shop might solve the spacer problem by having them weld in spacers. Maybe they could come up with another full mount under the outside mirror. I have serious doubt an outside mirror can be reliably added to my car, but have not given up yet. For now I keep the large towing mirror in my inside door pocket. If I have time, I can pull it out and use it to look around. I doubt this will ever prove practical when entering or exiting the highway, but it does help when I am about to back out of a parking space.

        I know I am not obsessing about a non-existent problem, because as I began began pushing envelope and driving more, including some trips on the highway, and even into Boston, I have had a few entrances that for one reason or other I did not handle well and felt I could not see clearly and was not safe. One mistake I find I make is (on the fly) misjudging the available spacing in the oncoming traffic. A few times as I approached the street at the end of my driveway the traffic was backed up and stopped from a traffic light I angled in at 135 degrees, where I can poke my nose in so stopped cars generally allow a merge after the light changes, but a couple of times before I could get into position the cars started to move, and I was trapped at a 135 angle and unable to see the on coming traffic. Solution, don't do this again, adjust my driving technique, when traffic is stopped even then angle in at 90 degrees. It will look weird and maybe make it more difficult to enter, but I will be able to see so it should be safe. Technique, technique... (Traffic circles remain a worry and I think I will just have to fudge this by slowing down enough (stopping is not expected) so I can angle.)

Bone pain
        Bond pain is common problem with multiple myeloma, but (so far) I have not had any pain from any of the 'holes' in my bones. The question is why not? This is an important quality of life issue. It took me months to understand that what the doctors were calling a 'hole' (in my femur) was really a hollowing out of the bone from the inside beginning at the marrow/bone interface. On an x-ray you can't tell if a hole is inside or outside, all you see is a contrast change.

        My understanding now is a multiple myeloma 'hole' (probably) doesn't hurt until it penetrates (or disturbs) the surface of the bone. For the most part bones don't have pain sensors, but bones are surrounded by a membrane that nourishes them called the periosteum, and it has pain sensors. (Sketches of the periosteum show little blood vessels from it going into the compact bone under it. The periosteum membrane is extremely thin, only about 100 microns, or 1/10th of a mm.) When you break a bone, the reason it hurts is that the bone break tears open the periosteum. Ok, maybe that explains my femur 'hole', but this explanation only goes so far. X-rays show I have lost 30% or so of the bone in one vertebrae of my mid back (T12), and it doesn't hurt either. How could its periosteum not be disturbed? Does it even have a periosteum? (Wikipedia says the outer surface of all bones (except for joints like the knee) is covered have by a periosteum, and some tiny bones like in the wrist.) When I asked the bone doctors how come T12 with its large bone loss doesn't hurt? The answer I got was, 'I was lucky'. What kind of an answer is this? How about some medical detail. Now this T12 back tumor was irradiated, but it didn't hurt before it was irradiated. Maybe the periosteum has reformed around my now reduced T12, after all when a broken bone heals the periosteum around it must heal too. So bone pain remains an open issue.

        The hope is that the radiation and chemo will halt the growth of these three large tumors (and many small ones).

Kidney damage
        Another common problem with multiple myeloma is kidney damage. The simplified explanation is that the kidneys filter various waste products and crap out of blood by running it through using a network of fine blood vessels, but since blood in multiple myeloma is not normal and can have too high a viscosity it slowly clogs up the filters in the kidney. (I am sure this is vastly oversimplified.) The usual marker here is creatinine, a muscle waste product. If the level of creatinine is high in the blood, it means the kidneys are not doing a good job removing it. My creatinine started off at 1.4 (slightly outside the normal range) and has come down to 1.2 (just inside the normal range). The Celgene sheet says revlimid is excreted (unchanged) by the kidneys. Wikipedia gives the half-life of revlimid in the body as 3 hours, so in 24 hours the kidneys have cleaned the daily dose.

        -- There are five types of heavy chains: IgG, IgA, IgM, IgD, IgE, and two types of light chains: lambda and kappa. Each type of heavy chain can have either lambda or kappa light chains there are thus ten possible types of immunoglobins.

     * -- Plasma calls produce light chains and heavy chains separately, which later assemble into the full immunoglobins. "For some reason" more light chains than heavy chains are usually produced with the excess light chains entering the blood steam (now called free light chains). The kidneys extract the free light chains from the blood and recyle the amino acids. (This explains why there is a baseline value for both lambda and kappa free light chains in normal people (in the same range of about 1 mg/dL +/- factor of 2). It's the excess light chains from normal (disease fighting) immunoglobins.)

        -- "Myeloma is classified into different types depending on their immunoglobulin heavy chain and light chain as follows: IgG (52%), IgA (21%), light chain (16%), Bi-clonal (2%), and IgM (0.5%), while IgD and IgE are rare. Patients with light chain myeloma are more prone to develop renal failure." (This begs the question, What is 'light chain myeloma' anyway?)
Light chain myeloma
       What is 'light chain myeloma'? Ans: Occasionally, the malignant plasma cells make only the light chain component of the antibody. These patients are said to have “light chain myeloma.” (I have the IgG lamda band, so good news here.)

Immune system weakened
        Another common problem with multiple myeloma is reduced immunity. Since the cancer is in the plasma making cells which turn into anti-bodies, the anti-bodies as a whole are not normal. I may see this. It took me more than two weeks this spring to shake off a cold, instead of the usual week. I read at the end a lot of multiple myeloma patients die of pneumonia. But to date I have not been able to really get my arms around this issue. It's all very vague and theoretical.
Anemia -- Low blood oxygen capacity

Notes on anemia from my early days on chemo (2014-2015)
        Anemia is defined as 'low blood oxygen capacity due to not enough health red blood cells'. In my case my blood oxygen terms (RBC, hematocrit, hemoglobin, etc) started off prior to chemo up to 30% below the normal range. During my first three chemo cycles as the cancer cells in my blood steadly declined (by about a factor of ten) the oxygen terms in my blood steadily improved to well centered in the normal range. The 'picture' painted for this is that there is only so much room inside bones for blood producing marrow, and the expansion of the cancerous blood plasma cells reduces the room available for normal marrow that makes oxygen and white blood cells, so a decrease in cancerous marrow cells allows normal blood marrow cells to expand.

        However, my 4th cycle blood numbers, while showing a nice continuing decrease in my M-spike, showed the red and white blood terms going into reverse, loosing the gain of the 3rd cycle, dropping to the lower end of the normal range or in one case (hemoglobin) slightly below the normal range. My doctor suggested this could be due to the chemo. In reading over the detailed Celgene revlimid proscribing sheet I see it shows revlimid caused anemia in about 1/3rd of those in a trial with 350 patients. (What their definition of amemia is I don't know.) I sense my oxygen numbers are important to how I feel. When they are low, I get tired easily, a few hours outside can wipe me out for the rest of the day.  (I also see a big decrease in IgG blood (920 => 622) and IgM (93 => 46) taking them both below the normal range. I don't really understand these terms.)

        When I look up references for anemia,  I have seen it defined as homglobin levels below 13-14 g/dl. In my blood work the normal range for hemoglobin is marked at [13.8 - 17.4 g/dl], so this amounts to saying that pretty much any hemoglobin level below normal constitutes anemia. A pencil note in one of my blood works, I think recording what my GP told me, says anemia is hemoglobin < 11 g/dL.  My hemoglobin numbers in Nov 2014 were in the 10-11 g/dL range, so clearly I was anemic prior to beginning chemo. At the end of my 3rd rev/dex cycle my hemoglobin was up to 15.5 g/dl, well centered in the normal range, but after steady increases for the first three cycles of chemo at the end of the 4th cycle there was a moderate decline to 13.7 (just barely below the normal range). This decline could very well be due to (the cumulative effect of) revlimid, since anemia is one of its common side effects, and my oncologist seems to think so.

Really bad anemia -- very low hemoglobin (9/20/17)
        In the last few weeks my quality of life has been badly impacted by extreme shortness of breath. I am Ok sitting or driving a car, but when I have to get up to walk just a little, it is a struggle. I feel exhausted. This has come on fairly suddenly. I read this extreme fatigue is perhaps the most common symptom of cancer as the cancer begins to take over from the chemo.

        From my reading extreme fatigue is often caused by low oxygen carrying capacity of the blood, and my hemoglobin value has recently dropped to a new low 8.4 g/dL. This is only 60% of low edge of normal (13.8 g/dL) and far lower than it has ever been in my three years of chemo. Even lower than when I was first diagnosed (9.9 g/dL)! I recently changed my inhaler from the powder based Incruse Ellipta to the mist based Spriva Respirmat and that didn't help. Many tests in 2017 of my lungs and heart have not found a problem. It makes sense to me that the most likely cause of my recent extreme fatigue is reduced oxygen carry capacity of my blood as indicated by the very low values of hemoglobin and RBC that my blood tests are showing.

        The question in terms of quality of life is what (if anything) can be done about it. I read a quick fix is a blood transfusion. Outside of my neck surgery, I have never had a blood transfusion. It comes with its own risks. I was half expecting that with my hemoglobin at 8.4 g/dL (9/19/17) my doctor might order one, but she didn't. Doing research I found that while this level was the trigger for blood infusions, the trigger has dropped to 7 g/dL.

5 g/dL risks
        Perspective on the risks of low hemoglobin come from  jehovah witness patients who refuse transfusions. At 5 g/dL half of them die from this because the heart cannot get enough oxygen to vital organs!
Hemoglobin raising hormones ---Brand names: Epogen, Procrit and Aranesp
        I had not yet begun to research treatment for anemia, when in late summer of 2017 I heard an interview on PBS radio with the authors of a new book, 'Living with Cancer', by David Ryan, chief of hematology/oncology at Mass General Hospital and Vicki Jackson, chief of palliative care at the same hospital. Mass General Hospital has a very good reputation for high quality care, and this book was clearly relevant to my condition, so I immediately ordered the book on Amazon. Here is Dr. Ryan in the book talking about severe anemia with shortness of breath and the use of erythropoietin as an alternative to blood transfusion to treat it. (pages 178 and 221).
        -- "When patients are severely anemic, they can feel shortness of breath, particularly when they move around", and he relates this to not having enough red blood cells.   (Yup, that is exactly how I feel.)

        -- "Typically your hematocrit needs to fall under 30 (30%) before you will feel shortness of breath, normally our hematocrit runs about 40."  (I meet this test, my latest hemocrit value is 25.8% .)

        -- "If your red blood count is low, you might benefit from a transfusion or the administration of a subcutaneous injection of erythropoietin, the body's natural hormone that boost red blood cell production."

        -- "Patients who could benefit from a transfusion might elect to take erythropoietin (epo) instead. ... A few years ago a couple of studies tied this drug to an increase rate of blood clots which meant doctors stopped using it for a while. Further studies have disputed these findings, and the use of epo now appears to be safe. There are still a number of doctors who are cautious about using it."

        Erythropoietin(short hand 'epo') is a hormone the body produces mostly in the kidneys (10% in the liver) to encourage more red blood cell production. It is given can be given as a subcutaneous injection. (It was used by Lance Armstrong as an (illegal) way to improve his performance), but for cancer patients it can be given intravenously weekly.
        -- Erythropoietin is a protein with an attached sugar (a glycoprotein). It is one of a number of similar glycoproteins that serve as stimulants for the growth of specific types of blood cells in the bone marrow. There is a blood test for this hormone called the 'epo test'. It requires an overnight fast.
        Erythropoietin is sold under brand names:  Epogen (Amben) and Procrit (Janessen). There is also a closely related, longer lasting hormone called Aranesp (Amgen). The first two appear to be the exactly the same drug. It has been on the market for 28 years sold by two different manufacturers. The Epgoen and Procrit prescribing documents say it can be given intravenously weekly to cancer patients: 40,000 Units weekly. This would fit nicely with my weekly dearatumumab infusion chemo.  From the prescribing document I see the threshold for use: hemoglobin <10 g/dL. At 8.5 g/dL I meet this threshold easily. Increases of 2 g/dL can be achieved. This manufacture of a body's hormone for use in clinical treatment was considered to be one of the big early sucesses of recombinant DNA technology. The response time is relatively slow, something like 0.5 g/dL in a week. Aranesp has been on the market since 2001 and differs just sligthly in its amino acid sequence.

        Epogen and Procrit
              -- Epogen® & Procrit® (epoetin alfa) Injection, for intravenous or subcutaneous use. Initial U.S. Approval: 1989

         Aranesp® (darbepoetin alfa) (a long acting version of Procrit). Approval 2001
                 There appears to be less emphasis in the Aranesp prescribing document for cancer patients.
                 For cancer patients it is given weekly subcutaneously, or at a higher dose subcutaneously every three weeks.
New hospital schedule to address my anemia (9/26/17)
        After two units of red blood cell transfusions over the last two days, I still have shortness of breath, but it is less.  I was able to shop at the market today without it nearly killing me as it did just a few days ago. According to one estimate two units of blood can increase your hemoglobin by 2 g/dL so my hemoglobin might now be [7 g/dL => 9 g/dL]. Since the livetime of red blood cells is about four months, this should hold for a while. We will see in a week, when my hemoglobin will next be measured.

        I now come to hospital weekly (tues) for labs, and a chair is also reserved in the infusion room.  What happen in infusion room varies and is below:

        1) Every week I get a subcutaneous skin jab (upper arm) of hormone Aranesp (darbepoetin alfa). This is prefilled syringe with a dose 200 mcg (calculated from 2.25 mcg/kg). (If it works for me, the prescribing document say it will take a month or two for my (potentially chemo damaged) marrow to start to pump out more red blood cells.)

         2) Every other week  a daratumumab infusion. This week was my 9th = (8 +1) daratumumab infusion. According to the daratumumab prescribing document, daratumumab for next two months is to be given every other week. Next week is my week off.

        3) If hemoglobin is low (< 8 g/dL), then a red blood cell infusion (one unit)

        4) If platelets are low (< 20 K/uL), then a platelet infusion.   My second chemo drug imid (Pomalyst) remains suspended (along with 162 mg aspirin) until platelets recover (> 50 or >30? K/uL).
Notes on  Erythropoietin
        From a book on Blood I find the following comments about Erythropoietin therapy for anemia.

        -- Erythropoietin therapy is very well tolerated provided that the patient's hematocrit is kept in the mid to high 30s. Properly treated patients enjoy significant improvment in quality of life including less fatique and enhanced appetite. The majority of MM patients treated with rhEPO achieve a significant improvement in red cell mass (> 2 g/dL hemoglobin). The response to treatment is prompt and sustained provided that adequate iron stores are maintained.

        There's a blood test for erythropoietin too. The normal level is 10-15 mcg/L (homeostatic conditions). This can give a window on how the kidneys are working. However, the erythropoietin doses given for therapy are far, far higher than normal body levels (10,000 mcg/L). Monitoring for the effectiveness of EPO administration is usualy done watching serum hemoglobin levels rather than EPO levels.

EPO vs blood transfusions (9/24/17)
        Researching this topic I find there is extensive literature going back more than 20 years as to whether it is better to use EPO (either thrice weekly subcutaneous injections or weekly IV), the recombinant DNA drug erythropoietin (Procrit) vs a blood transfusion to combat low hemoglobin (low oxygen carrying capacity) levels. This debate is not only in the context of cancer patients, but also kidney failure patients, patients undergoing surgery and even premature babies who often need blood transfusions.

Early 1990s EPO clinical trials
        I read the early phase 3 clinical trials in the early 1990s of erythropoietin were a spectacular success, close to a 100% effective response. Futhermore patients did not get refractive to erythropoietin, it continued to work with apparently little risk. However, these phase 3 clinical trials of EPO were done on patients with anemia due to renal (kidney) failure. In other words in these patients the marrow response to the hormone was Ok, the failure was in the oxygen sensing and/or hormone generation in their kidneys.

        The situation in MM patients is very different. The issue here is much more likely to be chemo damaged marrow not responding well to the hormone secreted by kidneys. Since the situation is so different with MM patients, the relevant literature on EPO for me should focus on the effectiveness of EPO in MM patients.

EPO treatment in MM patients
        From Multiple Myeloma Research Foundation

        -- If anemia is severe and requires immediate treatment, patients should receive a blood transfusion.

        -- Erythropoietic agents are generally well tolerated. However, recent studies have shown that these drugs have been associated with an increased risk of blood clots. Factors that can increase the risk of developing blood clots include: Treatment with some common myeloma drugs including Revlimid, Thalomid, dexamethasone, Adriamycin and Doxil.

        -- Preventive treatment with a blood thinner (such as heparin) may be considered for high-risk patients.

        -- Procrit/Epogen: 150 units/kg three times a week or 40,000 units once weekly
              Aranesp: 2.25mcg/kg once a week or 500mcg every three 3 weeks

        -- Supplemental iron may be given in addition to erythropoietin therapy.

        -- The effectiveness of therapy is measured by the increase in hemoglobin and hematocrit ( number and size of red blood cells). It takes some time for the body to produce new blood cells, so the effect of erythropoietic agents may not be seen for 2 to 6 weeks.

        ** -- Overall, about 60% to 70% of cancer patients receiving cancer treatment respond to erythropoietic agents.

        -- An early hemoglobin response to therapy (>1 g/dL rise after 4 weeks of therapy) in patients with treatment-related anemia is often associated with reduced transfusion requirements, higher hemoglobin response rates, and improved quality of life. Having adequate iron levels may also improve responses to erythropoietin therapy.

Blood transfusions
        -- Average adult has between 8-12 pints of blood. One unit of blood is ~525 mL, roughly the equivalent of one pint.

        -- ** The average patient requires around 4.6 units of blood (Canadian Blood Services website)

        -- The procedure usually takes 1 to 4 hours.  (My infusion time for one unit of red blood cells 1.5 to 2 hours)

         --  Red blood cell (RBC) transfusions in most hospitalized patients should be performed based on "restrictive," (7.1 g/dL ?) rather than "liberal," hemoglobin levels (7 - 8 g/dL), according to new clinical guidelines from the American Association of Blood Banks. Mar 26, 2012

        ** -- Each unit of packed red blood cells (PRBCs) is expected to raise circulating hemoglobin (HGB) by approximately 1 g/dL.

(details of a what is in the bag of red blood cells from a posting by an an obstetrician, Jeff Menegas)

        -- The (transfused) unit of blood looks like this. Originally 530 grams of blood is taken from donors. This is about 500 ml (blood), since blood is about 6% heavier than water. According to the Mayo Clinic, if it is from a normal female, it has a hematocrit of 34.9 to 44.5%, and so contains between 174.5 and 222.5 ml of packed cells. If it is from a normal male, it has a hematocrit of 38.8 to 50%, and so contains between 194 and 250 ml of packed (red) cells.

        -- It is then centrifuged, and most of the plasma is removed. The final product has a hematocrit of between 70 and 75%. If it is from the female, and her hematocrit is at the lower limit of the normal range, it has a final volume of between 233 and 249 ml (174.5/0.75 and 174.5/0.7), and if from a male at the upper limit of the normal range, it will have a final volume of between 333 and 357 ml (250/0.75 and 250/0.7).

     -- Typically the bag of packed red blood cells will say on the label "From 500 ml CPD (or CPDA) whole blood." CPD stands for citrate/phosphate/dextrose, an anticoagulant and preservative, and the extra A is for adenine, which extends the shelf life. Whole blood is not what is transfused, though. The original 500 ml is centrifuged, and the cells are removed. The cell portion, which is what most people think of when they see a transfusion, has a hematocrit of about 70 to 75%, meaning it is 70% red cells and 30% liquid, mostly plasma.

        -- Given that a typical hematocrit in an adult is about 40%, the original bag of blood will have something like 200 ml of packed red blood cells (40% of 500). If the unit has a final hematocrit, after processing, of 70%, then the total volume in the unit is 285 ml (200/0.7), but this is an average.

        -- As I said above, the only constant is the starting volume of 500 ml, and even this is not exact, since it is actually measured by weight, not volume, and takes the average blood density as 6% greater than water. So the starting point is not really 500 ml, but about 530 grams.

        -- All of this is due to the normal variations between individuals. The ONLY constant is what is written on the bag, "From 500 ml of CPD whole blood." This is visible on the above label all the way to the left, between the two messages in red.

Low platelet imid dose adjustment (9/25/17)
        In recent weeks my platelets have fallen very low with readings of 10, 11, 37 (month earlier 39, 42 K/uL). (150 K/uL is the low edge of normal)   At 10 and 11 I have had platelet transfusions, which at 10 raised the immediate level to 22. From the prescribing documents for the imids Pomalyst and Revlimid (both from Celegene), platelets this low should trigger a suspension of the drug until platelets recover, and following platelet recovery a permanent dose reduction. The thresholds are a little different for the two drugs:

            Pomalyst                <25 stop,  wait for >50,     resume at next lower dose    (4 mg, 3 mg, 2 mg, 1 mg)
            Revlimid                <30 stop,  wait for >30,     resume at next lower dose     (25 mg, 20 mg, 15 mg, 10 mg, 5 mg, 2.5 mg)

Zometa --- bone strengthening
        (update) I have been getting Zometa infusions monthly for six or seven months now. I find it gives me three 'bad' days (jittery, lot of time on toilet). Since in summer I like to go to Maine midweek, I schedule the zometa infusions on Fri.

        I learned something new from the infusion nurse today, which is that a patient must have blood work sometime within a month prior to the infusion. The reason she said (confirmed in a paper) is that Zometa can affect the kidneys, so kidney numbers (presumably creatine) need to be monitored.
        Beside chemo I am getting another regular treatment intended to strengthen my bones. This is an infusion of a bisphosphonate, in my case Zometa (zoledronic acid). My understanding is this treatment is given annually to elderly people with osteoporosis, but MM patients get it once a month. It is not chemo, because it doesn't target cancer cells, it just shifts the bone growth/absorption balance in the body more toward bone growth. It's painless and relatively quick, but it does required a trip to the hospital. My zometa infusion time now about 10-15 min, but my first zometa infusion took much longer (over 2 hours).

        The reason that my first zometa infusion took so much longer time I later learned is it that it also included 'hydration', an infusion of a large volume of saline solution equal to about 11% of the volume of my blood.  My doctor's notes say prior to chemo I was developing hypercalcemia, which is high calcium in the blood (from dissolving bones) and renal (kidney) insufficiency. The doctors seemed to be particularly concerned advising me to drink plenty of water. Increasing the volume of the blood is a standard treatment for hypercalcemia, and maybe helps with renal issues too. My highest calcium and creatinine blood numbers were calcium 11.0 mg/dl (8.4 to 10.4 normal) and 1.4 mg/dl (.6 to 1.3 normal). Obviously a 11% increase in blood volume instantly brought both concentrations down 10% and into the normal range.

        Zometa as a hospital infusion it is covered under medicare part B. It does have a serious risk which affects a small fraction of those taking it, death of part of the jaw. Other than this risk there are no side effects that I notice. Since for the first six months of chemo I have been meeting with my oncologist monthly, we soon shifted the monthly zometa infusions to an hour after to doctor's appointment, thus saving a trip to the hospital. The cost of a single Zometa infusion is [2,400 (drug) + 220 (injection) = 2,620]. My Medicare show unlike almost all other Medicare charges, Medicareapproves 100% of the amount billed, but it only pays about 10% of this amount. (I don't understand this.)

(update, Sept 2015)
        The monthly zometa infusion billings in summer 2015 run about 515 = [290 for the zometa + 220 for the 'injection into a vein']. Again the medicare billing is not too clear. In the lower detail section it shows medicare approves 100% of the billed amount and the amount I may be billed as zero, but at the top in what appears to be a summary it says the amont paid to provider is 252 and I may be billed 64. This looks like medicare is approving 315 for the procedure with my 64 being 20% of the approved amount. (Some months there an extra patient assessment charge of 85 thrown in which increased my payment to 80.)
        Bottom line: my out of pocket charges for monthly zometa infusions run 64 to 80. Below shows my out of pocket monthly costs for blood work is only about 8, so that means my annual out of pocket costs for routine [blood + infusion] comes to about 1k/yr.

        I began monthly bisphosphonate (zometa) infusions Oct 31,14, which is prior to beginning chemo. My docotor told me recently (aug 15) that the usual course of bisphosphonate treatment for MM is monthly for two years.

Cost of monthly blood work
        To track my cancer my blood is monitored monthly. The tests done have varied a little from month to month. My M-spike comes from a protein electrophoresis serum test which takes four days and is interpreted by doctor, who bills separately

        Medicare billing records show my monthly blood work (non including the doctor charge) runs about 350-400. All the tests are approved by medicare, but the amount that medicare pays the hospital is sometimes less than 20% of the billed amount. For example in june 2015 the hospital billed 401 and medicare paid the provider 70.  In july 2015 the billing was 354 with medicare paying 85. In both months the amount that I may be billed is shown as zero. The doctor charges for the electrophoresis test are billed at 142 and medicare approves 39 with my share about 8.

        Bottom line: my out of pocket charges for monthly blood monitoring (including the clinical doctor's interpretation of the electrophoresis test) is about 8 dollars. This is 20% of the doctors charge, the hospital charges fully paid my medicare.

        "Many multiple myeloma patients develop hypercalcemia, which is an increased level of calcium in the bloodstream. Hypercalcemia results from the destruction of bone from osteolytic lesions or sometimes from the development of generalized osteoporosis, in which all the bones are soft and porous and have lost calcium. Hypercalcemia in patients with multiple myeloma causes fatigue, lethargy and other symptoms. Severe hypercalcemia is a medical emergency requiring immediate treatment. Typically, hypercalcemia is treated with bisphosphonates and hydration."

        Hallmark features of MM according to the Mayo clinic are highlighted by the acronym 'CRAB -- Calcium elevation, Renal insufficiency, Anemia, and Bone disease'.

Vision issues
        When I had my annual eye exam, about six months after my diagnosis, for the first time in my life vision in my left eye could not be corrected. A (manual) scan of the retina of the left eye showed (dry) macula degeneration. Is this related to multiple myeloma or chemo or is it age/family related? It's true that my mother had her vision badly affected by macular degeneration, but that was she was in her 80s, much older than I am.

        Turns out that dogs get multiple myeloma too. Interestingly a lot of dogs with multiple myeloma end up with vision problems, they are going blind. Is this a hint that multiple myeloma in people can cause eye problems? My doctor tells me yes, it can happen but it's quite rare. Nothing can be done about age or family, but it is important to know if my vision issues are related to my cancer or to my chemo. Dogs don't get (much) chemo, so if my vision problem is related at all to my cancer the dog data would tend to (weakly) indicate it is more likely to be the cancer than the chemo that is the cause. (I wrote weakly because the one article I found about dogs vision problems said it was due to bleeding in the eye and retina detachment.)

        Looking at the published revlimid side effects paperwork I find it can degrade vision, affecting 10% of patients after two years, but differently than macular degeneration.

        ** "The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with rev/dex. (Celgene revlimid proscribing sheet)
'Eye' food supplement
       My eye doctor recommended taking a (food) supplement with carotenoids lutein and zeaxanthin, saying there is some clinical evidence this may help. I have not researched this, and I am generally skeptical of food supplements, but I started taking a pill for this. Why am I am not surprised that after taking this eye food supplement daily for six weeks I can sense no improvement, if anything my eyes are getting worse.
(Nov 2015)
        While my eyes continue to be variable, my impression is that they have been better in recent weeks and months than they were when last tested. I am going to have my eyes retested tomorrow, so we will see. I have been taking a food supplement pill daily with lutein (25 mg) and zeaxanthin (5 mg) since my last eye test. And perhaps more important for about the last six months, since my chemo transitioned to maintenance, I have not been taking the corticostereoid dexamethasone, and a lot of things in my body have improved (like my fingernails, and skin growths), so I am hoping my eyes have improved too, or at least not further deteriorated.
        So another daily pill I need to take. Now every day I take at least two pills: full dose aspirin and a lutein/zeaxanthin pill. On days 1-21 I add the (large) revlimid capsule, and at the beginning of each week the 'pulse' of dexamethasone requires taking five (tiny) 4 mg pills (20 mg/dose). So during a chemo cycle the number of pills I need to take daily is either 2, 3, or 8. I'm not a great pill swallower and the 25 mg  revlimid capsule is quite large, but I find it goes down easily. The 4 mg dexamethasone pills are tiny, so I do the five of these in two swallows. My oncologist gave me no specific instruction on when to take them. The clinical trial paperwork wanted the revlimid and dexamethasone taken an hour apart on an empty stomach. Too much BS for me, I take all my pills together after eating breakfast or lunch..

Overview -- How MM patients die (5/3/17)
How MM patients die
        My hematological oncologist at our last meeting was talking freely about how MM patients die. This is a change, as usually she don't talk about this. (Is this a hint?) MM patients can die in a lot of ways, but she was telling me two common ways. One is that they get an infection (like pneumonia) that they can't shake, and another is that become dependent of blood product transfusion (like platelets) and eventually they say enough is enough and just stop the tranfusion letting nature take its course.

        When I think about this, they are both explained by the nature of where MM cancer cells are located. MM is unusual in that the cancerous plasma cells that create antibodies, one of the four blood cells types, are located in the marrow of bone, typically in the large long bones, the ribs and vertebrae, though I already know of an exception to this in that the narrow in the small sphenoid bone behind my left appears to have a lot of cancer cells that have exploded out to form quite a quite large plasmacytoma (soft tumor composed of plasma cells) that affected my vision. I got (and still have) double visiion when looking right because the sphenoid bone plasmacytoma was pushing on the muscles that move the left eyeball reducing its range of motion.

        Thus MM cancer cells are effectively trapped growing in a fixed volume (assuming other bones are pressed into survive, which they might be). This is very different from cancers that form solid tumors in vital organs where the tumors can just grow and grow. As the cancerous plasma cells grow in number (which is what cancer cells do!) in this fixed volume, the space available inside the marrow for the cells that create the other three types of blood cells is reduced, so the number of white blood cells, red blood cells, plateltes, etc in the blood slowly goes down. In addition the antibody cells created by the cancerous plasma cells, since they are all clones (hence the 'M-spike', one of the MM  blood cancer markers), don't work effectively either. Hence once the cancer evolves immunity to all the chemo drugs and begins to grow, your blood gets all screwed up, the number of all four blood cell types begins to decrease. This I think explains a lot about how cancer patients are clinically affected, and how eventually they die.

        For example, low levels of white blood cells and anti-body cells, allow infections to take and not be shaken, because your immune is compromised. Low levels of platelets, which control clotting, leads to platelet transfusions, so essentially you don't bleed to death internally. To pursue this further requires some more knowledge of the nature of blood

Nature of blood
        Diagrams on Wikipedia show blood cell creation involves a long complex series of steps. There is a whole chain of events in the marrow to create the four basic types of blood cells. What really counts is the nature of the blood cells and plasma components that comes out and form your blood.

       Here's an introduction from the National Center for Biotechnology Information with a nice image of how blood in a test tube naturally separates into three layers due to density differences. Starting with the three separation levels they identify three basic types, but these further divide into many, many others (as a look at you own blood work will show). For example, as noted below, there are many types of what are collectively called 'white blood cells' that individually are tracked in blood work.

        Antibodies are a small but complex Y shaped protein, normally are all slightly different to fight a wide range of infections. The wide range of anti-body proteins are created by a similarly wide range of plasma cells.  MM is a cancer of one (or two) of the plasma cells that make antibodies. Antibodies are proteins, a sequence of amino acids, and like all proteins they are small molecules, so they are found floating around (effectively dissolved) in the watery plasma of the blood.

(source --

       The particular plasma cell that has gone cancerous pumps out a huge amount of a single type of antibody. This forms one of the diagnostic blood markers of MM. In the lab when antibody proteins are spread out by weight and diffusion constant, in health people they form a smooth curve since they are slightly different, but in most MM patients a spike will be found riding on the curve. The area under this spike is called the 'M-spike'. It is a measure of identical (hence monoclonal) antibody proteins in the blood, so in a sense it tracks the body average of how many cancerous plasma cells are in the bones. All proteins in blood work are measured in units of g/dL, so in my tracking table (above) I calculate the {M-spike/total protein] ratio}. This ratio was at 50.1% before I started chemo in Nov 2014, but within about six months my chemo had driven this ratio down to 3% to 4% (or less) where it has remained for the last two years. So M-spike (and this ratio) works for me, which is not true of all MM patients!

Marrow biopsy
        An early bone marrow biopsy (technically a bone marrow aspiration) into my hip bone, done with a long needle to extract a sample of its marrow, showed that cancerous plasma cells made up 70% of the sample, whereas normally it would be at less than 10%, meaning 70% of the available volume has been taken over by the expanding cancerous plasma cells leaving only the remaining 30% for the cells that create the other cells of the blood (check these numbers). This is a reduction in space by a factor of three (90% =>30%). No wonder the blood is all screwed up.

2nd look at stem cell replacement option
        From my research I find that interest in stem cell transplants, which just a few years ago was the gold standard for multiple myeloma, now seems to be lessening. My doctor while saying she supported my decision to not have a stem cell transplant and did not not think it unreasonable, still nevertheless occasionally brings it up, like at our last appointment. In the intervening months I leaned two new things about stem cell transplants. One is a guess I have that it may be a driver as to how long doctors push to stay on high dose chemo, because for bone marrow to be harvested and successfully reinserted the number of cancer cells it contains must be small. The harvest goal as I understand it is a CR (complete response), which in practical terms means a 95% or more reduction in cancer cells from the original baseline. Two,  I have discovered from reading multiple myeloma patent postings that there is an intermediate step that can be taken. After chemo drives down the cancer cells to low levels, even though some don't plan on having a stem cell transplant they go ahead and have marrow extracted from their bones, which is then frozen and can remain for years. This is insurance, it could provide an option in later years to do a stem cell replacement when chemo stops working. Based on the small mount of marrow that was extracted from my hip bone for my DNA assessment, I expect the more extensive marrow extraction is likely an unpleasant and moderately painful outpatient procedure, but since I haven't asked about this or researched it, I don't really know.

Chemo maintenance
        As I write, an important clinical decision in my chemo is coming up pretty soon, a transition from high dose dex/rev to a maintanence regimen. On MM forums I find that patients who have had stem cell transplants frequenty go long periods taking no drugs at all. Several recently completed clinical trials summarized in the New England Jouranl of Medine make a strong case for continuing to take revlimid, but at a lower dose. I see the same pattern of revlimid maintence in the ongoing phase 3 MM clinical trials. There the revlimid maintanence dose is given as 10/15 mg. What this means is 10 mg, but pushed to 15 mg if toxity can be handled and probably for younger patients. My doctor is dropping hints that her recommendation for maintenance chemo will likely be 10 mg revimid (no dexamethasone).

Clinical trial time lag
        Reading about the clinical trials and thinking about them, I begin to realize the huge time lag in this process. Sure the clinical trial is the 'gold standard', and for the medical community the lag is tolerable, progress slowly gets made and treatment improves. But to a patient with limited lifetime the situation looks somewhat different.

        Clinical trials for MM chemo are slow, really SLOW.... A phase 3 clinical trial needs to enroll 600-700 patients. This is 3% of all the patients diagnosed with MM in USA in a year! It takes a long time to recruit so many patients. As treatment options get more successful, the follow up time required to determine if a new treatment works better than the old treatment takes longer and longer. I see follow up times going out to six years. A MM clinical trial started in 2010 is scheduled to run to 2018 or 2020. And this doesn't include the time for phase 1 and phase 2 trials a new drug needs to reach the phase 3 stage. Bottom line when clinicians see (in limited testing) that a new drug or drug combination is working well and might be preferred over the current baseline treatment, it will take about a decade to confirm if this is right. Hence treatments for MM based on clinical trial are really based on thinking more that ten years old!

        One way to cut the lag is to play the odds. How successful have new MM drugs and drug combo been when tested? In some fields clinical trials fail all the time, but my seat of the pants guess is that for the last decade MM clinical trials have been remarkably successful (need to research this). If this is right, it means the drug companies are doing a great job, and the intuition of clinicians has been good.

        Seems to me what clinicians do is fairly stright forward. If three drugs with different mechanism are available, the obvious test is check if three different drugs work better than two with acceptable side effects.

        The drug companies make incremental improvements to reduce side effects, improve response, and/or make drugs easier to take. Millennium has a unique FDA approved drug, a proteasome inhibitor, for MM (velcade), but it must be admnistered by injection, so they develop a a proteasome inhibitor in pill form. How many years is it going to take to check out this new form of a a proteasome inhibitor? A lot. I see a 2012 announcement from Millennium that its new oral a proteasome inhibitor (MLN9708) has shown a high response in phase 1/2 testing, but in 2015 it's still an experimental drug, and the clinical trial I was offered was a phase 3 test of it.

Accessing my hospital records
        My experience has been accessing my Lahey patients records is a black hole. In all my early multiple meetings with doctors to stage my cancer and work up a chemo plan the subject never came up. At these meetings I got print outs of my blood work, an occasional copy of a paper, and oral descriptions of my DNA results. I first leaned that I could get a print out of my 'history' from a nurse in the zometa infusion room, who asked if I wanted it. Yes! It turned out to be many pages consisting of contemporaneous notes my doctors had written up after our meetings (who knew!) plus several sets of blood numbers. Until this was handed to me I no inkling this data existed. When I later told my doctor I had obtained my history, she didn't seem to know what I was talking about and asked me to bring it in to show her on my next visit, which I did. (I have found these doctor notes very useful in writing up this log. You can't remember everything you are told, and I find the notes contain a lot of information I was never told.) Later inquires about accessing my history to nurses in the injection room would yield only the platitude that 'your history is your history' and you have access to it.

        In a separate building from the hospital Lahey has patient document building. It's web site talks about obtaining records or a relatively steep fee, so I didn't pursue this. Someone told me (forget who, probably a nurse) that images (x-rays, etc) could be obtained free. So I telephoned and it was confirmed that images were free, and very quickly (day or two) I was able to pick up four DVDs full of images (some of which are below). However, the image I was most interested in, T12 bone loss, is not there (at least unable to find it in two complete passed the DVDs.)

        Come April 2015 and hospital is converting to a new electronic record system from Epic and a patient portal, called MyLaheyChart, is part of that conversion. The bs from Epic is that this Lahey portal provides patients access to their medical data and history. There is one link in the portal where they say copy this info to a thumb drive which you can give to another doctor so he will know your history. Oh, yea! My history is blank, no record of my cancer or my neck operation. Not only that, but my latest blood work, the only data available in the portal, is missing the most important number, the monoclonal M-spike, which tracks the amount of cancer in my blood. Some service to the patients this is.

Lahey new online patient 'portal' (4/15)
        In April 2015 finally added a patient 'portal'. Turns out this is part of big, very expensive conversion of the hospital to electronic records being subsidized by the government. The EHR (Electronic Health Records) vendor they chose is Epic who pretty much has a lock on most of the big medical centers in the US. This is a privately held EHR company with 8,000 employees! The 'mychart' patient portal is part of the EHR system. One aspect I immediately liked is that it provides a convenient way to email your doctor with questions, and twice I got replies in two days as advertised, but most of the portal is a bust.

        Here's a quick rundown of the problems (see appendix for details):

                        a) No history --- Doctors are told that the system supports patient care, they can easily look up the patient's records. Whether history is
                                       visible to doctors I don't know, but it's not available to me. There is no history in the portal prior to the go live date in April 2015,
                                       which mean no information that I have cancer or had an operation at the hospital seven months ago.
                        b) Most important cancer number in my blood work ('Monoclonal peak quant') is missing. I first thought this was a simple error, but I now
                                       suspect that this important data might have been deliberately withheld (supposedly so the doctor can go over it first). Ironic since
                                        my doctor already showed me the number prior to my even signing up for the portal.
                              (update) 'Monoclonal peak quant' showed up in my 5th cycle results (now it's called MONOCLNPK!), but my 4th cycle test results
                                        have never been updated, there it remains blank.
                        c) Data format stinks: every blood panel is a separate click, out of range blood values are not marked (H/L), a compact blood work summary
                                      is available, but well hidden (you need to click 'Download my record' and then 'Preview your Lucy record'). Well that's sure clear...

         From my reading what the Epic mychart portal provides is not so much due to its capability (it can do a lot), but on what features the sponsoring organization, i.e. Lahey, has chosen to implement.

MyLaheyChart (update 9/2/15)
        I just discovered a lot of detailed information about me in Lahey records. I've been very critical of their online portal ( because it didn't contain any historical information. My earliest records only went back a few months to April 2015 when the new (Epic) medical records system began at Lahey. However, I just discovered this week that older records have been added (no announcement!) and now go back to my time in the hospital (Sept 2014). I had a lot tests in my week in the hospital multiple MRI's, CT scans and x-rays. Turns out that the doctors that read the results type up (or dictate) detail reports on what they find.

      I found some interesting stuff. The x-ray guy finds I have a broken 9th rib ["likely pathologic fracture right 9th rib"]. NOBODY ever told me I had a broken rib! Another guy finds cysts in my liver. If your a hypochondriac, this makes good reading. Even more interesting I found during the neck operation that when they put the screws into my neck bones one of them didn't go in right, straying out of the bone into the spinal canal area, but they later fixed this. This is stuff the doctors won't tell you.

On my broken rib
        It might seem with the MM diagnosis, and multiple bone lesions, and broken neck all in the span of a few days that a broken rib is small potatoes, and in a sense it was. Was that the reason nobody told me about it? I don't think so.

        I think the issue here is the specialization of doctors. In the hospital my (chief) doctor is cervical surgeon and his team, he's a neck specialist. When I get out of the hospital, I am handed off to the radiation doctor who has negotiated (so she told me) to irradiate two areas: my neck lesion and a big T12 spine lesion, so that's her focus. Next in line in the doctor parade is my hematological oncologist who specializes in blood cancers. Her job is to assess the severity of my cancer and set up a chemo regimen. She doesn't do ribs either.

        At one point I asked for a consultation with a bone man because I was concerned about the stability of my left femur with its large 'hole' clearly visible on x-rays. He only looked at my femurs.

        None of them do ribs. The result is an x-ray finding of a broken bone, probably broken by the cancer, was never forwarded to me.

Simplistic Lehay portal info
       Below gives a hint about the quality of the portal. In the test results area most of the tests have an info link: "About this Test". I just clicked a few. Here's what the link of the "PROTEIN ELECTROPHERESIS, SERUM" test says:  (for starters 'Electrophoresis'' in the name of the test is spelled wrong!)
            "The test (protein electrophoresis test) separates proteins in the blood based on their electrical charge."   (Not really. Yes, the charge determines the (electrical) force pushing on a protein. But for a given charge what distance a protein moves depends on its diffusion constant, and that in turn depends on the size, weight and shape of the protein. Small, light protein molecules are able to diffuse (move) in a gel more easily than large, heavy proteins molecules. It is the combination of the charge and diffusion constant differences that cause the various proteins in blood serum to spread out in a gel strip so they can be identified.)
Dana Farber portal (2/16)
        Dana Farber cancer center in Boston is one of the teaching hospitals of Harvard medical school and is world famous as a treatment and research center for multiple myeloma. They have more than a dozen doctors and researchers who are full time specialists in the disease. I have recently begun seeing a doctor at Dana Farber in Boston, so I have access to its online portal where I can see my test results. I was hoping it would be better, meaning more patient friendly, than Lahey, but it's not, in fact it is worse.
Background on Boston hospitals
        For years now the bigger hospitals in the Boston area have been buying up the smaller independent hospitals, so that now in greater Boston there are essentially two groups of hospitals with common ownership. The suburban group, owned by Lahey, and the downtown group, owned by Partners Healthcare, which includes Dana Farber and Mass General. The electronic medical records and portals of both use Epic software.
        Here's a sample of my blood work as posted. Yikes!  No concern for the patient at all. All the blood components shown in the first panel excerpts (every one of them!) are identified only by a cryptic three or four letter shorthand. Would it kill them to write, say, after WBC (White blood cell count). I mean the page is mostly blank. But either they can't be bothered, or more insidiously it is done deliberately to keep patients from asking questions of their doctors. I don't think I am being paranoid. Look at my PLT (platelets). It is outside the normal range (Revlimid decreases platelets), but notice there is no 'H' or 'L' marked to indicate an out of range value.  Yet the same print out at the hospital, which looks nearly identical, has out of range values so marked. It was suggested to me by one of the blood technicians at Lahey, which also omits 'H' and 'L' online, that 'H' and 'L' might be omitted to keep down questions.

Dana Farber online portal blood results (CBC and Differential panel, partial, Feb 2016)
Dana Farber online portal blood results (CBC and Differential panel, partial, Feb 2016)

Dana Farber online portal blood results (SPEP panel, Feb 2016)
Dana Farber online portal blood results (SPEP panel, Feb 2016)

Blood collection issue
        The cryptic SPEP caused a problem when I had my blood taken at Dana. I always inquire if the blood panels include (and here I describe it several ways to the blood technicians)  protein electrophoreses, M-spike, monoclonal spike. These are the terms I use at Lahey. The Dana Farber blood technicians didn't know what I was talking about. I was taken aside while they consulted someone who told them yes the test was included. They then told me "SPEP panel" included what I wanted, but SPEP meant nothing to me. This is a serious problem of communication. Not only do the printed blood results use the cryptic SPEP, but this is apparently the only way the blood technicians know to describe the test.
Where's the M-spike?
       I am more disappointed by the results shown in the second panel. This blood panel and its key test are identified only as 'SPEP'. I have been at this 16 months, and I didn't know what this meant without looking it up. SPEP is shorthand for 'Serum Protein Electrophoresis'. Lahey blood results call this panel 'Protein Electrophoresis, Serum', you know, actual (medical) english. It's the protein diffusion test that measures the primary marker of MM the M-spike (or monoclonal spike). And here's the second problem and it is a big one. The M-spike value is in the 'pathology report', but the pathology report is not online. That's right a world class MM research center doesn't make the primary marker for the disease available to its patients online! Lahey routinely puts M-spike results online.

         It is not a question of prior approval. My doctor already gave me my M-spike results on the phone. He confirmed the pathology report is not on the portal. I found I can get the results in writing by calling the office and request they mail it to me, so I did, but this is just so stupid... I expected better of Dana Farber.

M-spike arrives online (after 10 days) (update 2/18/16)
        Ten days after my blood collection and a full week after my doctor called me to discuss the labs, the Dana pathology report appeared online with the M-spike data. Why the huge delay? Who knows. By the time it showed up online the hard copy I had requested had arrived in the mail.
How many multiple myeloma patients might my hospital be treating?
        A useful piece of information I would like to have as a patient is how many other multiple myeloma patients might my hospital be treating, but I find information like this very hard to extract, certainly I can't get my doctors to talk about it.

        Here's a back of the envelope calculation: 22,000 new patients are diagnosed with multiple myeloma each year in USA. Greater Boston has a population of about 4 million, let's call it 1% of US population, so that's 220 new multiple myeloma patients in greater Boston per year. Now how many hospital do they divided into. I really have no idea how many large (cancer) hospitals there are in greater Boston, but there must be at least ten in Boston alone, so a seat of the pants guess is 20, so that's 11 new patients per hospital per year or roughly one new patient per month per hospital. If the average patient survives, what five years (?), then the typical large hospital is treating 60 patients. If there are say 4 hematological oncologists on staff who handle multiple myeloma, then each oncologist gets (on average) 3 new multiple myeloma patients each year. But how are patients assigned since some staff members may be new to the hospital while longer serving staff may already have their quota of multiple myeloma patents? Let's say the 12 new multiple myeloma patients per hospital per year are assigned to two newer younger staff members, then each of them acquries a new multiple myeloma patient every other month.

        Thinking about it for a minute I see a couple of other approaches to getting a number. MM in the literature is described as being 1% of all cancers and 10% of blood cancers, so if the hospital would state how many cancer patients it manages, or even better how many blood cancers the that would give a number.

How much experience do new staff doctors have with MM?
        A corollary of my patient calculation just struck me. If new hematological oncologist on staff are only acquiring newly diagnosed multiple myeloma patients, then they probably have had little experience in treating end of life conditions. Their multiple myeloma patients have just not had enough time to get sick and die. (I am particularly interested in this because I see my oncologist only joined the hospital staff two years ago.)

        I asked this of a consulting oncologist doctor at Lahey and was told that new staff members who are likely to be replacing staff members who have "retired" (or departed) will typically take over their MM patients. (Sort of a boilerplate answer, but probably is partly true.)

'Happy talk' from doctors
        My regular oncologist goes lite on the 'happy talk', but in my one meeting with another oncologist (to get a 2nd opinion) I heard some things from him that I am skeptical of and would classify as 'happy talk'.

        One of these was a mention that MM bone 'holes' (hollowed out areas of the bone from the inside) were able to grow back. Directly contradicting this, or more specifically showing how unlikely this is, I found a paper that focused on a single patient where the dimension of 'hole' in his left femur was reduced in size by a factor of two. In other words the (partial) growing back of bone to reduce the size of a MM lesion is so unusual, and this was made clear in the abstract of the paper, that it justified a whole paper being published to discuss this happening in a single patient! So it can happen, but the consulting doctor implied (without actually saying so) that this was possible or likely to happen. Hence my characterization of it as 'happy talk'. [The status of a large 'holes' is of particular interest to me, because I too have a hole in my left femur (bigger than the one in the paper) and also substantial bone loss in my T12 vertebra.]

        Second comment I would classify as happy talk was the comment that patients diagnosed with MM in 2015 will survive 7 (or 8) years. Not only did this number seem high, but it was this was thrown out at the end of the meeting with no qualifications about staging, age, genetics or stem cell replacement, so for these reasons I am skeptical of this and consider it happy talk. I do occasionally see high numbers, but survival numbers in MM clinical trials, which admittedly reflect older treatments, are much less than this. However, Mayo Clinic does claim a median survival time is now about 8 years, so maybe the comment is reasonable. gives median survival time of less than four years for stage II and 2.5 years for state III (I am stage III), but cautions this is for people treated 5 to 25 years ago. This is probably hard data found in completed clinical trials, which would have begun at least a decade ago.

        -- "The average newly diagnosed myeloma patient 15 years ago, for example, was about one-third as likely as someone without myeloma to live another five years. By the end of the 2000s, in contrast, that same myeloma patient would be 45 percent as likely as someone without myeloma to live another five years." ( I don't see this a big improvement, and is saying as of a few years ago less than half MM patients were surviving five years.
        Mayo clinic, a leader in MM treatment, reports high numbers: close to 90% 3 years survival.
        -- "Although the disease remains incurable, with the introduction of autologous stem cell transplant (ASCT) and newer agents, such as thalidomide, bortezomib, lenalidomide, and carfilzomib, median overall survival (OS) has increased from 2 to 3 years a decade ago to greater than 8 years currently." (Mayo clinic, 2013). The reference given for this is survival time is this paper: Kumar, S.K., Rajkumar, S.V., Dispenzieri, A. et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008; 111: 2516–2520), but a look at this paper shows 50% survival time of less than four years! And as I scan the full text, I don't see any support in this 2008 paper for an 8 year survival claim. (As a footnote, the paper shows the median time to relapse after stem cell transplant was only 13 months. Yikes!)
Why multiple myeloma relapses
        Why multiple myeloma invariably comes back after chemo is an area of active research. Different teams have different theories. Research from Mayo clinic identifies the cause as immature cells are not touched be chemo and later they mature and reboot the cancer.


My Pictures
Yup, this is me...

xray taken during C1,C2 cervical fusion operation
positioning hardware during neck fusion operation (9/18/14)
Forked clamp holds the incision open, some of the screws into C1, C2 vertebra are in.
(jaw clearly shows my dental implant and various caps)

xray taken during C1,C2 cervical fusion operation.xray showing hardware for C1,C2 vertebrae fusion
left: x-ray taken during operation
right: x-ray check of c1,c2 hardware alignment a month after operation. (The rods are clamped
to the screw heads with sort of an  inside-out nut and bolt configuration.).

Neck incision for posterior C1.C2 cervical fusion (5 days post operation) .Neck incision for posterior C1.C2 cervical fusion (12 days post operation)
left: neck staples at home five days after operation
right: neck staples a week later (note the healing).
(The staples were removed a day later (10/1/14) by a nurse practioner at Lahey
who said the healing looked good, no sign of infection.)

In my adjustable Ossur Miami J neck collar
freaking stiff neck collar worn high (left) and really high (right)
right: Miami J c-spine immobilizer by Ossur (my collar was adjustable Miami J)
24 hours/day for a month after operation and during day for 2nd month
(It was supposed to be worn under the chin and tight where it gave the best support,
but that was very uncomforable and impossible to eat, so I usually loosened it a little and let it ride up.)

radiation mask --- bolted my head to table for radiation to neckradiation mask --- bolted my head to table for radiation to neck
my custom made radiation mask
used to bolt my head to the table during neck radiation

multiple myeoma lesion inside my left femur  (1.5 top-bot )
two x-ray views of large (1.5" top to bottom) 'hole' on outside surface of my left femur (contrast enhanced).
This bone tumor was not irradiated because it was not discovered until later, when my MM was staged.

It took me a long time to understand that what the doctors were calling a 'hole' was really INSIDE the bone.
It is a hollowing out of the bone beginning at the marrow/bone interface.
This 'hole' doesn't hurt, and the reason for that is probably that the 'hole' has not penetrated to the surface,
hence the pain sensor filled membrane around the bone (periosteum) is undisturbed.

donald e. fulton selfie head shot, Donald E. Fulton, donald e. fulton.donald e. fulton selfie -- with new years hat, Donald E. Fulton_2donald e. fulton selfie  --- with head radiation mask, Donald E. Fulton_3
left: summer 2014 before cancer diagnosis
center: selfie taken in early Jan 2015 (on chemo, 3.5 months after diagnosis and neck operation)
right: selfie in radiation mask (who says cancer can't be fun)

my hospital room at Lahey (room 38 in Central 7th floor) first morning in hospital (Tues 9/16/14)
(only picture I have taken during 7 day hospital stay)

        My radiation oncologist showed me beautifully clear images of my back, and went over in great detail my loss of bone in T12 vertebrae. My hospital documentaion dept has supposedly given me all my images (4 DVDs!), but I cannot find those T12 images. The closest images I can find are below and from comparison to an MRI I found online with T12 labeled, it does look like the verterbrae near the bottom with the weirdness is probably T12. I can't make any sense of the weirdness of T12 in these images. In the top images it appears to overhang the adjacent disks, but in the lower images the right side of the disks adjacent to T12 looked thinned.

multiple myeloma T12 bone loss (view1)multiple myeloma T12 bone loss (view2)multiple myeloma T12 bone loss (view3)
Vertebra T12 lesion (I assume) in various MRI views (9/18/14)
(left -- normal appearance)
(center, right -- T12 lesion visible near bottom)

T11 involved? Is this is this real or an artifact?
(It doesn't seem reasonable that a T12 lesion would 'extend' to T11, which is a separate bone,
and same darkening is seen in T7.)

Inventory of my MM bone tumors (12/17/15)
         'Multiple myeloma' refers to a characteristic feature of this cancer. It is found at multiple sites within the bone marrow (myelo-) with accumulations of tumor (-oma) cells. Unlike solid tumor cancers where cancer cells at least initially are localized, in multiple myeloma being a blood cancer the cancer cells spread thoughout the body almost from the start, so a MM patient typically has bone tumors throughout his body by the time the disease is diagnosed. (You have to consider you have cancer from "head to foot" I was informed by a resident leaning over me while being wheeled through the corridors of the hospital after my neck broke.) Hence the goal of MM chemo is to try to keep those many bone tumors in check.

        For 'fun' I thought I would pull together all the various references to my bone tumors discovered in readings of my x-rays, CT scans and MRIs in the fall of 2014 in my medical record and organized them by location. Why, because other than saying I have cancer 'from head to foot', I really have no idea where bone tumors have been spotted in my body.

        After taking my inventory I see my tumors are all in the classic areas that MM tumors are usually found: head, neck, spine, ribs, pelvis, and upper arm and leg bones. Soon after my C1,C2 fusion operation I had two weeks of cancer radiation of my neck and back. How narrowly the beam was focused on C2 and T12 I don't know, because in both cases there were tumors in adjacent and nearby vertebrae.

Update (5/9/17)
         A recent pet scan (in a sensitive setting!)  has much of my spine lit up like a christmas tree! (not clear what this means) Bone pain is common in MM patients, but I have had NO bone pain (aside from a little neck discomfort associated with my failed C1/2 fusion). That's good luck with all these bone tumors. Pet scans have found more tumors like in 2nd rib front and in sphenoid bone behind my left eye. The recent bone focus has been on the 9th rib, rear plasmacytoma, my most metabolically active tumor, last measured at 3 cm across (1.95") up from 2 cm just two months earlier.

         I had a 2nd round of head radiation to irradiate a tumor in the sphenoid bone behind my left eye that was affecting my vision, and I insisted that the nearby tumor on my jaw also be irradiated at the same time, which it was. Later scans show a huge chunk of my T12 vertebrae is just gone. For the last two years I have been getting in infusion of a drug monthly (Zomata) that works well to strengthen bones, same drug given to older women once a year to prevent osteoporosis.

Head and skull
        -- skull has "multiple" tumors ("well-defined lucent lesions")
        -- upper right jaw near the pivot has a tumor ("focal lesion in the right mandibular ramus")

Spine, cervical (neck)
        -- C2 has a "diffuse infiltrative tumor" with a pathologic fracture. In english a cancer caused broken neck. "The fracture line is oblique at the
                        base  of the C2 odontoid  process{ (vertical peg). The tumor involves "most of the C2 vertebrae" including the "superior aspect of
                        the C2 body as well as part of the lateral masses" and "large lytic C2 lesion with pathologic fracture through the body of C2".
        -- C3 has a tumor in "inferior aspect of its vertebral body and inferior endplate"
        -- C4 has a tumor in its "spinous process and inferior endplate"  (A biopsy of the C4 spinous process tumor was taken during my C1,C2 fusion
                       operation to confirm the diagnosis of multiple myeloma.)
        --  C6 has a "small focus" tumor in it "spinous process"

Spine, thoracic (chest)
        --  T1 has a tumor in its "left superior facet" (identified as the "right superior facet" in a summary). (Facets are small flat sliding cartilege
                      coated joints between vertebrae.)
                     T1 also has scattered bright spots that might be tumors, but "given the small size of these lesions, these are equivocal"
        -- 1.46" egg shaped abnormal growth (destructive lesion) in T12 vertebrae body, left side and rear. T12 has not compressed or fractured.
        -- one note says T12 tumor has expanded and is 'impinging' on the spinal cord (without compression), elsewhere it says tumors
                       are 'moderately' narrowing the canal openings of T12 and L1
        -- tumors of T12 and L1 are extending into the left nerve canal ('neural foramina', or canal between vertebrae where nerves leave
                        the spinal cord) (This is not the same as the large hole (canal) in the center of vertebrae for the spinal cord.)
        -- tumors ("destructive lesions") in T7, T11, and  L1. (vertebrae near T12)

Spine, lumbar (lower back)
        -- diffuse abnormal growths in entire lumbar spine
        -- tumor in L1 (directly below T12)
Spine, sacrum
        -- posible tumor in S1
        -- several turmors in the pelvis, most notably within the ('iliac wings' are the large flaring surfaces of the pelvis)
        -- lower rib on right side (9th rib) appears to have been broken by the cancer. (This might be the cause of some chest pain I had while
                     exercising weeks before my neck broke.)
        -- several small tumors (well-defined lucent lesions) in both upper arm bones ("proximal humeri") (humeri is the plural of humerus)
        -- large 1.5" (top-bot) well defined tumor in left femur (middle, outside edge, about 30% of dia). Possibly other small tumors in the left
                    and right femurs, but not visible in later x-rays of right femur. (I included x-rays of this femur tumor in this essay)

Details of cancer in my bones from MRI and CT scans during my hospital stay (Aug 30, 2015)
        Reading through my medical records on MyLaheyChart recently I was surprised to find a lot of information from tests taken during the time I was in the hospital (Sept 2014). (Not sure if this historic material has been newly made available online, or I just missed it.) I found two references (below) to my T12 vertebrae in a write up of a lumbar spine MRI (with and without gadolinium contrast) done 9/18/14, which was the day of my C1,C2 fusion surgery and prior to it. There is also a reference to T12 in a 9/16/14 abdomen and pelvis CT with contrast. This needs some translation, a work in progress.
        -- Bones: Diffuse, enhancing, neoplastic infiltration of the entire lumbar spine with deposits ranging from punctate through expansile, 37 mm (1.46") ovoid left T12 pedicle and posterior vertebral involvement. No lumbar compression or apparent sacral insufficiency fracture.

        -- Thoracolumbar junction: There is impingement upon without compression of the conus medullaris due to the large, dominant, left posterolateral T12 vertebral body and pedicle expansile. (Wikipedia says the 'conus medullaris' is a name for the spinal cord near the lumbar vertebrae L1 and L2. L1 is immediately below T12. Wikipedia says injury to 'conus medullaris' can cause back pain and bowel and bladder dysfunction.)
        1. Multiple additional osseous metastases, the largest involving the left posterior lateral aspect of the T12 vertebral body, likely amenable to biopsy. Probable pathologic fracture posterior right 9th rib with adjacent overlying atelectasis.  (What! A broken rib. No one has ever mentioned this. I did have some rib pain prior to my neck breaking.) (Atelectasis is lung tissue that is compressed)

        2. T12 lesion demonstrates moderate canal narrowing and extension into the T12-L1 left neural foramina. Recommend correlation for clinical symptoms and consideration of thoracolumbar MRI for complete characterization of spinal metastases.

Osseous structures:
        Scattered lucent destructive lesions among multiple vertebral bodies, the largest within the T12 vertebral body at the left posterior lateral aspect extending into the pedicle with associated canal narrowing and likely extension into the left neural foramina at the T12-L1 level. Additional lucent lesions noted in T11 and T7, possibly also S1. Probable pathologic fracture posterior right 9th rib with adjacent overlying atelectasis. Additional lucent lesions in the pelvis, most notably within the left iliac wing. Degenerative changes lumbar spine.

           1. Multiple additional osseous metastases, the largest involving the left posterior lateral aspect of the T12 vertebral body, likely amenable to biopsy. Likely pathologic fracture right 9th rib with overlying atelectasis.

            2. T12 lesion demonstrates moderate canal narrowing and extension into the T12-L1 left neural foramina. Recommend correlation for clinical symptoms and consideration of thoracolumbar MRI for complete characterization of spinal

C2 descriptions (few days prior to C1,C2 fusion operation)
        -- Metastatic lesion to C2

        Acute pathologic fracture of C2

        There is diffusely abnormal signal intensity involving almost the entire C2 vertebrae including the odontoid process and most of the superior aspect of the C2 body as well as part of the lateral masses. There is diffuse enhancement of the C2 vertebrae except for the oblique fracture line at the base of
the odontoid process. The alignment of the fracture fragments is significantly improved compared with the CT scan. The tumor is corresponds to the lytic lesion seen on CT. There is no cord impingement. There is extensive prevertebral edema from the anterior atlanto occipital membrane level to the C5-6 level. Joint effusion is noted at the atlantodens interval. There is also edema between the opisthion and the posterior arch of C1 as well as extending posterior to the occipital bone.

        The above findings are consistent with diffuse infiltrative tumor involving C2 with pathologic fracture.

Other focal areas of tumor involvement include the following:
        Anterior inferior aspect of C3 vertebral body, C4 spinous process, inferior endplate of C4, small focus in the C6 spinous process and left T1 superior facet. There are other scattered tiny foci of hypointense signal on T1 weighted images which also could represent tumor although given the small size of these lesions, these are equivocal. There is also focal lesion in the right mandibular ramus. The above findings are most likely due to metastatic disease although multiple myeloma or lymphoma can have a similar appearance and clinical correlation is recommended. PET-CT scan or bone scan could be obtained to evaluate for an accessible site for biopsy. (Yikes,  lesions in other bones of the neck: C3, C4, C6 and T1)

        1. Tumor involving most of the C2 vertebrae including the odontoid process with pathologic fracture through the base of the odontoid now with satisfactory realignment. Extensive prevertebral edema from the level of skullbase to C5.

        2. Multiple other areas of tumor involvement including C4 spinous process, inferior endplate of C4, inferior endplate of C3, spinous process of C6 and right superior facet of T1. Neoplastic (abnormal growth) lesion in the right ramus of the mandible. ('ramus of the mandible' is the upper section of the lower jaw)  Findings most consistent with metastatic disease, although lymphoma or multiple myeloma can have a similar appearance. Clinical correlation is recommended. (The bigger picture of this write up is that the cancer is affecting nearly all the bones of my neck C1,C2,C3,C6, T1 and even my jaw.)

Post operation
        Again noted is a a large lytic C2 lesion with pathologic fracture through the body of C2. Alignment of the fracture fragments is markedly improved status post fusion and is similar to the preoperative MR examination. Lytic lesions of the C4 spinous process and inferior endplate of C4. Postoperative air is seen in the region of the C4 spinous process which was also biopsied. Multiple other lesions are better delineated on recent MRI cervical spine examination.  (My surgeon later told me that the biopsy of the C4 spinous process lesion (chunk of bone taken from the projection of the C4 vertebrae out the rear) taken during the operation was used to confirm my MM diagnosis.)

        1. Immediate postoperative examination status post posterior C1-C2 fusion. No evidence of immediate hardware complication. Metallic streak artifact limits soft tissue evaluation, however no large hemorrhage is identified.

        2. Lytic C2 lesion with pathologic fracture. Alignment of the odontoid fracture is satisfactory and improved compared with prior CT scan.

        Extremities: Several small well-defined lucent lesions proximal humeri (upper arm bone).

        1. Multiple well-defined lucent lesions seen in the skull, proximal humeri (upper arm), proximal femurs (upper leg), and C2 vertebral body where there is a known pathologic fracture. Findings are most consistent with multiple myeloma.

Is that a lesion in my pelvis upper right? (10/21/14)
At first I thought maybe, but now I don't think so.
One, a similar density difference above it indicates it's probably in another plane, and
two, when I review male pelvises online, I find small density differences like this on the right side.
However, write up finds a tumor in "left iliac wing", which if this is a rear view, agrees with the density thing in the upper right.
(Nice view of my ball and socket hip joints, which seem clean)

One year follow up cervical CT scan (9/16/15)
        Prior to meeting with my surgeon for a one year follow up to my C1,C2 fusion operation to stabilize my pathological C2 dens fracture I had a new cervical CT scan (wo contrast). (This scan takes only 5 min.)

I now understand I was not the best (or was maybe a poor) candidate for a fusion operation to succeed, though no one ever said this to me. Here are a list of my negatives:

1)  Neck bones weakened by cancer  --- C2 body (or dens) broke in my sleep. Also C4 had a tumor that was biopsed during operation
2)  Radiation -- I had two weeks of daily radiation on my neck soon after the operation to kill the cancerous marrow cells. Apparently the radiation is a negative for fusion to succeed. (I need to research this.) The surgeon during the review asked if I had had radiation, implying it was a negative, but not saying so. I don't remember any of my doctors at the time mentioning that radiation might affect the ability of the bone to regrow.
3)  Cadaver bone graph material --- Best source of bone graph material for a cervical or spine fusion is from your own body. The raw bone is usually obtained from an incision in the hip and then powered. I had no hip incision. The surgeon specifically told me the bone came from a cadaver.
4)  Age --- 72
5)  Screw placement issues? --- There is reference to the one of the screws to being oriented properly, that it first penetrated the spinal opening. I presume that it had to be redrilled, but if this were in issue it should affect only one of the screw seatings.
        The key specifics are that bone has grown into only one of the four screws. The lucency around three screws is suggestive of screw loosening. (It would need to grow into all four screws for any motion between C1 and C2 to be removed.)  The fracture of the C2 body has only partially healed. Bone graph material (from cadaver) between the rear side arches of C1,C2 (interlaminar space) has not been well incorporated. [Note in this review the C2 fracture (or fractures) is described as in the body of the vertebrae. Does this means the 'dens'? My guess is probably yes, as the dens projects up from the body of C2.]

Failing or failed C1,C2 fusion
        The big picture here as I see it is that my C1,C2 fusion has failed (or is failing) though my surgeon did not use this word. It's 12 months and I read that 90% of cervical fusions have succeeded by this time. On the other hand my bones began in a weakened state, C2 fracturing while I was sleeping. Perhaps the first six months should be discounted. I think it's possible (but maybe not likely) that another six months may show some improvement. It was only a few months my chemo coticosteroid was stopped, and I can sense my body getting back to normal in a lot of small ways, also I am 7-8 months (of planned 24 months) into zometa infusions for bone strengthening. So there's a chance that another six months may show some improvement and that is the plan.

        Here is the (complete) analysis of the CT scan (1yr post operation) by a radiology resident obtained from my online medical record (with text excerpts and notes below).

        Evaluate status of arthrodesis (surgical fixation of a joint to promote bone fusion), status post C1-2 spinal fusion. History of multiple myeloma with pathologic fracture of C2.

        Patient is status post C1-C2 laminar screw and rod fixation for treatment of pathologic C2 vertebral body fracture. The left C1 and bilateral C2 laminar screws demonstrate periprosthetic (near hardware) lucency (opposite of opacity), suggestive of hardware loosening. Right-sided C1 laminar screw appears well seated. Persistent geographic lucency in the C2 vertebral body compatible with previously imaged neoplastic processes with partial interval healing of the anterior and posterior vertebral cortical lucencies, although residual cortical lucencies persist (Lucency shows up as a dark shadow around the screws.)

        Posterior-lateral bone graft material within C1-2 interlaminar space demonstrates inadequate bony incorporation. (Laminar is a name applied to a region of the vertebrae. It is the relatively thin bone that forms the rear arch around the spinal column.)

        No acute fracture or traumatic subluxation is identified.

        Straightening of physiologic cervical lordosis (normal curvature of the neck), unchanged. Vertebral body heights are maintained. Intervertebral disk spaces and facets demonstrate multilevel degenerative change. Disc height loss and uncovertebral hypertrophy (enlargement) at the C3-4 through C6-7 levels causing multilevel neural foraminal narrowing without high-grade central canal stenosis (narrowing).

        1. Postsurgical changes of posterior C1-C2 screw and rod fixation for treatment of pathologic C2 fracture.
        2. Inadequate incorporation of C1-2 posterolateral graft material.
        3. Periprosthetic lucency surrounding left C1 and bilateral C2 laminar screws suggestive of hardware loosening.
        4. Geographic lucency within body of C2 correlates to neoplastic lesion with partial interval healing of anterior and posterior vertebral
                 cortical fractures of the C2 vertebral body.
        5. Degenerative changes of the cervical spine, as detailed above.

        The jargon and abbreviations used in many papers on MM is intense, so here's some definitions:
                induction therapy     jargon for standard initial chemo treatment
                            refractory     jargon for disease that has become resistanet to (existing) chemo
                                   sCR        stringent Complete Response normalization of the free light chain ratios
                                                       as well as the absence of monoclonal plasma cells in the marrow.
                                   CR        Complete Response  -- > 95% reduction in monoclonal spike
                                VGPR     Very Good Partial Response -- 90% to 95% reduction in monoclonal spike
                                   PFS        Progression free survival
                                    OS        Overall survival
                                    RR        Response rate
                                   FLC        Free light chain ratio
                                 ASCT      Autologous stem cell transplant
                                  TRM       Transplant related mortality

        A 2012 open source MM book, very technical, each chaptor by different authors.



History and info on the thalidomide class of drugs
        My main chemo drug, lenalidomide (brand name Revlimid), is basically thalidomide, the drug that fifty years ago caused a whole bunch of babies to be born with no arms and fingers sticking out of their shoulders.

        Thalidomide must have a curious history. It became famous decades ago when Life magazine published pictures of babies born with no arms and fingers sticking out of their shoulders! It must have been considered a safe drug at the time as it was being given to pregnant women (to relieve anxiety I think). It had been developed in Germany in 1957. The baby disaster resulted in the drug being banned in 1961, but in 1998 it was (re)approved for the (chemo) treatment of multiple myeloma. Not so many years ago thalidomide itself was used as chemo for multiple myeloma, and lenalidomide (revlimid) is the result of an effort to modify it a little to make it more effective and reduce side effects.
Brief history of thalidomide (from Wikipedia)
        "Four years after thalidomide was withdrawn from the market (1961) for its ability to induce severe birth defects, its anti-inflammatory properties were discovered when patients suffering from erythema nodosum leprosum (ENL) (complication of leprosy) used thalidomide as a sedative, and it reduced both the clinical signs and symptoms of the disease. Thalidomide was discovered to inhibit tumour necrosis factor-alpha (TNF-alpha) in 1991. TNF-alpha is a cytokine produced by macrophages of the immune system, and also a mediator of inflammatory response. Thus the drug is effective against some inflammatory diseases such as ENL. In 1994 Thalidomide was found to have anti-angiogenic activity and anti-tumor activity which propelled the initiation of clinical trials for cancer including multiple myeloma. The discovery of the anti-inflammatory, anti-angiogenic and anti-tumor activities of thalidomide increased the interest of further research and synthesis of safer analogs."
        What is revlimid (lenalidomide)? The Celgene sheet says, "REVLIMID, a thalidomide analogue, is an immunomodulatory agent with antiangiogenic (angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels) and antineoplastic (acting to prevent, inhibit or halt the development of a neoplasm, i.e. a tumor.)" Wikipedia says it also has anti-inflammatory properties. It's a relative small small molecule consisting of three carbon rings with the formula C13H13N3O3. (Thalidomide is very close with the same three carbon rings and the formula C13H10N2O4.) Under Wikipedia 'immunomodulatory' I find this:
        "There are three generations of immunomodulatory drugs, with each successive generation being better tolerated and more active against inflammatory and malignant conditions.

           First generation - Thalidomide
            Second generation - Lenalidomide (revlimid) and pomalidomide
            Third generation - Apremilast (brand name, Otezla). Approved to treat arthritis.

        "Their mechanism of action is not entirely clear, but it is known that they inhibit the production of tumour necrosis factor, interleukin 6 and immunoglobulin G and VEGF (which leads to its anti-angiogenic effects), co-stimulates T cells and NK cells and increases interferon gamma and interleukin 2 production. Their teratogenic (development problems, i.e. no arms!) effects appear to be mediated by binding to cereblon. Apremilast, on the other hand, inhibits PDE4."

        Translation: The thalidomide class of drugs messes around with a lot of the functions of the immune system, and we don't have a clue as which of these effects makes it work against multiple myeloma cancer cells, but clinically we know it works.

        "Lenalidomide (revlimid) is the first analog of thalidomide which is marketed. It is considerably more potent than its parent drug (thalidomide) with only two differences at a molecular level, with an added amino group at position 4 of the phthaloyl ring and removal of a carbonyl group from the phthaloyl ring. Development of lenalidomide began in the late 1990s and clinical trials of lenalidomide began in 2000. In October 2001 lenalidomide was granted orphan status for the treatment of MM. In mid-2002 it entered phase II and by early 2003 phase III. In February 2003 FDA granted fast-track status to lenalidomide for the treatment of relapsed or refractory MM. In 2006 it was approved for the treatment of MM along with dexamethasone." (So there's nine years of history for the dex/rev treatment of MM.)

        Half life of lenalidomide in the body is 3-4 hours. It is removed by kidneys.

        Until I started reading up thalidomide in Wikipedia I had never heard of Pomalidomide. "Pomalidomide (3-aminothalidomide) was the second thalidomide analog to enter the clinic being more potent than both of its predecessors. First reported in 2001, pomalidomide was noted to directly inhibit myeloma cell proliferation and thus inhibiting MM both on the tumor and vascular compartments. This dual activity of Pomalidomide makes it more efficacious than thalidomide in vitro and in vivo. This effect is not related to TNF alpha inhibition since potent TNF alpha inhibitors such as Rolipram and Pentoxifylline did not inhibit myeloma cell growth nor angiogenesis. Up regulation of Interferon gamma, IL-2 and IL-10 have been reported for Pomalidomide and may contribute to its anti-angiogenic and anti-myeloma activities." Wikipedia shows it was approved in Europe in 2009 ('orphan designation') for treatment of MM.

        "Lenalidomide is believed to be about 1,000 times more potent in vitro than thalidomide in anti-inflammatory properties and pomalidomide about 10 times more potent than lenalidomide. It is worth noticing however that, when comparing lenalidomide and pomalidomide, clinical relevance of higher in vitro potency is unclear since maximum tolerated dose of pomalidomide is 2 mg daily compared to 25 mg for lenalidomide, leading to 10-100 times lower plasma drug concentration of pomalidomide."

        Here's the bottom line on pomalidomide from the FDA site. It's another Celgene drug that can be used with dexamethasone to (maybe) give a few more months after dex/rev has stopped working. Below seems to say it only worked in about 1/3rd of patients with a median extension of 7.4 months. (Another clinical trial data point showing that dexamethasone greatly enhances the effectiveness of this class of thalidomide drugs.)

        "On February 8, 2013, the U. S. Food and Drug Administration granted accelerated approval to pomalidomide (POMALYST capsules, Celgene Corporation) for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy.

        The approval was based on the results of clinical trial CC-4047-MM-002; a multicenter, randomized, open-label study in 221 patients with relapsed and refractory multiple myeloma who had previously received lenalidomide and bortezomib and were refractory to the last myeloma therapy. The treatment arms were pomalidomide alone or pomalidomide plus low-dose dexamethasone. The efficacy results demonstrated an overall response rate of 7% in patients treated with pomalidomide alone, and 29% in those treated with pomalidomide plus low-dose dexamethasone. The median response duration was not evaluable in the pomalidomide alone arm and was 7.4 months in the pomalidomide plus low-dose dexamethasone arm."

Who gets what
        "Thalomid-based therapy: Currently more than 70% of newly diagnosed patients receive a combination that includes Thalomid. Results of clinical trials indicate that combination treatment with Thalomid and dexamethasone produces anticancer responses in approximately two-thirds of patients, which is significantly improved over dexamethasone treatment alone.

        There are a large number of effective chemotherapy drugs now available for initial, standard-dose treatment of patients with multiple myeloma. The main goal of initial therapy of multiple myeloma is to produce a complete or near complete disappearance of myeloma cells in the body. Approximately 30-50% of patients can expect to achieve this goal.

        Alkeran-based therapy (melphalan): Prior to the widespread use of Thalomid the most frequently used regimens were Alkeran and prednisone and Oncovin, Adriamycin and dexamethasone (VAD). Alkeran-based therapy is still the most common treatment for patients who do not plan to undergo autologous stem cell transplant at some point in their disease course."  (outdated info from Texas Oncology)
Lahey Hospital and Medical Center
        My hospital is the headquarters of Lahey Hospital (formerly Lahey clinic) in Burlington MA (suburb of Boston) located about five miles from where I live. My broken neck was operated on in this hospital, and my oncologists works out of this hospital. This hospital is the teaching hospital of Tufts University School of Medicine and many of its staff member bios list them as Assistant professor of medicine at Tufts Medical School, which I have been told is something of a formality and does not mean they are doing any regular teaching in the medical school. Their wb site adds that besides Tufts "many of our physicians hold teaching assignments at Harvard Medical School and Boston University School of Medicine".

        Lahey Hospital & Medical Center, Burlington MA includes a 259-bed hospital (elsewhere it says 317 beds) with all private room accommodations; a 19-room operating suite; seven inpatient units; and medical, surgical, and cardiac intensive care units. Lahey web site says over 500 physicians and over 5,000 nurses and support staff. 24 hour emergency room (Level II Trauma Center). Lahey web site says 3,000 patients a day are treated at the Burlington headquarters. As a research center, Lahey Hospital & Medical Center offers patients access to clinical trials of new therapies for diseases such as cancer, diabetes, heart disease and cataracts. Research programs at Lahey Hospital & Medical Center encompass more than 200 clinical trial protocols and participation in numerous national and international studies.

        An article in the Boston Globe (2013) says acquistions have reduce the number of independent hospitals in the state to just 12 with only 2 remaining in the region north of Boston (Anna Jaques Hospital and Lawrence General Hospital). Competing with Lahey in the acquiring of hospitals is North Shore Medical Center, a member of Partners HealthCare, associated with Brigham and Women’s Hospital and Massachusetts General Hospital.

        Lahey is a non-profit (501(3) charity) whose IRS filing shows revenue over 700 million, assets over 400 million, and over 4,000 full time employees. They have been buying up local hospitals. Besides a Lahey satellite location in Peabody, they own, or are 'affiliated' with,' Winchester hospital, Beverly Hospital, BayRidge hospital (Lynn) and Addison Gilbert hospital (Gloucester). Latest online annual report is for 2011 (!) shows 20,000 admissions, 21,000 surgeries (about 60/day) and 7 million in contributions. In 2011 there were 463 medical center physicians plus 143 interns and residents supported by 1,100 nurses. The rest of the 5,000 staff are health and administrative staff. 8,000 inpatient surgeries, 52,000 emeergency room visits. Operating revenue about 1,000 million dollars with 400 million in assets. Salary and benefits about 600 million and 'profit' (excess of revenue over expenses) 60 million (6%).
Details of my neck C1,C2 fusion operation
        This information comes from my surgeon's Medicare billing records (09/18/2014, 10k total). It shows during the operation some bone was removed and used for a graft. My surgeon has never described to me the operation to me in any detail, so I don't know (for sure) what this graft was for. My understanding is that neck hardware will fatique in time, so that it's main job is to stabilize the bones to allow them to fuse. Hence my guess is that the graft was probably tiny pieces of bone inserted between C1 and C2 to encourage them to fuse.

        Something else I don't understand is how the screws into C1 and C2, which are into the (thick) sides,  holds in place the C2 (dens) projection, which is in the center and which my surgeon told me is what broke. (Is the C2 dens, which as I understand it normally touches and slides along the C1 front arch, perhaps glued to C1 to hold it in place?)

                Fusion Of Spine Bones At Skull Base, Posterior Approach (3.9k)                                                            (rear entry, fusion high in neck)
                Partial Removal Of Spine Bone And Growth At Upper Spinal Column (2.1k)            (probably the notch (biopsy) of C4 lesion for MM diagnosis)
                Insertion Of Posterior Spinal Instrumentation At Base Of Neck For Stabilization, 1 Interspac (2.4k)        ('1 Interspac' I think means one fusion)
                Harvest Of Bone From Same Spine Incision For Graft (1.0k)                                                                     (?? ask surgeon about this)
               Donor Bone Graft For Spine Surgery (0.6k)                                                                 (surgeon later told me bone for fusion came from a cadaver)

       The hospital's billing Medicare record for the week of my neck operation also has some interesting details (50k total):
                 MRIs ---  brain (3.2k), spine (5.4k, 2.9k)
                CT --- body scan (2.6k)
                 Blood administration (transfusion) --- (1.7k)   (I was not aware I had a blood transfusion)
                 Room and board (7 days, private room) --- (5.3k)

         Billing for monthly visits with my oncologist or follow up visits to surgeon
                 15 min ---  Medicare approves $53
                25 min ---  Medicare approves $81

Youtube C1-C2 fusion video
        Below is a very nice 5 min video with excellent animation showing how the hardware is inserted in a posterior C1-C2 fusion operation. The trick (not clear in my x-rays above) is that the head of each screw has an inside thread and a slot. Rods are dropped into the C1 and C2 slots, then nuts with outside threads are screwed in and tightened. In other words the rods are clamped to the screw heads with sort of an  inside-out nut and bolt configuration.

Scn captures from the C1-C2 fusion video (below) showing
(left) bars flying in
(right) nuts flying in


Sketches of posterior C1,C2 fusion operation
        -- The two vertebrae are fixed into position by direct screwing of the joints, the so-called transarticular fixation or fixation with screws into the pedicles and Massae laterles that are connected to a rod. Ultimately, in addition a fusion of bone is always required, which is placed between the two vertebrae and secured with wire. Thereby stability is ensured in the long run, even if the screws loosen or break; because the bone grows in.


x-rays of my operation show side clamps, lateral mass screw and pedicle screw shown here
(source --

Details of C1,C2 fusion operation, which looks like my procedure, from International Spine Center, Berlin:
Lahey online patient 'portal'
        After doing a lot of reading and speaking with some people at Lahey about the portal, I have some new perspectives. Three aspects of the portal data, which I think are piss poor, can all be 'explained' by a concern to minimize feedback (i.e. questions) from patients to doctors. This would include

                        a) Blood data is provided in patient unfriendly format (full of abbreviations like RBC, WBC, which are not explained)
                        b) Out of range values are not high lighted
                       c) 'Sensitive' data is (or may be) excluded

        It's possible the patient history is missing for the same reason. The patient history must exist inside the hospital database somewhere. The question is does it remain in the legacy system that keeps running, or has it been migrated to Epic and simply not been made visible to patients?

(update 3/4/15)
        My portal blood data has this introductory note: "This document contains information that was shared with Donald Fulton. It may not contain the entire record from Lahey Health." The first part of this statement is, of course, total crap. It will be a few days before I meet with my doctor to review the latest blood data now on the portal, blood collected 5/1/15. Also my 'Current medications' are all screwed up. The starting date is wrong on three of the four entries. And my main cancer drug, revlimid, is incorrectly listed twice, once under its brand name (revlimid) and once under its technical name (lenalidomide) with different starting dates. Jesus , what a mess!

        I suspect the portal ranks near the bottom of concern in all the changes associated with the big change over to the new record and billing system. I read all the top executives at a ME hospital got fired a few months after taking the Epic system live because billings were not entered properly by staff and fell off 50 million. Also I read a lot of patients have little interest in the portal.
        In April 2015 Lahey Hospital is making a lot of noise about its introduction of a patient online 'portal', called MyLaheyChart. According to the hospital patients can log on and get access to their records and lab results, contact their doctor, make appointments and a lot more. The introduction of the portal is apparently tied in with a big change in the record keeping at the hospital. My doctor recently told me the hospital was changing its computer record keeping, and a MyLaheyChart booklet says Lahey is "transitioning to Epic, a new electronic health record to improve and streamline your care." A Boston Globe article a couple of year ago said Lahey was planning to introduce a new 162 million dollar electronic record system. (What?)

        Epic is evidentily a big name in electronic records. Partner Healthcare (Mass General, etc) in 2013 announced they were going to go to Epic, but were years away from going live. A story about Epic and a ME hospital shows that a big change is the doctors and nurse need to enter into the computer everything they do, because that is how the charges are figured. In an Epic installation in UK five years of patient history were transferred to the Epic system.

        Quote from NYT article that electronic records system do no share with those made by other companies: "Epic and its enigmatic founder, Judith R. Faulkner, are being denounced by those who say its empire has been built with towering walls, delberately built not to share patient information with competing systems." "A research report from the RAND Corporation described Epic as a “closed” platform that made it “challenging and costly for hospitals” to interconnect with the clinical or billing software of other companies. Shortly after, Representative Phil Gingrey, a Georgia Republican and a doctor, assailed the company in public hearings in Washington for the same shortfalls."

        "A sort of Microsoft of the Midwest, built on a sprawling campus on nearly 1,000 acres of farmland near Madison, Wis., the privately held Epic has emerged as a leader in the race to digitize patient medical records. Its systems hold the health records of nearly half the country." There is a Wiki page for Epic. It says the company employs 8,000 people! Epic also provides electronic record systems for Cedars-Sinai Medical Center in Los Angeles, the Cleveland Clinic, Johns Hopkins Hospital, and The Mount Sinai Hospital.[4] [13] Epic software system (EHR) is a “de facto standard among the more complex academic health centers and multispecialty medical groups,” says Dr. John D. Halamka, chief information officer of Beth Israel Deaconess Medical Center in Boston and a professor at the Harvard Medical School. Only approved healthcare providers involved in your care can view your record. (So my doctor should be able to access my portal.)

Medical history
        As the info for doctors below shows, the Epic system has to contain the patients medical history to be useful to doctors. So where is it? Look at this: "With MyChart, you can securely access the Internet to view portions of your medical record." (from Yale hospital that uses Epic)

        How does the Epic EMR help manage patient care for my hospitalized patients? Ans: From the hospital, their private office or another location, physicians have easy online access to one centralized electronic chart with all of the patient’s information, including medical history, medications, allergies, laboratory and radiology results and more.

        Of course I signed up right away. One feature I like, and is a real step forward, is a simple way to communicate with your doctor (with a promised answer in two days). I have used this twice and it has worked well. What is not working well is the medical side: lab results, medical records, etc.

        Perhaps a minor quibble, because it is a one time thing, but to sign up required a trip to the hospital! To sign up you needed a (new) ID number, and the only way to get the required ID number was in person. I don't understand the reason for this nonsense, this mickey mouse. It didn't bother me personally because I am at the hospital all the time. My lab data is simple, it's just my blood numbers, should be totally standard, almost all patients have blood work done at some point or other. Here's what I found:

 1) Database problems --- Most important blood number to me as a blood cancer patient ('Monoclonal Peak Quant') is MISSING. I know the missing data is in the hospital computer system because a few days before I accessed the Epic portal during a visit to my doctor she handed me a printout of my latest blood numbers, and it's there. I compared all the blood numbers between the sheets my doctor gave me and the blood data I downloaded. The numbers are all the same, except the number showing the amount of cancer in my blood, the number my doctor focuses on at the end of every cycle, is missing from the portal data. Terrific. The entry for 'Monoclonal Peak Quant' under 'Protein Electrophoresis' is there in the blood format, but it's blank.
a) So is there an email or a contact to report problems with your data? There is not, which I find revealing. I reported the problems to my doctor asked her to feed it back. I said take a look at my records, but apparently she is unable to access my account. This is another screw up and will work to prevent problems from being identified and fixed.
 2) Sloppy programming --- Out of range blood values not marked. In the last six months I have gotten my blood data in several formats from the hospital and out of range values have always been marked with a 'H' or 'L', but not in the Epic blood format.

3) History missing --- The implied message to patients about the portal is that you use it to review your medical records and status, but the reality is much less impressive. There has apparently been no attempt (at least to date) to digitize even relatively recent hospital records (say for the last six months or year).  My health status: blank. My operation at the hospital a few months ago and dozens of follow up visits: missing. Epic or Lahey never say this, but it looks like the only data that will be online begins in April 2015 when the portal became available and hospital began transitioning to the new record keeping system. I like how this issue is never mentioned, essentially swept under the rug, who needs to look at their medical history.  My portal history has no mention that I have cancer. Essentially all that's there is my latest blood numbers, and as I detailed above, even that is screwed up with the key cancer value: blank

Health Summary:              "You have no health issues on file"
Current Health Issues:       "You have no health issues on file"
Medical History:               "You have no medical history on file"
Surgical History:               "You have no surgical history on file"
4) Crappy format --- I know the blood format well. Having a blood cancer I am very familiar with the various blood formats Lahey used until recently, which were quite compact printing out on 2 or 3 pages, which I keep in a notebook. When my blood data comes up in MyLaheyChart the screen fills with a SEPARATE link for each blood panel. What? Just to see your blood data takes 10 clicks, and worse under this are often more links like a 'detail' button, which of course is blank. This is something like 10-20 clicks to see what should take one click. Idiotic!

         Digging around on the portal (there are a lot of links) I found hiding, and it really is hidden, my blood data in a compact format. And what's the name of this link? If you can believe it, it is called: 'Lucy' record. If you click 'Lucy' you don't find it! No, you need to click 'Download my record' and then 'Preview your Lucy record'. If this isn't riduculous I don't know what is. How is the patient supposed to know that's where to look to find his compact blood data?  I even keep losing it. Freaking ridiculous. Maybe your doctor will tell you? Not mine, at my only meeting with my doctor since the portal opened I got zero info on using it. Nor should I, there are more important things to discuss in the limited time available with your doctor than getting a tutorial on the portal.

About the Lahey MM clinical trial I was offered
        At the time I had to chose I didn't know much about MM chemo regimens, so I didn't have any real perspective on this trial. And my memory is my doctors didn't provide any real perspective either, basically I was just handed the trial paperwork (several pages) to read. What this trial is testing is an upgrade to the (popular) RVD regimen (revlimid, dexamethasone, velcade regimen). A big practical problem with this regimen is that velcade is injected, so it requires a trip to the hospital every 3-4 days! Also velcade classically caused damage to nerves in fingers, which has been apparently reduced recently by injecting the drug under the skin.

        Millennium, who makes velcade, has developed a pill version of it (ixazomib or MLN9708) that they describe as "first oral proteasome inhibitor". This is one of several trials they are running to asses its effectiveness. In early 2015 (without giving any numbers) a press release from the company said that adding the new experimental drug to dex/rev significantly improved the time to disease worsening for refractory MM patients (vs rev/dex plus plecbo).
        I had first written the clinical trial I was offered was being sponsored by Celgene (makes of revlimid). Wrong! It's sponsored by Millennium Pharmaceuticals of Cambridge MA (now owned by Takeda of Japan), who make injectable botzezomib (velcade), have developed its pill equivalent. The pill is called MLN9708 in the trial documents, but a little digging shows its trade name is 'ixazomib'. It is taken once a week for 3 weeks of the usual 4 week cycle. The trial I was offered is for newly diagnosed MM patients and will go on for seven years! From below it appears the Lehay trial is what Millennium calls the TOURMALINE-MM2 trial. (I've been told in May 15 that Lahey has dropped the trial I was offered, maybe they couldn't get anyone to sign up!) Here is the linkto the trial on ClinicalTrials,gov. Millennium in other trials is testing the drug not only as chemo for newly diagnosed MM, but for relaped MM and as mainenance therapy after a stem cell transplant. These are phase 3 trials with a goal of enrolling about 700 patients, about 5 of which will come from Lahey hospital. The contact for the study at Lahey is Dr. Tarun Kewalramani, one of the 14 staff of the dept of  Hematology and Oncology.

Trial end date
       Trying to figure out when these trials end is a challenge. The paperwork I was given on this trial says it runs seven years. The gov site shows the study start date:  May 2013, and Estimated Study Completion Date: February 2021, or 8 years. There is also something called the Estimated Primary Completion Date: June 2018. Millennium on their site says: The study is estimated to be completed in May 2019. So there you have it, the study runs 7 or 8 years and it wraps up in either 2018, 2019, or 2021. Take your pick! Follow up in one spot is shown as 2.5 years, in another as 5 years. These trials take forever... And the dose of revlimid and dexamethasone is unchanged for the whole study!

About Ixazomib (Ninlaro) --- pill version of Velcade
        "Ixazomib (MLN9708) is an investigational oral proteasome inhibitor, which is being studied in multiple myeloma (MM), systemic light-chain (AL) amyloidosis and other malignancies. Ixazomib was granted orphan drug designation in MM in both the U.S. and Europe in 2011, and for AL amyloidosis in both the U.S. and Europe in 2012. Ixazomib received Breakthrough Therapy status by the U.S. Food and Drug Administration (FDA) for relapsed and/or refractory AL amyloidosis in 2014. It is also the first oral proteasome inhibitor to enter Phase 3 clinical trials. Four global Phase 3 trials are ongoing:

** TOURMALINE-MM1, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory MM;
TOURMALINE-MM2, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM;
TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant."

Checking the Millennium web site I find some preliminary information from the MM1 trial (for relapsed MM) is available now:
"Cambridge, Mass. and Osaka, Japan, February 10, 2015
        ** Takeda Pharmaceutical Company Limited (TSE:4502) today announced that the randomized, double-blind, placebo-controlled TOURMALINE-MM1 pivotal Phase 3 trial evaluating the safety and efficacy of ixazomib, the first oral proteasome inhibitor, conducted in patients with relapsed or refractory multiple myeloma (MM) achieved its primary endpoint of improving progression-free survival at the first pre-specified interim analysis. In the trial, patients treated with investigational ixazomib plus lenalidomide and dexamethasone lived without their disease worsening for a significantly longer time compared to patients who received placebo plus lenalidomide/dexamethasone."

FDA approval
        Nov 20, 15 Takeda press announcment says FDA has just approved its first oral oral proteasome inhibitor, now called Ninlaro, based on early results of the TOURMALINE-MM1 phase 3 trials. This trial is continuing as are three other TOURMALINE trials for the drug. The early results of the TOURMALINE-MM1 trial are to be reported on at the American Society of Hematology on December 7, 2015

        A NIH check of clincial trials  (4/15) shows about 20 clincal trials being run at Lahey, but curiously does not show this one. Only one MM clinical trial is on the list being run by Sloan with Lahey as a partner. But the listed trial, while it does use revlimid and dexamethasone, will be only 62 patients and is very different, it is (on a quick read) randomizing a stem cell transplant vs maitence. (Clinical trials are linked via Lahey Wikipedia page.)

        Update on Ninlaro here.

Time to progression
        Months to 'time to progresssion' is a common end point in MM literature. But what does this mean? I finally found a definition in a MM clinical trial (national cancer institute):

        Time to progression (TTP) was defined as the date of transplant to date of progression or death due to any cause, whichever occurs first. TTP was estimated using the Kaplan Meier method. Progression was defined per the 'International Myeloma Working Group' definition as one more of the following:

   ** 25% increase in serum M-component (absolute increase >= 0.5g/dL)
        25% increase in urine M-component (absolute increase >= 200mg/24hour
        25% increase in the difference between involved and uninvolved Free Light Chain levels (absolute increase >= 10 mg/dL)
        25% increase in bone marrow plasma cell percentage (absolute increase of >=10%)
        Definite development of new bone lesion or soft tissue plasmacytomas
        Development of hypercalcemia

Defintion of Time to Progression
        What does the first one mean? A 25% increase from what baseline? No, my minimum is low enough that the absolute increase applies. My minimum monoclonal M spike (after 8th cycle) reached less than the threshold of the M-spike test (done at Lahey), very close to zero (<0.05 g/dL). So in my case Time to Progression (TTP) M-spike threshold is 0.5 g/dL absolute (round numbers). This is a pretty low threshold, about 10% of my pre-chemo original baseline of 5.31 g/dL.

Below is the definition for TTP from the Interntional Myeloma Working Group:

Increase of > 25% from lowest response value in any one or more of the following:
   ** Serum M-component and/or (the absolute increase must be > 0.5 g/dL)
        Urine M-component and/or (the absolute increase must be > 200 mg/24 h)
        Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels.
                The absolute increase must be > 10 mg/dL. (I have a lambda cancer so this would be lambda - kappa FLC must be > 10 mg/dL)
        Bone marrow plasma cell percentage; the absolute percentage must be > 10%
        Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or
               soft tissue plasmacytomas
        Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL) that can be attributed solely to the plasma cell
              proliferative disorder. (This is only about 10% above the normal range: 8.4 to 10.4 mg/dL)
MM clinical trials
        One benefit of reviewing MM clincal trial using the chemo I am taking is to see what the thinking (guessing) is about drug combinations, dosage and cycles. I found a list of MM clinical trials on the Memorial Sloan Kettering Cancer center (NYC) home page and the Dana Farber Cancer Institute (Boston) home page. The Sloan Kettering list is much more searchable than Dana Farber list.
                                                                                27 MM trials             41 MM trials

Do stem cell transpants still have merit?
        There are several trials ongoing evaluating whether a stem cell transplant still has merit vs a modern chemo regimen for newly diagnosed MM patients. Phase 2 trials (50-60 patients) have been encouraging that drugs alone are effective, but phase 3 trials with x10 more patients are needed. Phase 3 trials are the gold standard by which over time progress in chemo is made. I found two MM phase 3 trials ongoing, but unfortunately both of them won't end for a few years (2018/20).

        This is particularly interesting to me, because I am (in effect) in the control group with no stem cell transplant. The general procedure is treat patients with chemo, then randomly half are assigned to have a stem cell transplant, and both go on maintenance. The maintenance is sometimes different for the two groups. (Obviously these are not double blind trials!)

        Phase 3 trial --- Lenalidomide (revlimid), Bortezomib (velcade), and Dexamethasone (RVD). Maintenance is revlimid 10-15 mg daily for one year. This is for newly diagnosed MM patients under age 65. Ends Sept 2018, 660 participants. Revlimid is provided at no charge.

         Phase 3 trial --- Study Comparing Conventional Dose Combination RVD to High-Dose Treatment With ASCT in the Initial Myeloma up to 65 Years. Ends 2018, 700 participants.. Maintenance phase (12 months): Cycle length: 28 days Dosage: Lenalidomide: 10 mg/day continuously for 28 days during 3 months and if the participant tolerates 10 mg/day without complication, a dose increase to 15 mg/day will be allowed. (Reviewing this I wondered if it might be the same trial as above, but it's not. They have different principle investigators, and the above trial is run out of the US, while this trial is being run out of France.)

        Phase 2 trial --- Lenalidomide and low-dose dexamethasone (LD) (four cycles).  Maintenance is LD (rev/dex) for non-transplant patients and L (revlimid) for transplant patients. Standard risk patients up to age 75 qualify. Ends Dec 2015, 62 participants. Lahey clinic is a collaborator in this trial.

        Phase 2 trial --- [Bortezomib + dexamethasone] vs [Bortezomib, dexamethasone, and lenalidomide]     Bortezomib, dexamethasone, and lenalidomide are often given together to treat newly diagnosed multiple myeloma (a cancer of the bone marrow). However, this combination of three drugs is associated with significant side effects. Trial is to see if same result can be obtain with two drugs [Bortezomib + dexamethasone] for fewer side effects. Lenalidomide would be included for non-responders.

For relapsed MM

        Phase 2 trial --- [Pomalidomide plus 2nd Autologous Stem Cell transplant]  vs [Pomalidomide/Dexamethasone]  End De 2016, 44 participants.

             My sodium is just a hair under normal at 133 mmol/L or 133 x 0.023g/L = 3.06 g/L. The humam male has about 5L of blood, so stores about 15 grams of sodium. Salt consumption is about 3.5 g/day of which 40% is sodium, so 1.5 g/day of sodium consumed (in salt). This means the blood electrolyte stores of sodium represent about 15g/(1.5g/day) = 10 days worth of salt consumption. (mmol is a mille-mole, atomic weight of sodium is 23, hence 1 mmol of sodium is 0.023 gram)
Protein Electrophoresis test
        Proteins in the serum (fluid) component of blood are spread out by atomic weight by a blood test called 'protein electrophoresis'. The proteins driven by an electric field (they are charged) diffuse along special paper. Smaller molecules diffuse faster than larger molecules so after a few hours (?) the proteins are spread out by size/weight. Multiple myeloma patients have a (huge) excess of a protein of  one particular atomic weight which is being turned out by the marrow plasma cells that have gone cancerous. This produces a band in the paper (see IgG band below). The density of this band is an measure of the cancerous plasma cells in the marrow. (I don't know how the density of this band is measured. It is given to three decimal places in my blood work. And clinically it is important that it be measured with high resolution and repeatability because the objective of chemo is a CR (complete response) which means reducing its value by a factor of 20 or more.)

Multiple myeloma monoclomal peak band in protein electrophoresis test

        MM serum monoclonal proteins can be one of several types. 1,000 multiple myeloma patients at Mayo clinic had this breakdown:

                                                IgG kappa                 35%
                                           ** IgG lambda                18%      (I have IgG lambda monoclonal peak)
                                                IgA kappa                  13%
                                                IgA lambda                  8%

        Prior to chemo my initial 'Lambda free light chain blood' density was super high at 379 mg/dl about x150 normal (0.57 to 2.63 range)!  Just two cycles of rev/dex chemo reduced this value to 2.74, just slightly above normal, and brought the kappa/lambda ratio into the normal range. After four chemo cycles 'Lambda free light chain blood' at 1.50 was well within the normal range.

        The 'G' and 'A' above refer to types of Immunoglobulin (there is also M, E and D). 'G' is the most common antibody as it protects against bacteria and viral infections.

Wikipedia --- Immunoglobulin light chain
        The immunoglobulin light chain is the small polypeptide subunit of an antibody (immunoglobulin). A typical antibody is composed of two immunoglobulin (Ig) heavy chains and two Ig light chains, which in a given antibody will be the same. There are two types of light chain in humans:

            * kappa chain, encoded by the immunoglobulin kappa locus (IGK@) on chromosome 2
           * lambda chain, encoded by the immunoglobulin lambda locus (IGL@) on chromosome 22

        The approximate length of a light chain protein is from 211 to 217 amino acids. The normal kappa to lambda ratio is 0.66 (0.26 to 1.65) when measuring free light chains, and a highly divergent ratio indicates cancer. My initial pre-chemo ratio was < 0.01, because my lambda free light chain was a sky high 379 (normal range .57 to 2.63).

Nice description of M-spike
        Very readable, clear description of M-spike and the underlying (monoclonal) marrow cells that create it from 'Pathology Student' site ( written by a doctor. Can you explain to me what the M protein in multiple myeloma is?

In the bone marrow aspirate above, you can see tons of malignant plasma cells.
A few look a lot like plasma cells, with clock-face chromatin and a hof and everything, but others look for all the world like blasts.
(source --

A. Multiple myeloma is a malignant, clonal disorder of plasma cells that originates in the bone marrow. It’s a relatively common disorder, accounting for 1% of all malignancies and 10% of all hematologic malignancies in adults. Patients present with painful, lytic lesions of the bones, recurrent and persistent infections, weakness, renal failure, and hypercalcemia. The prognosis is generally not great, but new chemotherapeutic agents seem to hold some promise.

       * Patients with myeloma have a monoclonal proliferation of plasma cells in the bone marrow, meaning that there are a ton of malignant plasma cells that all originated from the same initial cell. In the bone marrow aspirate above, you can see tons of malignant plasma cells. A few look a lot like plasma cells, with clock-face chromatin and a hof and everything, but others look for all the world like blasts. That’s one thing to remember about myeloma – malignant plasma cells don’t always resemble their nice little benign counterparts.

       * The malignant plasma cells almost always secrete immunoglobulin, and because they are monoclonal, they all secrete exactly the same form of immunoglobulin. This is very different than what you see in a patient without myeloma, where there are a bazillion different types of plasma cells, all making different types of immunoglobulin molecules. This huge mass of all-the-same immunoglobulin secreted by myeloma cells is called a “monoclonal gammopathy;” the normal immunoglobulins are called “polyclonal.”

       * Monoclonal gammopathy is so characteristic of myeloma that you can use it for both diagnosis of disease and follow-up of patients. You can detect the monoclonal immunoglobulin using serum electrophoresis (which separates the blood proteins into groups based on charge and size). There’s a predictable pattern of proteins in normal serum: albumin (the most abundant protein in the blood) migrates to a certain predictable point; other proteins migrate to different places (which are given different names – the alpha 1 region, the alpha 2 region and the beta region). Immunoglobulins migrate to a unique place called the gamma region, and because they are all different (in normal patients), they migrate to slightly different places within that region, giving a gentle bell-shaped curve or smear (depending on whether you’re looking at a tracing or the actual bands on the gel).

        * In myeloma, the immunoglobulin is monoclonal, so it all migrates to exactly the same spot on the gel! Which gives you a big spike (if you’re looking at a tracing) or a very distinct, crisp, strong band (if you’re looking at the gel itself). This spike is called an M-spike (you could remember M for either monoclonal or myeloma), and the corresponding monoclonal protein that it represents is called an M protein.

A few other things to note about this M protein:

1. You need to do electrophoresis on urine too, not just serum. Some cases of myeloma secrete only light chains (these are called Bence-Jones proteins), which are so small that they are passed in the urine (so if you only looked at the blood, you’d miss them).

2. While patients with myeloma have an increase in the total amount of immunoglobulin present in the blood (due to the large monoclonal immunoglobulin spike), they also have a decreased amount of normal, polyclonal immunoglobulins. So when you look at an electrophoresis, you’ll see this huge spike in the gamma region, but also a noticeable depression in the amount of the background normal immunoglobulins.

3. A little trivia regarding the kinds of immunoglobulin expressed by myeloma cells. The most common heavy chain expressed in myeloma is IgG (60%); next is IgA (20%). Rare cases express IgD or IgE, and IgM myeloma is virtually nonexistent (most cases of plasma cell lesions that express IgM turn out to be Waldenström macroglobulinemia). Almost one-fifth of all cases of myeloma secrete only light chains. And somewhere between 1 and 5% of all cases of myeloma secrete no detectable immunoglobulin at all! Which, without the familiar M-spike, would make for a pretty difficult diagnosis.

Cytogenetics and deletion 13
        The cytogenetics literature is a jungle of complexity. Everyone seems to have their own idea of how to pair up the DNA abnormalities with risk and prognosis. There is general agreement some variations are 'bad' [hypodiploid group with t(4;14)(p16;q32) or t(14;16)(q32;q23)] and a few are 'good' [hyperdiploid], but there is controversy about deletion 13. The first table on MM cytogenetic variations I discovered is here:

List of DNA abnormalities that affect severity of multiple myeloma
I have the hyperdiploidy variation (and deletion 13)
(Notice the 'poor' outcome for deletion 13 is when measured not with Fish, but with the less sensitive conventional test.)
['t' is a translocation, so t(4;14) means chromosome 4 is incorrectly connected to chromosome 14]

My cytogenetics test results
        Here is the key section of the multi-page written report from Mayo clinic of the cytogenetics test done on my extracted bone marrow cells prior to chemo (which I finally pried out of my doctor). It took me a while to understand that what is being looked at here is the (corrupted) genetics of my extracted myeloma marrow cells. My good hyperdiploidy variation is indicated by the extra one or two copies (above standard diploidy) that I have on chromosomes 3, 9, 11, and 15. My not so good deletion 13 (Fish) is shown as only one copy (monosomy) of chromosome 13.

cytogentics report from Mayo Clinic on my extracted bone marrow
(Wikipedia says 50% of MM patients have abnormalities in chromosone 14 and 50% have a partial deletion of chromosone 13.
I have the latter, but apparently not the former.)

        The 'appear' in the comment on deletion 13 ["Monosomy 13 does not appear to affect this favorable (hyperdiploidy) prognosis in multiple myeloma."] reflects the clinical uncertainty of whether or not deletion 13 as measured by the sensitive Fish test (as here) is unfavorable or should be disregarded. The comment "plasma cell clone" is, of course, medical jargon for the patient has multiple myeloma. The Mayo Clinic MM treatment guidelines have this to say about deletion 13: "Deletion 13 has long been considered an adverse prognostic marker. When detected on conventional cytogenetic studies, it does, indeed, portend a poorer prognosis, but if seen on FISH, in the absence of hypodiploidy, it doesnot retain its significance."

        Some propose three risk levels with deletion 13 forming an intermediate risk group, others put deletion 13 into the bad category, others think it is not really important as it is secondary term generally associated with hypodiploid. Also a lot of the references I find on cytogentics are quite old (2003 to 2008). Here is data supporting three risk levels with deletion 13 being an intermediate risk.

data supporting deletion 13 as an intermediate risk
(Fonseca et al have demonstrated that 3 distinct staging groups can be defined by the presence or absence of
t(4;14)(p16.3;q32), t(14;16)(q32;q23), deletion 17p13,and deletion 13q by FISH)
(source -- book 'Myeloma Therapy, Pursuing the plasma cell, edited by Sagar Lonial, 2008)

        A big complication with deletion 13 is how it is measured. The older test was insensitive, so if it picked up deletion 13 it was a bad sign. The newer Fish test is much more sensitive, so picking up deletion 13 in this test many think doesn't mean too much. Some studies showed patients with deletion 13 as measured by Fish responded to treatment as well as those without deletion 13. [The jargon is intense -- "In summary, the detection of deletion 13 in interphase cells is not as predictive as its observation in metaphase. One reason for the difference in prognostic value is that deletion 13 seen in CC (older test) is an indicator of the presence of abnormal metaphases and infers a more proliferative clone and higher tumor burden. Its role as a prognostic factor, therefore, could be indirect.] Oh, yea...

        All this is important to me because I have deletion 13 along with the 'good' hyperdiploid variation. My hematological oncologist focused on the hyperdiploid variation, saying clinical results indicate that 'good' hyperdiploid variation overrides the 'bad' deletion 13. What I have been trying to determine is to what extent my 'good' cytogenetics are compromised by also having deletion 13. First question is how was my deletion 13 measured? All I got from my doctor on cytogenetics was an oral summary, 'you have hyperdiploid variation and deletion 13'.

        In May 2015 meeting I brought up the deletion 13 issue with my doctor, saying I had no info on this except an oral statement that I had delection 13. In response she printed out the Mayo clinic report on my cytogenetics tests. While 6 pages long it has relatively little information, but a few pieces of info in it are interesting.

        Deletion 13 was determined by the Fish test. The Mayo clinic comment about my deletion 13 says simply: "At diagnosis hyperdiploidy is associated with a favorable prognosis in multiple myeloma. Monosomy 13 (deletion 13) does not appear to affect this favorable prognosis."

        No where else in the six pages does it (clearly) state I have hyperdiploidy (see next). It also says I have (secondary) DNA abnormalities: trisomy 3, 11, 15 and tetrasomy 9. Wikipedia says, "Trisomy 9 is a chromosomal disorder caused by having three copies (trisomy) of chromosome number 9", but I doubt that I have multiple copies of a whole genome, probably just a short stretch correlated with myltiple myeloma. [Jargon --- normally there are two copies of a DNA segment (from ma and dad), so its diploid. Monosomy means only one chromosome of the normal pair is present, so this is a deletion. Trisome means three chromosomes and tetrasomy means four, so these are both additions.] Wikipedia say the deletion or an addition of a whole chromosone (46 = 2 x 23 in humans) generally causes a fetus to be aborted. Down syndrome is a trisomy with three whole copies of chromosone 21.

Hyperdiploid explanation
        -- Karyotypes from multiple myeloma (MM) patients are complex but may be categorized either as hyperdiploid, displaying gain of odd chromosomes and some structural changes, or as hypodiploid or pseudodiploid, displaying loss of even chromosomes and frequent structural changes, including IgH rearrangements (1, 2).
        This is useful. My detail cyctogenetics results show probes for 15 DNA variations, and of these 10 were normal. The five that were abnormal: +3, +9 +11, +15, -13.  OK, I am hyperdiploidy because I have gains of four odd chromosones (+3, +9 +11, +15) plus the deletion of an odd chromosone (-13).
-- Chromosomal hyperdiploidy is the defining genetic signature in 40-50% of myeloma (MM) patients. We characterize hyperdiploid-MM (H-MM) in terms of its clinical and prognostic features in a cohort of 220 H-MM patients entered into clinical trials. Hyperdiploid-myeloma is associated with male sex, kappa immunoglobulin subtype, symptomatic bone disease and better survival compared to nonhyperdiploid-MM (median overall survival 48 vs 35 months, log-rank P = 0.023), despite similar response to treatment.
        Among 108 H-MM cases with FISH studies for common genetic abnormalities, survival is negatively affected by the existence of immunoglobulin heavy chain (IgH) translocations, especially those involving unknown partners, while the presence of chromosome 13 deletion by FISH did not significantly affect survival (median overall survival 50 vs 47 months, log-rank P = 0.47). Hyperdiploid-myeloma is therefore a unique genetic subtype of MM associated with improved outcome with distinct clinical features. The existence of IgH translocations but not chromosome 13 deletion by FISH negatively impacts survival and may allow further risk stratification of this population of MM patients. (2006 paper showing a slightly lower survival time with deletion 13, but for only 100 patients).
Variability of patient response to chemo
        These curves from a 2013 Italian MM clinical trial with 400 patients (comparing revlimid maintenance vs no maintenance) are broken out by category. The gentle downward slope (as opposed to a more rectangular shape) in nearly every category clearly shows that individual patient response to chemo has a very wide variability. Only the CR response (top center) shows a partially rectangular response. While the categories clearly matter, as far as I know the individual responses within them is entirely unexplained. It could be just random or due to so many small effects that it might as well be random. [Maintenance in this trial was 10 mg revlimid 'cycled' (21 days of 28), and maintenance started about ten months after high does chemo.]

Only the CR response (top center) shows a partially rectangular response.
Two curves right are without/with three known 'bad' cytogenetic variations
Revlimid maintenance in this trial was 10 mg cycled (21 days out of 28)
Ten months of high dose chemo preceeded maintenance.
(data from a 2013 Italian MM clinical trial with 400 patients)

As I wrote in an email
       Ok I have achieved CR (complete response), but the 64 dollar question now is how long before my cancer comes back? The answer is that the data in papers shows the time in an individual case is wildly variable. It could be 6 months, or 1,2,3,4 years, who knows. Good genetics, achieving complete response, right choice of maintenance chemo all improve the time on AVERAGE, but it's in an individual case it is a statistical game. Once you have done all you can, you just have to take it a day at a time.

Spectrum of MM patients
        Some useful perspective of my numbers is provided by Mayo clinic who have published data on about 1,000 of their MM patients when diagnosed. Most relevant is about 1/4th of all MM patients present with a broken bone (pathologic fracture) like me, and my staging beta2microglobulin of 6.9 puts me in the highest quarter of MM patients. The normal range for hemoglobin is 13.8 to 17.4. The data below shows 70% or so of MM patients have anemia with  (oxygen carrying) hemoglobin about 30% low. This is similar to me where my (minimum) hemoglobin prior to chemo was 9.9.


Accessing medical articles
        To have a say in what chemo regimen I am on I want to read underlying papers. I find summaries to be totally useless.  One resource worth looking into is the New England Journal of Medicine. This journal has published a lot of stuff on MM, and its homepage, at least for some papers, shows a link to 'free full text'.

        This info below on PubMed from Wikipedia (PubMed') is worth following up on. Many PubMed records contain links to full text articles, some of which are freely available, often in PubMed Central and local mirrors such as UK PubMed Central:

        The National Library of Medicine leases the MEDLINE information to a number of private vendors such as Ovid, Dialog, EBSCO, Knowledge Finder and many other commercial, non-commercial, and academic providers.[26] As of October 2008, more than 500 licenses had been issued, more than 200 of them to providers outside the United States. As licenses to use MEDLINE data are available for free, the NLM in effect provides a free testing ground for a wide range[27] of alternative interfaces and 3rd party additions to PubMed, one of a very few large, professionally curated databases which offers this option.

        Lu[27] identifies a sample of 28 current and free Web-based PubMed versions, requiring no installation or registration, which are grouped into four categories:

    * Ranking search results, for instance: eTBLAST; Hakia; MedlineRanker;[28] MiSearch;[29]
    * Clustering results by topics, authors, journals etc., for instance: Anne O'Tate;[30] ClusterMed;[31]
    * Enhancing semantics and visualization, for instance: EBIMed;[32] MedEvi;[33] (Note: CiteXplore was withdrawn from service on 15 February 2013,[34] replaced by Europe PubMed Central.[35])
    * Improved search interface and retrieval experience, for instance, askMEDLINE[36][37] BabelMeSH;[38] and PubCrawler.[39]
    * GoPubMed is a knowledge-based (Gene Ontology and MeSH) search engine for PubMed. GoPubMed is the semantic search engine for the life sciences.
    * Expertscape provides search and ranking of medical and biomedical expertise by specific diagnosis, technique, or other terminology. Results are based on analysis derived from most recent ten years of PubMed data.[40]
    * Search term forwarders like "OssiPubMed online". O. Groth., which runs searches on multiple external platforms derived from the original boolean search terms.
    * Reference-to-PubMed transcriptors like "OssiPubMed online". O. Groth., which retrieves the PMID from one-letter coded journal abbreviations to get the full-text articles.
    * Link-Out arborizers "OssiPubMed online". O. Groth., which tries to retrieve available PDF's from additional hosts.

        As most of these and other alternatives rely essentially on PubMed/MEDLINE data leased under license from the NLM/PubMed, the term "PubMed derivatives" has been suggested.[27] Without the need to store about 90 GB of original PubMed Datasets, anybody can write PubMed applications using the eutils-application program interface as described in "The E-utilities In-Depth: Parameters, Syntax and More", by Eric Sayers, PhD.[41]

What bones are affected by MM?
        -- "Meloma affects the places where bone marrow is normally active in an adult. This marrow is in the hollow area within the bones of the spine, skull,
pelvis, rib cage, and the areas around the shoulders and hips. The areas usually not affected are the extremities: the hands, feet, and lower arm/leg regions. This is very important, since the function of these critical areas is usually fully retained."
(Ref: Multiple Myeloma Handbook,

        -- "Even if the myeloma cells are at a higher level of 10%–60% of the total bone marrow, the growth rate can be very slow and represent asymptomatic or smoldering multiple myeloma (SMM)" (My number pre-chemo was 70% of marrow cells in my hip extract were myeloma cells.)

Antibody proteins
        The monoclonal M-spike that is tracked to assess the cancer level in the body is specific type of protein made by the cancerous plasma cells. Each plamsa cell can export into the blood thousands of these molecules/sec! While antibodies are considered 'large' proteins, they are tiny in comparison with the dimensions of a plasma cell, which is visible under a light microscope. Like all proteins an antibody is composed of a string of amino acids. An antibody string has a specific Y shape and is composed of two 'heavy' chains and two 'light' chains.

        -- "Each immuno globulin (antibody) is made up of two (identical) heavy chains and two (identical) light chains. There are five types of heavy protein chains: G, A, D, E, and M. There are two types of light protein chains: kappa and lambda. The typing of myeloma, done with a test called immunofixation electrophoresis (IFE), identifies both the heavy and light chains. Most myeloma patients, about 65%, have IgG myeloma with kappa or lambda light chains. The next most common type is IgA myeloma, also with either kappa or lambda light chains. IgD, IgE, and IgM myelomas are quite rare." (I fall into the 65% category with an M-spike of IgG lambda, meaning my monoclonal antibodies have G heavy chains and the lambda light chains.) "IgG myeloma has the usual features of myeloma."

Y shaped antibody protein
(Heavy chains are built up from about 500 amino acids and light chains from 215.)

        An important point, which is obvious from the structure (above), is that an immumoglobinm protein cannot not come from a ribosome (molecular machine) in one go. Almost for sure (though I have not found a reference that says this explicitly) it is made in four pieces (two heavy chains and two light chains), and the four pieces are post assembled into this Y shape. The two heavy chains are supposed to be the same and the two light chains are supposed to be the same, but are they always?

        Note there's a balance issue. Do the number of light chain molecules that are made match the number of heavy chain molecules? The answer is in a normal person they don't. One references says, "In normal circumstances, and for unknown reasons, plasma cells produce an excess of light chains compared to heavy chains" with the result that a small amount of (free) light chains can be measured in normal blood (0.57 - 2.63 mg/dL lambda).

        My own blood work shows clearly that MM (prior to chemo), for reason which I have not seen explained, caused the amount of free light chain in the blood to be extremely high (379 mg/dL), nearly x400 times the normal average, and the kappa to lambda ratio correspondingly very far from normal.

        --  ** Most people with multiple myeloma produce increased amounts of either kappa or lambda free light chains, which can be measured in blood. Consequently, the ratio of kappa to lambda light chains is abnormal in most people and is a sensitive indicator for this disease. This test is used to monitor progression and/or treatment.

More on 'Complete Response'
        I admit to being uncertain as to what constitutes a 'complete response' (CR). Was there more than one definition? Maybe one for blood, but a more stringent criteria used by clinical trials? From my initital reading it appeared that a reduction in M-spike of > 95% was considered a CR, and a reduction of (90% to 95%) was considered a 'very good partial response' (VGPR). My primary hemotological oncologist did not correct me when I referred to my M-spike reduction of 95.5% as a complete response, but a consulting hemotological oncologist implied that was not sufficient.

        The definitive word should probably be that of the 2006 International Myeloma Working Group, which was constituted just for the purpose of standardize MM terms and criteria. The section in the report on categories starts with: "Changes in the M-component level are the principal indicators
used for response evaluation", with the caveat that "M-component is a surrogate marker". So changes in M-spike is the 'principal indicator of chemo response with the caveat that it is a surrogate marker.

        Let me start with their definition of VGPR, one level down from CR:

        VGPR --- "Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum (plasma) M-protein plus urine M-protein level <100 mg per 24 h".
        Note from the definition (above) the VGPR criteria can be met in two ways, either by meeting an absolute criteria [M-protein not detectable on electrophoresis] or by a change criteria [> 90% reduction in serum M-protein combined with an absolute criteria on M-protein in urine]. Now in six months of chemo my doctors have never once tested my urine. I once asked about this and was was told it wasn't necessary, monitoring M-spike in the blood was sufficient, but apparently the international working group felt otherwise. With that caveat my 95.5% reduction (from baseline) in M-spike says I (at least) qualify for VGPR. Now here is the working groups definition of CR:
    CR --- Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and<5% plasma cells in bone marrow.
        This is a triple criteria, all of them absolutes: no soft tissue tumors, and immunofixation test on the serum must be negative and <5% plasma cells in bone marrow (2-3% is normal level). Now my bone marrow was extracted only once and that was at the beginning of chemo for cytogenetics testing. However, the M-protein in the blood is considered a stand in for the cancer in the marrow because within some (unspecified) tolerance it must track it. My pre-chemo analysis of my marrow showed 70% of the cells to be cancerous, so would it not be reasonable that a 95% reduction in the monoclonal antibodies in the blood means the marrow cells generating these monoclonal antibody proteins cells have also dropped by about 95%? This would mean an absolute cancer level in the marrow of 70% x 0.05 = 3.5%, which is less than the 5% criteria and just about normal.

        But what about the 'negative immunofixation on the serum'? At this point I don't know how this relates to M-spike levels. This gets into details of the thresholds of various tests. In table 4 of the report I find below:

        'Measurable disease (except for CR) in the report is defined as a serum M-protein >1 g/dl'.  This is a pretty high level. My M-protein after five rev/dex chemo cycles is at 0.24 g/dl, so it is, what, unmeasurable?

        -- 'Serum FLC (free light chain) assay is a highly sensitive marker of light chains in circulation that are unbound to intact immunoglobulin. The FLC ratio is an excellent indicator of clonality. Thus, normalizing of serum FLC ratio is a stricter indicator of CR'.

        My lambda free light chain pre-chemo was super high at 379 (.57 to 2.63 normal), which made my kappa/lambda free light chain ratio virtually zero (<0.01) (.26 to 1.65 normal). After five cycles of rev/dex chemo my lambda free light chain is 1.84 well centered within the normal range (.57 to 2.63 normal), and my kappa/lambda free light chain ratio is 0.82 also well centered within the normal range (.26 to 1.65 normal). So the report text says 'normalizing of serum FLC ratio is a stricter indicator of CR' and I meet that, but in the tables in the report there is no mention of the free light chain ratio!

'Complete response' discussion
        The Multiple Myeloma Research Foundation gives the following defintion of (chemo) responses:

Complete response (CR) --- A treatment outcome where there are <5% plasma cells in the bone marrow and no evidence of myeloma proteins in the serum or urine as measured by standard laboratory techniques.
Near Complete Response (nCR) --- A treatment outcome when there are <5% plasma cells in the bone marrow but there are detectable myeloma proteins in the serum or urine as measured by standard laboratory techniques.

Near complete response (near CR) --- Response to therapy where M protein is no longer detectable in the blood and/or urine using conventional tests, but is detectable with the more sensitive immunofixation test, and there are less than 5% plasma cells in the bone marrow.

Very good partial response (VGPR) --- Treatment outcome where there is a greater than 90% decrease in M protein; also known as very good partial remission.

Partial response (PR) --- Treatment outcome where there is a greater than 50% decrease in M protein; also referred to as partial remission.

        Notice the definition of 'Complete response'  ["A treatment outcome where there are <5% plasma cells in the bone marrow and no evidence of myeloma proteins in the serum or urine as measured by standard laboratory techniques."] is poor (read crappy). It may be usefully clinically, but to the patient the threshold value of the proteins (presumably monoclonal spike) is hidden. It depends on how sensitive the standard tests are and that is hidden away in some footnote.

Tom Brokaw perspective
        The most famous person in the public eye with multiple myeloma is the retired NBC newsman and evening news anchorTom Brokaw. He's two years older than me and was diagnosed with multiple myeloma just about a year before me when he was age 73. This is a guy who for a non-medical person is embedded deeply in the the medical system. He is on the board of several famous clinics (like Mayo clinic), one of his own daughters is a physician.

        As he tells the story when he got a back ache that wouldn't go away he makes two trips to see famous back guys at these top institutions. All these super specialists did is take an x-ray of this back and tell him to slow down. Pain persists, only on a later 3rd visit (yikes!) does someone actually take some blood, about the most benign of 'invasive' procedures, and they discover he has multiple myeloma. He returns home to Montana and immediately travels 150 miles to a fishing trip, big mistake he says. On the trip his back pain is so bad he barely makes it back home, and just four days after being diagnosed he can't get out of bed and has to be medivacked out of his Montana home to the Mayo Clinic in Minnesota, where he is found to have a compression fracture in his back. The irony here is that I discover I have cancer when a bone in my neck breaks, Brokaw in spite of being treated by multiple big names in the field fares little better, four days after his diagnosis he also has a broken vertebrae!

        He was advised by some to get a stem cell transplant, but as he tells the story, Ken Anderson of the Dana Farber in Boston advised that he skip the stem cell transplant and be treated with drugs and that's what he did. [We are going to go to "war" and various other nonsense.] I made the same decision to not do a stem cell transplant, the difference being that I (essentially) made the decision on my own based, on my research and my experiences in the hospital for a week for my neck operation, which was enough time in the hospital for me! My oncologist comment on my decision: It was not unreasonable'.

        Partly Brokaw's and my avoidance of a stem cell transplant is a function of age. My oncologist told me at diagnosis that not so long ago the cut off age for a stem cell transplant was 68 or 70 (I was 72 at diagnosis and Brokaw was 73), but that lately people older than me had had them. The age cut off being a tradeoff of the ravages to the body and risk vs benefit of the procedure. And partly, while not yet definitively proven, there are hints from clinical trials that the new generation of (so-called) 'novel' drugs, like rev/dex, are achieving results comparable, or nearly comparable, to earlier trials with stem cell transplants. Stem cell transplants became the 'gold standard' for MM at a time when only the first generation of drugs, like thalidomide, were available as an alternate treatment, and these first generation drugs were poorly tolerated, so at the time a stem cell transplant offered a chance, after a long recovery, of getting off drugs for a while. However, more recent clinical trials are showing that for even for stem cell transplant patients a maintenance of dose of revlimid, vs no drugs, considerably lengthens the time before the disease progresses.

        As best as I can tell Tom started on rev/dex and later Velacade was added. His Dec 2014 announcement about going on maintenance in six weeks indicates that his 'induction' therapy to drive his numbers down ran almost a year and a half. In my case I took rev/dex for six months and then went on maintenance (10 mg Revlimid). So far rev/dex has worked well for me, I achieved a CR (complete response) based on M-spike, which I am told only 10-15% of rev/dex patients achieve.

        When after diagnosis he asked how long he had, he was told five years. In Jan 2016 I saw Tom Brokaw live on TV (commenting on a primary election) and he didn't look too good, but he up and about, and he is one more year into chemo than I am. It's very frustrating for MM patients that Brokaw is not more forth-coming about his chemo. He writes a book and give speeches about his disease, but he never says specifically what drugs he is taking. All he does is drop hints that those on the MM forums try and interpret.

Roy Scheider
        Jaws actor Roy Scheider was diagnosed at 71 with MM in 2004, had stem cell transplant in 2005 and made it to 2008 where he died from complications of a staph infection. He was treated at Univ of Arkansas.
        Multiple myeloma overview arrticles
                This paper ('Multiple Myeloma: An Update', 2013) by a doctor from Oman has a very detailed overview of MM.

        2015 MM Patient Handook from International Multiple Myeloma Foundation (good technical reference)

        2013 Mayo clinic MM treatment recomendations (detailed paper, complete)

Multiple Myeloma spectrum
        There are two precursors to MM. The first is 'monoclonal gammopathy of undetermined significance' (MGUS), and this can advance to smoulding multiple myeloma (smouldering MM). When I dig into it, even though the terminology obscures it, MGUS is really a low level and slow growing MM. It's a lot like the slow growing prostrate cancer that most older men have that don't give them any symptoms. It affects 3% of people over age 50, and 5% over 70, so it is quite common. As these people age,  a few of them (about 1% per year) will progress to full blown MM. The clinical definition of MGUS is these three criteria:

        1) Monoclonal spike on serum protein electrophoresis of less than 3 g/dL
        2) Bone marrow infiltration by monoclonal malignant plasma cells of less than 10%
        3) No organ damage related to multiple myeloma (no renal failure (?), no hyperCalcemia, no anaemia, no bone lesions)
        In other words the patients have no symptoms, but up to 10% of their marrow plasma cells can be cancerous and these cells can produce a monoclonal M spike in the blood that can be remarkably large (3 g/dL). For perspective my pre-chemo M spike was 5.31 g/dL that after six months of rev/dex chemo has been reduced to 0.23 g/dL, which is less than 1/10th of the level that a non-symptomatic MGUS person may have. If the monoclonal level is above 3 g/dL and/or the amount of malignant plasma cells in the marrow is above 10%, then the condition is called 'smouldering MM' and while it is still a classified as precancerous, 50% of these patients will go on to develop full blown MM in five years.
M-spike tracking?
       MGUS seems to blow a hole in the theory that M-spike tracks cancer levels in the body. MGUS by definition means plasma cells make up less than 10% of the marrow cells (2-3% is normal). Yet somehow (not explained!) this relatively small level of cancerous marrow cells pumps out so many clonal anti-bodies that the M-spike can be as high as 3 g/dL. What? For comparison my M-spike was 5.31 g/dL and bone aspiration found that clonal plasma cells made up 70% of my marrow cells. (something doesn't computer here!)
        In other words there's a spectrum where cancer can exist in the marrow plasma cells but is slow growing and has not yet spread (metastasize) to form bone lesions. Lower levels are 'monoclonal gammopathy of undetermined significance' (MGUS), higher levels are 'smouldering MM', and once it has spread and bone lesions have formed it is (full blown) MM.
'The Role of CR  (complete response) in MM' --- excellent 2009 French paper
        This 2009 french paper (reprinted 2015) from journal Blood discusses in detail 'complete response (CR)', and its correlation with improved prognosis. They discuss that years ago the definition of CR was no cancer showing up in the standard electrophoresis test, i.e. monoclonal spike was below the threshold of the test. The paper gives the threshold of the electrophoresis test as (0.02   - 0.06 g/dL), which is x4 to x10 lower that my current (and likely plateau) of 0.23 g/dL. Over time as MM treatments improved (stem cell transplants, better drugs), the CR threshold was lowered to include that the immunofixation test also not detect cancer cells. This test is about twice as sensitive as the electrophoresis test. Even deeper levels of remission beyond CR have been defined amounting to (in effect) no detectable cancer in the body (blood, urine or marrow). To sort patients in this domain new and exotic tests are required.

        The reason for the focus on CR is that it is correlated (somewhat loosely) with improved prognosis, a longer time before cancer comes back ('time to progression', and sometimes longer life. The clinical implications of this are not so clear, and I discuss this elsewhere in this essay. The french authors of the paper are clearly of the opinion that the correlation of CR to improved prognosis implies that high risk patients should be treated to achieve CR, However, the facts are that regardless of the treatment goals only a minority of patients, often only a small minority, typically achieve CR.

       This paper gives the threshold of the tests, i.e. "lowest detected level of M component'. My laboratory tests measure M-spike in units of g/dL, so my 0.23 g/dL after six cycles is far (x4 to x10) above the threshold of the serum electrophoresis tests, not to mention immunofixation which is lower still by another factor of 2.

                Serum electrophoresis                          0.2 - 0.6 g/L       (0.02   - 0.06 g/dL)
               Immunofixation                                     0.12 - 0.25 g/L   (0.012 - 0.025 g/dL)

MM cure vs control debate
        According to the MM Beacon a leading doctor at Mayo clinic (S. Vincent Rajkumar) by been pushing to make the objective of MM treatment control of the discease and not agressively attempt a cure. In the important article below he makes a strong case not to obsess about achieving CR, saying it (probably) makes little difference for the 85% of patients that are standard risk. In the cure vs control debate he comes down on the 'control' side, which amounts to conservative treatment, don't throw everything at the cancer in the beginning trying to drive down to the CR level. The same OS will likely result, he argues, if newer and multiple drug combos are held for possible treatment later with a resultant better overall quality of life.

        There's also a link on the MM Beacon to a 2011 interview with Ken Anderson of Dana Farber discussing this issue. Anderson comes down firmly on the side of working to achive CR, so it's a good guess that this is probably the approach of the Dana MM team.

Here's a 2011 paper by Rajkumar (et al) and below quotes from it"
         "Approach to the treatment of multiple myeloma: a clash of philosophies' (Journal Blood)

-- "Distressingly, most myeloma phase 3 trials are designed with surrogate endpoints and typically fail to have well-designed quality-of-life studies built in that can shed light on how patients in different risk categories benefit from various interventions." (translation -- clinical trials are of limited use in deciding how to indivualize treatment for patients in different risk categories.)

        -- "Several papers have emphasized the importance of CR in MM (ref 26,27,31–35). This is a difficult topic to cast doubt on because, after all, who can be against CR? The main reason to be cautious in espousing CR is the correlation between increased response rates and increased toxicity. Striving blindly for CR may lead to unacceptable and unnecessary toxicity for some patients and come at too great a price."

        -- "However, oncologists willing to say that CR is not an important endpoint can quickly attain the pariah status. Despite this, we wish to highlight some important caveats about CR and illustrate its limited use as a surrogate endpoint in a disease, such as MM."

        -- "Unlike curable cancers, such as large cell lymphoma, CR in MM is not a surrogate for cure but rather a marker of profound tumor reduction. It is not a true CR because most CR patients will relapse with time. Indeed, in most studies that proclaim the benefit of CR, the median CR duration is short."

        -- "Thus, achieving immunofixation-negative CR status may need eradication of not just MM cells but also any premalignant monoclonal plasma cell populations present in a given patient. The existence of such clones is not in doubt and is evidenced by the fact that premalignant monoclonal gammopathy of undetermined significance almost always precedes MM (ref 37,38), and MM patients after therapy often achieve a prolonged remission from malignancy (symptoms and signs of MM) despite the presence of a residual stable monoclonal (M) protein. (I read 3% of older people have 'monoclonal gammopathy of undetermined significance', meaning there is an excess monoclonal protein in their blood but it's stable or progresses very slowly into clinical MM, analogous to slow growing prostate cancer in men, which is best left alone.)

        -- ** "Finally, and most importantly, we now know from ... that not every MM patient needs or benefits from achieving CR. Data show that patients with standard-risk MM (composing 85% of all MMs) have the same survival regardless of CR status, whereas achieving a CR appears to be critical for patients with high-risk disease."

        -- ** "Similarly, despite the doubling of the rate of CR/very good partial response with thalidomide and dexamethasone, or a tripling of it with the addition of lenalidomide to melphalan and prednisone induction, there was not even a hint of a difference in PFS or OS. There was, however, significantly greater toxicity."

        -- ** "But prolongation of PFS alone is not adequate because the seriousness and implications of a second cancer (from revlimid) are quite different from a rise in the monoclonal (M) protein by 25% (which is all that it takes to qualify as “progression” in MM)." (The latter is simply not correct. The international committee definition of progression is a greater than 25% rise in M-spike, but a rise that must also exceed 0.5 g/dl, so for anyone with a reasonable low M-spike (< 2 g/dl), the rise (from mimimum) of 0.5 g/dl applies. After ten months of chemo my M-spike level dropped below the threshold of the test (probably <0.05 g/dL), so that would make my M-spike threshold of progression 0.5 g/dl (round numbers).

**       I found a good reference point here. I looked at what monoclonal spike was needed to qualify for a clinical trial at Dana Farber for 'relapsed' mulitple myeloma patients. The qualification threshold includes a  monoclonal spike [> 0.5 g/dl]. It would be useful to look at other trials, many are listed on the Dana Farber site. (Exceeding this round number is probably a good shorthand for the disease having come back.)
        -- "Thankfully, in the case of lenalidomide maintenance, an OS advantage is emerging in one of 2 randomized clinical trials, and the risk of second cancers may be overcome if a significant survival benefit is confirmed." (Saying good things, circa 2011, about revlimid maintenance.)
Criteria for my MM progression (Aug 2015)
        What are the criteria to look for to determine if my MM is coming back? (Another 64 dollar question.) Even though I have been in maintenance for two months with low M-spike levels my doctor has said nothing about this. (Except in response to a question of mine that it is generally pretty obvious, whatever that means!) From the article above and similar references I think the working definition to use is an M-spike level of 0.5 g/dL. For perspective this is the level I was at in mid-March 2015 after four months of chemo and about 0.1 of the level I was originally at prior to chemo (5.31).
        The alternate definition I see widely quoted is a 25% increase in M-spike. Well my M-spike was reported this month as undectable (below the threshold of the test). So what's a 25% increase from an unmeasurable level?
        But looking at the M-spike is not enough. A possible, or maybe likely, leading indicator, is the lambda free light chain. The lifetime of the lambda free light chain in the body is very short (hours), so any rise of this parameter above the normal range (2.63 mg/dL) should raise alarm. In my first month of rev/dex chemo free light chain dropped 98% while M-spike, which has a lifetime in the blood of weeks, dropped 67%.

        Here's my best judgement (as of aug 2015, two months into maintenance) on the blood markers to look for to judge if the cancer is coming back:

               1) Increase of  lambda free light chain with a rise outside the normal range                         --  > 4 or 5 mg/dL raise alarm
            2) M-spike level rising above a baseline level                                                                     --   > 0.25 or 0.30 g/dL raise alarm
                                                                                                                                                             --   > 0.50 g/dL clinical threshold of reoccurance
What are the clinical implications of CR?
        This is a 64 dollar question?  I read varying opinions. It's easy to jump to the conclusion that if achieving CR leads to a better prognosis, i.e. a longer disease free period, possibly 4 years vs 2 years, then patients should be treated more aggressively to try and achieve CR. But the data only supports a correlation. A paper from a guy at the Clevland Clinic points this out and argues that the observed correlation my very well be just be a sorting of patients according to their genetics. (This makes a lot of sense to me.)

        He points out that MM is a very heterogeneous disease, meaning two seemingly similar patients treated the same way can have very different outcomes. The Clevland author puts this down to patient genetics, but I think it could just as well be due to individual variability that is not at all understood (biological noise). He argues that the small subset of patients that achieve CR are very likely just those with good genetics, these are the patients more responsive to treatment. He thinks it is a logical fallacy to use the known correlation as an argument to treat longer and more aggressively other patients to get to the CR level. It might be desirable, but just as well it might not be, the data doesn't support aggressive and/or extended levels of treatment. Trying to achieve CR in a wider subset of patients may very well lead to excessive over-treatment and a reduced quality of life.

        My primary hemotological oncologist and the consulting hemotological oncologist, both at Lahey, have not pressured me to take more treatment as after six months I am transitioning to a maintenance does of revlimid (no dexamethasone). Maybe this is a consequence of my age and choice that I don't want a stem cell transplant and that I have achieved a result that is probably as good as I can achieve with standard pill based chemo.

What about 'Very Good Partial Response'?
        Where it really gets interesting, at least to me, since I clearly have not achieved CR in six months of standard rev/dex chemo, is the 'Very Good Partial Response' (VGPR) category. I may be in this category. Many papers when they discuss favorable outcomes lump VGPR together with CR. A paper I read (from Mayo Clinic) discussed in detail patients' perceived 'failure' to achieve the CR target, and the author argued for 85% of patients it made no difference to their outcomes. In other words as he reads the literature only 15% (or less) of patients may benefit from more aggressive treatment to improve the depth of their response.

        I find definitions for VGPR are much harder to come by than definitions of CR, but the french paper (discussed above) has a definition for VGPR, and it is interesting. The VGPR threshold can be met in two ways, either by having an absolute level of cancer below a threshold or by a change in M-spike levels.  I find it rather curious VGPR can be met by an absolute cancer level OR a reduction in cancer level (due to chemo). I find the absolute level to be quite stringent (cancer not detectable by electrophoresis), but the reduction in M-spike (monoclonal spike) less so. I don't meet the absolute threshold as my cancer is detectable on the electrophoresis test, but I do (easily) meet the reduction in M-spike level (> 90% reduction), since 6 months of rev/dex chemo has reduced my M-spike level by > 95%, so according to this formal definition I am in the VGPR category.

VGPR        Serum and urine M protein detectable by immunofixation but not by electrophoresis, or 90% or greater reduction in serum M protein
                         plus urine M protein (< 100 mg/24 hours). [Reference is 2006 paper by Durie et al, "International uniform response criteria for
                         multiple myeloma', (journal) Lukemia]
I achieve CR (based on M-spike) (2/16)
        After six months of rev/dex my M-spike had dropped from 5.31 g/dL to .23 g/dL. Two months later (on maintenance) it suddenly became unquantifyable (meaning it was below the threshold of the test) and remained  unquantifyable for three months. I found the test threshold hard to pin down, but I think the Lahey M-spike test threshold was probably about .05 g/dL, since in the succeeding month a value of .07 g/dL was measured.
Does the M-spike test threshold depend on where the spike is?
        As of 2/16 with both Dana and Lahey protein electrophoresis results in hand I am less confident that I know what the threshold of the M-spike test is. I am beginning to suspect there may be more than one threshold, that it depends on exactly where in the spread out proteins the monoclonal spike (if any) falls, i.e. it depends on the background 'noise'. My M-spike data from Lahey does not identify the region where the monoclonal spike is located.

        Dana on the other hand breaks out the total protein value into five regional subcomponents: albumin, alpha 1, alpha 2, beta and gamma, with a value (g/dL) for each region. My one Dana reading that said my M-spike could not be quantified noting it was within the beta region. My beta region value is outside (to me far outside) normal region at 1.57 g/dL (normal .60 to 1.20 g/dL). This is over x30 times .05 g/dL. I asked my Dana doctor what the threshold value (in the beta region) might be, and got a weak reply (maybe) .1 g/dL.

        Both my regular hematological oncologist and my Dana MM specialist say I achieved CR (based on M-spike). This is a loose CR definition. It does not meet the more rigorous definition of CR for clinical trials, which requires, among other things, a marrow extraction to directly confirm < 5% plasma cells in the marrow. I did not have a marrow extraction to confirm my low M-spike readings.

        My Dana MM specialist looking at my M-spike results told me I was 'exquisitely sensitive' to Revlimid, because I had achieved CR on rev/dex. I asked was this unusual? He said only 10-15% of patients achieve CR on rev/dex.

'Understanding Protein Electrophoresis' notes
        I'm not aware that there was any attempt to 'correlate' my monoclonal reading with the amount of cancer in the bone marrow (as advised below). The only reference point (I presume) is the one aspiration of my hip bone. (review this). I have a vague memory that the clone cells in the aspiration were 50%? Does the ratio of M-spike to total protein qualify as calibration?

       ** -- The level of M-component on SPEP and UPEP reflects the amount of myeloma present. However, it is very important to realize that each patient is different. At the time of diagnosis, some patients have, for example, a very high spike in the serum but not such a high level of myeloma in the bone marrow
or bones. And the opposite is also true: some patients can have a low spike, but a lot of myeloma cells. Thus, at diagnosis, it is very important to correlate the spike level with the amount of myeloma in an individual patient. If the spike is low, this can be especially important, since small changes can be more important in terms of response to treatment as well as potential progression or relapse. (I don't think my spike was low. Prior to chemo beginning it was 5.31 g/dl and the threshold for MM diagnosis I think is 3 g/dl.)

        This is justification for six months of induction chemo

        -- If the treatment is working well, frequently there will have been substantial improvement (reduction) in the M-protein levels on SPEP/UPEP within the first 2–3 months. As noted above, the level of response can be quantified as >50% (partial response [PR]); >90% (very good partial response
[VGPR]); 100% (complete response [CR]). The classification of CR also requires that no M-protein is detectible using immunofixation (IFE) and that a bone marrow test shows no evidence of myeloma. Achieving the higher levels of response such as VGPR and CR will typically take at least another 2–3 months of
treatment (total of 4–6 months at that point). Several additional months of therapy may be required to achieve maximum response.

        --  This protein (M-spike), which is released into the serum or urine, is called a serum or urine tumor marker. Only a very few cancers have this type
of a marker which, in this case, makes it possible to assess the amount of myeloma at the time of initial diagnosis and track the amount of myeloma throughout the course of the disease. e. One can look at response to treatment, depth of remission, and, if necessary, the patient’s relapse using exact numbers, which is a unique advantage. For example, we can determine if a response is: Partial (PR)=50% reduction of M-protein; very good partial (VGPR) = 90% reduction
of M-protein; or complete (CR) = no protein detected. We can also identify a >25% increase in protein level, which we call relapse. (Where is the caveat tha the increase must be at least 0.5 g/dl!)

M-spike to total protein ratio (7/15)
        The ratio of [M-spike protein/total protein (both in g/dl)] is an interesting perspective and gives real meaning to the M-spike number, which is otherwise abstract. This test is done is plasma, which is what remains of blood when all the blood cells are removed. Here are my protein numbers for baseline (pre-chemo) and after 7 months (one month into maintenance), and my calculation of several protein ratios.

        Total protein consists of a large albumin spike with the balance globulin. The albumin spike typically makes up a little more than half of the total protein [55% (+/- 3%) nom], but pre-chemo because the (globulin) M-spike was so large the albumin spike was only 23% of total protein. At my lowest cancer levels (9 months into chemo) the M-spike fraction of total protein was less than 0.7%, whereas pre-chemo it was 50%.  Pre-chemo nearly all (97%) of the huge excess of IgG antibodies in my blood were monoclonal M-spike, but at 9 months < 5% of the much lower amount of IgG antibodies are M-spike. IgG has a high normal residual (0.75 - 1.4 g/dl), so changes in IgG per se are likely to be a weak indicator of disease progression, but the ratio of M-spike to IgG will probably be more useful.

(monoclonal spike)
Total protein
(6 - 8.2 g/dl normal)
(3.2 - 4.8 g/dl
(0.75 - 1.4 g/dl normal)
Total Protein
Total Protein
(total protein - albumin)
5.31 g/dl
10.6 g/dl
2.4 g/dl
5.46 g/dl
7 months later
0.19 g/dl
6.0 g/dl
3.5 g/dl
0.64 g/dl
9 months into chemo
(min cancer
baseline 8/31/15)
<0.05 g/dL
6.6 g/dL
3.7 g/dL
0.93 g/dL
12 months into chemo
0.12 g/dL
6.1 g/dL
3.4 g/dL
0.94 g/dL
16 months into chemo
(back to rev/dex 5/9/16)
0.25 g/dL
5.8 g/dL
3.4 g/dL
0.83 g/dL
2.0 months into new pom/carfilzomib/dex
0.20 g/dL
6.7 g/dL
3.5 g/dL
0.627 g/dL

        Pre-chemo my large M-spike of 5.31 g/dl increased the total protein to 10.6 g/dl (above the normal range), and M-spike was 50% of it. After seven months of chemo, my protein numbers are (probably) close to normal. Total protein has dropped to 6.0 g/dl, within the normal range, and the M-spike is now only 3.2% of it. Pre-chemo the normally large dominant albumin spike (see figure below) was only 23% of total protein, but after seven months with the drastic shrinking of the M-spike the albumin (spike) is now 58% of total protein. Immunofixation showed my multiple myeloma cancer puts out an IgG protein (most common type of multiple myeloma). This is confirmed in that pre-chemo the IgG in my blood (5.46 g/dl) measured just slightly higher than the M-spike (5.31 g/dl). The near agreement of these two numbers is reassuring that both tests look to be accurate. After seven months, IgG has dropped drastically (factor of x8.5) to 0.64 g/dl and the M-spike (0.19 g/dl) is only 30% of it.

        -- The crucial information comes from SPEP (serum electrophoresis). By calculating the size of the “spike”, which depicts the amount of monoclonal protein (done by measuring the area between the top of the spike and the baseline of the graph), one gets the percentage of the total protein that represents the M-protein. (Translation: while M-spike is reported in absolute units, the value is actually obtained by measuring total protein in absolute units and then scaling it by the ratio of M-spike to total protein.) For example:
               *  Spike is 60% of total protein
                *  Total protein = 12 grams/deciliter (g/dL)
                *  Spike level = 7.2 g/dL (60% of 12) (This g/dL value is what would show up in blood work.)

        Both the total protein and percentage of monoclonal protein change over time. With response to treatment, the spike can drop to 40%, and total protein to 9 g/dL, for example. This gives a spike level of 3.6 g/dL, which is a 50% drop in M-protein, or a partial response. (Note my numbers above are quite consistent with this excerpt from the booklet by the International Myeloma Foundation on electrophoresis protein testing.)

Left: normal                                                                                             Right: multiple myeloma adds a spike right (in beta or gamma region)
Plasma proteins spread out by electrophoresis.
Albumin (left spike) is normally dominant, a little more than half the total protein.
All the small spikes together are the globulin proteins.
(source --

IgG testing advantage
        My type of antibody is IgG. A paper explains that IgG tends to occur in the gamma region, which from a testing viewpoint is an advantage because in the gamma region there is "very little background from other serum proteins". In contrast IgA and IgM tend to occur in the beta region and are partially obscured by normally existing proteins, so "there is no reliable way to quantitate the M-spike in the beta region".
Dana Farber lab breakout of protein data (2/18/16 update)
        My Lahey electrophoresis tests do not identify the region of my M-spike, but my Dana Farber test result does. While Dana Farber identifies the monoclonal paraprotein as IgG lambda, it notes that it is in the beta region, and they were unable to quantified it. The breakout of my total protein at Dana Farber is as follows: (data taken 2/8/16). (Note Lahey blood work (at least as reported to the patient) reports only albumin and total protein with no mention of alpha 1, alpha 2, beta, or gamma.)

                                            albumin             3.19   g/dL         (3.20 - 5.30)                         low ratio of albumin to total protein (47%)
                                           alpha 1               .26   g/dL          (.10 - .40)
                                            alpha 2               .81   g/dL          (.50 - 1.00)
                                            beta                   1.57   g/dL          (.60 - 1.20)                            quite high
                                            gamma                 .97   g/dL          (.80 - 1.70)
                                               total protein    6.80    g/dL          (6.4 - 8.3)                            consistent with past Lahey readings

        Two things are odd in the above numbers, neither of which my doctors have commented on. One, albumin is only 47% of total protein. This is quite a bit lower that the valued as measured by Lahey labs over the last year or so. In my Lahey data aftter the first two months of chemo it has remained in the range of 52% to 58% or (55% +/- 3%), and this is consistent with what I read that albumin protein component is normally a little more half of total protein. Two, the beta range value is quite high, far outside the normal range, and this is where they found my monoclonal spike, yet still the Dana Farber clinical doctor said the M-spike was too small to be quantified.

        A couple of thoughts come to mind. I wonder if maybe my IgG (1.06 g/dL) might have 'moved' from its (usual) gamma region into the beta region?  If so, what might this mean? On albumin maybe the two labs don't interpret what is the albinum component in the same way. Albumin in online plots is normally shown as a large isolated spike at the beginning (or end) of the diffusion, and this is consistent with the above data where the adjacent alpha 1 region is only .26 g/dL. I would think (guess) that the definition of these regions would be fairly standardized, but maybe not. If I add the alpha 1 value to the albumin value, the albumin/total protein ratio is increased to 51%.

        Hopefully the picture will clarify soon because three weeks after these Dana labs I am scheduled to get a new set of Lahey labs. It might be desirable to meet with one of the doctors at Lahey who does this interpretation to try and understand the test better.

        I haven't physically seen the machine that scans the diffusion, but I suspect it displays a curve like those shown above and automatically measures the area under the entire curve. This is reported on blood work as 'total protein'. The technician (or pathologist) then manually moves two markers to define the edges of the M-spike. This allows the machine to figure the ratio of the area of the M-spike to the total protein, and the fraction of the total protein area under the M-spike is then reported in absolute terms (g/dL) as the value of the M-spike.

        In my table of numbers when my pre-chemo M-spike was 5.31 g/dL, my total protein was 10.6 g/dL. This means my M-spike was initially almost exactly 50% of my total protein. My initially albumin of 2.4 g/dL was down roughly 30% in absolute terms, but because the total protein was inflated (by the M-spike), it was only 23% = (2.4 g/dL/10.6 g/dL) of total protein vs the 52-58% it normally is.

       Useful booklet from International Myeloma Foundation with some good info about the electrophoresis test for MM. They have a related booklet on the free light chain assays (see next paragraph)

Value of kappa/lamda ratio in monotoring MM patients for relapse (7/19/15)
        On a MM forum I saw reference to paying close attention looking for signs of relapse to what was called  Free Light Chain Ratio (FLCR). A free light chain in the plasma is a fraction of the immunoglobulin. The key # to watch turns out to be the kappa/lamda ratio (normal 0.26 to 1.65). Multiple myeloma clones will either be kappa or lamda type. So the ratio will go offf on the high side for those with a kappa MM and off on the low side for those with the more common lamda MM. My myeloma is the lamda type. My pre-chemo 'lamda free lt chn bld' was a sky high 379, so with kappa in the normal range, my kappa/lamda ratio is virtually zero (< 0.01 in my blood work).

(update 1/2/16)
        It looks like I am beginning to see this leading action. While my cancer levels are still low, they have ticked up for the last three (or four) months. My latest free light chain reading (12/29/15) shows a big move, and this concerns me. I have yet to see my corresponding M-spike value (due to new year holiday it is delayed), but I bet it will be up considerably from .12. I think the significance of the kappa/lambda ratio should be discounted somewhat as my kappa free light chain is also rising. Over the last 12 months my numbers have shown I may have some kappa involvement in my cancer.

        Below shows a steady increase in my numbers, both M-spike and lambda free light chain, over a six month period while on revlimid maintance. Noteworth is lambda free light chain exceeding 10 mg/dL which clinal trials use as a threshold for disease progression. My first remission ended a couple of months later (5/16/16) when an MRI found a (large) plasmacytoma growing behind left eye that was causing double vision.

                     date                    M-spike (g/dL)          lambda free light chain (mg/dL)       kappa/lamda ratio
               ----------                ------------------          ------------------------------------     ----------------------
               9/28/15                      < .05                                        3.11                                       1.17
              10/26/15                         .07                                        3.18                                       1.00
                12/1/15                         .12                                       4.08                                       0.95
              12/29/15                         .16                                        6.41                                       0.65
                1/13/16                         .18                                        6.39                                       0.70
                1/26/16                         .16                                       8.41                                       0.53
                2/23/16                         .22                                      12.00                                       0.38
                  3/2/16                        .22                                      13.60                                       0.28
                3/22/16                        .31                                      15.30                                       0.26

       In my blood work the section is called: Immunoglobulin Free Light Chain Blood, and it has three entries: kappa free lt chn bld, lamda free lt chn bld and the ratio of the two. Here's my latest light chain numbers (July 2015, six weeks into maintenance). Kappa is a tad high, but chemo has driven my lamda (clone) number down from pre-chemo 379 to 2.37 within normal range, and more importantly the ratio is well within the normal range too.

                kappa free lt chn bld           2.59                     (0.33 - 1.94)   mg/dL
               lamda free lt chn bld           2.37                     (0.57 - 2.63)    mg/dL
                kappa/lamda ratio              1.09                     (0.26 - 1.65)

        -- M-protein may consist of intact immunoglobulin, free light chains, or both.  (This many be true, but free light chains are measured in mg/dL while intact immunoglobulin are measured in g/dL. My highest fraction was before chemo where my M-spike was 5.31 g/dL while my lambda free light chain was 379 mg/dL. This means the free light chain was 7% of the total. But just a month into chemo with M-spike at 1.82 g/L and free light chain at 8.17 mg/dL the free light chain fraction was only 0.4% of the total, hence it's only significant at very high levels of cancer.)

        -- Patients Who Benefit the Most From the Serum Free Light Chain Assays Are: People with myeloma who have abnormal serum free light chain results at the start of treatment. (that's me) Monitoring with the serum free light chain assays often allows a rapid assessment of the effectiveness of treatment.

        The International Myeloma Foundation has a related booklet discussing serum free light chain assays (kappa/lamda ratio), and how it is useful for monitoring MM patients because it is very sensitive.

MM marker without a measurement of M-spike?
        Looking at my protein ratios (calculated above) I am wondering if a low Albumin to Total Protein Ratio (23%) is a marker for multiple myeloma that might be picked up by 'routine' blood testing. In other words is an electrophoresis test ever done as part of a routine checkup? Or is IgG in the blood routinely measured? Even without specifically measuring the M-spike (monoclonal) spike my numbers show it substantially throws off IgG (pushing it far above normal) and the albumin to total protein ratio (less than half of normal).

A/G ratio
        When I research this, I find that albumin and total protein are sometimes measured in it routine blood work, so my odd ratio might have detected my multiple myeloma before my neck broke, which clearly would have been a plus. However the standard lab test is not the [albumin/(total protein) ratio], it is called the [albumin/globulin ratio or A/G ratio], which is calculated as [albumin/(total protein - albumin)]. Total protein is made up of the albumin protein spike and a bunch of small protein spikes which all together are called globulin. The multiple myeloma M-spike is a spike in one of the globulin proteins. (on a quick read it was unclear if the standard blood work requires an electrophorsis test to measure these proteins)
        I read the A/G ratio is normally a little above 1, which means there is a little more albumin than globulin. In other words albumin is a little more than half the total protein. This is consistent with my 7 month data where my albumin measured 58% of total protein.
        My platelet count has bounced around but remained in the low end of normal for my six months of chemo. However, my first month into maintenance my platelet count dropped to 122, substantially below the normal range (150 -  450). Platelet cells in blood are responsible for clotting. The lifetime of a platelet cell is short only 7 - 10 days (much less than my 28 day chemo cycle). Platelets are made in the marrow all the time by large cells called megakaryocytes. My infusion nurse recently mentioned that my low platelet count going into maintenance might be due to stopping dexamethasone. She said some platelet diseases are treated only with dexamethasone. The excerpts below confirm that she was right. Corticosteroid (dexamethasone is a corticosteroid) is the drug of choice to treat some forms of low platlet count.

        -- If for any reason your blood platelet count falls below normal, the condition is called thrombocytopenia. Normally, you have anywhere from 150,000 to 450,000 platelets per microliter of circulating blood. Because each platelet lives only about 10 days, your body continually renews your platelet supply by producing new platelets in your bone marrow. [Normal range for platelets in my blood work is shown as (150 -  450 K/uL), so clearly 'K' stands for 1,000]

        -- Treatment for low platelet count (thrombocytopenia): Your doctor may prescribe corticosteroids, also called steroids for short. Steroids may slow platelet destruction. These medicines can be given through a vein or by mouth. One example of this type of medicine is prednisone. (This confirms what the nurse told me that some platelet diseases are treated with corticosteroids.)

        --  If your condition is related to an immune system problem, your doctor may prescribe drugs to boost your platelet count. The first-choice drug may be a corticosteroid.

        -- Dangerous internal bleeding can occur when your platelet count falls below 10,000 [10 K/uL] platelets per microliter. (Nurse told me her concern
                   is when platelets are less than 100 K/uL)

History of myeloma
        Discovered a german site with a lot of detail about MM including by far the best history of MM I ever seen. It includes some interesting details of new drugs. It's a good technical overview of MM. It is written for doctors: 'Phyician's guide - consise review'. In a table titled: 'Tests Required To Monitor Therapy Responses' there is the following: blood tests (which I get monthly), but also urine, bone evaluation (skeletal x-rays, bone density (DEXA scan) as a baseline to evaluate effectiveness of biphosphonates, bone marrow (aspiration and biopsy for periodic monitoring).

        -- Besides activation of osteoclasts, the other characteristic feature of myeloma bone disease is inhibition of osteoblasts, which are responsible for new bone production and bone healing.

        -- * An important new observation is that the cholesterol-lowering statins (HMG-CoA reductase inhibitors, e.g., Lipitors; Mevacor'v), can enhance osteoblast activity and promote bone healing. In addition, VELCADE® (see relapse treatment) has been shown to promote bone healing, at the same time that it is a potent anti-myeloma agent. (This is the first I have heard of statins as being useful in promoting bone healing.)

        --  The predisposition to infections is perhaps the single most characteristic feature of myeloma patients besides the strong tendency for bone disease. Myeloma patients are susceptible to both viral infections and infections with "encapsulated" bacteria such as pneumococcus. However, in the face of neutropenia and the effects of high-dose chemotherapy, and with the added local effects of implanted catheters (e.g. Hickman catheter), the whole range of bacterial, fungal, and opportunistic infections can occur in myeloma patients undergoing therapy.

        -- About 70% of myeloma patients present with pain of varying intensity, often in the lower back or ribs. Sudden severe pain can be a sign of fracturing or collapse of a vertebral body. (I have been lucky, because I have not had this problem, at least to any significant extent. I did have a few incidences of  rib pain a few months preceeding my broken neck, but it has not reoccurred.)

        -- Pneumococcal pneumonia is the classic infection assoiated with myeloa at presentation, other bacteria, such as streptococci and staphylococci, are now frequently isolated.

        -- Hypercalcemia (excess calcium in blood) is present in 10% - 15% of patients at diagnosis. (I did have some elevated calcium in my blood. My first infusion of 2hr increased by blood volume 11%, thus immediately decreasing the concentration of calcium by 11%. (Excess calcium is a problem because it affects the kidneys.)

        -- A combination of serum beta2 microglobulin and serum albumin provided the simplest, most powerful, and reproducible three-stage classification (International Staging System introduced in 1996)

        -- Responding patients go from a high-risk to a lower-risk status until, ideally, no signs of myeloma are left, or they achieve a stable plateau phase, but with measurable residual disease. The time required to achieve the plateau phase is variable, ranging from 3-6 months (rapid response), to 12-18 months (slow response).

        --  Indications for the need to start treatment can be summarized as CRAB features: Calcium elevation; Renal problems; Anemia; or Bone issues.

        -- There is a strong reluctance in many centers to harvest stem cells without a clear plan for use, typically immediate use. This reluctance arises from protocol priorities, cost/utilization constraints for harvesting and storage, as well as numerous other factors. Nonetheless, many patients request and want their stem cells harvested, even though they may not be enthusiastic about immediate high-dose therapy.

        -- For patients with severe local problems such as bone destruction, severe pain, and/or pressure on nerves or the spinal cord, local radiation can be dramatically effective. The major disadvantage is that radiation therapy permanently damages normal bone marrow stem cells in the area of treatment. Wide field radiation encompassing large amounts of normal bone marrow should be avoided. A general strategy is to rely on systemic chemotherapy to achieve overall disease control, limiting the use of local radiation therapy to areas with particular problems. (This is what I had)

        -- Bisphosphonates - Bisphosphonates are a class of chemicals that bind to the surface of damaged bones in patients with myeloma. This binding inhibits the ongoing bone destruction and can improve the chances of bone healing and recovery of bone density and strength. A randomized study utilizing the bisphosphonate pamidronate (Aredia®) showed particular benefit in patients responding to ongoing chemotherapy. It is currently recommended that bisphosphonate therapy be used as an adjunctive measure in myeloma patients who have bone problems (see Figure 5). Other bisphosphonates are now available including clodronate, an oral formulation in use in Europe for the treatment of myeloma, and zoledronic acid (Zometa®), approved in the U.S. and Europe as treatment of both hypercalcemia and bone disease. Several new bisphosphonates are in clinical trials. One, called ibandronate, is now available in Europe.

        -- Two new concerns have emerged related to chronic bisphosphonate use. The first is kidney damage and the second is a condition called osteonecrosis of the jaw (ONJ). Both conditions are fortunately relatively uncommon. Kidney function must be serially monitored (especially serum creatinine before each treatment dose), particularly with Zometa use. If the serum creatinine increases by 0.5-1.0 mg/dL, dose and/or schedule adjustments for Zometa® may be required.

        -- ** For Zometa, one of the simplest adjustments is to extend the infusion time from 15 minutes to 30-45 minutes, which reduces the risk of renal impairment. (2008)  (my infusion time is 15 min)

        -- ** The International Myeloma Working Group (IMWG) recommends discontinuing bisphosphonates after one year of therapy for patients who achieve complete response and/or plateau phase. For patients in whom disease is active; who have not achieved a response; or who have threatening bone disease beyond two years, therapy can be decreased to every three months. (2008) (As of Dec 2015 I have been getting zometa infusions monthly for about a year and my schedule shows them continuing for at least a few more months. Mmy understanding is that the plan is zometa continues for two years.)

        -- Infections are a common and recurrent problem in patients with myeloma. A careful strategy for infection management is required. Antibiotic therapy should be instituted immediately if active infection is suspected.     (part 1)     (part 2)

Bone remodeling
        Osteoblasts and osteoclasts are the two (factors) that control bone remodeling. (I love these two names, differing by only one letter.) Osteoblasts build up bones and osteoclasts 'reabsorb' them. The balance between these two is important in MM, because the cancer somehow shifts the balance to osteoclasts causing (net) bone destruction. The purpose of Zometa as I understand it is to shift the balance back. The fact that 'osteoclasts are descended from stem cells in the bone marrow' may be relevant. Bone destruction leads to high levels of calcium in the blood of untreated MM patients.

        -- Bone may seem to be stable and unchanging, but in fact, bone is constantly being remodeled. Bone remodeling is triggered by a need for calcium in the extracellular fluid, but it also occurs in response to mechanical stresses on the bone tissue.

        --  Unlike osteoblasts, which are related to fibroblasts and other connective tissue cells, osteoclasts are descended from stem cells in the bone marrow that also give rise to monocytes.

Bone remodeling site

Multiple myeloma drugs
        When myeloma chemo drug combinations are listed by either brand name or technical name it just looks confusing. How are these drug combinations put together? Actually it is pretty simple. First group drugs by their class of action. A chemo drug combination for multiple myeloma is then assembled pretty much the same way that ordering is done in an old style chinese restaurant: one from column A, one from column B, etc. In the case of multiple myeloma each drug in the combination will typically have a different class of action, a different method of attacking the cancer. (A few drugs are considered boosters or are added to counter side effects such as deep vein clotting.)

      Many of the drugs fall into families. A drug will be found, perhaps serendipidesly, to be somewhat effective against the disease, but will often have bad side effects This is a first generation drug. The drug companies then seach for variations of it that is some conbination of reduced side effects, easier to administer and increased effectiveness. If the drug companies results in the lab are confirmed in clinical trials, then it becomes a 2nd generation drug. And often there will be 3rd generation drug in the clincal drug pipeline.

        For example, the primary chemo drug I take, Revlimid (lenalidomide) is a second generation drug. It is a variation on thalidomide, which was a first generation drug and had a lot of bad side effects. Wikipedia describes these drugs as having anti-angiogenic (prevention of blood vessel growth) and anti-inflammatory properties. Specifically, in vitro, lenalidomide has three main activities: direct anti-tumor effect, inhibition of angiogenesis, and immunomodulatory role. In vivo, lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity. 3rd generation drug in the same family is pomalidomide, whose brand name is Pomalyst in the US and Imnovid in Europe. (Yikes two brand names for same drug, same manufacturer!) [Another recent variant on thalidomide is apremilast (brand name Otezla), but it is not used in MM and is thought to work via a different mechanism.] All are manufactured by Celgene.

        Another family is Velcade (bortezomib) from  Millennium Pharmaceuticals. This is a first generation drug, the first proteasome inhibitor approved for humans. Although widely used to treat MM, it has two bad problems,  it must be given by injection in hospital and it causes widespread peripheral nerve damage. A 2nd generation version of velcade is carfilzomib (brand name Kyprolis) from Onyx, but it is also given by injection. A 3rd generation drug in the velcade class, but which is given by pill, is in development, in fact is was the subject of the clinical trial I was offered. It is currently known as MLN9708 (ixazomib).

Documentation with little concern for patients
        My complaint here is not about doctors per se, but the whole medical establishment. Reading postings on the Beacon Myeloma forum there is continuing confusion about cancer tracking values, specifically the kappa and lambda free light chain proteins. The source of the confusion is that the blood work of some patients have values expressed in mg/L while others report the value in mg/dL. Good grief. Here we see the medical establishment in action. We see little to no consideration for patients. Basically they don't give a shit. Nobody can be bothered to do the simple thing of organizing and standardizing the units on basic blood work. And while they are at it how about standardizing the names for the blood tests. When I review my blood work I see several different formats and names for standard blood tests and this is over only ten months and all taken at the same hospital!

Don't give a shit #2 (update 2/16)
        Celgene is the manufacturer of my tier 5, 10k/month chemo drug, Revlimid. Before they will allow a pharmacy to dispense the drug a patient is required to do a telephone 'survey' with the company, which amounts to three questions and then listening while they read a long list of the many possible serious side effects of the drug. This same statement has been read to me over a dozen times.

        The statement is a doozy. Every side effect is described only by its technical name. I remember a couple of xxxxpenias and myocardial infarction. Clearly this list was compiled for doctors, yet it is being read to every patient every month. Why do they do this, when it would be virtually no effort to give both the technical name and usual name for each side effect?  I would suggests two possible reasons. One, the company just doesn't give a shit if the patient understands the side effects or not. Two, this is driven by lawyers, who just want to be able to say in court that the patients were warned, and who don't care whether the statement is understandable or not.

        I saw the same problem in biology. When I was writing an essay on photosynthesis a while back, I was continually confused by the various units in different papers. When I looked up one common biochemical protein in Wikipedia, it told me the protein was also known by 13 other names, which it proceeded to list. 14 different names for the same protein! Yikes, idiots. Physicists don't do this. They get together periodically and standardize notation so students are not confused by units. For example, when I was in HS the common unit of frequency was 'cycles per sec', but when I was in engineering school an international meeting decided to change it to 'hertz', and in the classroom frequency immediately became 'hertz', cycles per second never again mentioned.

        And a biggy, where is the equivalent of the programmer's 'verbose' command? Most of the blood work pages are totally blank, just white space, the names of the tests on the left, the normal values on the right and 80% of the center part of the page is blank. When blood work is provided for a patient it need not be, should not be, in the shorthand format doctors use. After all they do this everyday, they know WBC means 'white blood count', but this should be spelled out for the patient. A large number of blood tests are listed in this cryptic abbreviated manner. There's plenty of room on the mostly blank page to add explanatory notes. Of course it's easier to just provide a copy of the doctor's blood report to the patient, so basically that's what they do. It hard not too conclude that no one in the medical world gives a shit about helping the patient understand his blood work, which for someone with a blood cancer like me is vital.

        It gets worse, a few months after the Lahey portal became active, the 'H/L' out of range markings on the blood work provided to the patientsuddently disappeared. I know that in blood work formated for internal hospital use, like in the infusion lab which I have seen, the H/L out of range markings remain. A lab technician taking my blood suggested to me that the reason the hospital's new patient blood work provided no longer labels out of range lab results (H or L) may be a deliberate choice to minimize questions. I'm betting this is right. Some patients probably run down the list and ask about every 'L' value, which the doctors find tendious and likely argue is mostly a waste of value patient/doctor interface time, and I would agree this has some merit. Still my point is many serious ill patients, especially those with blood cancers like me, are ill served by a decsion like this.

        Even the protein (anti-body) in the blood that is the main tracker of MM goes by a bunch of names:

                    --  M-spike
                    --  M-protein
                   --  monoclonal spike
                   --  monoclonal protein
                    -- paraprotein
                    -- monoclonal immunoglobin protein
                    --  M protein of monoclonal protein (Mayo clnic covers all the bases!)

        Good grief!

Abbreviations everywhere
        Now that I am sensitive to customer unfriendly abbreviations I am seeing them everywhere. In the last few days I stumbled on some beauties.

        Cannon camera --- Camera is connected to my PC via USB, and in Windows Explorer I am searching for the directory with the pictures. The pictures are in a directory named 'DCIM'. What the hell does this mean?  Why can't Cannon label the directory something like maybe, oh,  'pictures' or 'photos'? I mean, this is a camera!  With a little googling I find  'DCIM' stands for 'Digital Camera Images' and there's a historical reason for DCIM, and even on most  phones pictures are  found in a DCIM directory.

        Fidelity Charitable --- If an appreciated security is donated to charity, the allowable tax deduction is its 'fair market value', but this can be differeent from the cash the charity receives when it is sold by them a few days later. Fidelity Charitable labels the fair market value as 'FMV'. Good grief.  (I had to make a phone call to figure this out.) OK, maybe there is some rational for this abbreviation, but just like with blood work the online screen could be expanded to say 'FMV (Fair Market Value)'.

Experiences of others with MM chemo
        One of the problems with MM chemo is a sense of isolation. I can't get my doctors to tell me about how any of there other patients respond to chemo or even give a sense of the process. The information is always just dribbled out as to what to do next with no overview. I have some understand of why from their perspective it is better not to say much, but still the patient unless he researches hard (or perhaps joins a support group) is left with little perspective on how his treatment is going.

        So I set out to try and find the experiences of others with MM (how their M-spike responded to chemo, etc), but it is surprisingly hard to find much of anything. I figured people would plot up their numbers (like I just did) and post them, but an image search has turned up very little. (One of the problems here, common in biology, is that there is no standard name for the M-spike also known as monoclonal spike, paraprotein). Here's an M-spike plotted up apparently from a guy with smouldering myeloma. This is a precursor to MM with a monoclonal spike, but not yet the full symptoms of mulitple myeloma. At first I was puzzled as to why with such a high M-spike his chemo was delayed so long, but then I noticed it began just after his M-spike exceeded 3 g/dl. This is one threshold for MM diagnosis, so my guess is that his diagnosis at this time changed to MM. He's gotten a 'partial response' (> 50% reduction I think), but from the shape of the curve it doesn't look like he is going to get to 0.32, which would be a 90% reduction to qualify for VGPR. Unfortunately there was no info on the site as to what his chemo was.

decline from 3.2 to 0.7 g/dl in five cycles
(source --

        One source is the forum on the Myeloma Beacon, which is a large dedicated MM resource. The difficulty here is finding what you want in the thousands of posts. (The Beacon internal search engine doesn't find much. Google does better if you know the name of the poster.) Two Beacon posters have caught my attention. One began his chemo at almost exactly the same time as me, and he has posted a detailed running commentary (at first day by day). His chemo included velcade and you can see its problems. A second prolific poster (Chris Hill) was diagnosed about four years ago and after a few good years on maintenance has begun to relapse, so this gives a more extended perspective.

Chris Hill
        This young guy was diagnosed four years ago with super bad numbers (8.9 M-spike). [rev/dex + velcade] drove his M-spike to 0.1 in less than six months. He had a transplant and was off all meds for a nearly a year. When his numbers ticked up, he brought them down with rev/dex chemo getting a stable 15 months. This got him to 3.5 years, but then numbers again ticked up, so his chemo was tweaked with a newer proteasome inhibitor kyprolis (carfilzomib) added to rev/dex (instead of velcade (bortezomib)), and this drove his M-spike down to 0.1 again. But this second plateau after his 'relapse' only lasted about six months and his numbers are ticking up again. He's had a lot of problems and pain in his four years and for much of the time has been largely tied to the hospital since both proteasome inhibitors are injected twice a week. (Not to mention the huge cost of revlimid, 3 weeks in the hospital for the transplant (150k) and 100k+  for the injections with no medical insurance.)
        Chris is a young man, 43 at diagnosis. When he was diagnosed in 2011, he was in bad shape with a super high M-spike of 8.9 and lots of bone issues including several compression fractures in his back . (In 2011 he claims his bones were fine and that MRI had even shown some lesions healed and that the pain in his back is from disc issues). He had been feeling very tired and had bad nose bleed for 8 months (no health insurance) before he went to ER. His hemoglobin was 7.3, close to half of normal (me 9.9), so they immediately transfused him, then it dropped to 6.3 and his platelets were really low at 63k and he was bleeding all over the place. His marrow aspiration was 85% (or 80%) cancer (me 70%). He says his genetics is good. (He focuses (unfairly) on how bad deletion 13 is and is glad he doesn't have it. I have deletion 13.) He characterizes his MM as 'aggressive' since it can shoot up fast when he is off chemo. He posts on Beacon and also on his Facebook page, which can be accessed. His cancer is IgA.

        His M-spike dropped spectacularly with [rev (25 mg)/dex (20 mg) + velcade] chemo going from 8.9 to 0.1 g/dL, and he had a confirming 2nd marrow aspiration, showing cancer had dropped from 85% (or 80%) to 2%. His initial 8.9 g/dL he says was the highest his oncologist had ever seen and the 2nd highest a MM oncologist at John's Hopkins had ever seen. It dropped to 2.2 (75%) after two three week cycles and to 0.5 after four cycles. He could not raise the funds for a transplant, so he went without chemo for a few months and surpassingly from this low base (2%) his M-spike rapidly shot up (.76 g/dL) in  two months and to 1.7 one month later with no chemo, and even when chemo (dex + velcade, no revlimid) was restarted in another month 2.3 then 2.9. When revlimid was then added to the chemo, his numbers started down.

        After he had a bone marrow transplant (three weeks in hospital at Johns Hopkins). He is told it will take six months for his immune system to come back (he wears a mask when out) and a year before his energy returns! Six months post transplant his M-spike is 0 (which probably means < 0.05). He was off therapy for 10 months and his M-spike stayed at 0.1 and then started to rise. He went back on rev/dex in 2013 where his M-spike stayed at 0.5 for 15 months and then began to rise. That's when he added Kyprolis, which is an injection and requires two trips to the hospital per week. He has pictures of nasty bruising at the injections sites. One cycle of the new chemo in early 2015 dropped M-spike from 0.8 to 0.4, to 0.2 after two cycles and to 0.1 after three cycles then to 0. He says Kyprolis is 1,700/dose, which at six per cycle would be 133k/yr. His platelets are quite low at 82,000, so he bruises easily. Dexamethasone gives him terrible headaches and bad back pain, and he claims it is bad for bones and reduced potassium in the body. (I checked and my potassium in six months slowly drifted down, but remained in the normal range.)

        Note even though his new [rev/dex + Kyprolis] chemo was effective dropping his M-spike to virtually zero (0.1 or 0), he still only got a stable five months from a new chemo regimen after his first relapse before his numbers started to rise again. This is four years in with a stem cell transplant.

        -- End of 2014 I became refractory (resistant) to the Revlimid and Dexamethasone chemotherapy I was on. It's common as Multiple Myeloma genetically mutates so it can overcome the chemo you are using. January 2015 I started a new very promising new Chemotherapy called Kyprolis, added to the Revlimid and Dexamethasone. It worked until 2 months ago when my numbers started creeping up again, showing it wasn't working. So I got about 5 months out of it. Once the numbers started climbing we decided to try one more month to see if it was a fluke, if it would slow down, or keep advancing. (7/2/15 post)

        -- Wondered why back has been hurting more the last few months. Partially due to the myeloma making me osteoporitic, and partially due to the long term use of dexamethasone, a steroid I take with my chemo as it keeps bones from utilizing calcium and minerals to build themselves. (Is this true?, research this) Hill is right about this. Long term usage of dexamethasone can indeed cause "decrease calcium absorption and increase its excretion" so bones can be affected leading to "pain and osteoporosis". "You may also experience muscle pains because dexamethasone can cause you to lose potassium". (

Carfilzomib (kyprolis)
       Kyprolis (carfilzomib) and velcade (bortezomib) are both proteasome inhibitors. Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins, like the p53 protein. Velcade (from Millenium) was first and kyprolis (from Onyx Pharmaceuticals) is newer. kyprolis is on fast track approval (costs 10k/month). At present it is only approved by FDA as a substitute for velcade.

        K_Shash is not too different from me. He (or she) is diagnosed at age 67 in Nov 2014. His chemo treatment is almost exactly concurrent with mine. Like me he has multiple bone lesions. 30% cancer cells in his marrow (vs 70% for me). His chemo is RVD, which is rev/dex (15 mg revlimid, 20 mg dexamethasone, 3 wks on 1 wk off) with (infusion) velcade added (once a week). His plan is to stay on RVD and avoid a stem cell transplant.

        My initial lambda free light chain value was x144 higher than the upper end of normal (379/2.63 = 144). My lambda free light chain response to chemo was rapid and deep with a 98% decrease in the first cycle. My kappa/lambda ratio pulled into the normal range after just two cycles, and my lambda value was normal in four cycles. (Curiously my doctor has never talked to me about my free light chain response!) A comparison is provided by a frequent poster on Beacon who posts under the name: K_Shash. He apparently is in the minority of MM patients who doesn't have an M-spike, because he says his main cancer marker is a free light chain protein, in his case the kappa free light chain.

        He gives the initial kappa free light chain value as 853 mg/dL, which would make it x440 higher than the upper end of normal (853/1.94 = 440), and a kappa/lamda ratio of 127 (0.26 - 1.65 normal). (However, he may have messed up his units, so it might be 853 mg/L or 85.3 mg/dL). He had a reduction in his kappa free light chain of 80% in his first cycle and 98% after three cycles, whereas I had a reduction of 98% in my first cycle and 99.3% in three cycles. It took him 8 months for his kappa free light chain to get into the normal range, and his kappa/lamda ratio of 1.74, while close, was still not quite normal (0.26 -  1.65).

        Reading K-Shash's posts I see his doctors treated him like my doctor treated me, in the sense that they only look ahead to the next month so the patient has no overview of where the chemo process is going or how long it is likely to take before maintenance. And with velcade, which requires a trip to the hospital probably twice a week (because it is an injection), a switch to maintenance and less (or no) velcade becomes a BIG deal.

        Here's another interesting Beacon poster. This guy (Rafael M Santiago) is an MD age 62 diagnosed with MM in Sept 2014. He is stage 1 with no chromosomal abnormalities. Like me he is on rev/dex taking zometa (25 mg revlimid, 40 mg dexamethasone). In his first cycle he is having terrible problems with side effects. He says he passed out three times after meals, so after one cycle his revlimid was reduced to 20 mg.

MM for Dummies
        This site has MM stories from about 50 people:

Other blood cancers
        The three main blood cancers in terms of frequency are
                    Lymphoma                             52%                                74,000 cases in US/yr
                    Leukemia                               34%                                48,000 cases in US/yr
                    Multiple myeloma                14%                                20,000 cases in US/yr

        Half of all blood cancers are lymphomas, but they are quite different from multiple myeloma because they are based in the lymphatic system, whereas leukemia and MM are both based in the bone marrow. As far as I can tell, neither leukemia or lymphoma has a blood marker like the M-spike of MM. Protein electrophoresis test, which is used to measure the blood marker for MM, is not used in other blood cancers.

        This is significant in a clinical setting because it means this test is used only for a minority of patients a hematological oncologist treats. It means scheduling blood collection a week or so before results are needed is probably unique to MM patients, since it takes four days or so for the results to become available. (This may explain why the scheduling of my blood collection sometimes gets screw up.) This test not only has a diffusion, but it is not fully automated, a a doctor is needed to examine and interpret the resulting protein band.

        With a little digging I find there's an interesting similarity between MM and lymphomas, but with a twist. In lymphomas the cancer making cells (lymphocytes?, a type of while blood cell) are in the lymph system, so the lymph system serves the roll the marrow in bones does for MM! The cancerous cells in the lymph system feed lymphomas into the blood, but because the marrow is unaffected the normal blood cell production is unaffected, so what happens is that the blood is essentially normal except that many clonal cells from the cancerous lymph system added to it. This explains why when the lymphoma cancer making cells congregate we don't get a bone lesion as in MM, but instead a solid tumor in one or more of the lymph nodes.

        In leukemia the cancerous cells are in the marrow as with MM, so normal blood cell production is affected. In other words MM is more closely related to leukemia than lymphoma because in both cases the cancerous cells reside in the marrow of the bones. Marrow based cancerous cells in leukemia put lymphoma cells into the blood too. The difference between leukemia and lymphoma being the source of the monoclonal lymph cells in the blood.

        -- Hematological malignancies may derive from either of the two major blood cell lineages: myeloid and lymphoid cell lines. The myeloid cell line normally produces granulocytes, erythrocytes, thrombocytes, macrophages and mast cells; the lymphoid cell line produces B, T, NK and plasma cells. Lymphomas, lymphocytic leukemias, and myeloma are from the lymphoid line, while acute and chronic myelogenous leukemia, myelodysplastic syndromes and myeloproliferative diseases are myeloid in origin.

        One reference lists 35 (!) subtypes of lymphoma.  Lymphomas are types of cancer derived from lymphocytes, a type of white blood cell that populate lymphatic system. While lymphoma is called a blood cancer, it appears most commonly as a solid tumour in the lymph nodes of the neck, chest, armpit or groin. This localization makes it treatable with radiation (as well as chemo). Hodgkin's lymphoma is usually found in the lymph nodes of the neck and head. 74,000 people in USA are diagnosed with lymphoma (65,000 non-hodgkins and 8,500 hodgins) each year (about x3.7 times the number of MM cases).

non-Hodgkin lymphoma
        The Aug 2015 news story that the Red Sox manager, John Farrell, in the middle of the season was suddenly leaving due to a diagnosis of lymphoma piqued my interest in looking into other blood cancers. All three types of blood cells (really the marrow cells making them) can go cancerous. A doctor at Dana-Farber said Farrell's cancer is probably B-cell non-Hodgkin lymphoma and will be treated with 9 weeks of chemo and radiation. Farrell's case is probably stage 1, which means it is in only one lymph node and has not spread. Non-Hodgkin lymphoma is the 5th most common cancer in US (about 70,000 cases/yr in USA). There are many variations of this cancer. The overall 5 yr survival rate is 69%, but some types are considered highly curable (90%). Wikipedia says the suspected cause of some lymphomas is a virus.

        Multiple myeloma, a cancer of the blood plasma cells, make up only 10% of blood cancers. Is this important to me clinically?  I suspect it is. It is my understanding that hematological (blood) oncologists treat all the blood cancers. If that is right, it means MM patients with their unique problems make up only a small fraction of the patients these doctors are treating, though I see hints that some of them my specialize in specific blood diseases.

Hodgkin lymphoma
        A lymphoma identified long ago by a doctor named Hodgkin is today (surprise!) known as Hodgkin's lymphoma and all other lymphomas are as a group called non-Hodgkin's lymphomas. Hodgkin's lymphoma differs from the other lymphomas is that it is particularly radiation sensitive.

        Leukemia is a cancer of white blood cells. Leukemia is based in the bone marrow, whereas lymphoma are based in the lymphatic system. 48,000 people in USA are diagnosed with leukemia each year (about x2.5 times the number of MM cases). One reference lists 9 subtypes of leukemia. Abnormal white blood cells of leukemia can come either from lymphoid cells or myeloid cells.

        -- Leukemia is cancer of the blood and bone marrow. It develops when bone marrow, which produces blood cells, forms abnormal white blood cells that divide out of control. Normal white blood cells are the body's infection fighters, but these abnormal white blood cells, called leukemia cells, don't die at the same rate as normal blood cells. Instead, they accumulate and crowd out normal cells, like red blood cells, platelets, and normal white blood cells and their precursors, in the bone marrow.

        -- Two categories of immature precursor cells produce white blood cells: myeloid cells and lymphoid cells. Myeloid cells produce red blood cells, platelets, and several white blood cells types, known as granulocytes. Granulocytes circulate in the blood and fight infections by killing and digesting bacteria. Lymphoid cells develop into lymphocytes, another type of white blood cell that is found in both the blood and the lymphatic system.

Multiple  myeloma
        There are many subtypes of lymphoma and leukemia cancers, and for that matter multiple myeloma (MM) too. In MM the monoclonal anti-bodies can have either lambda or kappa light chains. In some MM patients there is no (significant) M-spike just an excess of lambda or kappa free light chains.

        -- B lymphocytes start in the bone marrow and move to the lymph nodes. As they progress, they mature and display different proteins on their cell surface. When they are activated to secrete antibodies, they are known as plasma cells.

        -- Multiple myeloma develops in B lymphocytes after they have left the part of the lymph node known as the germinal center. The normal cell line most closely associated with MM cells is generally taken to be either an activated memory B cell or the precursor to plasma cells, the plasmablast.[14]

        Above seems confusing, but I think the explanation is that there are an extra steps in the simplified view that cancerous marrow cells turn out identical antibodies. From these comments in Wikipedia it seems the marrow turns out B cells (or B lymphocytes) that are released into the blood. When they encounter an infectious agent (technically bind to a specific antigen), they turn-on (jargon is they get activated), proliferate and begin to turn out anti-bodies. The process is actually extremely complicated. Wikipedia (B cell) list 7 (!) steps in the development of B cells.

        --  Antigens are usually proteins and polysaccharides, and less frequently, lipids. This includes parts (coats, capsules, cell walls, flagella, fimbrae, and toxins) of bacteria, viruses.

Excerpts from 'Multiple Myeloma Patient Handbook' Myeloma Canda
MM biochemistry
        -- When myeloma cells enter the bone marrow, they attach to other, structural cells of the bone marrow known as stromal cells. Once attached to stromal cells, interactions occur that stimulate the myeloma cells to continue reproducing.

        -- Chemical messengers called cytokines are produced that stimulate the growth of myeloma cells and prevent the cells from dying naturally. Interleukin 6 (IL-6) is one of these chemical messengers.

        -- The myeloma cells secrete chemicals called growth factors that promote the creation of new blood vessels that usually accompanies the growth of malignant cells (a process called angiogenesis). One of the most important of these growth factors is vascular endothelial growth factor (VEGF).

        -- As the myeloma cells invade the bone, they may cause multiple areas of damage that weaken the bone. Thes areas are known as osteolytic lesions, or lytic lesions for short.

Drug mechanisms
       Thalidomide is an immunomodulatory agent. Instead of destroying myeloma cells (like chemotherapy drugs), thalidomide interferes with the underlying processes that promote the growth and reproduction of myeloma cells. Lenalidomide (Revlimid) like thalidomide is an immunomodulatory agent but is more potent and has a different side effect profile from thalidomide. Lenalidomide has multiple mechanisms of action that affect both the cancer cell and its microenvironment. Thalidomide:

               • inhibits factors that promote the growth of blood vessels (Vascular Endothelial Growth Factor or VEGF and basic Fibroblast Growth Factor or bFGF) that help to feed tumours

                • modulates the level of several chemicals (called cytokines) that the cancer cells use to communicate with one another and orchestrate growth and reproduction (e.g., Tumour Necrosis Factor – alpha or TNF-alpha, interleukin 6 or IL-6, interleukin 2 or IL-2, and interferon-gamma or IFN-gamma)

                • alters the expression of chemicals involved in acute rejection, such as cytokine secretion and cell growth

        Bortezomib (Velcade) is a proteasome inhibitor, one type of the new generation of “biological treatments”. It works by acting on the myeloma cells and the cells with which they interact to inhibit plasma cell growth and reproduction and to promote cell death.

        A number of new therapies are in development. At the time this handbook was printed, among the clinical trials underway in Canada were a new proteasome inhibitor (carfilzomib), a monoclonal antibody (elotuzumab), histone deacetylase inhibitors (panobinostat, vorinostat) and pomalidomide, a new immunomodulatory agent.

Spine fractures
       -- Vertebral fractures (fractures in the spine) have traditionally been treated by a procedure called vertebroplasty, in which cement is injected into the affected vertebrae to stabilize it. A newer alternative is kyphoplasty. In kyphoplasty, a balloon is inserted into the compressed vertebra and inflated to raise
up the collapsed section. The cavity is then filled with a bone cement, stabilizing the vertebrae and preserving the reestablished height.

       -- The M-proteins produced by myeloma are cleared from the body in the kidneys. Over time, the elevated levels of abnormal M-proteins in the blood and urine can damage the kidneys. This is why renal function is assessed regularly by creatinine testing of the blood.

Pain killers
       -- Although non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Motrin® or Advil®), naproxen (Naprosyn® or Aleve®) and diclofenac (Voltaren®) are common and effective painkillers, people with myeloma should avoid them, particularly if they have kidney damage.

        -- Because of the increased risk of infection, myeloma patients may require antibiotics before any dental work.

        -- A review of patients at one of Canada’s largest myeloma centres, the Princess Margaret Hospital in Toronto, found that 2% of patients taking
pamidronate developed osteonecrosis (jaw death). It can occur spontaneously but appears to be more likely following dental work, particularly traumatic work such as extractions. The risk of osteonecrosis appears to be higher among those taking zoledronic acid (Zometa®), compared to pamidronate (Aredia®).

        --- Restorative work such as fillings, bridges and crown and root canals are probably safe, provided wounds are as small as possible and all rough edges are carefully smoothed.
Blood test machines
Flow cytometry or (fluorescence based flow cytometry)
        This is a fluorescence based procedure to count and identify cells. It is used to diagnose some blood cancers like leukemia. It is an automated way to identify characteristics of individual cells at high speed. Cells are excited with a laser and how they fluoresce is measured. The cell identification can be made very specific by uses of anti-bodies with fluorescing tags that bind to proteins of the cell membrane.

       Another technique that uses fluorescence. FISH or Fluorescent in situ hybridization s not a blood test but a cytogenetic test. It uses probes that bind to the DNA and fluoresces can identify translocations, etc.

Free light chains ---
        Plasma cells output both anti-bodies (2 heavy chains + 2 light chains) and free light chains. MM plasma cells make a lot of free light chains, a higher ratio of free light chains to anti-bodies than normal plasma cells.  Kidney problem can cause both the lambda and kappa free light chain levels to rise. The ratio will separate out cancer from kidney problems. At low (normal levels) variations of 25-50% can occur. Warning sign cancer is coming back is progressive increases, especially > 50% increase on successive readings.

Freelite is trademark of Binding Site Group, Birmingham UK

Half life of IgG
        -- Under normal circumstances, most serum proteins that are too large for renal filtration (> around 60 kDa) are removed by pinocytosis, a process that occurs in all nucleated cells as they obtain their essential nutrients from plasma. This accounts for the half-life of IgA and IgM, which is constant at around 5 - 6 days. By contrast, IgG has a concentration-dependent half-life of approximately 21 days due to recycling by FcRn receptors.

        --  At low IgG concentrations, when FcRn receptor protection is maximal, the IgG half-life extends to several months. In such cases, serum IgG levels are particularly slow to indicate responses to treatment, and sIFE (serum immunofixation) may remain positive long after a tumour has been eradicated (as demonstrated by bone marrow immunophenotyping). Serum IgG concentrations may therefore be an unreliable indicator of tumour production rates in patients with IgG MM. (see figure)

Wow, looks a lot like the graph of my numbers!
CZE = capillary zone electrophoresis
IFE = serum immunofixation
SPE =  serum protein electrophoresis
(source --

        --  Orlowski et al. reported that rapid normalisation of the FLC kappe/lambda ratio - after the first or second cycle of therapy - was highly predictive of prolonged time to progression. (My ratio was nearly normal after two cycles).

        The fast response of free light chains can be very useful to evaluate if a new chemo regimen is working. Freelite (wikilite) gives this example (below):
Blue is the free light chain and as new chemo is begun it quickly falls. They point to the interval of 2-3 months were the IgG (red) is falling and that in isolation would be considered a good sign, but the blue has not pulled into the normal range giving advance warning that the chemo is not working and sure enough after 6-7 months the IgG and free light chain start to rise.

(blue) Lambda free light chain responds rapidly to new chemo,
but critically it settles out around 5-6 mg/dL, substantially above normal range.
This is a leading indicator that the new chemo regimen is not working.
(source --

        ** The not so subtle message from the free light chain people is if a new chemo regimen doesn't quickly bring the free light chain into the normal range it's a bad sign, and it may be time to change chemo soon rather than waiting for the slowly responding IgG to show a rise.

Clincial indicators of disease progression
        ** -- Difference (involved - uninvolved) free light chain  --- French viewgraphs (2014) use absolute difference [(involved - uninvolved) free light chain > 10 mg/dL] as in indicator of disease progression.   (yes) This seems to fit with nicely with my data so I added this column to my numbers table.
             -- M-spike absolute increase > .5 g/dL  (no)
            -- new bone lesion, plasmacytoma   (yes)
             -- hypercalcemia (> 2.65 mmol/L, attributable to MM)  (no)
            -- increase in >25% (absolute increase > 10%) in bone marrow plasmocyte  (not tested)

Clinical indicators of disease relapse
           -- One of more of
                        - new soft tissue plasmacytoma or bone lesion  (yes)
                        - and/or increase in size of existing plasmacytoma or bone lesion
                     - and/or hypercalcemia (> 2.65 mmol/L)   (no)
                        - and/or decrease in hemoglbin (< 2 g/dL)   (no)
                        -and/or rise in serum creatine (> 2 mg/dL or 177 micromol/L)  (no)

Patients blog about free light chain
        I found an interesting discussion from a MM patient with undetectable M-spike (few years following a stem cell transplant) who is carefully monitoring his free light chains and is beginning to see a (small) increase. The comments to the blog posting are interesting too because others are reporting their free light chain numbers. Here is his plot of his free light chains. He has a kappa cancer, so both his numbers tend to rise, whereas I have a lambda cancer, so I need to watch for my lambda free light chain rising and my kappa/lambda ratio falling. In four months his free light chain ratio has roughly doubled, but at 2.08 it is barely above the high end of normal (1.65). (In normal anti-body proteins the light chains are twice as likely to be kappa vs lambda, which might explain why the basic light chain ratio has kappa in the numerator.)

        In the comments discussion someone says (circa 2014) until the ratio is greater than 10 no doctor will recommend treatment, except perhaps a bone marrow check, and that it takes a ratio greater than 50 to really get their attention. (This strikes me as doctors not fully cognizant of the power of a leading indicator.)

MM patient plotting up his free light chain data over 18 months.
red -- kappa/lambda free light chain ratio (1.65 normal upper range)
yellow -- kappa free light chain (1.94 normal upper range)
(soure --

Hevylite Assay -- heavy free chain test
        The Freelite chain people (The Binding Site in UK) have developed a new sensitive test to measure heavy free chains (hevylite assay). It was approved by FDA in 2014 for IgG. In 2014 a poster reports to getting this test done by going to his doctor to discuss this, and then his blood sample was sent off to the Mayo clinic. (Mayo clinic is one of only two labs doing the test according to the Hevylite site.) Another possible leading indicator to keep an eye on.

        The Mayo clinic new HevyLite/Binding Site test is called: 'Immunoglobulin Heavy and Light Chain (HLC) Pairs, IgG Kappa and IgG Lambda '. From this name it looks to me like this test is measuring excess 1/2Ys of antibodies, i.e. equal number of IgG heavy chains paired with a light chain, and the test will measure both kappa and lambda light chains paired with the IgG heavy chain. (Mayo offers similar tests for IgA and IgM heavy chains.

Hevylite testing is useful for:
        • Distinguishing between broadly migrating monoclonal proteins and restricted polyclonal immunoglobulin responses

        • Quantitating monoclonal IgA, IgG, or IgM proteins that are difficult to quantitate on serum protein electrophoresis

        • Providing a more specific quantitation of the monoclonal protein than quantitating total IgA, IgG, or IgM

        These results can be used when monitoring previously diagnosed IgA, IgG, or IgM multiple myeloma patients and is used in conjunction with other laboratory findings

Drugs used in Multiple Myeloma (sept 15)
        Starting from lists of MM drugs at and a booklet on myeloma from the Leukemia and Lymphona society I pulled together this list of MM drugs. Combinations are assembled with drugs from different classes.

        At the present time the main cancer drug for a newly diagnosed MM patient is generally revlimid (an anti-angiogenic and immunomodulator) or a general cancer drug like melphalan. They tend to be paired with either a corticosteroid, like dexamethasone, or a proteasome inhibitor, like velcade, or both. Two new classes of drugs on the horizon are  Panobinostat (histone deacetylase inhibitor) and humanized monoclonal antibodies, like Elotuzumab and Daratumumab. Both monoclonal antibodies are still experimental (no FDA approval). Elotuzumab is further along, now in phase III trials. The monoclonal antibodies, being antibodies, are huge molecules (20,000 atoms) compared to the other drugs.

MM drugs organized by class
       Here's are all the MM drugs organized by their mechanism of action. When I do this, it's discouraging that there are only two classes of MM drugs with any track record: anti-angiogenic & immunomodulators and proteasome inhibitors. The other two classes: histone deacetylase inhibitor and humanized monoclonal antibody have just gotten their first (limited) FDA approval in 2015 and can only be used in relapsed patients. At present (1/16) I have only taken one drug from the anti-angiogenic & immunomodulator class. My preferred proteasome inhibitor would be Ninlaro, the only proteasome inhibitor that's a pill, but I need to do some research to see how available it really is.

Anti-angiogenic & immunomodulator
      * lenalidomide (Revlimid, rev) (2006)     anti-angiogenic & immunomodulator     2nd generation thalidomide      Celegene Corp               pill, + dex
                                                                      (Revlimid is a multiple myeloma monster that dominates in first-line and second-line indications with
                                                                       $5.7 billion billion (Celgene?) in expected sales this year. (business press)
                                                                             (several beacon posters report good results with only rev + dex. Tom Brokaw is though to have
                                                                              taken rev/dex for six months and then added velcade for a year (RVD) to get to a CR.)
      * pomalidomide (Pomalyst) (2013)          anti-angiogenic & immunomodulator     3rd generation thalidomide       Celegene Corp               pill, + dex
                                (Imnovid in EU)                GoodRx says, 100% of Medicare Part D and Medicare Advantage plans cover Pomalyst.
                                                                         pom:  4 mg (1,2,3 mg), cycled 21 of 28 days cycle, take between meals
                                                                          dex:   40 mg/wk (20 mg on two consecutive days/wk of carfilzomib)

Proteasome inhibitor --- Proteasome inhibitors come in two forms, boron based (Velcade, Ninlaro), and epoxyketone based (carfilzomib, oprozomib)
        bortezomib (Velcade, BTZ) (2003)        proteasome inhibitor (boron)   injection         Millennium Pharmaceuticals (owned by Takeda)
                                                                               (one beacon poster reports  neuropathy worse after being off velcade two months, doctor is
                                                                                sending her to pain doctor and it looks like velcade caused nerve damage is permanent.)
                                                                        Velcade is given at a dose of 1.3 mg/m2 intravenously or as an injection under the skin on days 1, 4, 8, and 11
                                                                              of a 28 day cycle.
                                                                        cyclophosphamide added to Velcade/dex (VCD or CyBorD) has proven effective in several trials
     * ixazomib (Ninlaro) (2015)                   proteasome inhibitor (boron)  in pill form (once weekly) approved by FDA 11/20/15        Millennium Pharma
                       (MLN9708)                            (doses: 4 mg, 3 mg, 2.3 mg, recommended dose 4 mg, three pills in 28 day cycle, to be used with rev/dex)
                                                                      Ninlaro is considered to be a second-generation proteasome inhibitor because it has improved characteristics
                                                                                and activity over Velcade. Laboratory and animal studies show that Ninlaro inhibits the growth of
                                                                                myeloma cells, including those that are resistant to Velcade. Ninlaro and Velcade differ from
                                                                                carfilzomib in that they are boron based.
     * carfilzomib (Kyprolis) (2012)                proteasome inhibitor (epoxyketone) FDA approved in 2012 for MM     injection    Onyx Pharmaceuticals
                                                                         (further FDA approval (2nd line) in July 2015) (Onyx was recently bought by Amgen for 10 billion.)
                                                                              Amgen web site describes carfilzomib as a second generation proteasome inhibitor.
                                                                             (one beacon poster had port installed for Kyprolis and reports bad pain)
                                                                               infusion (10 min) six times a month (days 1,2  8,9  15,16 of 28 days cycle)
                                                                               (two consecutive days for three weeks, then week off)
                                                                               dexamethasone is given prior to the infusion (to minimize side effects of the infusion)
                                                                               One treatment widely discussed on Myeloma Beacon is [carfilzomib + daratumumab (Darzalex)]
        oprozomib (ONX 0912)                       proteasome inhibitor in pill form,  (epoxyketone), phase 1/2 trials reported Dec 2013,  Onyx Pharmaceuticals
                          (PR-047)                                Oprozomib is an orally bioavailable analog of carfilzomib (
                                                                         "In summary, similarly to bortezomib, carfilzomib and oprozomib exert potent cytotoxic effects
                                                                          on myeloma cells under continuous and physiological dosing conditions."  Blocks the 20S proteasome.
                                                                          Oprozomib was granted orphan drug status for the treatment of multiple myeloma in 2014.
                                                                          In November 2013 Onyx Therapeutics initiated a randomised, double-blind phase Ib/III trial to assess the
                                                                           maximum tolerated dose, safety, tolerability and efficacy of oprozomib in combination with pomalidomide
                                                                           and dexamethasone ... in patients with primary refractory or relapsed and refractory multiple myeloma
                                                                          (NCT01999335). The trial completed enrolment of planned 314 patients in the US in June 2015.
        marizomib (NPI-0052)                         marizomib is in the same class of agents as Velcade® (bortezomib), but it has a different structure.
                                                                            Given by infusion. Being developed by Triphase Accelerator. In phase I trials.

Proteasome inhibitors can be purchased with prices at pharmacy, The site also shows a lot of chemical information about each drug
         with links to literature and clinical trials.

Humanized monoclonal antibody    Monoclonal antibody drug (MoAbs).  Side effects with this class of drugs are quite minimal and are similar
                                                                     to other chemo drugs. They are widely used in other cancers, but just beginning to be used in MM.
                                                                     Infusion reactions are common.
                                                            Immunotherapy is a new cancer treatment approach that is receiving a lot of press. It activates the body's immune
                                                                    system to fight diseases, including cancer. Darzalex (daratumumab) is the first drug of this type for MM.
      * daratumumab (Darzalex)             humanized monoclonal antibody targets proteins on the surface of myeloma cells. Used as single agent
                     (HuMax - CD38)                    or in combination with revlimid + dexamethasone, or velcade + dexamethasone. Daratumumab is a human
                                                                    monoclonal antibody (mAb) with broad spectrum cytotoxic activity. It targets the CD38 molecule,
                                                                     which is highly expressed on the surface of multiple myeloma cells.  Once daratumumab is bound
                                                                     to the CD38 protein on cancer cells, it signals for the immune system to kill the cells. Infusion.
                                                                     Phase I/II. Jassen  Biotech (subsidiary of Johnson and Johnson) with Genmab (Danish, who developed
                                                                     the drug). Daratumumab is a human IgG kappa monoclonal antibody.
                                                                     Myeloma Beacon ; "Since there are CD38 positive cells in the lung tissue and especially in the bronchial
                                                                     lining, why did they even decide to try Darzalex for a patient with COPD? Why not start with Empliciti,
                                                                     which primarily affects cells with SLAMF7 (the second most prevalent marker on myeloma cells)?"
                                                            Preliminary results of an ongoing multicenter Phase 1b study showed that the combination of Darzalex and
                                                                   Pomalyst-dex resulted in a high 71% overall response rate in heavily pretreated patients.
                                                         Approved (really preliminary approval) by FDA in Nov 2015 to "treat patients with multiple myeloma
                                                                who have received at least three prior treatments." (FDA site) "Darzalex was approved under the agency’s
                                                                 accelerated approval program (breakthrough designation and a priority review),  which allows the approval
                                                                 of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect
                                                                 on a surrogate endpoint reasonably likely to predict clinical benefit to patients. (business press says Johnson
                                                                 & Johnson wants to position this drug as a front line treatment for MM.) Some data from two phase 3 trials
                                                                 are now available: Pollux and Castor. Ph 3 clinical trials compared [rev/dex + daratumumab] to [rev/dex].
                                                                 Percent with VGPR (or better) was 74.5% (17% had a partial response). (This is far better than elotuzumab's
                                                                 33%!) It looks like daratumumab PFS (prgression free survival) time will be better than elotuzumab because
                                                                 at 18 months its response curve is flattening out at 75%.
                                                                      At the time of disease progression, various options will be available to Mr. Fulton. Among them I would prefer
                                                                      a daratumumab-treatment regimen such as daratumumab plus bortezomib (Velcade) (plus dex) based on the
                                                                      CASTOR trial. Bortezomib could be administered on days 1, 8, 15 of the 28 day treatment cycle to minimize
                                                                      the risk of toxities, expecially peripheral neuropathy. The dose of bortezomib could also be reduced from 1.3
                                                                      to 1.0 mg/m2 if there's a progression of neuropathy symptoms.(consulting Dana Farber hematological oncologist)
                                                                       Note, the mention of a 28 days cycle.. This indicates the writer is not that familiar with Castor trial because
                                                                             the trial and also the current daratumumab prescribing document use a threee week (21 day) cycle when
                                                                             the drug is paired with Velcade.
                                                                            Outline of ph3 Castor clinical trial
                                                                            New England Journal of Medicine paper on Castor trial results Aug  2016 -- 'Daratumumab, Bortezomib,
                                                                                  and Dexamethasone for Multiple Myeloma'
                           Slide talk on the Castor trial
                                                                      New England Journal oct 2016 paper on Pollux trial, 'Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma'
                                                            Infusion once a week for two months, then every two weeks for four months, then once a month.
                                                                (get this!) "The infusion will be completed in 15 hours"!! (Thise infusions are SLOW. Prescribing sheet shows
                                                               1st infusion is 6.5 hr and subsequent infusions are 4 hr!  135k/yr (first year) to 76k (second year)
                                                                Infusion reactions are common, but just on the first infusion, 46% of people are affected.
                                                                As  I read the infusion rate table in the presciring document I get (for 1,000 ml) 5 hr for the 1st infusion and
                                                                2.5 hr for subsequent infusions at 500 ml, but there are a host of premeds required and very often the infusions
                                                                 are interrupted by complications. One poster says his 1st infusion took 12 hr.
        elotuzumab  (Empliciti)              humanized monoclonal antibody targets SLAMF-7 proteins on the surface of myeloma cells. Used in combination
                           (HuLuc63, Elo)            with revlimid + dexamethasone. Infusion Phase III. Two year results. Bristol-Myers Sqibb
                                                                and AbbVie. Phase III with FDA Breakthrough Therapy Designation. Infusion schedule: every week for
                                                                first two cycles, then every other week (until disease progression). A complication with the infusions is that
                                                                dexamethasone pills (28 mg) must be taken 3 ro 24 hr in advance (take 7 pills at home in morning) and 8 mg of
                                                                dexamethasone must be infused 45-90 min before elotuzumab (plus a bunch of other pills in advance).
                                                                In Ph III clinical trial [rev/dex + elotuzumab] was conpared against [rev/dex]. Percent with VGPR (or better)
                                                                 was 33% (46% had a partial response). Mechanism of action: elotuzumab targets SLAM7 (Signaling
                                                                 Lymphocytic Activation Molecule Family member 7 protein) on MM cells and natural killer cells, which are
                                                                 activated by elotuzumab.
Daratumumab vs elotuzumab (3/26/17)
        Clear advantage Daratumumab, far better patient response (74.5% v 33% for VGPR) and likely a longer disease free progression time too. In choosing a monoclonal antibody drug for my next chemo my doctors seem to be favoring daratumumab over elotuzumab, but why? I have not yet had a chance to ask them, so to try and answer this question I reviewed the ph 3 trial data as given in prescribing documents of both drugs. In the trials both drugs were used with rev/dex and compared against rev/dex, so the data can be used to compare them against each other. Here are PFS plots for daratumumab and elotuzumab.

Ph3 trial data from daratumumab prescribing document                           Ph3 trial data from elotuzumab prescribing document
74.5% of daratumumab patients had a VGPR (or better) response                  33% of elotuzumab patients had a VGPR (or better) response

        The PFS plot for daratumumab looks much better than elotuzumab, at about 18 months (available data) the daratumumab plot is flattening out near 75%. There is no flattening in the elotuzumab plot, so it looks likely that daratumumab will have a longer PFS time, but how much longer is not known because the data is not in. Probably much more important are the response numbers. Far more patients responded to daratumumab than elotuzumab. 74.5% % of daratumumab patients reported a VGPR (or better) response, while only 33% of elotuzumab patients achieved a VGPR (very good partial response) or better.
        [rituximab (Rituxan)]             MD Anderson cancer site mentions this monoclonal antibody in connection with MM, but the manuf web site makes
           no mention of MM, just lymphomas and leukemias. References in the literature for this drug to back 18 years!
                                                                Rituximab is a monoclonal antibody against the protein CD20, which is primarily found on the surface of immune
                                                                system B cells. Manuf by Genetech/Biogen.
        Denosumab (for bone disease)
        Siltuximab (Sylvant)             Monoclonal antibody that binds to interleukin-6. Evaluated for other cancers. Encouraging results have been reported
                                                                in 2009 from a phase II trial for relapsed or refractory multiple myeloma. In 2014 FDA approved for another
                                                                cancer. Jannsen Biotech. By infusion.
        pembrolizumab (Keytruda)   Phase 3 trials for other cancers (melanoma and lung cancer), but being evaluated in early trials for MM
               ( MK-3475)                              Being deveoped by Meerk

Histone deacetylase inhibitor
        panobinostat (Farydak) (2015)  inhibits enzymes known as histone deacetylases (HDAC), causes apoptosis of malignant cells. Oral capsule.
                                                           FDA approved for MM in Feb 2015. "Farydak is the first HDAC inhibitor approved to treat multiple myeloma.
                                                           It is intended for patients who have received at least two prior standard therapies, including bortezomib
                                                         (velcade) and an immunomodulatory agent (revlimid). Farydak is to be used in combination with bortezomib,
                                                          a type of chemotherapy, and dexamethasone, an anti-inflammatory medication." (FDA site) Marketed by Novartis
                                                 “Farydak has a new mechanism of action that distinguishes it from prior drugs approved to treat multiple myeloma."
                                                         This drug appears to have a lot of risk. (toxic) In Nov 2014 an FDA panel decided the advantages did not out
                                                          weight the risks. The manuf then resubmitted, and got approval by more tightly restricting the candidate MM
                                                          population. The clinical trial (193 participants) showed only that adding Farydak was better (by 5 months) than
                                                         (velcade + dexamethosone). This FDA "accelerated" approval is really only preliminary approval. The manuf is
                                                          required to do more tests demonstrating clinical benefit. "The (FDA) accelerated approval program provides
                                                          earlier patient access to promising new drugs while the company conducts confirmatory clinical trials."
                                                 Yikes --- "73% of patients had dose interruptions or modifications, 87% experienced Grade 3/4 adverse events, and
                                                           33% were hospitalized due to adverse events. The efficacy advantage was modest" (FDA farydad
                                                           summary review). This is a drug that can be used only after revlimid and velcade (or ninlaro) have been used.

         vorinostat (Zolinza)     2011 Merck reported phase III results. Trial tested (Zolinza + Velcade) against Velcade alone in relapsed MM patients.
                                                            As I read the results, the benefits were modest with significantly more side effects.  This is a pill. It is not FDA
                                                         approved for MM, but it is for a lymphoma. The Wikipedia (Zolinza) page makes no mention of this drug
                                                           for MM. This drug is not new, it has been around since 2006, and since it has a wide spectrum of possible
                                                           anti-cancer uses the manufacturer keeps trying it on different cancers, many (or several) of the tests it has failed.
                                              Since I see nothing on the Merk site after 2011 or on Wikipedia about MM, I suspect its MM response was a failure too
                                                          or its benefit too small (even though that's not how Merck describes it to this day on its site!). Yup, I find this
                                                         on the Multiple Myeloma Research Foundation site --- "Merck is no longer pursuing an FDA indication
                                                          in multiple myeloma. However, since Zolinza is FDA-approved for another cancer, doctors may prescribe it
                                                          off-label for myeloma based on the data supporting its effectiveness."

                                              Wikipedia describes its mechanism of action this way:
                                                         "Vorinostat has been shown to bind to the active site of histone deacetylases and act as a chelator for zinc
                                                          ions also found in the active site of histone deacetylases. Vorinostat's inhibition of histone deacetylases results
                                                        in the accumulation of acetylated histones and acetylated proteins, including transcription factors crucial for the
                                                         expression of genes needed to induce cell differentiation."

            azacitidine (Vidaza)   Cytotoxic drug FDA-approved for the treatment of myelodysplastic syndromes (MDS) being evaluated in combination
                                                         with Revlimid-dex in relapsed or refractory myeloma. From Celegene. Chemical analog of cytidine. Approved
                                                          by FDA in 2004 for myelodysplastic syndrome.

General anti-cancer drug used for MM
        Doxil (Doxorubicin)             Doxil is a chemotherapy drug used in myeloma treatment. Doxil is an anthracycline antibiotic that works by
                                                       intercalating the DNA found in multiple myeloma. The drug has been used in traditional chemotherapy regimens
                                                       for many years. Phase 3 MM trial showed that used with Velcade it extended time to disease progression from
                                                       6.5 months to 0.3 months, Janessen Products

Experimental (nov 16)          bb2121 from BlueBird bio (Cambridge) (financed by 10 million from Celgene) is reporting Phase 1 (CRB-401) trial results.
                                                      of a customized T cell theapy. Just 9 patients, but good response. Bluebird's infused treatment is a member of an
                                                      emerging potent new type of cancer therapy called CAR T cells. Patients T cells are removed and genitically altered
                                                      to target the protein called BCMA found on cancerous blood plasma cells, then infused back in.
                                                      (individual gene therapy)

Excellent overview of most of these drugs

        Drugs marked '*' I have taken. Revlimid with the corticosteroid dexamethasone (rev/dex) was my initial chemo. When I relapsed and became refractory to Revlimid after about 20 months, Pomalyst was substituted as the anti-angiogenic & immunomodulator, dexamethasone was continued and the proteasome inhibitor carfilzomib (injection) was added (pom/carfilzomib/dex).
Drugs to counter chemo 'side effects' (9/21/17)
        After three years on continuous chemo drugs, my quality of life is affected more by the so-called 'side effects' of the chemo drugs than the underlying cancer. Every time my chemo has been changed the new drugs brings a (largely predictable) new set of side effects that attacks the body. I am  jittery (cause ???), my lungs have taken a lot of damage (from carfilzomib), and my feet are numb (from proteasome inhibitor Ninlaro).

Extreme shortness of breath
       In recent weeks (9/21/17) the biggest impact on my quality of life is a crippling shortness of breath. When I get out of the shower, I need to lie down for 5-10 minutes before I have the energy to comb my hair. After walking slowly around the market picking up a few groceries, I feel the need to sit down for a few minutes on a bench in the market before I have the energy to carry my packages out to the car. Yet when I am sitting down, or driving a car, I feel totally Ok.

Low hemoglobin levels in blood
       I am pretty sure I know (physically) the reason for this. My latest blood work shows my hemoglobin as of (9/13/17) is only 8.4 g/dL. This is only 60% of the lower edge of normal (13.8 g/dL),. This is far lower than in my whole three years of taking chemo drugs. My lungs have tested Ok, my heart has tested Ok. With this low number of red blood cells in my blood (RBC is also 60% of low normal) my blood just does not have the oxygen carrying capacity to get the oxygen from my lungs to the muscles that need it.

Low number (or poor quality) red blood cells
       While I read that normal red blood cells have a 'lifetime' (how defined?) of about four months, my blood work for aug 2017 into early sept 2017 shows a decline of hemoglobin of 38% [13.5 g/dL (near normal) => 8.4 g/dL] in just under five weeks. Either something is destroying my red blood cells, or more likely they are emerging from my chemo damaged marrow not fully formed or in an immature state. In fact my memory is the blood technicians looking at my blood under a microscope have commented that the size and shape of some of my red blood cells do not look normal. Red blood cells are basically just bags of hemoglobin, so there is a close relationship between red blood cell count (and quality) and the amount of the oxygen carry molecule hemoglobin in the blood.

Drugs to increase hemoglobin and RBC (red blood count)
        With this introduction to the oxygen carrying capacity of the blood I recently learned from the recent book of the chief hematological oncologist at MGH (Mass General Hospital) that he speaks of treating multiple myeloma patients with this problem using a drug called erythropoietin. This is a manufactured drug that is apparently the same (identical?) as a hormone the body naturally manufactures (in the kidneys primarily) to regulate hemoglobin in the blood.
Eerythropoietin (EPO) blood test
       One thought that immediately jumps to mind is that low hemoglobin might be due to the kidney damage, the kidneys not putting out the required level of erythropoietin. The good news is there is a special blood test that can measure the level of erythropoietin in the blood called the 'erythropoietin (EPO) test'.
Erthropoietin (brand names: Epogen and Procrit) --- hemoglobin raising hormone
        Ryan, the chief hematological oncologist of MGH (Mass General Hospital), in his new 2017 book 'Living with Cancer" suggests a common alternative to a blood transfusion for cancer patients when hemoglobin levels are low is a drug called erthropoietin (short hand 'epo'). This is actually a hormone the body produces mostly in the kidneys (10% in the liver) to encourage more red blood cell production. Seems likely this is a key part of feedback loop that regulates the level of hemoglobin in the blood.

Risk of deep blood clots
       Ryan notes that a significant drawback to giving this drug is that it can cause deep blood clots (which means strokes when they move), but that recent data has shown that the risks are lower than once thought. However, the clear implication of Ryan's language in his book is that he is using (and recomending) this drug in his treatment of cancer (mulitiple myeloma?) patient at MGH to treat anemia, low red blood cell counts.

            -- Erythropoietin is a protein with an attached sugar (a glycoprotein). It is one of a number of similar glycoproteins that serve as stimulants for the growth of specific types of blood cells in the bone marrow. There is a blood test for this hormone called the 'epo test'. It requires an overnight fast.

        This drug can be given as a subcutaneous injection (It was used by Lance Armstrong as an (illegal) way to improve his performance.), but to cancer patients it is given intravenously weekly.

Epogen (Amben) and Procrit (Janessen)
        Erythropoietin  is sold under brand names:  Epogen (Amben) and Procrit (Janessen). This appears to be the exactly the same drug (it has been on the market for 28 years) sold by two different manufacturers. The Epogen and Procrit prescribing documents say it can be given intravenously weekly to cancer patients: 40,000 Units weekly. This would fit nicely with my weekly daratumumab infusion chemo.  Threshold for use: hemoglobin <10 g/dL. At 8.5 g/dL I meet this threshold easily. The response time is relatively slow, something like 0.5 g/dL.

              -- Epogen® (epoetin alfa) Injection, for intravenous or subcutaneous use. Initial U.S. Approval: 1989

        Procrit® (epoetin alfa)
              -- Procrit® (epoetin alfa) Injection, for intravenous or subcutaneous use. Initial U.S. Approval: 1989

        Aranesp® (darbepoetin alfa) (a long acting version of Procrit). Approval 2001
              There appears to be less emphasis in the prescribing document for cancer patients. For cancer patients it is given weekly subcutaneously, or at a higher dose subcutaneously every three weeks.

        I wouldn't be opposed to the idea of Procrit or Aranesp (a long acting version of Procrit), but I have seen a number of blood clots induced by these drugs, several in myeloma patients, so though the risk is less than they originally thought, it is still not zero. That in combination with the risk of blood clots on Pomalyst (which you will be starting again soon, hopefully) may compound the clot risk. Again, I am not opposed, but we should discuss it further.
Huge risks of activated immune system (12/3/16)
        Long article in NYT details how 20% for single drugs (and 50% for combination of drugs) of cancer patients being treated with 'immunotherapy drugs' that activate the immune system are having major organs destroyed:  'Immune System, Unleashed by Cancer Therapies, Can Attack Organs' By MATT RICHTELDEC. 3, 2016. Doctors tend to shrug, and say this is evidence that its workng, and diabetes (with destroyed pancreas) is better than dieing.

        -- “We are playing with fire,” said Dr. John Timmerman, an oncologist and immunotherapy researcher at the University of California, Los Angeles, who recently lost a patient to side effects." The promise comes with real risks. A 2015 paper in The New England Journal of Medicine showed that use of these drugs carried a risk of side effects that were severe, required hospitalization or were life-threatening 54 percent of the time. “It’s at least that high, at least,” Dr. Kluger said. But, she noted, most of the side effects are manageable through immune suppression, such as with steroids.

Proteasome inhibitors
        -- Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins. Multiple mechanisms are likely to be involved, but proteasome inhibition may prevent degradation of pro-apoptotic factors such as the p53 protein, permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro-apoptotic pathways. For example, bortezomib causes a rapid and dramatic change in the levels of intracellular peptides.[1] Proteasome inhibitors are being studied in the treatment of cancer, and three are approved for use in multiple myeloma. (Wikipedia -- Proteasome inhibitors)

        -- Bortezomib's boron atom binds the catalytic site of the 26S proteasome. Bortezomib (Velcade) was approved in 2003, the first proteasome inhibitor for use in the U.S. Carfilzomib irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome. It was approved by the FDA for relapsed and refractory multiple myeloma on July 20, 2012 under the brand name Kyprolis.

        -- Proteasomes are protein complexes inside all eukaryotes and archaea, and in some bacteria. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds.

      -- The ability of proteasome inhibitors to induce apoptosis (programmed cell death) in rapidly dividing cells has been exploited in several recently developed chemotherapy agents such as bortezomib (Velcade). (Wikipedia)

        -- Proteasome inhibitors have effective anti-tumor activity in cell culture, inducing apoptosis by disrupting the regulated degradation of pro-growth cell cycle proteins. This approach of selectively inducing apoptosis in tumor cells has proven effective in animal models and human trials.

        -- The results highlight that the proteasome is a novel biochemical target and that inhibitors such as PS-341 represent a unique class of antitumor agents (1999 paper).

        -- Notably, multiple myeloma has been observed to result in increased proteasome-derived peptide levels in blood serum that decrease to normal levels in response to successful chemotherapy.

2011 review of Proteasome Inhibitors
        Bortezomib (Velcade)  ---- based on boron atom, Millennium/Takeda
        MLN9708  (ixazomib) (Ninlaro)  --- also based on boron atom,  Phase 3 trials, Millennium/Takeda
        Carfilzomib --- based on
        ONX 0912
        NPI-0052 -- Marizomib, infusion
Pomalyst and Kyprolis (6/13/16)
        FDA approval of both Pomalyst 2013 and Kyprolis 2012 is for patients previously treated with velcade, but doctors are free to ignore that.

        GoodRx reports Pomalyst is covered by all Medicare Part D plans.

Comments from 2013
       Vincent Rajkumar, Mayo Clinic says Pomalyst is an important addition for the treatment of multiple myeloma, and it is very well tolerated.

       In a large clinical trial of Pomalyst in heavily pretreated patients, nearly all of whom were refractory (resistant) to Revlimid, about 1/3rd had some response (most a partial response) to Pomalyst, but the effected lasted only a few months. So there's some evidence that Pomalyst makes sense as a replacement for Revlimid, if Revlimid has stopped working.

        Kyprolis will be mainly used for patients who have pronounced neuropathy (nerve damage) due to Velcade.

        -- The investigators note that the efficacy of the Revlimid (lenalidomide)-Velcade-dexamethasone (Decadron) combination appears to be lower than that of the three-drug combination of Kyprolis (carfilzomib), a newly approved drug in the same class of drugs as Velcade, combined with Revlimid and dexamethasone.

        -- In a trial of the Kyprolis-Revlimid-dexamethasone combination involving patients similar to those in the current study, 77 percent of patients responded to treatment, and the median progression-free survival was 15 months.

        --  Phase 2 trial (2014, 64 patients) Revlimid-Velcade-Dexamethasone (rev/vel/dex) Trial In Relapsed Multiple Myeloma,. The median progression-free survival was 10 months after the start of treatment. The median overall sur­vival was 30 months from the start of treatment.

        -- Initial results of a large, head-to-head clinical trial (2015) show that relapsed myeloma patients treated with high-dose Kyprolis and dexamethasone had twice the progression-free survival of relapsed patients treated with Velcade and dexamethasone. Median progression-free survival in the Phase 3 trial was 18.7 months in trial participants treated with high-dose Kyprolis (carfilzomib) and dexametason (Decadron), compared to 9.4 months in in patients treated with Velcade (bor­tez­o­mib) and dexamethasone.

        -- In particular, patients who received Kyprolis during the study were more likely to experience heart failure, kidney failure, high blood pressure, and breathlessness than the Velcade-treated patients. At the same time, peripheral neuropathy occurred less frequently in the Kyprolis-treated patients in the EN­DEAV­OR trial than the Velcade-treated patients.

        In November 2015, the FDA granted accelerated approval for Darzalex, which is a first-in-class immunotherapy treatment (a monoclonal antibody), which works by helping your immune-system cells attack cancer cells. Darzalex is approved for patients who have received at least three prior treatments for multiple myeloma, meaning the disease has become resistant to the other treatments or has progressed within a short period of time after the last treatment.

Dana Farber is researching Darzalex
        Darzalex clinical trial investigator Paul G. Richardson, M.D., Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, said:

        “Multiple myeloma is a highly complex disease and remains incurable, with almost all patients relapsing or becoming resistant to therapy … With DARZALEX, we have a promising new immunotherapy, which has shown pronounced efficacy as a single agent with an acceptable adverse event profile. This is especially important for treating these heavily pre-treated patients in whom all of the major classes of currently available medicines have failed.”

        The FDA accelerated approval was based on two open-label studies: In a study of 106 patients receiving Darzalex, 29 percent experienced complete or partial reduction in their tumor burden, lasting an average of 7.4 months. In a study of 42 patients receiving Darzalex, 36 percent had complete or partial reduction in their tumor burden.  (Note only a minority of patients responded at all, and this is typical of immunotherapy, and survival time was 7 months.)

        Darzalex is given as an infusion; potential side effects included the following: Infusion-related reactions (experienced by half of patients):  Fatigue,
Back pain, Fever and nausea, Cough, Low white blood cell count, Low red blood cell count (anemia), Low levels of blood platelets (thrombocytopenia)

        --  Advanced options include immunotherapy to help your body fight the cancer and new methods for stem cell transplantation. In addition, we are actively pursuing answers to reducing the side effects of multiple myeloma and its treatment. For instance, we were instrumental in finding that bisphosphates often can decrease bone-related events in multiple myeloma.

        Chemotherapy -- Drug therapy is the usual starting point in treating multiple myeloma. MD Anderson offers the most up-to-date and advanced chemotherapy options. Liposomal drug delivery is an innovative method that can help chemotherapy be more effective.

        Immunotherapy -- MD Anderson is among just a few cancer centers in the nation that are able to offer targeted therapies for some types of multiple myeloma. These innovative new drugs stop the growth of cancer cells by interfering with certain proteins and receptors or blood vessels that supply the cancer with what it needs to grow. Possibilities may include:

        Monoclonal antibodies, including Rituxan® (Rituximab)
        Biological therapies that develop antibodies to destroy cancer cells
        Proteasome inhibitors, such as bortezomib (Velcade®)
        Immune modulators, such as thalidomide and lenalidomide, that modify the environment of the tumor cell and allow it to die
        Small molecule treatment, such as panobinostat
        Cytokine therapies
        Vaccine therapy
        Bisphosphonates help reduce high calcium levels and decrease the risk of bone fracture

        -- Celgene and Juno Therapeutics, Inc. agreed on a long-term collaborative partnership to bring CAR T-cell therapies and T cell receptor technologies to market for cancer patients. (aug 2015)

        -- For the study, the patient’s T cells were genetically engineered to contain a receptor for a tumor antigen known as cancer-testis antigen (CT antigen), two of which are present in about 60 percent of patients with advanced myeloma. With the CT antigen receptor, the T cells were equipped to spot the myeloma and subsequently employ the immune system to find and destroy it. The results showed that 14 out of 20 patients (about 70 percent) had a near-complete or complete response three months after treatment; median progression-free survival was 91.1 months, while the overall survival lasted 32.1 months. (study by University of Maryland Medical Center)  (This study first did a stem cell transplant before injecting the modified T cells.)
(from a NYT article on immunotherapy (July 2016)
        Drugs called checkpoint inhibitors are the most widely used form of immunotherapy for cancer. They block a mechanism that cancer cells use to shut down the immune system. This frees killer T-cells — a critically important part of the immune system — to attack the tumor. Four checkpoint inhibitors have been approved by the Food and Drug Administration and are on the market. They are given intravenously.

        Another form of immunotherapy, called cell therapy, involves removing immune cells from the patient, altering them genetically to help them fight cancer, then multiplying them in the laboratory and dripping them, like a transfusion, back into the patient. This type of treatment is manufactured individually for each patient, and is still experimental.

        Bispecific antibodies are an alternative to cell therapy, one that does not require individualizing treatment for each patient. These antibodies are proteins that can attach to both a cancer cell and a T-cell, that way bringing them close together so the T-cell can attack the cancer. One such drug, called Blincyto, has been approved to treat a rare type of leukemia.
new drug I've read about

        filanesib (Arry-520)           (novel mechanism!)      Filanesib is a highly selective, targeted KSP (kinesin spindle protein) inhibitor with a mechanism of action distinct from currently available myeloma therapies such as immunomodulatory drugs (IMiDs®) and proteasome inhibitors. In phase 2 trials (2014-2016) & (13-16) for Relapsed and Refractory Multiple Myeloma . Being tried on patients with disease refractory to carfilzomib and/or pomalidomide. (?? conflicts with trial data) Intravenous.  Anderson cancer center testing

       Potential selection marker for filanesib is (alpha 1-acid glyycoprotein (AAG). Never heard of this. Described as an "acute phase serum protein used to diagnose and monitor inflamatory disorders." This protein binds to filanesib. They seem to be saying this protein has to be low for filanesib to work because it attenuated filanesib in vitro. AAG is measured in g/L (graphs show 0 to 2.8 g/L).

21 slides     being investigated alone and with dexamethasone (booster)

        Being tested (phase 2) as a supplement to carfilzomib (proteasome inhibitor):  carfilzomib (Kyprolis)   vs     (carfilzomib + falanesib)

Criteria for entry into phase 2 trial
**          -- A monoclonal Ig (M-protein) concentration on serum protein electrophoresis (SPEP) of > 1.0 g/dL.
**            -- Involved serum free light chain (FLC) level > 10 mg/dL, provided the serum FLC ratio is abnormal.
Papers (3/16)
         (Velcade + rev/dex) vs rev/dex   ** velcade extended PFS from 1.5yr (rev/dex) to 2.5 yr       800 patients  Conclusions: The use of KRd after first relapse led to a 1-year improvement in median PFS vs Rd (rev/dex).  six infusions (10 min) per month


Cyclophosphamide (cytoxan) (1959)  nitrogen mustard alkylating agent, Cyclophosphamide induces beneficial immunomodulatory effects,
                                                                 quite toxic  (substitutes for Revlid in patients that can't tolerate Revimid)
Melphalan  (1964)                          alkylating agent,  nitrogen mustard alkylating agent
Vincristine                                       general anti-cancer drug, hair loss
Liposomal Doxorubicin (doxil) (2007)  anthracycline antitumor antibiotic, general cancer drug, hair loss. Used with velcade.

* Dexamethosone                             synthetic corticosteroid drug  (used with Revlimid as popular 'rev/dex' and Pomalyst as 'pom/carfilzomib/dex' )
Prednisone                                      synthetic corticosteroid drug

* Zoledronic acid                             bisphosphonate, Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma
Pamidronic acid                               nitrogen-containing bisphosphonate, used to prevent osteoporosis

Plerixafor                                         (mobilizes stem cells for later transplant)
Carmustine                                        alkylating agent in chemotherapy, (used in preparation for stem cell transplant), general cancer drug

* acyclovir  (generic Zovirax)        anti-viral used to prevent the chickpox virus (varicella-zoster) remaining in the body from becoming active
                                                                    again and causing shingles (herpes zoster). Available 400 mg and 800 mg pills.
                                                                    My dosage: 400 mg, three times a day (1,200 mg daily).
                                                         Usual Adult Dose for Varicella-Zoster (chickenpox): 800 mg/four times a day (3,200 mg daily dose)
                                                         Usual Adult Dose for Herpes Zoster (acute): 800 mg orally every 4 hours (5 times a day) (4,000 mg daily dose)
                                                         Usual Pediatric Dose for Herpes Zoster (12 years or older): 800 mg orally every 4 hours (5 times a day)

valacyclovir (Valtrex)                     available in 500 mg and 1,000 mg pills. My dosage: 1,000 mg daily

Anti-viral pill size
        To prevent a proteasome inhibitor (like calfilzomib) from activating the chickpox virus which many people have in their body (including probably me) an anti-viral need to be taken daily. Recommended for me by my Dana Farber consultant is acyclovir 400 mg TID (TID means in latin 'ter in die' or three times a day) or valacyclovir 1,000 mg daily.

        The (heart shaped) pill size of 400 mg acyclovir I obtained from my local pharmacy is 11 mm (largest dimension). For reference my pomalyst capsule is 17 mm long (measured), and I have no problem swallow it. Some valacyclovir 1,000 mg capsules are even bigger (21/22 mm long). Valacyclovir 1,000 mg may be available in 17/18 mm capsules, but I know valacylovir 500 mg is available in a 17/18  mm long capsules. Ref: (1/2^.333 = .79 and .79 x 21.5 = 17)

        A trip to my local CVS shows that their 500 mg valacyclovir is the 17/18 size capsule (M122, white) and their 1,000 mg is the 21/22 size capsule (M123, white).

        So options for fewer easier swallowing anti-viral are either take two (moderate size) 400 mg acyclovir morning (with food) and one 400 mg evening with pom (no food).  I see 800 mg is the usual adult and even pediatric dose when treating chickenpox and shingles, so 800 mg does not seem unreasonable.  Or switch prescription to (relatively large) valacyclovir 500 mg and take one morning and one evening. The former is preferred.

        I asked my doctor about taking acyclovir 2 x 400 mg morning (with food) and 400 mg evening (no food) and the response was 'perfectly reasonable', so that's the plan.

Combinations used in clinical trials
        Revlimid and dexamethasone (Rd)                                            (rev/dex)
     * Pomalyst, carfilzomib, and dexamethasone                                (rev/carfilzomib/dex)
        Melphalan, prednisone, and Revlimid (MPR)                           (added alkylating agent (Melphalan) and prednisone substitutes for dex)
                                                                                                           earlier version was Melphalan, prednisone, and Thalidomide (MPT)
        Cyclophosphamide, prednisone, and Revlimid (CPR)              (added alkylating agent (Cyclophosphamide) and prednisone substitutes for dex)

                      Mar 2016 paper with 600 patients showed adding an alkylating agent to Revlimid did not improve progression time.

Toxic side effects of various MM drugs (6/10/16)
        Kyproli --- seems to have a ton of toxic side effects. Most worrying is that a #1 serious side effect is pneumonia, which I read causes 20%
                              of MM deaths.
        Ninlaro --- just added to cycled rev/dex whose schedule doesn't change. Ninlaro is taken just three days a month, three of the same days dex
                            is taken. Most serious side effects are diarrhea and low platlets, but peripheral neuropathy (nerve pain) is also listed.
        Velcade --- can be given once a week for 2 or 3 weeks a month. Velcade can reactive shingles virus in body (causing painful rash), so a
                              'medication' may need to be taken to prevent shngles.
                       ** -- List of serious side effects in much longer with velcade than Ninlaro.
                            --  "Prompt dose reduction and a change in the schedule of Velcade administration are essential in managing peripheral neuropathy
                                    should it develop."
                           -- once-weekly Velcade dosing is used more frequently because it has been associated with fewer side effects
                            -- Subcutaneous administration of Velcade may also lessen the development of peripheral neuropathy.
                           Hence this argue for velcade once a week, subcutaneous (in theigh or belly fat) with a rapied dose reduction it nerve pain
                                 develops. Poster report this nerve pain (hands and feet) is often permanent nerve damage.
       Revlimid ---  Common side effects of rev/dex include the following, all of which I have: Diarrhea and constipation, fatique, insomnia, back pain.
                                "Some side effects such as mild or moderate diarrhea can be managed with additional medications."
                                "Revlimid significantly decreases the risk of myeloma disease progression. " (didn't work well for me)

Good reference for side effect of many MM drugs (seems to be just a compendium of manuf proscribing statements)

Ninlaro -- Recent status change
        On 11/20/15 Millennium Pharmaceuticals announced that its pill version of velcade, which has been in phase III clinical trials (experimental name MLN9708), has been approved by the FDA for use with rev/dex in relapsed MM. It's the only FDA approved oral proteasome inhibitor in pill form. This FDA approveal is based on (early, partial) results of the TOURMALINE-MM1 phase 3 clinical trials, which are to be reported on at the Annual Meeting of the American Society of Hematology on December 7, 2015. This study is continuing and there are three more TOURMALINE phase 3 clinical trials of this drug in progress (related to MM).

TOURMALINE-MM1, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma (early results have resulted in FDA approval for ixazomib in Nov 2015 and are to be reported at a hematological annual meeting Dec 5, 2015)
(TOURMALINE-MM1 phase III clinical trial (relapsed MM) uses 4 mg Ninlaro pill, three pills/28 day cycle. Revlimid is cycled)

TOURMALINE-MM2, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (clinical trial I was offered)

TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)

TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone autologous stem cell transplant (ASCT) (Millennium press announcement of may 2015 says first patients enrolled in this study.)

        Looks to me like Ninlaro is probably available, or will be soon, because a detailed (23 page) prescribing document is online here. I left a note with my oncologist asking if this FDA approval means it is likely to be available soon.

       Millennium says protease inhibitors (by which they mean velcade) have a long established history treating MM, and with the TOURMALINE clinical trials they are exploring the use of their new protease inhibitor in oral form (ixazomib) in "every major multiple myeloma patient population", so clearly they have expectations (or hope) that this pill will be useful as a general MM chemo drug. The TOURMALINE-MM-4 trial, which just began enrolling patients in 2015 (may 2015), is of particular interest to me because I didn't have a stem cell transplant and am now on (revlimid) maintenance. My understanding is that when the FDA approves a drug clinicians are free to use it 'off label'.

        A MM blog has an interesting discussion of Ninlaro, including its cost, and other new MM drugs:

Ninlaro update (4/5/2016)
Ninlaro (ixazomib) price (4/5/16)
        Ninlaro is now showing up in drug price search sites. This is a once a week pill, three pills per 28 day cycle. The MA drug discount site shows the price without insurance is $3,000/pill (round numbers) or (8,694  to 9,214 for a three pill cycle). It is available through local pharmacies, the lower price (500 saving is Stop and Shop pharmacy). It is available in 4 mg, 3 mg and 2.3 mg. Price is same for all doses. Blink Health gives a comparable price (90k for 30 pills).

        My medicare part D insurance coverage is provided by Cigna. I find (see below) Ninlaro is in Cigna's list of covered drugs. It's appoval is for use with rev/dex. I spend 11 months of the year in part D catastrophic coverage, so this reduces my out of pocket cost 95% (9k/month to 450/month).

Ninlaro in Cigna pharmacy list (prior approval), capture 4/5/16

Medicare Part D insurance coverage
       Next day (4/6/16) I called Cigna, my Medicare part D insurer, to confirm Ninlaro is in the Cigna formulary. It is, but with two restrictions. One is three pills/28 day cycle. (Why is this not shown online!) Two, is prior approval required. It was explained to me on the phone that either I, or my doctor, can request this approval. Cigna then consults with doctor before granting approval. This can be expedited to 24 hrs. The number to call to request coverage is: 877-813-5595.

Ninlaro update (2/1/2016)
        As I write it is 2.5 months since FDA approval of Ninlaro, and I still had no idea if was available, so I decided to make some phone calls. Today I called a speciality pharmacy where I am a customer (Cigna Speciality Pharmacy), a pharmacy I know handles expensive tier 5 cancer drugs because I get my Revlimid from them monthly. Ninlaro wasn't on the list of drugs that the customer service person had available, but she said it might be in limited distribution, so she contacted the pharmacists. When she returned she said the answer was good news and bad news.

        She said it could be ordered, but was not presently in stock. However, Cigna would require 'prior approval' for this new drug, which formally means the doctor must contact the pharmacy and (typically) explain the patient need for it. Now what this means in practice is hard to say. Is the 'prior approval' requirement here a low or high barrier? If Ninlaro is viewed as interchangeable with Velcade (from the insurance company point of view, not mine), a prior approval bar might be tricky. For example, they might decide to only approve it if you live xxxx miles from an infusion facility. I suspect the only way to find out if it's really available would be with prescription in hand. Maybe I can find info on MM forums. I did find a forum posting about the wholesale price given by someone at Takeda at the time of the FDA approval to inquires by the forum.

        Here's what I know about Ninlaro as of 2/1/16

Available                                    maybe  (can be ordered, but not in stock says Cigna Speciality Pharmacy)
Covered by Part D                      maybe (prior approval required at Cigna)
Price                                           8,670 (wholesale) for 28 day cycle (forum posting 11/21/15 on MM Beacon)
Dosing                                        3 pills in 28 days cycle (beginning of week 1,2,3)
National Drug Code                   63020-078-02,   63020-079-02,   63020-080-02            (indentifies:   manuf - drug & dose - package)
         FDA search, (Wiki, National drug code)
        She also gave me the National Drug Code for Ninlaro and said she was marking it on the paperwork, so if I called again, the drug could be found. (As I wrote it, it was only for lowest dose, above is from FDA site.) This is an FDA list of regiestered and approved drugs. Entering 'Ninlaro' in the 'FDA search' link (above) as proprietary name brings up three entries for Ninlaro [078 (2.3 mg), 079 (3 mg), 080 (4 mg)].

        FDA in 2015 gave "accelerated" approval to Farydak, which has a new mechanism of action, but it has only been clinically tested with Vecade (not revlimid) and is to be used with Velcade. "Accelerated" FDA approval means the drug is available on the hope that it will prove clinically beneficial, but the phase 3 clinical trials are still ongoing (with I guess no reported results yet)!

Compassionate Use (1/10/16)
        There's a way to access new drugs in the pipeline, those without FDA approval, via what is known as FDA Compassionate Use program (see link below). I first heard about this in the long PBS series on cancer, and recently it was mentioned in a NYT front page story about the head of the FDA drug approvals. A request to access a drug must be filed with the FDA. The article said the FDA receives about 1,000 compassionate use requests a year and approves 99% of them. The requests have to come from a physician.

        Here's an FDA site on its compassionate use (also called expanded access) program:

MM treatment history
        "Prior to 2003, the prognosis for a patient diagnosed with multiple myeloma was very grim, as the standard therapies were largely ineffective. People diagnosed with multiple myeloma rarely lived beyond three years. However, in 2003, the FDA approved bortezomib (Velcade®), a new therapy for myeloma, advanced with LLS support. This marked the first new effective treatment for myeloma patients and more than tripled survival rates for some patients. Other promising therapies followed, including lenalidomide (Revlimid), an oral therapy, and thalidomide (Thalomid ®), approved within a month of each other in 2006, giving myeloma patients even more options and more hope, extending lives and improving quality of life. Over the past 15 years, approximately 40 percent of therapies approved by the FDA to treat cancers have been specifically for blood cancers." (I find it very odd that thalidomide was approved the same time as revlimid as revlimid is a 2nd generation thalidomide that is more effective and with far less side effects.) (from Leukemia & Lymphoma Society, which supports MM research)

FDA approval 'zoo'
        What does FDA approval mean anyway? According to the FDA web site FDA approval is required to market a drug in the USA. So in practical terms I would expect once a drug in the developmental pipeline gets FDA approval, it will soon be available for doctors to prescribe. A Q&A web site on this topic says how long it takes for commercial availability of a drug after FDA approval depends on the company. If the company is pretty certain that it will get FDA approval, say with a generic where it is only necessary to demonstrate equivalence, it may stockpile the drugs in advance. Other times a company may wait for FDA approval before beginning to ramp up the manufacturing and distribution process.

        The general requirement for FDA approval of new drug is that the company submit data showing that the drug is both safe and effective. In the 'old days' this meant a new drug would typically would get FDA approval only after successfully completing phase 1,2 and 3 clinical trials.

        Phase 1 is to establish dosage and can be just a dozen people
        Phase 2 is larger and the goal is to establish the drug (at the dose determined from phase 1) is safe, though it may sometimes provide 'hints'
                         that a new drug is effective
        Phase 3 is a large, long trial demonstrating effectiveness over existing regimens. In chemo drugs for MM this is often a double blind trial with
                         700 or so participants where the new drug is compared against a placebo. Trials for MM often extend five years or more. When the
                         time is added to set up the trial, recruit hundred of patients, and write up the results, the total time for a large phase 3 trial can be
                        7-8 years.
        Such a long pipeline for new drugs has resulted in consumer groups and politicians pressuring the FDA to expedite the drug approval process. The result is a 'zoo' of FDA approvals, some of them quite surprising. A drug my gain FDA approval from early results of a phase 3 trial (while the trial continues), or even FDA approval from phase 1 and phase 2 alone with phase 3 trial acting as a "confirmation" of the 'hints' of effectiveness from the phase 2 trial. Both of these approvals have been seen in MM drugs gaining FDA approval in 2015. The FDA granted 'priority review' and 'orphan drug' designations for Ninlaro.
Accelerated FDA approval
        FDA Accelerated Approval Program allows for earlier approval of drugs that treat serious conditions ... based on a surrogate endpoint. A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval.  (Farydak received an accelerated FDA approval though I can't determine what the surrogate marker is.)

        Drug companies are still required to conduct studies to confirm the anticipated clinical benefit. These studies are known as phase 4 confirmatory trials. If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug.  If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.

Breakthrough Therapy
        Intended .... to treat a serious or life threatening disease ... and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. If a drug is designated as breakthrough therapy, FDA will expedite the development and review of such drug.

Priority review status
        Priority review status is granted if a drug would be a significant improvement in safety or effectiveness in the treatment of a serious condition. (Ixazomib was given priority review by the FDA. It also has orphan drug status.)

Options for relapsed muliple myeloma
        While my cancer numbers are now low, driven down by rev/dex chemo, and I am on revlimid maintenance (10 mg), but at some point virtually guarenteed this regimin is going to stop working, and my cancer levels are going to start to rise. So this is the time to research chemo options for patients who are relapsing from rev/dex chemo. (search term: 'relapsed multiple myeloma')

        I asked my hemotologist about this, and she suggested go back to rev/dex but supplement it with velcade (This was a few weeks before the FDA appoval of Ninlaro, the pill version of Velcade.)

        I read one option is go back to the chemo option that worked initially.

        *** A 2015 article in Mayo Clinic newsletter discusses "New 3-drug treatment for relapsed multiple myeloma" which was recently published in the New England Journal of Medine:

        "In the treatment of relapsed multiple myeloma, the addition of carfilzomib (proteasome inhibitor like velcade) to a currently accepted two-drug combination produced significantly better results than using the two drugs alone." "Patients taking three drugs — carfilzomib, lenalidomide and dexamethasone — stayed free of disease progression for 26 months on average," he said. "No one has reported anything like this before for relapsed multiple myeloma." "Researchers found that adding carfilzomib to standard treatment with lenalidomide and dexamethasone resulted in an additional 8.7 months of remission, bringing it to 26.3 months — almost 50 percent longer than the 17.6 months of remission under the standard two-drug combination. This was a phase III clinical trial with 792 patients. (This is encouraging, two more years after a relapse.) Note Mayo is the lead researcher of this drug, so is not unbiased.
        So a key issue is the pros and cons of velcade vs (newer) carfilzomib, since both are injectable proteasome inhibitors made by different companies. Certainly carfilzomib comes with a long list of serious side effects.

Injection protocol
        Onyx web site shows the recommended injection protocol is six injections during a four week cycle: two consecutive days for three weeks of a four week cycle. The infusion (into a vein) is fast, just 10 minutes. This is for one year, then for next six months it's scaled back a little to four injections per cycle: two consecutive days every other week.

        Of course, the little shits at Onyx on the many web pages devoted to kyprolis carefully conceal the cost of the drug, but you can be sure it is expensive. So much for republicans claiming that medical costs will come down if patients shop around. The drug companies make this very difficult.

Will Medicare pay?
        After 15 months of dealing with Medicare and my cancer I still don't have a clue as to how to check for whether a drug, a test, a consultation, or procedure would be paid for my Medicare. With new (and likely super expensive) cancer pills being appoved by the FDA for MM this could be 100,000 dollar issue for me in the future. I find this on the web site:

        "Talk to your doctor or other health care provider about why you need certain tests, items or services, and ask if Medicare will cover them. For more information, call 1-800-MEDICARE."
        All I get from my oncologist is warning that a test or drug I inquire about may not be paid for by my insurance, but no hard specific information. In over a year I have never gotten any specific medicare costing or coverage information from any of my Lahey doctors who I sense avoid the topic like the plague. My local GP is different. Last winter I needed two routine vaccines, one was give to me in his office, but he told me I would be better off getting the other from a pharmacist, because that way it would be covered by Medicare.

Vertebrae terminology and anatomy
        Vertebrae have a basic shape, described by a common terminology, that is consistent through the whole back and neck. The center hole, of course, is for the spinal cord, which is protected by being enclosed in a flexible bony sheath. In the neck (cervical) vertebrae two additional small holes on the sides are for blood (artery) vessels to the brain. The bulk of the bone, which is toward the front of the body, is called the 'body' and provides weight bearing. Notice it is more massive in the lower (lumbar) vertebrae, which must bear the weight of the chest, arms and head, and smallest in the neck (cervical) vertebrae which only bears the weight of the head.

        The bony loop around the spinal cord has three main regions: 'body' (front, bot in figure), 'pedicle'(s) (side extensions) and 'lamina'(s), which form the rear section of the loop. Also in the main loop in the upper back and neck between the pedicle and and laminar are 'facets'. The figure below left shows that the facet is sort of a flattened (lubricated) area of the lamina as its joins the pedicle. The figure below right shows the facets of the vertebrae align and slide on each other (sort of like the knee). Bony projections that stick out from the loop tend to be called processes. These projections serve as attachments points for ligaments and muscles. All the vertebrae have a projection (process) to the rear of the body, and as the figure below left shows these (spinous process) tilt downward. Notice in the figure below left how tightly interlocking the rear projections are and how their upper and lower facets line up allowing each vertebrae some (controlled) motion relative the vertebrae above and below.

        In the neck I know these rear projections form a mechanical stop which determine how far back you can tilt your head, and very likely the rear projections of the vertebrae in the spine provide a hard limit as to how far back you can arch your back. Holes are called foramen, both the big one for the spinal cord and little ones for the blood vessels. The holes for the blood vessels (transverse foramen) in the neck are (in effect) created by the pedicle regions splitting. The inside split is then called the pedicle and the outside split the lamella.

Vertebrae terminology
(source (left) --
(source (right) --

Cervical anatomy
        My main interest is of course C2 (axis) which in my case is what the cancer broke. In terms of the terminology of vertebrae C2's vertical 'dens' projection sits right on top of C2's 'body'. C2's dens projects up into the main hole of C1 (atlas) forming a pivot about which C1 (and the skull) rotate as the head turns side to side. As a pivot it cannot be weight bearing. So the weight of the skull (via C1) is born by the two large facets on the upper side of C2 that mate with matching lower facets on C1, the facets providing a sliding joint that allows +/- 45 degrees rotation between C1 and C2, rotation that I have lost permanently because of my C1,C2 fusion operation.

        The interface between the C1,C2 vertebrae is quite unusual. A striking feature of spinal anatomy diagrams is a (spongy) disk exists between each of the bony vertebrae, but that is not true of the C1,C2 interface. There is no C1,C2 disk. A fundamental reason is that the C1 vertebrae has no body, and disks go between the (weight bearing) vertebral bodies! The video I saw about C1 and C2 called them 'atypical' vertebrae. The weight of the head presses down on flat spots toward somewhat to the sides of C2, and it transmits that force to C3 through C2's body and C2,C3 disk. The distance between the C2 weight bearing facets and the C2 body forms a lever arm, and the stress on this lever arm is lowered by the facets being toward the front not too far from the body and dens.

        The C1,C2 weight bearing interface rather than being a disk is a sliding (cartilage like) joint on both sides of the bony loops that allows C1 (and the skull) to rotate +/- 45 degrees with respect to C2. These sliding joints support allthe weight of the head. In all other vertebrae interfaces the weight bearing is through the 'body' of the vertebraes and the intervening disks. The fact that the body of the C2 vertebrae on the top side is not weight bearing allows its shape to be modified and to project up in the front forming a 'dens' that servers as a pivot point around which the front rounded arch of C1 turns. And C1 is unusual too in that it has no body. Where the body would normally be, which is toward the front, it has an anterior arch that pivots on the C2 dens as the head rotates.

        Notice in the figure above right how at the rear all the vertebrae seem to interlock. A side view shows between the body and the large rear processes (projection) the bones neatly line up. At this interface both the top and bottom vertebrae are flattened and have cartilage (forming a facet) such that two (small) sliding joints are created one each side of each vertebrae. This helps interlock the vertebrae together, but still allows some (limited) movement between them.

        This is particularly important to me as I have had C1,C2 fused, so I need to get as much rotation as possible from my other other neck (and back) vertebrae facet joints. Eleven months after my operation, a physical therapist has begun to work these C2 to C7 facet joints to as she says 'stabilize' and 'loosen' them up.

Fracture of dens (Wikipedia 'Axis')
        I either had a type II or III fracture of C2 dens, though I would need to confirm this will my surgeon. At my one year follow up I asked my surgeon this question. He said it was a type II fracture, or (maybe) type II/III since it looks like there was some extension into the body.

        -- C2 (axis) forms the pivot upon which the first cervical vertebra (C1, atlas), which carries the head, rotates. Fractures of the dens, not to be confused with Hangman's fractures, are classified into three categories according to the Anderson–D'Alonso system:

               Type I Fracture - Extends through the tip of the dens. This type is usually stable.

                Type II Fracture - Extends through the base of the dens. It is the most commonly encountered fracture for this region of the axis. This type is unstable and has a high rate of non-union.

                Type III Fracture - Extends through the vertebral body of the axis. This type can be stable or unstable and may require surgery.

How the C1,C2 dens joint really work
        My cervical surgon says the dens does not provide lateral support, but when he described how lateral support was provided, I'm not sure he understood I was asking about how the head is supported when the head is horizontal.
        Found an excellent video (see under picture) focusing on C1,C2 that shows how the C1,C2 dens joint provides lateral support for the head. C1's front (anterior) arch and the C2 dens projection are touching, so the skull cannot move to the rear. But I have always wondered how the skull is prevented from moving laterally forward. The narration in the video provides the answer. A ligament runs across C1 between its two side lateral masses that goes around the back of the dens! To keep it from interfering with the spinal column this C1 ligament must be attached to the side masses quite far forward. This ligament also protects the spinal cord by keeping the dens off to the side (really the front) of the C1 large center hole. So there's the answer: C1 (and hence the skull) is supported laterally by the big, strong C2 den with a C1 bony arch on one side and a C1 ligament on the other. The C2 dens, of course, is structurally connected to the spine.

C1 dens encircling ligament
        After writing about the C1/dens ligament (above), I found the figure below (right). It clearly shows that C1 has a thick side to side ligament that does (as I had presumed) wrap closely around the C2 dens. Thus it's clear the lateral stability of the head is provided by this encircling of the C2 dens. In this way the strength of the spinal column can support the weight of the head when the bending over with the head horizontal.
        This understanding helps answer another question that has been bothering me since the operation. How did the C1,C2 fusion operation, fixing the C2 to C1, hold the dens (and weakened bone) in place so the fracture could heal? I can see now that with the body of C2 attached to the body of C1 with hardware the dens in held in place laterally by the C1 anterior (front) arch and a C1 right to left ligament on the back side, and at least when the body is upright, gravity will pull the dens down.

Left: C1 (atlas),C2 (axis) dens joint (video screen capture)
(these look like real bones)
Right: C1 ligament that wraps arund the C2 dens
(source, left --
(source, right --

Here's C1 rotating about the C2 dens

C1 pivoting on C2's upward projection (dens) allows the head to substantially rotate
(C1's anterior (front) arch has an inside round facet joint with cartilage where it mates with C2's dens)
(source --

Reviewing my scans
        I have figured out something about reviewing my scans (CT scans, MRI scans, and x-rays) at home. Lahey records charges a lot for copies of my medical record, but (weirdly) they provide DVDs of patient scans for free. However, there's a problem with reviewing scans on your home computer, and I am pretty sure I have figured out what the problem is.

        The problem was clearly demonstrated with the CT scan of my neck done 9/16/15, one year after my C1,C2 fusion operation, and just an hour prior to my visit with my neck surgeon. The CT scan was on the screen in the room where I was waiting for the doctor to come in, and I was using the mouse to move it and look at it. The screen display at the hospital was very nice with the screws clearly standing out as they were (automatically) hi-lited in a different color. The whole neck was displayed in 3D and with the mouse I was able to easily rotate the image. When the doctor come in, he zoomed into the screws and showed me a dark shadow near one of them indicative of lack of bone growth into the screw. However, when I got the DVD of this CT scan I saw nothing like what I had seen in the doctors room. The same thing happened in Oct 14, where the excellent view of my T12 bone loss showed to me by my radiation oncologist, I could never find on the DVD provided.

Primitive viewing software provided to patient
       I think what is happening is this. The hospital has state of the art, expensive, software that can take the raw CT and MRI images and create polished 3D images for viewing. But what the patient gets included, when his images are requested from the hospital, is a very basic (primitive) software package that can only step through the raw images and make contrast adjustments. No 3D modelling software is given to the patient. The result is little information is available to the patient from CT scan and MRI images. For example, I couldn't see the screws at all at home, whereas in the hospital they stood out clearly, much less the luciencies around the screws. X-rays may be the exception, I don't know how much more the hospital software can process x-ray, though I could hazard a guess that one thing it may be able to do is take calibrated measurements.  I should research this. I might be able ot find better display software online.

Free healthcare software
        A quick Google shows there are free software viewing packages for CT scans available (geared to doctors), though I would think it likely that the manufacturers of CT machine have proprietary package. Below are  a few that showed up searching 'ct viewing software'. Some of these call themselves 'Dicom Viewers' as a common file format is Dicom.

        Wikipedia lists the following Dicom viewers: 3DSlicer   DicomIR   Drishti  GIMIAS  Ginkgo CADx  InVesalius    ITK-SNAP   OsiriX    Voreen    Xebra. These all have their own Wikipedia pages. Scrolling down brings up a box of  'Free healthcare software', see
                       patient posting recommending Mango for Windows                                   Mango   (big package, lots of options)
                        simple viewer -- For those of you looking to view medical images without having to download or install any software, try Jack's Imaging. Its a web based drag and drop viewer that works with all medical images!

                                        ImageJ is an java/nih viewer  poster uses it with CT and MRI images (customer unfriendly)
                             OsiriX is the standard, open source free (?) viewer. Powerful 3d viewer. Apple only.

Protein electrophoresis equipment
General overview of protein electrophoresis equipment and procedure
        I stumbled onto a maker of equipment for protein electrophoresis (Bio-Rad). Their 47 page document showed me there is a lot of scientific use for electrophoresis equipment. The cells of every living thing (plants, animals, bacteria) are made up mostly of proteins and with the use of a mortar and a centrifuge the proteins can be extracted so they can be put into electrophoresis equipment. Electrophoresis can be used to determine a lot of things, for example the molecular weight of an unknown protein, hence there are literally hundreds of variables in the process. In its 47 pages there was no mention of using Bio-Rad equipment to analyze blood.

        The impression I get is that there is a lot of manual technician steps in this process: sample preparation, loading and unloading the gel case, fixing and staining the developed gels, digitizing the stained gels. Below are notes from Bio-Rad's 47 page overview of their equipment and procedures (Guide to polyacrylamide gel electrophoresis and detection):

        -- sample preparation: solids (mammal tissue, plant leaves) ground to fine powder in nitrogen cooled mortar then centrifuged;
                    bacterial samples centrifuged (several times to remove all the cellular material);
                    blood samples must be prepared by removing all the blood cells, but surprisingly blood is not mentioned in sample preparation
        -- table top box might contain a dozen vertical each 6-8 inches long, 1 mm thick
        -- samples (pre-heated to 100C!) are entered at the top and diffuse downward
        -- voltage 10-20 V/cm or (200 V across gel (@ 30 ma, 6 watts)
        -- operating voltage is limited by ohmic heating of the gel
        -- 30-40 min typical diffusion time
        -- diffused gels are floated off the gel plastic holder into water (washed for 15 min)
        -- separated proteins in a gel can't be seen with naked eye so they are stained with a protein stain
        -- staining requires: solution to fix the protein, exposure to a dye, wash to remove excess dye (30 min wash)
        -- most popular stains are a blue dye (Coomassie Blue) and florescent stains
        -- florescent stains seem like they are more specialized, more expensive and need a camera or florescent scanner
        -- staining time typically 2.5 hr
        -- 10:1 variation in sensitivity of the various blue stains
        -- Bio-Rad offers a 'stain-free' florescent system too
        -- after staining (blue) bands visible to naked eye
        -- in modern labs the blue stained gel (electropherogram) is digitized by dedicated equipment
        -- three ways to digitize: flat bed densitometer, which is a modified document scanner;
                     CCD camera with a light box illumination  (CCD can be cooled to reduce noise);
                    laser scanners are used with florescent dyes (powerful as frequencies can be matched to specific proteins)
       -- specialized software processes the digitized gel image

Bio-Rad electrophoresis equipment

Blood electrophoresis

        -- Supporting media fall into two main classes: 1) supports which allow separation of molecules solely on the basis of net molecular charge (e.g. cellulose acetate, agarose gel);  2) supporting media exerting a sieving effect on the compounds being separated (e.g. polyacrylamide gel): the gel can be considered as a porous medium in which the pore size is of the same order as the protein molecules. The result is that a molecular sieving effect is observed in addition to the electrostatic separation and hence the resolution power of these gels is much greater

        --  There are about 25 or more serum proteins bands observed on polyacrylamide gel in comparison with six bands observed on agarose gel. The many bands seen with polyacrylamide support medium present a complex picture that is hard to interpret and appears to help little in routine clinical laboratory diagnosis. Except for specialized purposes, polyacrylamide cannot be recommended for routine serum protein electrophoresis.

        -- Proteins are amphoteric molecules: they are either uncharged or negatively or positively charged particles, depending on the pH of a buffer used for analysis. The buffer helps to maintain a constant pH, and it ensures that each protein will maintain a constant charge throughout the course of the separation.

        -- If the buffer of pH 8.6 is used the most of proteins are negatively charged and move toward the anode at a rate dependent on their net charge

        -- ** Albumin has the highest mobility from all of the fractions. (This explains which way the diffusion goes. Albumin is a small mobile molecule so it ends up at the far end of the diffusion, whereas the gamma and beta regions, where the IgG monoclonal spike is found, are at the near end near the buffer, gamma being the nearest.)

        -- Proteins therefore, are usually denatured (unfolded) in the presence of a detergent such as sodium dodecyl sulfate (SDS) that coats the proteins with a negative charge. (Wikipedia)

        -- In most proteins, the binding of SDS (polyacrylamide gel electrophoresis) to the polypeptide chain imparts an even distribution of charge per unit mass, thereby resulting in a fractionation by approximate size during electrophoresis. SDS is a strong detergent agent used to denature native proteins to unfolded, individual polypeptides. When a protein mixture is heated to 100 °C in presence of SDS, the detergent wraps around the polypeptide backbone. In this process, the intrinsic charges of polypeptides becomes negligible when compared to the negative charges contributed by SDS. Thus polypeptides after treatment become rod-like structures possessing a uniform charge density, that is same net negative charge per unit length. The electrophoretic mobilities of these proteins will be a linear function of the logarithms of their molecular weights. (In other words this technique with heating and a detergent unfolds the proteins and critically imparts a charge on the protein proportional to its length.)

        -- The gamma band - immunoglobulin (IgA, IgD, IgE, IgG and IgM). Paraproteins (in multiple myeloma) usually appear in this band. (Wikipedia) (However, this is apparently not the case for me where Dana Farber labs reports my monoclonal (IgG) spike is in the beta region.)

        -- The types of gel most typically used are agarose and polyacrylamide gels. Each type of gel is well-suited to different types and sizes of analyte. Polyacrylamide gels are usually used for proteins, and have very high resolving power for small fragments of DNA (5-500 bp). Agarose gels on the other hand have lower resolving power for DNA but have greater range of separation, and are therefore used for DNA fragments of usually 50-20,000 bp in size, but resolution of over 6 Mb is possible with pulsed field gel electrophoresis (PFGE). Polyacrylamide gels are run in a vertical configuration while agarose gels are typically run horizontally in a submarine mode.

        -- ** Agarose gels (extracted from seaweed) do not have a uniform pore size, but are optimal for electrophoresis of proteins that are larger than 200 kDa. Polyacrylamide gel electrophoresis (PAGE) is used for separating proteins ranging in size from 5 to 2,000 kDa due to the uniform pore size provided by the polyacrylamide gel. (Wikipedia) (In other words polyacrylamide gel works over a wike range of protein mass (5 - 2,000 kDa) whereas agarose gel only works well for larger proteins (> 200 kDa).

        -- * Question: what is kDa (weight) of blood proteins? Human albumin has a molecular mass of 66.5 kDa.  In the region between beta and gamma is found C-reactive protein (110-144 kDa). IgG is 150-170 kDa (144 kDa = heavy chains 50 kDa each, light chains 23 kDa each).

        -- ** (My IgG monoclonal falling in the beta region must mean is it a little smaller than typical IgG protein. There's an easy explanation of this. IgG antibodies may have a range of sizes, so the IgG mass numbers given are averages, whereas an M-spike is a clone of a particular IgG antibody.)

Electrophoresis for multiple myeloma
        A 2005 article (for medical types) says the gel used when serum proteins is spread is agar.

        -- Gamma region is composed predominantly of antibodies of the IgG type.

        -- An M protein is characterized by the presence of a sharp, well-defined band with a single heavy chain and a similar band with a kappa or lambda light chain. (I don't understand this. Isn't the M-spike a complete antibody? They seem here to be describing free light chains, but that can't be right because concentrations of those are tiny, measure in mg.)

        -- Definitive diagnosis of multiple myeloma requires 10 to 15 percent plasma cell involvement as determined by bone marrow biopsy. At MM diagnosis the M-spike is normally 3 g/dL or higher. Less than this and the dignosis is usually Monoclonal gammopathy of undetermined significance.

        -- Monoclonal antibodies cannot be excreted by the kidneys, but free light chains are excreted by the kidneys into the urine, so a small fraction of MM patients whose cancerous plasma cells to not secrete (monoclonal) antibodies, their MM diagmostic signal is high levels of free light chains in the urine.

        -- A liter is the volume of a cube 10 cm on a side, hence 1 uL (or 10^-6 L) is a cube 1 mm on a side. There are more than a million red blood cells in 1 uL of blood!

Beckman Coulter
        Paragon CZE 2000 was a pioneering automated (capillary) electrophoresis system for clinical use made by Beckman Coulter. Their site claims nearly all electrophoresis system use their technology.  For capillary electrophoresis they redirect to Sciex


Big picture of MM treatment options

        Now about two years into chemo for MM, I have some perspective on treatment options for MM. While doctors tend to tell patients here are a lot of drug options for MM, that's not really true. For those patients avoiding a stem cell transplant and going down the newer route of what is often called 'novel agents' of targeted MM drugs, the treatment choices are few. Sure there are a lot of drugs, but when you look at their mechanism of action, you find there really are only TWO established classes. By established I mean MM drug classes whose original members have a decade or more track record. Within each class there are first, second and sometimes 3rd generation of drugs as the manufacturers tweak the formulaS working to make the drug more effective with fewer side effects.

        One class is the anti-angiogenic & immunomodulator typified by thalidomide and its various improved analogues Revlimid and Pomalyst. This class of drugs are all from Celgene, which have them wrapped up in patent protection. The second class of drugs are proteasome inhibitors typified by Velcade (bortezomib) and a second generation competitor carfilzomib (Kyprolis). Here there are two companies, Millennium Pharmaceuticals (now Takeda) maker of Velcade and Onyx Pharmaceuticals (now Amgen) maker of Kyprolis, both of which have an infusion version and are working on a pill version. Only one pill (Ninlaro from Takeda) at this point has been approved by the FDA and is on the market (2015), the other proteasome inhibitor pill (from Onyx) is still in clinical trials.

        I figured out this class arrangement by every time I heard mention of a MM drug I added it to this essay and did a little research on it, which is easy to do since most drugs have a wikipedia page and drug manufacturers are quick to set up web sites dedicated to their 'hot' new drugs. And was surprised to see that time and time again the 'new' drug fell into a well established class. (see MM drugs organized by class)
        The headline news in 2015 is that after Amgen bought Onyx for 10.4 billion it layed off 300 of the 500 Onyx staffers. Well that's encouraging..., especially since I am now on infused carfilzomib (Kyprolis) made by Amgen.  (Patient sharing web site from Amgen for carfilzomib.)
        It's sort of a dirty little secret but your MM oncologist really only has a two step plan to offer you. At least two steps that have a track record and work fairly well for a lot of MM patients. Sure there is always the cutting experimental edge but this is the end game, response rates are low and added survival time is measured in months. I have talked to three cancer doctors, my regular haematological oncologist, who I see frequently, a consulting haematological oncologist at a world famous MM research center, who I see ever few months, and another haematological oncologist from which I sought a second opinion. Not one of them laid out this big picture, that MM treatment is essentially a two step process.

        The goal of both steps is a remission, i.e. driving the cancer load in the body down to low levels. With MM patients this is critical as the cancer is ussually widespread throughout the body (metastatized) before the cancer is even diagnosed, so the patient depends on the chemo holding the cancer levels low enough so that his bone (and other) tumors do not grow. The first remission is statistically the longest and probably with the best quality of life as you are taking fewer drugs and they may be all in pill form. The median (50%) remission time for the common rev/dex (Revlimid + dexamethasone) chemo is roughly two years. (I got only 1.5 yrs) When the cancer outruns your initial chemo, your first remission is ended and you transition to a new class of drugs to try for a second remission. Statistically this remission will be shorter and not as deep.

        The nature of clinical thinking here can be glimpsed by the jargon the doctors use among themselves to describe this step one to step two chemo transition for MM, but which I will bet is rarely told to patients. My doctors notes after my first remission ended read like this: "Relapsed and refractory IgG lambda myeloma with multiple new sites of bone lesions/plasmacytomas." Recommendations for new chemo are describes as "salvage therapy".
        This is where I am now. I am still less than two years from diagnosis (23 months), but my first remission already ended a few months ago, and I am a couple of months into step two hoping for second remission. In step two I take three drugs, not two as before, and one of them is by infusion, so I much more tied to the hospital and spend a lot of time there.


End of 1st remission,
switch to new pom/carfilzomib/dex chemo

4.5 month overview -- 2nd remission (11/18/16)
        It's time to sum up. How am I doing on the new pom/carfilzomib/dex chemo after 4.5 months? The answer according to my blood work is pretty well. A quick perspective is just look at the movement of two key blood numbers for MM (free light chain and M-spike): up is 'bad' and down is 'good'. The general pattern of both of these numbers since the chemo change has been downward and their settling in to what appears to be a new and relatively low plateau, a '2nd remission' if you will. So the big question going forward is how long this '2nd remission' will hold.  And since blood work is only an 'approximation' of what is happening in the body, what will the next Pet scan show?

Free light chain (11/18/16)
        Using the plotting function in MyLaheyChart here are my free light chain values from the first of the year. I have had from the beginning an IgG lambda cancer so the relevant curve below is the orange one at the bottom. Notice the dramatic drop in lambda free light chain at 7/1/16 when chemo was changed from rev/dex. During the first six months of 2016 while on rev/dex, it was bouncing around near 10 mg/dL (8 to 15 mg/dL), far above normal and at a level which clinical trials use as a threshold of disease progression. Later an MRI showed at this level a large plasmacytoma had grown behind my left eye that was affecting my vision. With the change in chemo it dropped quickly to the upper end of the normal region and in the 4.5 months since it has settled nicely into the normal region.

        Free light chain is important to track because prior to the chemo change, which my (consulting) oncologist at Dana Farber was recommending, he said he was looking to drive the free light chain down into the normal region, and the new chemo has done this. In the last two months my IgG lambda monoclonal spike has been joined by a smaller IgG kappa monoclonal spike (two cancerous cell lines!) The kappa free light chain (blue, top) was down in the normal region months before the chemo change. The small pop up (one data point and only to 4 mg/dL) on the right I dismiss as most likely noise.

Chemo change to (pom/carfilzomib/dex) decreases lambda free light chain   -- Multiple myeloma
kappa (blue) and lambda (red) free light chains (1/1/16 to 11/16/16)
6/27/16 marks the chemo change, and clearly it caused a big drop in lambda free light chain (red, bottom)
from 10 mg/dL (disease progression threshold) into the normal region (< 2..63 mg/dL)
(solid lines indicate the boundry of normal regions)

Plot of my M-spike(s) numbers for 2016 (updated 12/12/16)

M-spike(s) ---  IgG lambda and IgG kappa for 2016 with three changes in chemo:
rev maintence dose increase (10 mg => 20 mg) (2/29/16)
rev maintence => rev/dex  (3/25/16)
 rev/dex => pom/carfilzomib/dex (6/27/16)

        I've plotted my M-spike data for 2016 to go with the free light chain plot. I have marked on the plot the three changes in chemo that occured during the year. It's a complex plot with two M-spikes. When the IgG kappa spike pops up in recent months I plot it along with the sum of the two M-spikes. I've included a 0.04 g/dL baseline, my best guess for the quantitative threshold of the test. The lambda M-spike has come down nicely since the change to pom/carfilzomib'dex chemo, but SLOWLY taking 4.5 months to drift down from .26 to .07 g/dL with a recent pop up to .12 g/dL.

        It's taken more than four months but the M-spike has finally following the light chain down. Prior to the shift from rev/dex chemo my M-spike was running about ,25 g/dL, which is about half the disease threshold. After a couple of months it had dropped only a little (.17g/dL), so I was disappointed. then up popped an IgG kappa M-spike, so now I had two M-spikes! Each spike is monoclonal, so the cancer load is the sum of the two spikes, and looked at this way in late sept and early oct the area under the two M-spikes (total) was back up .25g/dL, no change. But in the last month (oct to nov) the M-spikes have drifted down. My latest lambda M-spike is 0.07 g/dL, and the kappa M-spike is there but can't be quantified. However my best guess is the M-spike measurable threshold is probably around 0.05 g/dL, so the total of the two M-spikes can easily be .05 + .07 = .12 g/dL. From this point of view the drop in the M-spike is less impressive more like half (.25 g/dL => .12 g/dL). (For gods know what reason MyLaheyChart won't plot it)

Update on new pom/carfilzomib/dex chemo (8/24/16)
       The transition to 2nd chemo regeim is a crucial point in a MM patient's life, because frankly there aren't a lot of good options after step two!

        As I write it's 8/24/16 and I have now completed two full cycles of pom/carfilzomib/dex. Pom/carfilzomib/dex chemo was begun on mon June 27, 2016. I am now a couple of days into the 3rd cycle and the data from the completed 2nd cycle is begining to come in.  I had my blood tested every two weeks on the new chemo, so that has given me four data points for the two cycles, and it's been kind of a wild ride.

        On a change of chemo where a downward trend is expected the blood component to monitor is the free light chain. It responds more rapidly, without a lag that affects M-spike. Here are my recent (lambda) free light chain numbers (in mg/dL). The normal range for lambda free light chain is (0.57 - 2.63).

date (2016)
lambda free light chain
(0.57 - 2.63)
june 27
last number on rev/dex
(av of last 7 numbers is 10.0)
new chemo --- change to pom/carfilzomib/dex chemo
cycle 1
of new chemo
july 11
first number on new pom/carfilzomib/dex chemo
july 25
cycle 2
of new chemo
aug 8
2nd cycle of pom/carfilzomib/dex chemo has +35% dose increase in carfilzomib
aug 22
(average of first 4 new chemo numbers is 3.3)

Wild ride!
        The initial drop from 10.80 mg/dL after just two weeks on the new chemo to 3.25 was very encouraging. The new chemo looked like it was going to work!  The next reading two weeks later at the end of the first cycle continued the downward trend to 2.93 mg/dL not far from the top end of the normal range of 2.63 mg/dL. To put this in perspective free light chain had been hovering around 10 mg/dL for a while on rev/dex, and this is the threshold clinical trials use to indicate disease progression. A pet scan did in fact show I had some disease progression at this level, including two plasmacytomas. The new chemo quickly dropped the free light chain down by a factor of 3, which looked good.

        However the next number two weeks into the 2nd cycle, where the dose of carfilzomib had increased by 35%, was a shock because it rose 40% (2.93 => 4.11). This looked BAD, because it seemed to indicate that after just one month into the new chemo the cancer was already beginning to find a way around it and growing! However, two weeks later at the end of the 2nd cycle a pleasant and unexplained surprise, the free light chain dropped down (4.11 => 3.30) close to where it was initially. A wild ride. So now maybe after two full cycles a trend is emerging, which is that the new pom/carfilzomib/dex chemo has reduced lambda free light chain by about a factor of three from rev/dex chemo, taking it from the clinical trial disease progression threshold of 10 mg/dL down to a level to about 1/3th of it or 3.3 mg/dL. A definite improvement.

Free light chain is noisy
        With more numbers come more perspective. When I look back in my master table at free light chain values while still on rev/dex I see it varied around quite a bit. Sure in seven readings from Apr to June 2015 it averaged about 10 mg/dL, but individual readings varied from 8 to 13. In other words free light chain is (as an engineer would day) is noisy, it varies around a little. With this perspective the four readings under the new chemo average 3.4, and the bounce from 2.93 to 4.11 and back to 3.30 is probably best explained as just noise. The new pom/carfilzomib/dex chemo looks at this point that it has decreased my free light chain about a factor of 3. Whether this is low enough to stop my tumors from growing remains to be see. A new Pet scan is coming up, which should provide some perspective.

        In early oct 2016 the kappa free light chain shows a marked jump that stands out clearly in the graph below (blue) to 3.71 mg/dL well outside its normal range (1.94). This combined with a newly visible kappa M-spike that was still rising (0.11 g/dL) was worrying, but with two additional readings over the following month it now appears that this single high kappa free light chain reading looks more like noise.
        In May 2016 about 20 months after diagnosis my cancer status changed dramatically. My 1st remission ended with the discovery of two plasmacytomas (soft cancerous tissue mass) and several active bone lesions. This is bad....

        For about 4-6 weeks prior to the change in status I began having some vision issues, I couldn't see my large screen TV across the room clearly. I finally figured out this was due to double vision when my eyeballs were oriented right in my head. Looking straight ahead or eyeballs to the left I could see clearly. This report to my doctors of double vision lead to a brain (head) MRI which found a large soft cancer mass (plasmacytoma) behind by left eye in the sphenoid bone. This triggered a full body PET scan which located a second plasmacytoma in my rear left 9th rib, which likely fractured prior to my diagnosis, as well as three metabolically active lesions (mandible, pelvis, 2nd rib).

        For two weeks (5/23/16 to 6/3/16) the plasmacytoma behind my left eye was treated with radiation (20 grays) to shrink it, during which at my insistence rev/dex was continued. An active lesion in my mandible (jaw) was also irradiated at the same time. The finding of growing plasmacytoma and bone lesions means that even though my M-spike is still down 95% (.25 g/dL), about half the level normally defined as disease progression (.5 g/dL),  my current rev/dex is no longer working effectively and a new chemo treatment will be needed. However, my free (lambda) light chain, which has hovered for months near 10 mg/dL, is at the about at the level normally defined as disease progression. It is substantially above normal (2.63 mg/dL), and getting this number down into the normal range will be a target of the new chemo (said the Dana Farber specialist).

Timeline of chemo change (summer 2016)
        5/16/16                     MRI finds large plasmacytoma in sphenoid bone behind my left eye. Triggered by my reports of double vision.
        5/19/16                     Pet scan (whole body) finds several metabolically active bone lesions.
        5/23/16 - 6/3/16       Two weeks of radiation of left eye plasmacytoma and jaw lesion (rev/dex chemo continued during radiation)
        6/13/16                     Meeting with Dana Farber MM specialist who recommends switching to pom/carfilzomib/dex chemo
        6/27/16                    pom/carfilzomib/dex chemo begins (carfilzomib soft started at 75% of final strength for first cycle)
        7/11/16                     first look (1/2 cycle) at lambda free light chain on new chemo shows a nice drop (10.8 mg/dL => 3.25 mg/dL),
                                                  not too far from the upper end of normal (2.63 mg/dL)
       (9/12/16)                   Follow up appointment scheduled with Dana Farber doctor (8:00 blood, 9:00 doctor)

Relapsed and refractory
        Doctors notes from a June 13, 2016 meeting with a specialist at Dana Farber describes my condition as "relapsed and refractory IgG lambda myeloma with multiple new sites of bone lesions/plasmacytomas." Recommendations for new chemo are describes as "salvage therapy".

New agressive chemo for 2nd round --  pom/carfilzomib/dex (7/11/16)
        First quick look (just two weeks in) at the switch from rev/dex to pom/carfilzomib/dex chemo shows a good initial response.

Message to my oncologist (7/12/16)
         In just two weeks (1/2 cycle) into my new pom/carfilzomib/dex chemo my lambda free light chain, which for the last five months has hovered around 10 mg/dL (8 to 13), a level associated with disease progression, has dropped by a factor of three to 3.25 mg/dL, getting close to the upper end of its normal range (2.63 mg/dL).  I'll take this as good news.

Doctor's reply
        Agreed, I was happy to see the results. Finally some good news!

Email to family and friends (7/13/16)
        My first peek at how my cancer will respond to my new 2nd generation chemo is good.

        The blood objective the Dana Farber doctor mentioned was to drive my leading cancer indicator (lambda free light chain) down into the normal region. It was sky high when I was diagnosed at 379 mg/dL, but for months has hovered around 10 mg/dL, which clinical trial use as a threshold of disease progression, meaning above this level bone tumors can grow.

        Just two week into the new chemo, still soft starting at 75% of its final strength, dropped the lambda free light chain from 10.8 mg/dL to 3.25 mg/dL. A nice drop and not too far from the top end of the normal region at 2.63 mg/dL.

Some not so bad things about carfilzomib injections (7/26/16)
        Having completed one full cycle of carfilzomib infusions and the first week on my second cycle I have some reflections on the need to go the hospital six times a week for the infusions. The protocol for carfilzomib is two infusions a week on consecutive days for three weeks followed by a week off. While the actual carfilzomib infusion is 10 min, with the saline given before and after the visit to the infusion room, scheduled for 1.5 hr, typically runs long approaching 2 hrs.

        The most important good thing is that my first preliminary peek at my numbers shows that my new pom/carfilzomib/dex chemo seems to working for me. My lambda free light chain (I have a lambda MM), which is a leading indicator, in the first two weeks dropped from 10.8 mg/dL (slightly above the disease progression threshold) to 3.25 mg/dL (not too far above the upper end of the normal range). I was naive to a protease inhibitor and since my rev/dex first remission ended after after only 20 months with a bang (finding of two plasmacytomas), my Dana Farber consulting doctor recommended what he said was the most active of the protease inhibitors, carfilzomib, which is taken by infusion as opposed to the new Ninlaro which is a pill.

        The infusions don't hurt so I take a book and read. The only side effect from the infusions I have had is some minor black and blueing and muscle swelling near the site of the needle. When the carfilzomib is delivered by the pharmacy and about to put into the tubing, the protocol to avoid a mistake is to have a second nurse come over to verify that the markings on the bag match what is on the Epic screen and my wristband. I presume the same sort of double checking happens in the pharmacy, but of course I have no way of verifying this.

        So the diffusions don't mess up my summer travel plans I schedule all my infusions for mon and tues. For me this works out well allowing me to get to ME mid week for a few days avoiding the weekend traffic. The infusion room at Lahey hospital is large and friendly place with nice nurses easy to talk to, and you get to know each other because you are there so often for so long. That's a plus.

Carfilzomib risk breakdown
        Here is some perspective on serious (grade 3/4) adverse effects of carfilzomib from a Canadian report on tht Aspire phase 3 clinical trial. This was a trial that compared (carfilzomib + rev/dex) to (rev/dex) for 18 months in relapsed MM patients. The total adverse effect percentage of 83.7% for carfilzomib looks extremely high, but the chart below from the Canadian report shows the details. Roughly 17% (72) of the 400 had very serious problems (cardiac failure, deep vein thrombosis, etc), but about half of the reported events were neutropenia (low white blood count) and thrombocytopenia (low platlets).  The excess severe events vs control was more like 7.5%,

(source ---

Aspire phase 3 clinical trial results for carfilzomib (2015)
        This phase 3 trial reported in the New England Journal of Medicine in 2015. One reviewer commented that "the patient population was predominately a relapsed and early-relapse population—both features that favor better outcome." Here's the key results of the Aspire Phase 3 trial, adding carfilzomib to rev/dex vs rev/dex. Carfilzomib was given for 18 months, rev/dex was continued.  (from the Canadian report).  I eyeball the 50% point of disease free prgression to be 28-29 months (median = 26.3 months).

        This trial is close to my personal history. For a few months after my numbers started to rise in early 2016 I was put back on rev/dex. Withthe discovery of plasmacytomas in may 2016 the proteasone inhibitor carfilzomib was added to my chemo, and differing from the trial (slightly), 3rd generation Pomalyst was swapped in for 2nd generation Revlimid used in the trial. I responded quite well to the change, see 'Plot of my M-spike(s) numbers for 2016' (above).

Aspire Phase 3 trial, adding carfilzomib to rev/dex (Crd) vs rev/dex (Rd)
(source ---

Dana Farber update on my cancer (jan 2017)
        Latest meeting notes from Dana Farber say my response to date of therapy, meaning the three drugs I have been on since the beginning of summer 2016, has "quite impressive", and I am tolerating them "quite well". It detailed how my blood cancer numbers are quite low (referencing the M-spike plot I made and brought with me). surprisingly there was no mention of my good recent Pet scan. So it says 'ideally' I should remain on these three drugs 'until disease progression', i,e. until they stop working for me.

        The fly in the ointment, however, is that my shortness of breath and getting run down is worrisome to him given that carfilzomib (the infused drug) has a known tendency to damage the heart and lungs. And I know the longer you take drugs like this the more likely they are to do damage, so he is advising that follow up tests be done to check out my heart and lungs.

         I hope they don't find anything, because if they do he told me carfilzomib would be swapped out (in a heartbeat) for the new drug daratumumab, which I know is pretty much the end of the line for MM chemo (though of course he doesn't tell me this). In clinical trials its response rate was lousy (only about 1/3rd of patients responded) and not for very long.

        Nothing much new here that except for the clinical concern for my heart and/or lungs possible being affected by the chemo and the reason I am run down. It's fully consistent with my earlier prediction I will 'likely' die in 2017 and 'very likely' to die in 17/18. Even in the 'ideal case' getting to the end of 2017 without disease progression would mean I would be on pom/carfilzomib/dex chemo for 18 months, and that is a long, long, time on this chemo with its well known toxic side effects. I am meeting with my oncologist at Lahey soon, and my expectation is there will be agreement with the Dana Farber specialist and will schedule another acoustic flow heart test and a simple lung test or two.

My oncology history summary
        Below is my oncology history attached to jan 2017 Dana Farber meeting notes. It is a concise summary of the high points of my voluminous cancer history.  I don't really know who assembled this, but I suspect it was done at Dana Farber either by my oncologist there, or possibly by a physician assistant. Probably dictated as my detail history (I have 92 pages) was read through. This history summery runs from sept 2014, when I was diagnosed, to late june 2016, when chemo was changed to pom/carfilzomib/dex after my first remission ended with a plasmacytoma found behind my left eye. (The numbers and tests look right, but missing is a quick (2.5 wk) change in chemo between the ending of 10 mg revlimid maintenance and return to 25 mg Revlimid/dex in spring 2016, which was a doubling of Revlimid (no dex) to 20 mg. It had no effect of the rising numbers, so was quickly abandoned.)

Data Farber MM oncology history summary of Don Fulton (1/18/17)
nCR  --- near Complete Response (for M-spike)
len --- Revlimid (lenalidomide)

Data Farber meeting notes (1/18/17)
        The relevant section on chemo says, 'It would be ideal to remain on current therapy until disease progression, but if dyspnea (shortness of breath) prevents this, then daratumumab could be swapped in for carfilzomib.' As of the date of this meeting I had been on 'current therapy' (pom/carfilzomib/dex) for about 6.5 months (since june 29, 2016). While the term 'dyspnea' is used (below) my shortness of breath cmes only from my history is neither sudden nor very severe.

Data Farber MM meeting notes of Don Fulton (1/18/17)
dyspnea --- Difficulty in breathing, often associated with lung or heart disease and resulting in shortness of breath.

Creatinine lab values disagree
       The Dana Farber notes (above) refer to a creatinine level of 1.49 mg/dL (on 1/18/17). This is higher than Lahey has measured for two years and indicates some impaired kidney function,  yet Lahey labs has measured the same parameter (creatinine) twice within 30 days, once preceding and once  after the Dana meeting, and both times got 1.1 mg/dL, well within the normal region indication good kidney function. Puzzled.

        It distress me that two major labs can't agree on a value from what I assume is a highly automated test, available within the hour.

Two cancers? -- surprising & discouraging new result
(10/3/16) (10/17/16)

        I have an IgG lambda cancer. This is was the monoclonal anti-body found to be hugly elevated in my blood when I was diagnosed with MM in sept 2014 and has been tracked for over two years, But in the last 6 weeks or so another M-spike an IgG kappa has also appeared and unlike IgG lambda it has been growing: .05, .07, .09, 0.11 g/dL. So as of 10/3/16 two M-spikes nearly the same size are reported: lambda at 0.15 g/d and kappa at 0.11 g/dL. The increase of the kappa M-spike to 0.11 g/dL was accoumpanied by a big jump in its associated kappa free light chain to 3.71 mg/dL well outside of its normal range (1.94 mg/dL is the upper end of its normal range). This was discouraging.

        But I have noticed in the past that my free light chain numbers are noisy, so was somewhat reassured that two weeks later (10/17/16) my kappa free light chain jumped back down to 1.95 mg/dL, just a hair outside its normal range (1.94 top). As of this writing my M-spike numbers for 10/17/16 are not yet posted.
Recomended new chemo
        A Dana Farber MM specialist after reviewing my plasmacytomas and blood levels has recommended changing to a new chemo plan. As a patient naive to a protease inhibitor, he recommends going to what he calls the most active anti-angiogenic & immunomodulator (pomalidomide, Pomalyst) plus the most active proteasome inhibitor (carfilzomib, Kyprolis) plus dexamethasone, the corticosteroid I am now taking.

        pomalidomide, Pomalyst              4 mg days 1-21
                                                                           (pill, cycled, 3rd generation thalidimide, from Celgene)
        carfilzomib, Kyprolis                   20/27 mg/m2 days 1, 2, 8, 9, 15, 16 of a 28 day cycle
                                                                           (infusion mon/tues at hospital for three wks with a week off, from Onyx Pharma)
                                                                           (20/27 means the dose is lower the first cycle, then if well tolerated increased 35% on following cycles)
        dexamethasone (dex)                    20 mg on days of carfilzomib (see below)
                                                                           (40 mg/wk, coordinated with Kyprolis infusion to minimize its infusion side effects)
                                                                           (Note I question whether this is correct as it means not taking dex on the week off! My oncologist
                                                                            and I have agreed that I will continue with 2 x 20 mg dexamethasone during the 4th week of the cycle.)

        Recently I have been on rev/dex (25 mg Revimid + 40 mg/wk dexamethasone). The chemo change can be viewed as follow: an anti-angiogenic & immunomodulator drug remains, but is upgraded from 2nd generation Revlimid (rev, 25 mg) to 3rd generation Pomalyst (pom, 4 mg), both are pills from Celegene. In addition a protease inhibitor is to be added. The recommended protease inhibitor is Kyprolis (carfilzomib, Onyx Pharmaceuticals), which in an infusion (six times a month). The corticosteroid I am now taking, dexamethasone (40 mg/wk, ten 4 mg pills), remains but is to be taken in 'two pulses/wk' (20 mg each) on days of Kyprolis infusion.

Monitoring (7/10/16)
        The blood objective mentioned by the Dana Farber specialist is to drive my lambda free light chain down into the normal range (< 2.63 mg/dL). In recent months is has been running about 10 mg/dL, which most clinical trials use as the threshold for disease progression. In two or three months both Lahey and Dana Farber doctors speak of repeating MRI and/or Pet scans to see what is happening inside.

        One of the annoyances of this new chemo is that Celgene specifies that Pomalyst, unlike Revlimid, is not to be taken with (two hours separation), and I heard this from my oncologist too. So while I take the bulk of my pills in the morning, I need to remember after dinner every day to set a timer for two hours to take pom (and the 3rd anti-viral acyclovir pill).

Effect of food
      The Pomalyst prescribing statement has this to say about food. Taken as prescribed (without food) the plasma concentration peaks in 2-3 hours after the dose (pill). Taken with high fat meal or high calorie meal the peak plasma concentration is delayed by 2.5 hr, which seems to me totally unimportant in a pill taken once every 24 hours, and the peak plama concentration is reduced by 27% (high fat) and 8% (high calorie) when tested in healthy volunteers.
        My view of this is that taking Pomalyst in the morning with a light breakfast of Instant Grits (0 fat, 100 cal, plus milk) would (worst case) result in a very small reduction (few per cent) in dose in terms of the peak serum concentration.
Wait a minute!  (7/29/16)
        Poking around the Celgene web site I find Celgene's Pomalyst food recommendations are contradictory! Some Celgene documents do in fact say Pomalyst should be taken without food (2 hr before or 2 hr after a meal), but other Celgene documents say explicitly that "Pomalyst may be taken with or without food". This latter recommendation is in fact found in the Pomalyst  detailed prescribing document from Celgene (link below), marked Revised June 2016, so I tentatively take this as definitive. Celgene has apparently changed its mind (or is it a typo?). Or maybe it's just a judgement call since the reduction in peak serum concentration with food, say a light breakfast, appears to be fairly small.

        I question the dosing of dexamethasone outlined above (copied from the notes of Dana Farber doctor). Note that it specificies dexamethasone be taken only on the days of  carfilzomib infusion, but this is six times a month for three weeks with a week off. What no dexamethasone on the week off during the 28 days cycle? This was not the way it was done with rev/dex. And it's not the way I see the dosing in the two clinical trials of pom that I checked.
        The dexamethasone dosing information in the Pomalyst (section 14.1) speaks only of dexamethasone as used in clinical trials, which was 40 mg given on days 1,8,15,22. In other words dexamethasone is continued in the 4th week of the cycle, the 'off' week!
Heart risk of carfilzomib
        The detail prescribing sheet for carfilzomib shows the absolute level of heart attacks of those taking this drug in clinical trials to be about 6 to 8%. The non-carfilzomib group had about half this level of heart attacks, so round numbers the raw odds of carfilzomib causing a heart attack is about 4% or 1 in 25.

Did I recently have a mild heart attack? (6/14/16)
        Probably not, but I might have had some minor heart muscle injury or death.  I have had no discussion of these results with a doctor yet, but my heart numbers are all a little above normal. What comes to mind is that on 5/30/16 I had an 'episode' for a couple of hours with distress in my chest that faded away. Was this maybe a mild heart attack? At the time this did not occur to me, but it might fit with the lab results.

Initially I misread  troponin I test result
        Got faked out here for a few hours as I initially misread the troponin I rest result as 4 ng/mL. This (high) level would be consistent with already having had a mild heart attack (probably the chest pressure episode I had on Memorial day 5/30/16 for a couple of hours), but the actual troponin I result is 0.04 ng/mL (x100 times smaller!) (measured 5/14/16).
        Carfilzomib (Kyprolis) can affect the heart so prior to beginning the new chemo I had several heart tests: ECG, echocardiogram (ultrasound), and monitoring of blood related proteins in the blood. I have no baseline here as I have never had my heart tested. Here are the results:

            ECG (12 lead)                                     Borderline ECG   (same as EKG?)
                                                                        Sinus bradycardia    (pulse < 60 beats/min)
                                                                       Abnormal R-wave progression, early transition


        This test can show visible damage to the heart muscle tissue.

            troponin I                                            0.04 ng/mL   ("troponin I is undectable in most healthy individuals")      normal: 0 to 0.30 ng/mL
                (blood protein)                                          (0.30 ng/mL is the 99% percentile)
                                                                       (one reference: > 0.40 ng/mL means probably myocardial infaction, i.e. a heart attack)

        A troponin test measures the levels troponin T or troponin I proteins in the blood. These proteins are released when the heart muscle has been damaged, such as occurs with a heart attack (ischemia -- lack of blood flow to the heart muscle). The more damage there is to the heart, the greater the amount of troponin T and I there will be in the blood. Tropin test is very sensitive and can pick up minor damage to the heart, which before 1990s was usually missed. Typically troponin I rises in the blood a few hours after a heat attack then slowly rolls off, sustaining for a week or two.

        Even a slight increase in the troponin level will often mean there has been some damage to the heart. Very high levels of troponin are a sign that a heart attack has occurred. Some people who have ischemia don't experience any signs or symptoms (silent ischemia). Most common symptom is chest pressure or pain. Troponin elevation in isolation does not confer a high mortality rate.  However, the presence of increased troponin is one marker of severity of underlying illness and as such has been used to identify people at higher risk of bad outcomes

        Elevated troponin levels can persist 1-2 weeks after death to heart muscle (due to blockage of heart blood vessels). This test was done (6/14/16) 16 days after my chest 'episode' on Memorial day (5/30/16).

            beta natriuretic peptide (BNP)           113 pg/mL                (6/14/16)          (0 to 80 pg/mL normal, < 100 indicates no heart problems)
                (brain peptide?)     (mean BNP =  31.0 pg/ml in those aged 65-74 years)

           beta natriuretic peptide (BNP)              23 pg/mL                (update 10/3/16)       normal
           beta natriuretic peptide (BNP)              40 pg/mL                (update 2/13/17)       normal

        BNP is a substance secreted from the ventricles or lower chambers of the heart in response to changes in pressure that occur when heart failure develops and worsens. The release of BNP appears to be in direct proportion to ventricular volume expansion and pressure overload. BNP increases with right or left systolic or diastolic heart failure. It is an independent predictor of high left ventricular end-diastolic pressure. BNP levels decrease after effective treatment of heart failure.  BNP levels of more than 100 pg/ml have a greater than 95% specificity and greater than 98% sensitivity when comparing patients without congestive heart failure (CHF) to all patients with CHF.

                    BNP levels below 100 pg/mL indicate no heart failure.
             *  BNP levels of 100-300 pg/mL suggest heart failure is present.
                    BNP levels above 300 pg/mL indicate mild heart failure.

New tests --- Brain MRI and whole body PET scan (5/18/16)
        In my regularly scheduled meeting with my oncologist recently I mentioned that I had had some trouble coordinating my eyes (double vision) in the last month or two, but curiously only when watching TV. When I look around the room or are driving, I can see fine, with the caveat that for the last year or two I have some blurring in my left eye (which comes and goes) that my optometrist says (after peering into my eyes with a microscope) is due to some astigmatism visible in the central region of my left retina.

Why just double vision watching TV? (1/18/16)
        I think I just figured out why I've only sensed double vision while watching my TV, but not in driving or looking around. I was assuming it had to do with motion on TV, but that's not it. Tonight I noticed double TV images when there is no motion.

        I have two large screen TV's I watch from my easy chair in the living room. One across the room, where it has been for years,  is a regular TV. The second large screen TV I use as my computer monitor, and since I have a TV tuner in my computer it also work as a TV. My easy chair is angled between them. I need to look right about 30 degrees for the TV and left about 20 degrees for the TV monitor.

        ** I now see the double vision is occuring when I need to look right (relative to the angle of my body).The proof it is a (right/left) angle thing is that if I reposition myself in the chair to angle my body slightly to the right of the TV, the double vision goes away (or pretty much goes away). I can't really figure out the angle of my eyes relative to my head.

PET scan
       My oncologist scheduled an MRI to check if the cancer was involved with my vision problem. She had another MM patients with an eye plasmacytoma. The MRI apparently does shows something, which was described over the phone to me as a possibly a  mass pushing on the left optic nerve, but after two days I have been unable to pry the MRI report out of the hospital, so I have not read it. Based on the MRI results a PET scan has been scheduled, which my initial understanding is that it will (crudely) show how much the mass is growing, really how much glucose it is extracting from the blood, a measure of its metabolic activity. Wikpedia says 90% of PET scans are done to see if cancer is metastasizing.

        Got not details, but the MRI seems to show I may have had a possible mini-stroke (no symptoms that I am aware of), so I will be scheduled to meet with neurology to be checked out.

Cost of diagnostic tests and radiation treatment (may 2016)
        Of course when an MRI and Pet scan were ordered in may 2015 to assess the state of my MM the costs of the tests and treatment were never mentioned. I found out the costs only from Lahey billing received July, 2016. The largest charges on the July bill are shown below. They mostly hospital services billed related to the MRI, whole body Pet scan and two weeks of radiation treatment for the plasmacytoma behind left eye (and at the same session jaw lesion) found by the MRI. As below shows in round numbers the MRI costs 3.3k, Pet scan 13.3k and two weeks of head radiation (eye and jaw) 10.9k. Really a little more than this when related physican services are included.. Here are the largest items on the bill:

MRI (5/16/16)                  Pharmacy, Magnetic Resonance Imaging                                                        3,328
Pet scan (5/19/16)            Nuclear medicine, Pharmacy, "other imaging services"                                12,202
                                              Physician services related to 'Pet imaging for CT attenuation"                 1,084
Radiation  (5/20 - 5/31)   Radiation Theraputic and/or chomtherophy administration                            9,676
                   (5/23/16)            IV therapy ?                                                                                                1,223
                                                                                                                                                      total   27,513
                Hospital services for May 2016 (total)                  26,912
                Physician services for May 2015  (total)                 3,960
                My share of 30,872 total billing for May 2016        1,594   (5.16%)

High cost of carfilzomib and daratumumab infusions!
(7/26/16) (10/17/16) (12/1/16) (10/14/17)

        I had two infusions of carfilzomib (pom/carfilzomib/dex) three weeks out of four for about nine months (july 2016 to april 2017) or about 59 infusions total. In round numbers SS paid the hospital 1,700 per infusion (hospital billed 6,400). This is an annual cost of about 133k.

        In summer 2017 I had nine weekly daratumumab infusions. Per infusion these were much more expensive than carfilzomib. My insurance records show that SS approved about 6,400 per infusion (hospital billed 19,000 per infusion!). This is an annual rate of about 134k (daratumumab infusion rate drops off with time). And this was for a chemo drug I did not respond to!

Carfilzomib billing decoded (12/1/16 update)
        I have been unable to get the hospital to explain my billing for carfilzomib infusions, but playing with the numbers I made a breakthrough. Let's look at the funds received by the hospital for an infusion and ask the question at what billing from me would the funding for the infusion meet the ideal goal of Part B of an 80/20 cost split. We just need to solve this little equation where x is my billing and 1,699 is the payment Medicare provides to the hospital:

                                                        x/(1,699 + x) = .2                      (set my fraction of total cost as seen by hospital at 20%)
                                                           x = .2 x 1,699 + .2 x
                                                        .8 x = .2 x 1,699
                                                          x = .25 x 1,699                       (set patient billing at 25% of the amount Medicare pays provider)
                                                           x = 425                                   (yes, this is what I am being billed)

        With the assumption that the hospital has set its billing to me so that I am contributing 20% of the cost and Medicare 80% of the cost we find that the amount I should be billed is just in fact what I am being billed! This cannot be an accident, it is clearly intended. Why it is intended is another question. It is my understand is that under Part B the hospital is allowed to charge 20% of 'Medicare approved' charges, and since Medicare (for whatever reason) approves nearly the entire hugely inflated billing (in excess of 6,000) I could be getting billed about x3 more than I am, up around 1,200. So the question on the table now is this. Is the hospital doing this out of the goodness of their heart, or perhaps fairness for someone without Medigap coverage, or are they constrained somehow by Medicare rules? (See the answer below)

        I see this phrase being used for Part B: 'reasonable charge' --- Medicare (Part B) pays 80 percent of what Medicare considers a "charge" for the item or service.

        -- If the provider participates in Medicare, he or she "accepts assignment," which means that the provider agrees that the total charge for the covered service will be the 'amount approved' by Medicare. Medicare then pays the provider 80 percent of its 'approved amount', after subtracting any part of the beneficiary's annual deductible that has not already been met. The provider then charges the beneficiary the remaining 20 percent of the approved "reasonable" charge, plus any part of the deductible that has not been satisfied.

        In other words the hospital (assuming it 'accepts assignment' which it must because it is taking Medicare patients) must accept that the 'total' charge for a procedure under Part B is what Medicare has determined to be  'reasonable'. Since Medicare then pays the provider 80% of the total charge, the hospital is constrained. The maximum the hospital can bill the patient is the remaining 20% of the total cost (or equivalently  25% of the payment it accepts from Medicare).

Must collect about 25 percent of Part B expenses from beneficiaries
         "By law, (Medicare) must collect about 25 percent of Part B expenses from beneficiaries", ( Note this is another equivalent way to look at the usual Part B cost sharing usually quoted as 80/20 of total cost. A patient billed at 20% of the total cost is being billed at 25% (20/80 = .25) of the cost to medicare.  This is consistent with how I am being billed for carfilzomib infusions, but it doesn't explain why the "Medicare Approved" amount for each carfilzomib infusion (as shown on my Medicare account) is more than x3 higher.

Reasonableness check (12/1/16)
        We can also do a reasonableness check on the numbers for my carfilzomib infusion.

                                        2,124     Medicare 'reasonable charge' is 1.25 x 1,699 (Medicare paid provider)
                                    -  1,699     Medicare paid provider
                                          425       patient billing (max)  (20% of total cost)

        So is 2,124 in funds collected by the hospital from Medicare and the patient sufficient to buy the drug and pay for the infusion?  Ans: yes. I am familiar with discount drug search engines and some of them include carfilzomib. With the MA drug discount card search engine (below) I found 30 vials of 60 mg carfilzomib (my dose is 56 mg = 2.07 x 27) for sale with 'discount' coupons for 59,270. This is 1,976 per vial. 1,976 for a vial means the drug cost is 93% of the Medicare reasonable cost, a nice fit, and close to the ratio that was billed. After purchasing the drug for the discount price of 1,976, the hospital has (148 = 2,124 - 1,976) to pay for the cost of the infusion.  The reasonable test is passed.

infusion drug carfilzomib discount price
(Kyprolis is the brand name of carfilzomib)
(60 mg vial is correct for me as my dose is 56 mg = 2.07 x 27 mg)

(10/17/16 update)
        Why am I being charged $450 (425 to 475) out of pocket for every carfilzomib infusion?  Typical numbers are shown in the June 28,16 entry below: Total charges 6,375 with Medicare paying 5,940 leaving a patient balance of 433. Total [6,375 = 5,754 pharmacy (drug) + 621 various hospital services]. My fraction of the drug cost should be 5%, because it is covered by part D catastrophic coverage .05 x 5,754 = 288. If I am being charged 20% of the hospital charges, it would be .20 x 621 = 124, and 124 + 288 = 412 (close, but still less than the 433 on my bill. (1.24 is for supplied dexamethasome pills that medicare A/B does not cover, but I would think part D should cover.)

        I checked the details of the June 28, 16 charges by logging onto my Medicare account. The key Medicare numbers agree with the hospital billing, but adds a (puzzling) detail that is missing from the hospital billing [Amount paid to provider = 1,699]. This looks to be the typical Medicare mark down. It is 26.7% of hospital 6,375 total charges. If so, then my 5% part D share of drug cost (288) is being inflated by nearly 4:1! says "Part B covers chemotherapy for hospital outpatients. This is me. Medicare part B usually pays only 80% of approved charges, but in a detailed list of coverage ( it says for chemotherapy give in a doctor's office or free standing clinic' the patient pays applies 20%, but for chemotherapy given in a "hospital outpatient setting", which is me, it says a "copayment" applies. It doesn't detail the copayment, but the definition section says a copayment is "usually" a set amount. I never make a cash copayment. On a later nearly identical infusion billing my 433 payment is labelled "coinsurance"
        Here's the billing details of the 6/28/16 infusion (typical of my carfilzomib infusions summer/fall 2016)) as shown on in my Medicare account. Note the 1,699 is in the column labelled 'paid to provider'. 'Paid to provider' looks like the typical Medicare markdown.  The hospital bills 6,375 (including 5,754 for the drug carfilzomib) and medicare only pays 26.7% of this, a x3.75 markdown.
        Somehow this doesn't smell right. If Lahey is accepting 1,699 for an infusion, which apparently is both the drug cost and the infusion labor, why is not the 20% part B coinsurance not much lower. Is my copay being figured on the inflated 'retail' price? However, I don't know how to separate the drug cost (95% part D coverage) from the infusion labor (628). [Note at this point I did not understand that the drug costs for an infusion given in a hospital outpatient seting are covered by Medicare Part B not Medicare Part D. Medicare Part D applies to drugs the patient buys from drug manuf via pharmacy, but with an infusion it is the hospital that is buying the drugs.]
Lahey carfilzomib infusion billing for 7-26-16 and Medicare payment (10/25/16)
        The 7/26/16 infusion is a simple case, no labs or other extra charges. For this one outpatient infusion the hospital billed medicare 6,375.29. Medicare approved virtually the whole amount (6,373.65) excluding only 1.64 for five steroid pills I am given prior to the infusion.

        The key question is how is the 429.73 "coinsurance" calculated. There is no information on the Lahey billing nor my account on the Medicare site that explains the 429.73. It seems to come out of thin air. I sat down with Lahey billing people today and was assured this infusion billing is covered under medicare Part B that Part D is not involved and that is consistent with what it says on the bill (Medicare A and B). I made a follow up phone call to the billing people (Tayla, ext 5918) same day after reviewing my billing and was unable to make sense of the numbers. (If Medicare part B only pays 80% of medicare approved charges, which is what medicare tells patients, why was I not being billed 1,274.73, which is 20% of 6,373.65?  I was told Lahey hospical has a contract with Medicare and that where the coinsurance number comes from.

        So today (10/25/16 ) over the phone  I made a specific request of Lahey billing to detail how the 'Adjustment, coinsurance' of 429.73 for the infusion on 7/26/16 (below) was calulated. Break it out, detail the contract they have with Medicare. This will require analysis and a follow up letter (hopefully by next week).

Playing around
      Playing with the numbers (as engineers are wont to do) I see something interesting. Lahey was paid 1,684.47 by Medicare, and they billed me (and I paid) 429.73. If I add these two payment together and ratio it to the total approved medicare charges of 6,373.65, I get an interesting ratio: very close to 33%  [(1,684.47 + 429.73)/6,373.65 = .3317].  (The unapproved medicare charge is nothing,  just 1.64 for the five corticosteroid pills.)

Lahey billing for infusion 7/26/16

my medicare account showing infusion costing detail for 7/26/16

my medicare account showing infusion costing detail for 7/26/16
Note here a single carfilzomib infusion is billed as 60 mg.
This is the size of the a full vial (see above), even though based on my surface area I am only given 55 mg or 56 mg
of the 60 mg, the balance is discarded.

my medicare account showing infusion costing detail for 3/6/17
Note here the cost of a single carfilzomib infusion cost has two billing entries: 55 mg (5,422) and 5 mg (493).
Based on my body surface area my dose is 55mg (or 56 mg). This billing makes it clear that the discarded 5 mg is billed at about 500.
For a part B 80/20 split this would mean I am being billed about 100 for the discarded 5 mg of the 60 mg vial.
Note also that the total cost of the 60 mg carfilzomib vial here is [5,422  + 493 = 5,915],
whereas about eight months earlier (7/26/16) the cost for the same 60 mg vial was 167 less (5,748).

from my account Medicare web site

details from my account Medicare web site

        I'm always a little confused by the difference between 'Medicare Approved' and 'Paid provider', which here is huge, but I think the explanation is the former applies to the details of the medical care provided, while the latter applies to the cost of that medical care.

44.2k/yr out of pocket cost of new chemo! (10/23/16)
        My cost for six infusions of carfilzomib of a 28 day cycle is 2.7k (6 x 450), which is far in excess of my cost for pom (688)! This means my 2nd generation pom/carfilzomib/dex chemo is costing me (out of pocket) [(6 x 450) (carfilzomib + 700 (pom) = 3.4k/cycle] x 13 cycles = 44.2k a year. Yikes!
Total new chemo retail cost
        Total new chemo costs (excluding doctor appointments), most of it paid by the taxpayer, can be figured as follows:

                carfilzomib                 5,754/infusion x 6 infusions per cycle x13/cycles/yr = 448.8k
                pom                                                 688/cycle x 20 (part D) x 13 cycles/yr = 178.9k
                                                                                                                                         627.7k  (total retail cost for pom/carfilzomib/dex)

        I am picking up 44.2k (7.0%) of the 627k total and 93% is being picked up by the taxpayers in the form of medicare part B and part D.


       I need to investigate for 2017 if a medigap ( or supplemental) policy, which claim they cover coinsurance and copayments of medicare part B, would reduce my infusion costs. gives the price of a medicare policy is 8-9k if in good health, and 13-14k if in poor health.
        I have been looking at my hospital billing for my carfilzomib infusions and trying to make sense of them. Here is the online (Epic) billing for the first four pairs of my carfilzomib infusions which occur on adjacent days. Where their are three entries for a pair of days, there was also a meeting on the day with a doctor or a nurse practicioner.

hospital 6/28/16 infusion billing
(shows my out of pocket cost for this single infusion is 433)


6/27 and 6/28                                                                                             7/5 and 7/6


7/11 and 7/12                                                                                                 7/25 and 7/26

       It appears that the hospital charge for a single carfilzomib infusion is between 6,275 and 7,008, though why it would vary day to day I have no idea since the process appears to me to always be the same. Where there is doctor or nurse practitioner office visit associated with reviewing the infusion this added charge is 253 to 495, and it includes the associated blood lab test that precedes the office visit. The first infusion of the second cycle at a 35% higher dose is 5,870. (The last infusion (7/26) is the day I am writing this and the cost doesn't look like its completely billed.)

        Note the bulk of the charge is loaded onto 'pharmacy'. Each infusion in the first cycle shows a pharmacy charge of 5,754. Add some handling cost in house for the pharmacy and that seems to imply that the hospital is saying it is paying Onyx about 5,500 dollars for each dose of carfilzomib! Does Onyx really charge 5.5k per dose of carfilzomib? (research this)

       So bottom line for a cycle of six carfilzomib infusions the hospital is billing roughly 40 thousand dollars (36 -47k) about 33k of which is for the drug itself!   I am covered by basic Medicare and I am pretty sure as an inhouse hospital procedure the cost of these infusions, both the drug cost and infusion cost should be covered by Medicare B.

Medicare billing games?
        It my observation from reviewing other of my hospital bills that hospitals, at least my hospital, plays a little game with Medicare, billing far higher than what it knows Medicare will pay and what it will have to accept (typically x3 to x5 higher). The only Medicare entry in the online billing above is labelled Medicare payments and adjustments. This doesn't help because the adjustments are not broken out from the payments.

Description errors
        Some of the description of the charges are just plain wrong.

        Flat wrong --- July 12 was an infusion day the charges reflect that with pharmacy showing a 5,754 charge, yet the title is "Hospital Encounter with Klaudia Hunter at the dept of Radiation .... on July 12. The charges are right, but the title is flat wrong. Dr. Hunter is my radiation oncologist. My records show I did have a brief office visit with her on this day (July 12) preceeding the infusion to review my earler two weeks of radiation, but Dr. Huner has no connection whatsoever with calfilzomib infusions. Lahey billing seems to have merged two unrelated visits here naming the radiation doctor in the name of infusion apparently because her office visit preceded it within some time window. But scheduling was done this way for travel convenience. Of course if I have a review meeting is coming up, I schedule it on a day and time near an infusion to save another trip to the hospital. Lahey billing seems to be totally confused by this!

        Some flat wrong naming happens on July 11. On this day I did have both an office visit with my oncologist preceding the actual infusion. On the billing for July 11 we find the office visit charge and infusion charge with identical names. "Office Visit with", but showing the usual 5,754 pharmacy, so a very strange "Office" visit, the other billing (for the real office visit) has no pharmacy charge.

        Misleading --- Even the usual names for the charges is poor and misleading. The name of my Lahey oncologist appears in most of the charges as follows: "Test Visit with" or "Office Visit with". Gees. Sure my oncologist  has authorized all my carfilzomib infusions, but during an infusion session there is no "visit" with her, I meet only with the infusion nurses.

        Pattern emerging ---  More than once in these charges I find Lahey billing naming getting 'confused' (if that is the word) by closely scheduled procedures, which it conflates or mixes. This makes patient review of charges a nightmare.  I really don't see how this is possible in a properly set up fully electronic system, unless is done specifically to make review of charges by the patient difficult or impossible. On short form list of charge, which is what is first presented, the name for a charge is all that is visible. The billing images included here are rom a charge "detail' window I had to bring up.

    Continuing... I will come back to this when I get later more date. At some point the cost of the infusions will show up on the Medicare site and that should be more revealing.
Transient ischaemic attacks (or mini-stroke)
        Minor strokes and TIAs (transient ischaemic attacks or mini-strokes) occur when there is an interruption of blood flow to the brain - they can cause weakness to the limbs or problems with speech or vision and symptoms usually disappear within days. Transient ischaemic attacks (also known as mini-strokes) - symptoms resolve within 24 hours but the majority resolve within 10-60 minutes. The chance of going on to have a major stroke - with more permanent symptoms - is higher in the days after an attack.

        A new study in the Lancet recommends that in the event of a mini-stroke take aspirin immediately, saying that the benefits of 'immediate aspirin' are "highly underestimated". Their study shows it can reduce the risk of a major stroke later by factor of five (from one in 20 to one in 100 per day).

MRI results (5/16/16)
        Here's an image from the recent MRI of my head with the bad news that I have a (likely) plasmacytoma behind my left eye that was not present when I was diagnosed about 20 months ago. The plasmacytoma is the white region in the upper right of the image. (MRIs use an outside perspective, so the left eye as seen from the outside is on the right side of the image.) A call from my oncologist tells me the growth is not in the brain, but between the eye and a bone behind the eye orbit called sphenoid bone. A radiation doctor tells me the plasmacytoma is inside the sphenoid bone where the marrow should be.

        This bone can clearly be seen bowing outward in the image below and pressing on a long white structure behind the eye, which is likely one of the long muscles (lateral rectus) that moves the eye right/left. This is the likely explanation of why I have double vision when look right with my eyes. The plan is to use radiation (10 sessions over two weeks @ 20 Gy) to kill the cancer cells that make up the plamacytoma and shrink the mass. Whether the bone will unbow remains to be seen.

Radiation level of 20 Gray (Gy)
        My radiation doctor told me, confirmed by the Wikipedia article Gray (unit), that radiation dose used in cancer treatment ranges from 20 to 80 Gy, but blood cancer cells are quite sensitive to radiation allowing a relatively low dose of 20 Gy to be used. This is enough to kill them and has the benefit that burning side effects of radiation treatment are mild.

        However, my plasmacytoma is in a bad spot for radiation right between the eye and brain. Radiation to the eye is likely to cause dry eye and over time (years) cause a cataract to grow (darkening of the cornea). Technically one Gy is a "derived unit of ionizing radiation dose in the International System of Units (SI) defined as the absorption of one joule of radiation energy per kilogram of matter."

(5/16/16) Plasmacytoma is (large) white area behind my eye in upper rught corner.
It is apparently INSIDE the (greater wing) of the sphenoid bone displacing the marrow.
Similar area behind the other eye that is dark and is the marrow of the bone.
The right sphenoid bone can be seen bowing outward into the eye area.

MRI findings
        1) "Etraconal mass on the left. This is suggestive plasmacytoma."
                (The plasmacytoma is the white mass in the image, in (or associated with) the sphenoid bone that separates the eye from the brain.)
        2) "Small calvarial met versu myeloma in the right parietal region."
               ('Parietal calvarial lesion 'is a bone lesion in the large top/rear of the skull. Here it is on the right measuring 5 mm appearing since last study.)
        3) "Small left frontal infarct which is acute to subacute in the region of the superior frontal gyrus posteriorly."
                (Infarct is medical jargon for stroke, a localized area of dead tissue resulting from failure of blood supply, either a blockage
                 or breaking open and bleeding into the brain.)

        The medical jargon here is pretty intense and requires translation.

                    diplopia (subacute) --- just the technical term for double vision (which is what I see when looking a little left at TV)
                    greater wing of the sphenoid (bone) --- flat bone that forms the back of the eye socket toward the outsides
                                                                        (it doesn't appear that the optic nerve goes through it, it goes through a bone toward inside)
                    lateral rectus (muscle) --- a muscle that moves the eyeball right and left
                    parietal calvarial lesion --- a lesion in the large top/rear of the skull (right, 5 mm, new)
                                  MRI:   "Small right parietal calvarial lesion, 5 mm has appeared since last study. Previously described lesion
                                               is no longer present.
                    T2 bright focii centrum semiovale ---

                   calavarial --- skull (or skullcap)
                   parietal  ---  major bone of the skull in the top and back of the head
                    infarct ---  a small localized area of dead tissue resulting from failure of blood supply (in other words a stroke)
                   superior frontal gyrus --- one third of the frontal lobe of the brain. All Wikipedia says about the function of this region of the brain is that it involved with self awarness and when stimulated an awake patient could be made to laugh.
                    stroke --- Stroke, also known as cerebrovascular accident (CVA), cerebrovascular insult (CVI), or brain attack, is when poor blood flow to the brain results in cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. If symptoms last less than one or two hours, it is known as a transient ischemic attack.

                sagittal (plane) --- right/left vertical plane
                 axial (plane) --- horizontal plane
                 coronal (plane) ---  front/back vertical plane
                MIPS ---  maxium intensity projection (volume rendering of 3D data)

Diverticulitis (May & Sept 2016)
        Note finding (above) in May 2016 PET scan report --- "Colonic diverticulosos, most prominently within the sigmoid colon." Reference to diverticulosos has (apparently) also shown up in the report of the 2nd PET scan of sept 2016.

        -- Diverticulosis happens when pouches (diverticula ) form in the wall of the colon . If these pouches get inflamed or infected, it is called diverticulitis.

(source --

        My oncologist thinks the two episodes I have had in recent weeks of a few days of abdominal distress coupled with a low grade fever may be due to diverticulitis, which is pouches in the (sigmoid) colon getting infected. She has proscribed a seven day course of two antibiotics: ciprofloxacin (twice a day) and metronidazole (Flagyl) (three times a day). They are typically given together because they kill a much wider range of bacteria (aerobic and anaerobic as well as protozoa). This is five more pills a day as both of these antibiotics come in (huge) 500 mg tabs. These drugs are very inexpensive.

Diverticulosos and diverticulitis basics
       References say diverticulosos (little pockets in the colon) are common, that 50% of people have them by age 60, and about 10% of people with these pouches will develop diverticulitis (infection). Diet recommendations to help avoid diverticulitis are all over the map. Most say a high fiber diet (with a lot of water) is preferred as it softens the stool, but a few sources say exactly the opposite avoid high fiber foods. I love popcorn and it would seem logical that it should be avoided due to its hulls, but references point to a paper in JAMA (Harvard study with 47,000 people, aug 2008) that says popcorn did not increase the risk of diverticulitis.
1st PET scan results (5/19/16)
        The pet scan identified two soft tissues masses ("likely plasmacytomas") and four MM lesions that are metabolitically active. The report notes T12, where I had significant bone loss prior to being diagnosed and which was irradated in Sept 2014, says has minimal FDG uptake. Also identifed hyperdensities in the pancreas and liver (possible cysts) with recommened follow up on 1-2 years for the pancreas.

        SUV  --- 'Standardized Uptake Value' used to characterize Pet scan hot spots
                        Dr, Hunter told me Pet scans displays are normalized to some reference part of the body and what is displayed is the differential.
                        As I suspected, she said Pet scans results are somewhat crude (approx, windowed, etc).

       Soft tissue massses
                  1) same mass seen in the MRI (in) left sphenoid wing (behind the left eye)
                                     SUV 16.2  (intense focal uptake), 2.2 x 1.6 cm  (very high SUV)
                   2) soft tissue mass associated with 9th posterior right rib, 4 x 3.2 cm
                               [Sept 16, 2014 --- "Probable pathologic fracture posterior right 9th rib with adjacent overlying atelectasis."]
                              (In other words 9th rib likely had broken prior to my diagnosis in sept 2014. This lesion has probably been metabolically
                                   active since then and has now formed a huge (4 x 3.2 cm) adjacent soft tissue mass. Did this bone break ever heal?
                                   Is the rib bone maybe open allowing the monoclonal plasma cells to spill out? )

       MM lesions (active)
                  3) left mandible (jaw)
                                     SUV 7.6, 1.1 cm  (mid-range SUV)
                                    (discussion with radiation doctor places lesion this high up in the madible near the hinge)
                               [Sept 16, 2014 --- "Neoplastic (focal) lesion in the right ramus of the mandible"]
                                   Curiously at staging a mandible lesion in the ramus was found, but on the opposite (right) side!
                 4) 9th rib, right posterior  (with associated huge soft tissue mass, 4 x 3.2 cm)
                                    (9th rib is low, right rear, attaches to the spinal column at T9)
                              [Sept 16, 2014 --- "Probable pathologic fracture posterior right 9th rib with adjacent overlying atelectasis."]
                 5) 2nd rib, left anterior  (2nd rib is high up, left front)
                  6) left ischium, extending to ischial tuberosity  (lowest part of the pelvis, or sitz bone, two loops)
                                   SUV 5, 2.9 cm
                                   (This ischium lesion appears to be quite close to the left pelvis/femur ball and socket joint
                                             and extends into the adjacent lower loop of the pelvis called the ischial tubeosity.)

                   ischium bone (extending to ischial tubeosity) --- lower part of the pelvis, below the ball and socket joint, sometimes called sitz bone
                                                                                                     because the body sits on it

     I got my a disk of my recent PET scan and trolled (three times!) through the 4,000+ images to find those showing the lesions (tumors) and plasmacytomas referenced in the PET report. Prior to the test a radioactive sugar is drunk. The test then looks for areas of the body have the most radioactivity and displays them in yellow, the more radioactivity the brighter the yellow. The test is optimized to pick up lesions (tumors) that are feeding (growing), so it shows where in the body there is active cancer. (not quite right --- What was drunk prior to the scan was a contrast material for the CT. The radioactive sugar is injected via IV.)

1st PET scan images (5/19/16)
     The report of the PET scan identified six active areas: four bone lesions (two in ribs, one in lower pelvis, one in the jaw) and two soft tissue masses (plasmacytomas): behind the left eye and one associated with the 9th rib lesion. The four thousand plus images on the disk are arranged in 20 or so views of the body.

        I read on a Beacon MM forum that PET scans can only find tumors that are larger than 1 cm.

Identifying the mandible tumor
       After reviewing my PET scans I have some concern that the right location for the mandible has been chosen for the radiation. There appear to be three (or maybe two) hot spots. There's one in the low center about where the teeth are. I first though this was the mandible tumor, but the alternate radiation oncologist says no, and I now agree as the location does not look right. I have no idea what his hot spot really is.

        The radiation oncologist identified the mandible tumor on the screen as a quite dim blurry B&W spot that I can find on only one scan. He did this quickly identifying the first image he found. Also he did not do the radiation plan, so he might be wrong here. In the images below I favor and am showing the 3rd candidate which is close to what he found, My candidate appears to be in the right location with one image even seeming to show it high up on the left mandible (near the hinge) which agrees with what the alternate radiation oncologist said. Plus my images are quite bright which agrees with the report said, an SUV of 7.6.

This 1st pet scan iimage shows 4 metabolically active lesions and plasmacytomas below the head.
-- 9th rib lesion and assoicated plasmacytoma are the larger black spot in the rib cage on right side of body
                                       [right posterior (near spinal column) with associated large plasmacytoma (4 cm x 3.2 cm)]
-- 2th rib lesion is the small black spot in the rib cage higher up on left side of body
[2nd rib lesion left anterior (front)]
-- pelvis lesion is small black spot in crotch on left side of body
(near the pelvis/femur ball and socket joint)
not visible on this image are the two active areas in the head: left mandible (jaw) lesion and plasmacytome behind left eye
(Report notes "non-specific muscular activity within right shoulder"
(no mention in report of the long radiation stripe in the left lower arm)

9th rib lesion right posterior with associated plasmacytoma (frontal view)
SUV  15.1

9th rib lesion right posterior with associated plasmacytoma (top view)
(9th rib lesion and associated soft mass are quite close to T9 in the spinal column)

Radiologist report on 1st PET scan (may 2016)

2nd PET scan images (9/6/16)
        Here are new PET scan images (comparable the images above) taken 2.5 months into new pom/carfilzomib/dex chemo. These are the brightest images I was able to find on the Sept 2016 PET scan CD, and they match up quite well with the images taken earlier in May 2016 on rev/dex chemo. It's clear the 9th rib plasmacytoma is less bright,, maybe half, but the definitive reading will come from the radiologist. The 2nd rib plasmacytoma doesn't now show up, so (if it exists) it is now below the PET size/brightness threshold.

-- 9th rib right posterier plasmacytoma (upper left in image) in Sept looks considerable smaller
than in May 2016.
-- Earlier 2th rib lesion (front) was small black spot in the rib cage higher up on left side of body
but in Sept is does not show up
However, there are three smal dots that are new in Sept 2016
in the body center and near the left elbow

-- 9th rib right posterier plasmacytoma (upper left in image) in Sept is quite a bit less bright
than in May 2016.
SUV  6.5  (previously 15.1)

-- 9th rib right posterier plasmacytoma in Sept is quite a bit less bright
than in May 2016.

side view of 9th rib right posterier plasmacytoma (upper right) (Sept 2016)

-- 2th rib left anterior (front) in Sept is quite a bit less bright
than in May 2016 (compare to below)

Radiologist report on 2nd PET scan (sept 2016)

Radiologist report on 2nd PET scan (sept 2016)

Pet scan images of right tibia (sept 2016)
        Trolling through the Pet images here is what I find for the 'suspicious findings' in the report of the "right tibial and peroneal veins" (names of veins in the lower leg)  Recommends ultrasound to "exclude DVT" (deep vein thrombosis), which is blood clot in a deep vein, usually in the legs.


Pet scan images of right oral cavity (sept 2016)
        Trolling through the Pet images these are the 'indeterminant findings' in the report of the "right oral cavity, diving ranula in the differential, correlate with ENT (ear, nose, throat) exam".

3rd PET scan images (1/11/17)
       The 9th rib plasmacytoma in the 3rd Pet scan images below looks a little brighter than in the 2nd Pet scan of sept, but that's because I brightened the image using ADCSee. Prior to the gamma adjust to my eye the brightness of the 9th rib plasmacytoma looked basically the same as it did four months ago. I don't see anything around the head, eyes or jaw, though the resolution of this whole body scan limits what can be seen in the head.

(1/11/17) (1/16/17)
        I have not seen the pathologist report yet, but I've carefully gone through the images on the Jan 2017 PET disk and the only active cancer area I see is the (pre-existing) 9th rib posteria plasmacytoma.  Need to see what the new SUV reading will be, but it looks to my amateur eyes that there has been little change in my Pet scan in the last four months.

       Yes, the official read of the Pet scan pretty much agrees with what I see. Only one plasmacytoma visible (9th rib right posteria) that is judged to be a little bit brighter and bigger than four months earlier. When compared with the previous Pet scan in Sept 2016 (Pet #2), it is just slightly (10%)  brighter (SUV 7.1 vs 6.5) and a little larger (2 cm vs 1.5 cm). Of course, it would have been better if it was smaller, so is this an inflection point pointing to higher levels to come, or just noise in  a stable situation?

        "Finding: Slight worsening of metastatic lesion (bone not identified as a plasmacytoma) posterior right 9th rib, approx 2 cm max SUV 7.1, prev 1.5 cm, max SUV 6.5. No obvious FDG Pet evidence active disease remainder of the body."

        "Impression: Persistent/slight worsening metastatic disease posterior right 9th rib. Stable disease the remainder of the body."

Radiologist's report on 3rd Pet scan (1/11/17)

        It is interesting to compare this 3rd Pet scan after six months on pom/carfilzomig/dex chemo to the 1st pet scan reading prior to this chemo. Even though the resolution of a full body scan is not good in the head region, the 1st pet full body scan clearly showed a bright spot (plasmacytomas) behind the left eye, one on the jaw, and a plasmacytoma on the 2rd rib left front in addition to the bright 9th rib right posteria plasmacytoma. I had two weeks of radiation to the head region to treat the plasmacytoma behind the left eye and the bright spot on the jaw too. Only one of these four plasmacytomas (9th rib right posteria) are visible on Pet scan #3.

Pet scan #3 (Jan 11,2017)
(6.5 months into pom/carfilzomib/des chemo)
[9th rib right posteria plasmacytoma is the black dot on
left side of image ('R') in the rib cage opposite the mid upper right arm (humerus)]

Pet scan #3 (Jan 11,2017)
-- 9th rib right posteria plasmacytoma
(6.5 months into pom/carfilzomib/des chemo)
SUV --- 7.1 (2 cm)

Pet scan #3 (Jan 11,2017)
-- 9th rib right posteria  plasmacytoma
(6.5 months into pom/carfilzomib/des chemo)

Pet scan #3 (Jan 11,2017)
-- 9th rib right posteria plasmacytoma
(6.5 months into pom/carfilzomib/dex chemo)

Pet scan #3 (Jan 11,2017)
Area around eyes
(I don't see any indication of a plasmacytoma behind left eye)

4th PET scan images (3/22/17) (3/29/17)
        The purpose of this 4th pet scan is to establish a baseline for a pending change in chemo. As evidenced by rising free light chain (4.55 mg/dL lambda free light chain) and M-spike (.17 g/dL) readings in the last couple of months my cancer has evolved around the pom/carfilzomib/dex chemo I have been on since 6/29/16 ending my 2nd remission of 8.5 months. I have an aggressive form of MM as evidence by several (five) plasmacytomas (two in ribs, pelvis, jaw, sphenoid bone behind left eye) seen last spring prior to beginning pom/carfilzomib/dex chemo. Months on this chemo has reduced my plasmacytomas (plus two rounds of radiation over 2.5 years) seen on a pet scan to one (9th rib posterior), but my hematological oncologist is concerned that with rising blood cancer numbers new plasmacytoma may have popped up. Also she wanted a baseline before beginning an experiment with the proteasome inhibitor Ninlaro substituting for the protease inhibitor carfilzomib (beginning 4/3/17).

'Metastatic'  (right lung)  is a reference to a possible metastasis of the cancer to the lung, i.e. a possible new plasmacytoma.
        Right lung is described as having
" New reticular nodular opacities subpleural distribution superior segment right lower lobe and posterior segment right upper lobe."
(I disagree that the growth of the 9th rib, posterior plasmacytoma (in last 9 weeks) is "slight",
since SUV doubled (7.1 => 14.1) and size increased 50% (2 cm => 3 cm))
Radiologist's report on 4rd Pet scan (3/22/17)

        My quick read of the images (prior to the expert read) is that the only one plasmacytoma is clearly shown (yup). This is the existing 9th rib, right, posterior. Looks to be that it is quite a bit brighter than the pet scan two months ago (1/11/17), perhaps close to where it was at the 1st pet scan last spring prior to beginning pom/carfilzomib/dex chemo (yup). The SUV reading will tell the story. It is now about a week since the test and expert analysis of it has still not been posted on MyLaheychart. But a few days ago my doctor messaged me after reading the report saying I was right, it has bright (grown) a lot, I think she implied the SUV had about doubled. If so, all the shrinkage of 8.5 months on pom/carfilzomib/dex chemo has been lost in just the last 11 weeks (since the 3rd pet scan).  Obviously this is bad news especially since both free light chain and M-spike are probably still far below the disease progression thresholds (at least that was true at the the last blood sampling about three weeks ago)!  I am beginning to wonder if it is a mistake to try Ninlaro for a month and give this plasmacytoma another month to grow. Would it make sense to schedule two weeks of radiation to beat it back? Is it just acting as a source of plasma cancer cells that can more easily spread around the rib cage and the spine? This will a topic to review with my oncologist at our next meeting in a week (4/417).

        There were 3,300 images on the pet CD. In a couple of hours I pulled the images below from the CD and posted them online in this essay (below). Something which I doubt any other patient at the hospital has ever done. I took my time here scrolling back and forth, I am pretty sure these images are the best views of the 9th rib plasmacytoma.

black spot upper left on image is the plasmacytoma 9th rib posterior
4th pet scan (3/22/17)

        The front view below also a weak brightish spot on the left lower down in the ribs that might be a (new) plasmacytoma, but it doesn't show in the whole body scan or other close up views.

4th pet scan (3/22/17)

4th pet scan (3/22/17)

4th pet scan (3/22/17)

           After reading the radiologist report, I went back and looked at the lungs. Do I see opacities in the right lung?  When researching my pet images I at first got faked out. I thought the two large yellow areas were the lower lobes of the lungs. Wrong! The lungs start high up in the chest and are pretty much black on pet scans (and trasparent on x-ray). Online pet scans of a lung with a cancer show a bright yel spot in a field of black. The two large bright areas I am pretty sure are the right lobe of the liver and on the left the spleen (or possibly the left lobe of the liver). Below them the two much smaller, brighter areas are the two kidneys.

        The right lung weirdness that the radiologist noted must be the faint yellow in the large right field of black. Another look throught the images of the 4th pet scan shows this is best right lung image I can find, and I am not sure it isn't just an artifact of the heart.

Right lung weirdness noted by diologist is probably the faint yellow in the black area above the large bright liver right lobe.
(right --- reference online pet chest cavity showing organ locations.)
(source --
4th pet scan (3/22/17)

        Lots of false positives in this side view image (below left), for example just look at the face and jaw, but it also seems to show possible 'hot spots' running up and down the spine. When I was diagnosed MM, the cervical surgeon found cancer up and down my next bones, C2 had broken and the surgeon biopsied  C4 to confirmed my MM diagnosis.

          (left) Weak hot spots along the spine?                                   (right) T12 notch from 1st pet scan (5/19/16)
Nicely shows the MM caused notch in T12 vertebrae                                                                .                 .
4th pet scan (3/22/17)                                                                                        .

        Note the expert read of a a hi-res CT scan of the lungs taken about the same time reported "lytic vertebral lesions", in other words evidence of cancer lesions in the vertebrae of the back, consistent with the left Pet image above.

        The images above clearly shows the 'notch' in T12 vertebrae. A third to half of the supporting part of T12 had been eaten away by my cancer before I was diagnosed in sept 2014. I saw detailed images of this at the time by the radiologist who did the radiation of my neck. To date this loss of vertebrae bone and obviously strength of spine has caused me no problem, but this is a big worry if chemo stops working. A growth of cancer here would lead to a crushing of T12, and in fact the radiologist in 2014 said at some point in time this was likely to happen.

        So to keep watch on this I have carefully compared this 4th pet image of the T12 notch (3/22/17) to a image showing the T12 notch from my 1st pet scan (5/19/16) about a year earlier, (side by side above) and to the extent that the resolution allows, they look the same. I see no deepening of the notch in the last year, most of which I have been in a second remission on pom/carfilzomib/dex chemo.

        The head does not have much resolution in a full body scan. I still have double vision looking right, so either the plasmacytoma behind the left eye sill exists or the bending of the sphenoid bone remained after (or if) the plasmacytoma in it shrank. I asked about the radiologist on duty about the resolution of the scan and was told about 5 mm across if bright, which is pretty consistent with what I found on a MM forum that plasmacytomas have to grow to about 1 cm across before they will show up in pet scans.

area around the eyes. I don't see anything definitive here.
4th pet scan (3/22/17)

5th PET scan images(7/10/17)
Known rib plasmacytomas
        My quick overview of the 5th pet scan prior to getting the radiologist report is that the two known rib plasmacytomas are clearly larger.  Most significantly the largest plasmacytoma in my body, 9th rib, right posterior has increased in size substantially, far larger than it has ever been before. And this growth has all been since the last pet scan four months ago. The intensity figures show in addition the known bright core there is a now a surrounding large area of diffuse brightness. There are hints that the low intensity diffused area has expanded to (or into) the spinal column (T9). Probably not good.

Posssible new plasmacytomas
        There are several black dots on the 5th pet scan that were not there four months ago. Some may be real, others artifacts. One (upper right on image) is clearly the existing 2nd rib, left front plasmacytoma that was in the 1st pet scan of 5/19/16, but was reduced enough by the introduction of pom/carfilzomib/dex chemo that for about a year it disappeared from the whole body view in pet scans 2, 3, and 4, which was the scan of 3/22/17 prior to beginning the Ninlaro chemo. Well it's back, so it must have grown either after the cancer became refractory to carfilzomib and/or in the nearly four months of pom/Ninlaro/dex chemo.

        There is a black dot on right arm near (or below) elbow, probably in the upper part of the lower arm bones (radius and ulna). This is new, it has never shown up on earlier scans, so it is might indicate a new plasmacytoma, though I can't find it on the intensity view.

        The are two interior black dots that are more problematical, both near the large 9th rib plasmacytoma. The upper one is connected to the large T9 plasmacytoma and is likely at the T9 vertebrae. The other is below more toward the right, so it looks like it might be in the 10th or 11th rib.

        Curiously the long narrow black stripe in the right shoulder shown in the 1st pet scan is now back. Is this activity maybe due to a crack in in the scapula bone?

        There is not enough resolution in a full body scan to see the plasmacytoma behind my left eye.

Second look at pet5 images --- jaw activity
        A second look at my pet5 images the next day has resulted in five more images posted. Two of the images show a hot spot in the jaw region. Three side images were taken without shifting the closeup focus. The left image clearly shows the one well known vertebrae in my back with the deep notch. This is T12, and by counting it allows the two spine hot spots to be localized. I count them to be on T8 and T9.

My 5th pet scan summary (prior to radiologist report)
        The two known rib plasmacytomas (9th rib, right posterior and 2nd rib, left front) are definitely bigger with the 9th rib plasmacytoma appearing to have expanded greatly in a diffuse way including extending toward (or into) the spinal column at T9 vertebrae. If this is right, it is probably not good. There is a hint that there might possibly be a new plasmacytoma in the upper region of the right arm lower bones (ulna or radius), but it doesn't show up in the intensity images. A black dot in the 10th or 11th rib is unexplained. More images show activity in the jaw region. The activity in T8 is unexplained.

Confirms a chemo change needed
        The big picture here is that the recent significant growth in my rib plasmacytomas shows my existing chemo is just not working, things are growing wild inside (with lambda free light chain at 8.42 mg/dL and M-spike at .15 g/dL). This confirms my latest blood work that indicated that a chemo change was probably needed as my lambda free light chain had a big jump to close to its disease progression threshold of 10 mg/dL. So together they clearly show a change in chemo is needed at the end of this cycle (another step up the chemo ladder!).

        My doctors prefer changing to a regimen build around the most effective humanized antibody drug (new drug class for me) daratumumab, and I don't disagree. What daratumumab should be paired with is another story, and here I don't agree with my doctors. They perfer pairing it with a proteasome inhibitor (Velcade), the Castor clinical trial, I want to pair it with an imid (Pomalyst), the Pollux clinical trial.

wide black region (upper left on image) is the plasmacytoma 9th rib right posterior, clearly larger.
small dot (upper right on image) is very likely the 2nd rib, left front plasmacytoma seen in 1st pet scan
small dot (left side of image) below elbow of the right arm is possibly a new plamacytoma in right radius or ulna (two lower arm bones)
5th pet scan (7/10/17)

Compare 5th pet full body scan (above 7/10/17) to earlier pet full scan images below:  left, 4th pet scan 3/22/17 and  right, 1st pet scan 5/19/16

left -- 4th pet scan 3/22/17                                                                                                   right -- 1st pet scan 5/19/16

plasmacytoma in 9th right rib posterior showing new low intensity diffused area
(no hint of activity in right arm in this image)
(5th pet scan 7/10/17)

plasmacytoma in 9th right rib posterior showing new low intensity diffused area
(5th pet scan 7/10/17).

plasmacytoma in 9th right rib posterior
appearing to show its low intensity diffused area extending to spinal column (T9)
(5th pet scan 7/10/17)

More pet5 images

two images showing intesity in the jaw region
(5th pet scan 7/10/17)
. .
(left)  lowest vertebrae with deep notch is T12
(center) hot spot appears to be on (inside of) T8
(right) hot spot appears to be at T9
(5th pet scan 7/10/17)
Notes from radiolist report on 5th pet scan (8/18/2017)
        The radiologist report by radiology resident (dictated)) of the 5th pet scan is a disappointment. Rather than focus on the cancer it's mostly a body review. It fails to follow up on some new black spots on the initial whole body image. Not does it comment on what I see as a metabolitically active area in the jaw. The summary concerns only the known 9th and 2nd rib plasmacytomas. The extension of the large 9th rib plasma cytoma to the spine, which I have an image of, it not addressed.

Organs described as normal in appearance in 5th pet scan
        lungs, liver,  pancreas, kidneys, stomach, bladder, small and large bowel (with moderate colonic diverticulosis), spleen, prostate/ seminal vesticles, aorta and IVC, biliary ducts, thryoid, adrenal glands, peritoneum (lining of abdominal caviry)


6th PET scan images (10/18/17)
        About 5-6 weeks before this pet scan I had stopped chemo because I had developed a second cancer (MSD) that basically shut down my marrow. My body is not making blood, specifically not making red blood cells and platelets. I have been surviving in recent weeks only I have been getting twice a week red blood cell transfusions and platelet transfusions. My M-spike at this time is about .5 g/dL (its disease threshold) and lambda free light chain a little above 20 mg/dL (more than double its disease threshold). So it is not surprising that my long existing right posterior tumor in my 9th rib has clearly been growing.

pet6 radiologist report (10/19/2017)

(radiolist text above reordered and expanded)
        Ribs --- Compared to prior scan, the (9th rib) right posterior chest wall lesion has markedly increased in size and intensity. The left anterior 2nd rib lesion has significant increased in size and intensity of FDG activity.

        Lungs --- Right posterior pleural (thin fluid filled cavity around lungs) lesions have also increased in size. New lower periesophageal adenopathy (swollen lymph node in lung) with increased FDG uptake. Right axillary adenopathy (swollen lymph in arm area) with increased FDG uptake, new since last scan. There is diffuse increased activity in both lung parenchymal (lung parenchyma is the portion of the lung involved in gas transfer).

        Liver --- Possible new uptake in the dome of the liver. No other significant focal uptake in the soft tissue of the abdomen and pelvis.

        Bones --- Interval development of multiple foci of uptake in right humeral head (humerus is the upper arm bone), left glenoid (shoulder), right side of the sternum (sternum or breastbone is a long flat bone shaped like a necktie located in the center of the chest), multiple pelvic bones and bilateral femora (femur is thigh bone)

IMPRESSION: Interval worsening of metastatic multiple myeloma.
        I suppose the only 'good' news here is no mention of activity in the tumors in my back, neck, or head.
1st Pet images from 5/19/16 (continued)

        This image (below) clearly shows the notch in T12 vertebrae.

shows (pre-existng) loss of bone in T12 vertebrae (center of spine in this image)
(T12 treated with radiation in sept 2014)
(No emission from T12, so this lesion does not appear to be metabolically active)
1st pet scan (5/19/16)

2nd rib left anterior (front) (may 2016)

left mandible lesion (near hinge. side view)
(treated with radiation)

(my candidate for) left mandible lesion (top view)
(treated with radiation)

(my candidate for) left mandible lesion (near hinge. front view)
(Note, this view appears to show the hot spot high up on the mandible near the hinge.)
(treated with radiation)

left pelvis lesion (side view)
(near pelvis/femur ball and socket joint)

left pelvis lesion (front view)
(near pelvis/femur ball and socket joint)

plasmacytoma behind left eye
(bright yellow upper right in this image)

MRI image of plasmacytoma behind left eye ("in the sphenoid bone")
(treated with radiation, june 2016)

MRI faces
        Here's some fun MRI images of my face, as found on my brain MRI disk (may 2016) with only a little exposure adjust and cropping.

Yup, three sequential MRI images of my face

Pelvis anatomy
        My pelvis lesion is described in the PET report as "left ischium, extending to ischial tuberosity".  The PET reference to 'ischium' to is not clear. The anatomy sketches disagee about just exactly where the 'ischium' is located. Left shows the 'body of the ischium' is close to (and  (probably) just behind) the hip ball and socket joint, but right labels as the ischium a region slightly lower (that left labels as ischial tuberosity!). "Ischial tuberosity' is the beginning of the lower bone loop which extends down from the body of the ischium.

PET reports describes active pelvis lesion as
"left ischium, extending to ischial tuberosity, SUV 5, 2.9 cm"
(Report and PET images put the lesion in the lower region of pelvis (ischium) a little below the socket for the ball of femur
and extending about an inch down the long looping sitz bone (ischial tuberosity).)

Radiation for 9th rib plasmacytoma?
        Could radiation be used on the 9th rib plasmacytoma?  I was initially just assuming it could be, but then I read in forums that you can't irradiate the same region twice. So the question is, Is the 9th rib rear plasmacytoma too close to the T12 area? How close can be figured from the figure below of ribs and vertebrae. T12 is just above L1. This figure shows that one rib comes into each vertebrae, that the 9th rib comes into vertebrae T9. The 9th rib plasmacytoma is a little to side of the spinal column and three vertebrae above the T12 radiation center. The answer likely depends on how tightly the T12 radiation was targeted.

shows the 12 ribs connect to the spinal column
at T1 to T12 of the thoracic spine.
In other words the 9th rib connects to T9.
(T12 is directly above L1 vertebrae)

Imaging considerations
       -- Lytic lesions (bone lesions) become apparent on conventional radiography (X-rays) when 30–50% of the bone mineral density is already lost.

CT scan
       --  CT findings in multiple myeloma consist of punched-out lytic lesions, expansile lesions with soft tissue masses, diffuse osteopenia, and fractures.
                    (CT is better at finding small lesions than x-rays.)
       -- It is important to note that MRI predominately reflects marrow infiltration, which may or may not be associated with bone destruction.
                  (In other words use MRI to look at marrow.)
        -- Typical myeloma lesions are marrow based and have low signal intensity on T1-weighted (MRI) images  and a high signal intensity on T2-weighted sequences.
        -- Bone scintigraphy is of limited use in multiple myeloma. Bone scintigraphy uses technetium 99-m labelled diphosphonates and relies on the osteoblastic response and activity of the skeletal system for uptake.

Pet/CT scan
     **   -- The presence of more than 3 FDG-avid focal lesions was the leading independent parameter associated with an inferior overall and event-free survival. The prognosis of high-risk patients in this study not achieving complete FDG suppression was poor, which supports the use of serial PET/CT examinations in high-risk patients to individualise therapy and prompt changes to alternative therapies. Importantly, persistent FDG positivity can occur when bone marrow and M-component markers are negative.

       -- Positron emission computed, tomography (PET/CT) is a tomographic nuclear imaging technique that uses a labelled radiopharmaceutical such as 18flouro-deoxy-glucose (FDG) injected into the patient, followed by tomographic scanning approximately 10–40 minutes later. Tumour cells can be imaged with this technique due to their high metabolic rate and the resulting high glucose demand, allowing tumour cells to be distinguished from normal cells.

        -- Currently, PET/CT is being evaluated in patients with multiple myeloma and may detect early bone marrow involvement in patients with apparently solitary plasmacytoma, to assess the extent of active disease, detect extramedullary involvement or evaluate treatment response.

        -- Active myeloma is FDG positive for focal and diffuse abnormities and FDG uptake decreases rapidly after effective therapy.

        -- Persistent FDG positivity correlates with early relapse as is discussed later. This rapid response to treatment is converse to that seen with MRI where there may be a time lag of 9–12 months in the reversal of MRI abnormalities despite successful therapy.

        -- False-positive PET/CT scans may arise from inflammatory changes due to active infection, chemotherapy within the preceding 4 weeks, or radiation therapy within the preceding 2-3 months.

        --  Later in the disease cortical breaches may occur, and further local spread from bone may be seen, producing masses in the surrounding soft tissues.

"Extra-medullary" myeloma plasmacytomas
        **  --  Overall survival for patients with extramedullary disease in the soft tissue was 30 months (2.5 yr) from initial myeloma diagnosis, compared to 45 (3.75) months for patients with extramedullary disease adjacent to a bone. Overall survival from time of diagnosis for patients without extramedullary disease was 109 months (9.1 yr). (Extramedullary plasmacytomas are soft tissue tumors not assoicated with any bone.)

       * -- Multiple myeloma is a cancer in which malignant plasma cells build up and form tumors ("plasmacytomas") inside the bone marrow.

       ** -- Czech researchers recently found that extramedullary disease that develops in the soft tissue of a myeloma patient is associated with poorer prognosis than extramedullary disease that develops adjacent to a bone.

        -- During the course of their disease, multiple myeloma patients sometimes develop what physicians call  "extra­medullary plasmacytomas" or "extra­medullary myeloma." In medicine, when something is described as "extra-medullary," it means it is located outside of the bone marrow. It occurs when malignant plasma cells collect together and form tumors in parts of the body other than a patient's bones. This can occur in any myeloma patient, but it appears to be more common in patients with relapsed or refractory multiple myeloma.

        -- “Extramedullary disease occurring in a patient with myeloma is generally considered a more aggressive disease. (These extramedullary lesions can grow quickly.)

        -- A large study showed that 85 percent of multiple myeloma patients with extramedullary disease had a tumor in the muscles, tendons, fat, and other soft tissue surrounding the axial skeleton, which includes the skull, rib cage, and vertebral column.

        -- The Annals of Oncology study mentioned earlier found that approximately 13 percent of myeloma patients develop extramedullary disease. Specifically, 7 percent of myeloma patients have extramedullary disease at diagnosis, and 6 percent of patients develop the disease during the course of their myeloma.

        -- Extramedullary multiple myeloma is uncommon. In one review of 432 patients with multiple myeloma, only 19 (4.4%) were identified as having extramedullary multiple myeloma

        -- “When a myeloma patient develops extramedullary disease, it means that the myeloma is relapsing and is becoming more aggressive.

        -- (30 patients from 1998 to 201) Extramedullary disease at relapse was most commonly found in the liver (25 percent), lungs (21 percent), lymph nodes (17 percent), and mouth (13 percent).

        -- (greek study) From the time of their initial myeloma diagnosis, the median overall survival for patients who developed extramedullary disease was 38 months (3.2 yr) , compared to 59 (4.9 yr) months for patients who did not develop extramedullary disease.

        -- CT in the followup of treated disease may demonstrate the resolution of extramedullary disease.

Treatment options for extra-medullary" myeloma plasmacytomas(2011)
        -- Results of several clinical trials have shown that Velcade (bortezomib), Revlimid (lenalidomide), and pomalidomide may improve outcomes for myeloma patients with extramedullary disease. However, most of these studies are small, and the role of novel agents in treating extramedullary disease in myeloma patients is still unclear.

        -- Results of a small study published in the European Journal of Haematology (abstract) showed that extramedullary disease disappeared in three out of four myeloma patients treated with Velcade.

        -- Another small study that also was published in the European Journal of Haematology (abstract) found that 61 percent of myeloma patients with extramedullary disease responded to Revlimid, with 44 percent experiencing complete tumor disappearance.

        -- In addition, a study published in the journal Leukemia (abstract) reported that 31 percent of myeloma patients with extramedullary disease responded to treatment with pomalidomide, with 15 percent of patients experiencing complete tumor disappearance (see related Beacon news).

        -- (reader comment) Velcade didn't do anything, he had it the third time. End of August started with pomalidomide and within only one week the soft tissue manifestations had disappeared completely. In the first cycle of pomalidomie he developped a bad rash/itching, but now, in the third cycle it's completely gone. CT showed, that also inside his body the extramedullary manifestations were nearly gone right now. Doctors gave him only a few months because of the very aggressive growth of these extramedullary manifestations - now he feels really good.
Solitary bone plasmacytoma

Solitary bone plasmacytoma
        This is a closely related disease to MM, but is more limited that usual MM because at diagnosis there is only single tumor.

      * --  Solitary bone plasmacytoma is a plasma cell disorder characterized by the formation of a single tumor in the bone. The tumor, also called a plasmacytoma, occurs when abnormal plasma cells originating in the bone marrow accumulate on the interior surface of the bone. However, in patients with solitary bone plasmacytoma, these malignant plasma cells are typically not present throughout the bone marrow itself or in the soft tissues surrounding the bone.

        -- Unlike multiple myeloma, solitary bone plasmacytoma does not include the presence of abnormal plasma cells throughout the bone marrow or in the soft tissues surrounding the bone, a condition known as extramedullary myeloma. It is likely that the location of the bone tumor is the same location at which the abnormal plasma cells initially originated in the bone marrow.  “That is why in roughly 50 percent of cases, solitary bone plasmacytoma is curable by radiating that one site alone,” said Dr. Rajkumar.

        --A previous retrospective study involving 206 patients with solitary bone plasmacytoma indicated that patients who received localized radiation therapy had a lower rate of relapse (12 percent) than patients who did not receive radiation (60 percent).

        -- “Our radiation therapy specialists advise 40 Gy, similar to most practices elsewhere,” said Dr. Raymond Alexanian of the MD Anderson Cancer Center in Houston. Evidence-based guidelines published by the United Kingdom Myeloma Forum recommend at least 40 Gy over the course of 20 radiation sessions.

Current Diagnostic Imaging Techniques For Multiple Myeloma (2014)
        * -- There have been studies investigating the value of MRI and PET/CT for evaluating a myeloma patient's response to treatment. Currently, the evidence suggests that, of the two, PET/CT may be more effective at tracking treatment response.

        -- According to current guidelines from the International Myeloma Working Group, whole body X-ray skeletal surveys should be considered the gold standard for detecting lytic bone lesions in patients. X-ray skeletal survey typically takes much longer than other imaging techniques because it usually requires at least 20 separate scans.

        --  PET/CT can detect both extramedullary and medullary (bone) disease.

        -- Computed tomography (CT) is more sensitive than traditional X-rays. CT can detect smaller bone lesions and can better assess the fracture risk of a patient. CT scans can also reveal extramedullary disease, which occurs when myeloma cells form tumors outside of a patient’s bones

        -- Whole-body CT scans are superior to x-rays in the detection of bone lesions in multiple myeloma patients. “Low-dose, whole-body CT was significantly better than [x-rays] in detecting lesions in the spine, ribs, sternum, and flat bones,” said Dr. Princewill.

        -- In the United States, the standard method for detecting bone lesions is through a radiographic (x-ray) skeletal survey. However in Europe, studies have demonstrated that whole-body computerized tomography (CT) scans are better than x-rays for detecting bone lesions.

        -- MRI scans are particularly useful for visualizing the bone marrow in myeloma patients. In this regard, the technique is considered more sensitive than either X-ray skeletal surveys or CT scanning.

        -- For patients with symptomatic multiple myeloma, the European researchers believe that screening using either whole-body x-ray or low-dose CT should be mandatory at the time of diagnosis.  However, they point out that both PET/CT and MRI have been found to be more sensitive, and have shown a higher detection rate of lesions in symptomatic patients, than X-rays and CT alone. Based on these findings, they recommend that MRI be considered as a complementary diagnostic tool, given that it provides excellent results when used to image the spine and pelvis.

        -- At least two studies have shown, for example, that patients whose PET/CT scans continue to show a tumor burden ("abnormal FDG uptake") after treatment tend to have a higher risk of progression, and shorter overall survival, in comparison of patients with no abnormal FDG uptake after treatment. (That said, studies on the use of PET/CT in response assessment have been limited to patients who have received a stem cell transplant.

        --  PET-CT was more reliable than MRI for evaluating a patient's response to therapy.
Types of (general) chemotherapy drugs
        -- Alkylating agents
                    Alkylating agents  directly damage DNA (the genetic material in each cell) to keep a cell from reproducing. These drugs work in all phases of the cell cycle and are used to treat many different cancers, including leukemia, lymphoma, Hodgkin disease, multiple myeloma, and sarcoma, as well as cancers of the lung, breast, and ovary. Because these drugs damage DNA, they can cause long-term damage to the bone marrow. In rare cases, this can lead to acute leukemia.

             Alkylating agents are divided into different classes, including:
                      Nitrogen mustards: such as mechlorethamine (nitrogen mustard), chlorambucil cyclophosphamide (Cytoxan), ifosfamide, and melphalan.

        -- Other types of cancer drugs
                    Other drugs and biological treatments are used to treat cancer, but aren’t usually considered chemotherapy. While chemotherapy drugs take advantage of the fact that cancer cells divide quickly, these drugs target other properties that make cancer cells different from normal cells. They often have less serious side effects than those commonly caused by chemotherapy drugs because they are targeted to affect cancer cells, not normal, healthy cells. Many are used along with chemotherapy.

        -- Targeted Therapies
                      As researchers have learned more about the inner workings of cancer cells, they’ve created new drugs that attack cancer cells more specifically than traditional chemotherapy drugs. Most attack cells with mutant (altered) versions of certain genes, or cells that express too many copies of a certain gene. These drugs can be used as part of the main treatment, or they may be used after treatment to keep the cancer under control or keep it from coming back.

Examples of targeted therapies include:
                Imatinib (Gleevec)
                Gefitinib (Iressa)
                Sunitinib (Sutent)
             * Bortezomib (Velcade)

Appendix 2

Plasmacytoma (1/8/17)
         Plasmacytomas can only be tracked by Pet scans. My first Pet scan was in 5/19/16 to follow up on the plasmacytoma discovered behind my left eye by an MRI a few days earlier. This led to a change in chemo from rev/dex to pom/carfilzomiz/dex. On the new chemo a follow up Pet scan was done after 2.5 months (9/6/16). It showed "no new lesions", "interval good response to theapy" and "largest residual discease posterior right 9th rib, decreased in size and intensity (max SUV 6.5, previous 15.1)"

        A 3rd is Pet scan is scheduled 1/11/17. This will be four months after Pet scan #2 and 6.5 months into pom/carfilzomiz/dex chemo. The trend of my blood numbers on the new chemo for the last six months has been good. Free light chains (both) have remained in the normal region, and my M-spike(s) have shown a general downward trend with the latest (mid Dec 16) values at 0.12g/dL, or about 1/4th of the threshold 0.5 g/dL threshold.

        My first remission ended because MRI and PET scan found several plasmscytomas. One behind my left eye, a big one and a small one in by ribs. My oncologist said plasmacytomas are rare in MM patients, maybe 5% get them. But more importantly plasmacytomas are associated with poor survival. A little research confirms that that is right. My plasmacytomas appear to be confined to my bones (ribs, sphenoid bone behind eye).

Multiple myeloma
        B cell (triggered by invading 'antigens' virus, bacteria, etc) => plasma cells => antibodies. In other words it seems like plasma cells are the immune systems factories for generating antibodies, which to into the blood to actually disable the invading antigen. The antigens cause the B cells generates a particular plasma cell so that's its immuniglobins will attack the antigen.

        The big concern seems to be plasmacytomas that form away from the bone (extramedullary) in various organs of the body. It is not clear how this applies to me. All my plasmacytomas are either in bones, or maybe just spilling out. What are plasmacytomas really? How bad are they if they are in bones?  I did a little research.

       -- When plasma cells become cancerous and grow out of control, they can produce a tumor called a plasmacytoma. These tumors generally develop in a bone, but they are also rarely found in other tissues. (www.cancer. org)

        -- Plasmacytomas can also invade soft tissue in the body. Plastacytoma in soft tissue can press on nearby areas and cause pain such as the throat, tonsils or sinus (multiple myeloma research foundation)

        -- Extramedullary," it means it is located outside of the bone marrow. During the course of their disease, multiple myeloma patients some­times develop what physicians call either "extram­edullary disease," "extra­medullary plasmacytomas," or "extra­medullary myeloma. "Extramedullary" myeloma is myeloma that is outside of the bone marrow. It occurs when malignant plasma cells collect together and form tumors in parts of the body other than a patient's bones. This can occur in any myeloma patient, but it appears to be more common in patients with relapsed or refractory multiple myeloma.“Extramedullary disease occurring in a patient with myeloma is generally considered a more aggressive disease,” according to Dr. Rajkumar. (Mayo clinic)

        -- A large study published in the Annals of Oncology in 2009 showed that 85 percent of multiple myeloma patients with extramedullary disease had a tumor in the muscles, tendons, fat, and other soft tissue surrounding the axial skeleton, which includes the skull, rib cage, and vertebral column. The remaining 15 percent of extramedullary disease cases affected the lymph nodes, liver, kidney, airways, skin, and breast.

        -- “When a myeloma patient develops extramedullary disease, it means that the myeloma is relapsing and is becoming more aggressive", said Dr. Rajkumar.

        -- Results of several clinical trials have shown that Velcade (bortezomib), Revlimid (lenalidomide), and pomalidomide may improve outcomes for myeloma patients with extramedullary disease.

        -- Another small study that also was published in the European Journal of Haematology (abstract) found that 61 percent of myeloma patients with extramedullary disease responded to Revlimid, with 44 percent experiencing complete tumor disappearance. A study published in the journal Leukemia (abstract) reported that 31 percent of myeloma patients with extramedullary disease responded to treatment with pomalidomide, with 15 percent of patients experiencing complete tumor disappearance (see related Beacon news).

        -- Plasmacytomas crowd out normal cells in the bone marrow as well as invade the hard outer part of the bone and then spread into the cavities of the large bones in the body.(multiple myeloma research foundation)

Refractory myelema
        I am also a little unclear about 'refractory' multiple myeloma. Relapsed myeloma I understand. According to Dana Farber notes I am both relapsed and refractory.

        -- Refractory myeloma is when myeloma is not responsive to therapy. Refractory myeloma may occur in patients who never see a response from their treatment therapies or it may occur in patients who do initially respond to treatment, but do not respond to treatment after relapse.  Translation: This seems to mean a MM patient has tried one (or any) particular chemo and has not responded.

        Plasmacytoma is a plasma cell neoplasm which forms tumors when plasma cells become malignant and grow out of control. Plasmacytomas crowd out normal cells in the bone marrow as well as invade the hard outer part of the bone and then spread into the cavities of the large bones in the body. Plasmacytoma in the bones may cause pain or broken bones.  Plasmacytomas can also invade soft tissue in the body. Plastacytoma in soft tissue can press on nearby areas and cause pain such as the throat, tonsils or sinuses.

        Note, the definition of plasmacytoma seems to be a little loose. It's clearly a collection of grouping together of cancerous plasma cells, but it can be inside a bone or outside (extramedullary) bone, meaning a tumor anywhere in the body.
Treatment --- Because these things are localized they can be treated with radiation (or sometimes surgery). The tumors are radiation sensitive, meaning that they these cells can be killed with about half the dose used on solid tumors. Not only does this mean less side effects, but half days needed, like two weeks vs a month.

Three types
        There are three distinct groups of plasmacytoma defined by the International Myeloma Working Group:
                 1) solitary plasmacytoma of bone (SPB)
                 2) extramedullary plasmacytoma (EP)
                 3) multiple plasmacytomas that are either primary or recurrent.

        In medicine, when something is described as "extramedullary," it means it is located outside of the bone marrow. So "extramedullary" myeloma is myeloma that is outside of the bone marrow in the soft tissue and organs of the body.

        **  When a myeloma patient develops extramedullary disease, it means that the myeloma is relapsing and is becoming more aggressive. The results are consistent with those from previous studies and demonstrate that myeloma patients who develop extramedullary disease have poorer overall survival than those who do not. They conclude that myeloma patients with extramedullary disease exhibit a particularly aggressive and treatment-resistant form of myeloma, posing unique therapeutic challenges.

        ** From the time of their initial myeloma diagnosis, the median overall survival for patients who developed extramedullary disease was 38 months (3 yr), compared to 59 months (5 yrs) for patients who did not develop extramedullary disease. (note these are small studies)

        -- A large study published in the Annals of Oncology in 2009 showed that 85 percent of multiple myeloma patients with extramedullary disease had a tumor in the muscles, tendons, fat, and other soft tissue surrounding the axial skeleton, which includes the skull, rib cage, and vertebral column.
The remaining 15 percent of extramedullary disease cases affected the lymph nodes, liver, kidney, airways, skin, and breast. Extramedullary disease at relapse was most commonly found in the liver (25 percent), lungs (21 percent), lymph nodes (17 percent), and mouth (13 percent).
Sphenoid bone
       Here is the sphenoid bone that separates the eyes from the brain. The greater wing of this bone is where the plasmacytoma behind the left eye is located. While it's not clear to me and is not spelled out in the MRI report, the radiation doctor says the mass is "inside" the bone.

Proteasome and 'proteasome inhibitor' drugs
        -- Proteasomes are protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, proteasomes are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by which cells regulate the concentration of particular proteins and degrade misfolded proteins. (Wikipedia)

       My interest in the proteasome protein complex and understanding what it does is because a key component of my 2nd line chemo has been the infused drug carfilzomib, described as a 'proteasome inhibitor', which according to it prescribing document "irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome." Specifically it causes the suppression of proteasome chymotrypsin-like (CTL) activity.

        One of the major side effects of carfilzomib is lung toxicity, which after taking it for a few months became a concern as I began to develop shortness of breath (dyspnea) that slowly got worse. After about 8 months (7/16 to 3/17) on carfilzomib a pulmonary functional test DLCO (Diffssion capacity of lung for CO) showed my oxygen intake per breath was only about half of what it should be for someone my age. According to the prescribing document 28% of patients on carfilzomib report dyspnea (shortness of breath) with it reaching grade 3 in 4% of patients. I think this probably includes me, but clinicians don't talk to patients about grades so it's hard to be sure, but after 8 months on carfilzomib and a very low DLCO measurement I was sent to a lung doctor for a lung evaluation that is to include a high resolution CT scan to evaluate damage to the small air sacs of the lung.

Side effects 'grades' 1-4
        Grade 1       Mild -- Transient (goes away after a short time) or mild discomfort; no limitation in activity;
                                   no medical intervention/therapy required
        Grade 2       Moderate -- Your daily activity is affected mild to moderately – some assistance might be needed;
                                   no or minimal medical intervention/therapy required.
        Grade 3       Severe -- Your daily activity is markedly reduced – some assistance usually required;
                                  medical intervention/therapy required, hospitalisation or hospice care possible.
        Grade 4       Potentially life threatening or disabling -- Extreme limitation to daily activity, significant assistance required;
                                 significant medical intervention/therapy, hospitalisation or hospice care very likely.
       (Grade 5)       Fatal

Fatique example
        Grade 1 -- Normal activity reduced by less than 25%
        Grade 2 -- Normal activity reduced by 25% - 50%
        Grade 3 -- Normal activity reduced by over 50%, can't work
        Grade 4 -- Unable to care for yourself

Ninlaro (Ixazomib)
       Another proteasome inhibitor I will be giving a quick trial to is Ninlaro, the pill equivalent of (injected) Velcade, which has been a staple in MM chemo for a decade. It too is a proteasome inhibitor, but it contains boron and attacks a different target on the proteasome to inhibit it. It's prescribing document says, "ixazomib is a reversible proteasome inhibitor. Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome".

        So both of these proteasome inhibitors inhibit chymotrypsin-like activity, but Ninlaro does it by targeting the beta 5 subunit of the 20S, which is different from carfilzomib's target (N-terminal threonine-containing active sites of the 20S proteasome).
Prroteasome complex
         Wikipedia has this sketch (right) of a proteasome complex showing a cylindrical structure made up of four (blue) rings and red end caps. Its job is to rip apart damaged proteins, which are fed into its hollow core aided by enzymes called proteases. It's cell clean up to prevent junk and damaged proteins in the cell from hanging around.  Each of the four stacked rings that make up the core consist of seven proteins. The inner two rings contain seven betasubunits, and this is where the destruction of the degraded protein occurs. The outer two rings contain seven alpha subjunits and form a gate through which the protein to be degraded enters. Note that Ninlaro targets the beta 5 subunit. Where on the proteasome are the carfillzomib targets (N-terminal threonine-containing active sites), is not clear though Wikipedia says the alpha subunits N-termini form a gate that suggests that this may be the target of carfilzomib.

         My infused cancer drug carfilzomib is described in its prescribing document as a 'proteasome inhibitor' (not a protease inhimitor). Multiple myeloma cancer cell death is somehow promoted if operation of the the proteasome is shut down, so loosely speaking cell protein clean up is inhibited. Since this appears to be a general cell function, why this would more strongly affect cancer cells than normal cells I have never seen explained. It seems complex, and I get the impression the biochemical pathways affected are not fully understood.

  -- ** Notably, multiple myeloma has been observed to result in increased proteasome-derived peptide levels in blood serum that decrease to normal levels in response to successful chemotherapy with Velcade.

-- Lactacystin (precursor of Velcade) covalently modifies the amino-terminal threonine of catalytic beta subunits of the proteasome, particularly the beta5 subunit responsible for the proteasome's chymotrypsin-like activity. This discovery helped to establish the proteasome as a mechanistically novel class of protease: an amino-terminal threonine protease.

 -- * Proteasome inhibitors have effective anti-tumor activity in cell culture, inducing apoptosis (cell death) by disrupting the regulated degradation of pro-growth cell cycle proteins. This approach of selectively inducing apoptosis in tumor cells has proven effective in animal models and human trials.

--  proteasome inhibition may prevent degradation of pro-apoptotic factors such as the p53 protein, permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro-apoptotic pathways. 

       Since proteases exist widely I can't figure out why inhibiting them works against MM. I'm not sure the researchers do either. as they end up saying in vitro Velcade can dramatically change the peptide balance of the cell. And this is reflected clinically in peptide levels seen in the blood. Velcade major side effect has been that it also affects nerve cells leading to numbness and damage of nerves apparently in the fingers and toes. Ninlaro has been formulated to minimize this nerve damage (peripheral neuropathy).

Heart tests (6/14/16)
        Here are the test results of several tests done on my heart prior to starting pom/carfilzomib/dex chemo. The reason for these tests is assess the health of my heart and establish a baseline since the proteasome inhibitor of my new chemo (carfilzomib) has a real potential to cause heart attacks. (I need to research this). The reason given below is stated: Baseline prior to cardiotoxic chemotheapy.

        None of the first three tests are entirely normal.
                          BNP at 113 pg/mL is out of the normal range (0 to 80 pg/mL)
                          Troponin, which is 'undetectable in most health individuals', has a low but measurable value of 0.04 ng/mL    (0 to 0.30 ng/mL)
                        ECG (same as EKG) is described at 'boderline' (abnormal R-wave progression)

        but the (ultrasonic) echocardiogram, which takes a detail look at the motion of the valves and ventricles of the heart, looks pretty good.



My 'one minute' right eye blindness
1 min vision loss symptoms  (8/9/16)
        Upon waking and opening my eyes in bed I was horrified to find that I was essentially blind in my right eye. The lower half of the visual field was blank, the upper half had images, but very abnormal with high contrast and sparkly noise. After one minute or so while sitting on the toilet the problem resolved, normal vision fully returned in my right eye in just 1-2 seconds.  All during this time vision of my left eye remained normal. Also there was no pain. It's now been a week and the problem has not returned.

Result of eye tests (8/22/16)
       The many detailed eye tests, including a retina tomography machine that combines with many images of the retina from different angles with a computer into a 3d images of the retina, showed both my eyes are in good condition, "structurally sound". However, while I didn't ask, I think the focus of all these tests was the retina. The images of the retina nerves rising to form the optic nerve bundle looked normal.

Best guess of cause of transient vision loss (8/22/16)
       The best guess from my neuro-opthomologist was that I most likely had transient reduced blood flow to the right eye in one of the branching arteries (see below) between the carotid (neck) artery left and the eyeball right.  (Below is actual image the doctor pointed to, which I later found online.)

Doctor's initial guess of the cause of my one minute vision loss in my right eye:
 a transient blood blockage in one of the small branching arteries
between the carotid artery (left) and the retina in the eyeball (right).
(source --

        One reference says a (permanent) blockage of one of the ophthalmic arteries is an ophthalmic emergency, but prognosis is poor, only 20% of eyes will retain any useful vision. Translation: You are screwed. Before treatment can clear any blockage, critical structures in the eye will have died from lack of oxygen and you are blind in that eye.

Eye-brain visual pathway
        Images below show the pathway from the eyeballs to the back of the head, where the occipital lobes of the cerebral cortex are located. The optic nerves from the two eyes pair up at the optic chiasm about 1" behind the eyes and then the optic nerves of the two eyes travel across the brain in the same bundle to the back of the brain where the visual cortex is located.  So this limits where a blood clot or possible tumor (plasmacytoma) could be located so that it affects only one eye with the the other eye normal. Looking at these images I see two possibilities for the loss of vision in only eye. Something affects the optic nerve somewhere between the retina and the optic chiasm, or two a reduction in blood flow to the right eye where nerves of the retina bundle to form the optic nerve.

Sphenoid bone
       The sphenoid bone behind the right eye is another possible candidate given my cancer history. The sphenoid bone has two holes through which optic nerves from the right and left eye passes. Three months ago plasma cancer cells were running riot in the sphenoid bone behind the left eye, in that case producing double vision by pushing the bone out to press on muscles that move the left eyeball. While the sphenoid bone forms in pieces during development, these pieces are merged in an adult, so it may very well be that the marrow sections of the regions of the sphenoid bone behind the two eyes are merged into one chamber. (However, I don't know that this is true.) The radiologist reading my recent MRI taken 9 hr have the transient vision loss did not see any impingment of the optic nerve as it passes through the hole in the sphenoid bone.

Pituitary gland
       I read one source of visual problems in the brain that commonly affect only one eye arises from problems with the pituitary gland. This small gland is located just below the optic chiasm. It can develop tumors causing it to expand and squeeze the optic chiasm, or bleed which can put pressure one of the still separate optic nerves as they approaches (or enter) the optic chiasm. However, I have not seen any info that this would cause a transient visual problem lasting just a few minutes. So an obvious question is do I have a plasmacytoma in the pituitary gland. (The radiologist reading my latest (Aug 2016) brain MRI makes no mention of a the pituitary gland.

Oxygen to the optic nerve
        Surprisingly the optic nerve as it exits the eye is described as a bundle (1 million or so) of very long axons of nerve cells originating in the retina. (Axons of nerve cells in some animals are known to be feet long.) The Wikipedia page on the optic nerve is horrible technical, but it seems to say the retina axons do not end at the optic chiasm, but continue right back to the optical cortex at the rear of the brain. So how is oxygen supplies to the optic nerve?  Is is supplied by the source in the retina?
(left image) --- nerves from the right and left eyeballs pair up at the optic chiasm,
and then travel together in a bundle to the visual processing region in the back of the brain.
(right image) --- shows the location of the pituitary gland relative to the optic nerve
    (source left --
(source right --

MRI images from 8/9/16
         Quick call from my oncologist says the radiologist review of these MRI images was negative. Nothing new of interest was found. The plasmacytoma in the sphenoid bone behind the left eye, which was irradiated, is seen to have shrunken from three months ago.

        So that means we have no clue as to the cause of the 1 min loss of vision in the right eye.

New Test Results (aug 2016)

Updated view of the plasmacytoma behind my left eye

        Four images I captured from 8/9/16 MRI disk. The first pair shows almost no difference between the right and left eyes (second is just a contrast change). This is after two weeks of radiation and 6 weeks of (new) pom/carfilzomib/dex chemo. The lower pair of images shows the plasmacytoma is still present though smaller (maybe 50%) than in May 2016. The bowing of the sphenoid bone is gone. The fifth image below for reference is the view of the left eye plasmacytoma in May 2016 while on rev/dex chemo and prior to radiatiion.

(update 11/8/16)
        Even though these Aug 9, 2016 images show the bowing of the spenoid bone seems to be gone after two wks of radiation and 6 wks of pom/carfilzomib/dex chemo my double vision as of Nov 8, 2016 when looking right remains about the same as prior to treatment. Is the plasmacytoma growing, has the bowing returned?

        On a second look at the 4th MRI image below it may be that the white triangle of the plasmacytoma, even without the sphenoid bone bowing, is pushing a little on the eyeball muscles acting like a wedge?

(left) Image shows the spheoid wings behind the two eyes and they are virtually idential.
Also the well defined boundary between the eyes and the sphenoid bone is nearly identical.
(right) Here there is a contrast difference between the two eyes.

(left) Image shows the round (hot) spot plasmacytoma behind the left eye. This is probably the 'round spot' the radiologist mentions in his report.
(right) Another view of the hot spot plasmacytoma between the left eye.
The bowing of the left wing of the sphenoid bone (evident in the May 2016 image below)
into the lateral muscles of the left eye is now gone.

For reference -- comparable MRI image taken 5/16/16 prior to radiation and change in chemo
showing large plasmacytoma (white) behind left eye.
Shows the sphenoid bone bowing out interfering with muscles moving the left eye

Radiologist report on my 8/9/16 brain MRI
        The summary of my right eye loss of vision symptoms in this report is pretty accurate, but it's also important because it is the first look at the plasmacytoma behind my left eye since it was irradiated and chemo was changed.. (signed by Philip Kousoubris MD)


Retinal tomography -- 3d images of retina (8/23/16)
        I don't remember the exact name of the hi-tech retinal test I had, but I know it involved using a laser to take images of the retina from different angles and tomography combining those images with a computer to get a 3d look at the retina. From what I see online this may be 'Heidelberg Retinal Tomography' which specializes in looking at the retina around the hole (optic disc) where the retina nerves (about a million) come together to turn down into the hole (in sphenoid bone) and form into the optic nerve. I got print out of my test results from this test (scans belows).  Note green indicates no problem and nearly all the test results are color coded green.

        I have not researched this tomographic test, so I have no idea what these individual views of the retina mean, but they are nearly all color coded green, indicating the images are normal. The neuro-ophthalmologist in charge looking at these results, which were part of a huge bank of eye tests on the same day, said my eyes are "structurally sound".



Arteries and veins of the neck

        I recently had an ultrasound test of the carotid arteries of the neck, which turned out to be "normal", which must mean no blockages found. The technician told me the test measures the (local) velocity of the blood (correct). The reason for this test is to see what blockages I have (if any), because plaques in the neck if broken off could have been responsible for the 1 min blindness I had in my right eye (upon waking) a few weeks ago.

What to do if this happens again?
       Amazingly, I was never advised by all the eye people I saw what to do if this happens again! It's a stoke or a mini-stroke, what do you do when it begins, while it is happening? I didn't think to ask. You have no way of knowing initially if this is a TIA and will resolve itself in minutes (with no harm), or if this will continue and leave you blind or with permanent brain damage. Is there nothing effective you can do, or are there things worth trying?

        Is this a legal issue, like we told you do X, you do X and still you go permanently blind, so you may sue the doctor for malpractice. So if medically there isn't any reliable strategy to recommend, doctors are advised to say nothing?  There is essentially nothing about this online ('What to do while waiting for the ambulance') except call 911 because you get to the hospital faster taking ambulance. How long does it take the tissue of the eye to die. No idea.

 Raise blood pressure in head?
        I think the reason there is no universal advice as to what to do if you think you are having a stroke is that there's two possible causes for a stroke. It can be blocked artery, but it can also be a bleeding artery in the brain, and their treatments conflict. A pressure increase may make sense if it's a blockage, but it may make a bleeding problem worse. So the first thing an emergency doctor would want to determine is what is the cause of the lack of blood.

        There's an effective drug for dissolving a clot, but it can only be given within the first 3 hours. This is the reason to hustle to the hospital.

Ischemic Stroke Treatment.
        The only FDA approved treatment for ischemic strokes is tissue plasminogen activator (tPA, also known as IV rtPA, given through an IV in the arm). tPA works by dissolving the clot and improving blood flow to the part of the brain being deprived of blood flow. If administered within 3 hours(and up to 4.5 hours in certain eligible patients), tPA may improve the chances of recovering from a stroke.
        Using common sense I would think the best thing to do for a stoke or mini-stroke while it is happening is increase the blood pressure in the head. You are trying to force blood by a blockage, or break the blockage free.  Lie down, or even better lie down with the feet raised. In my case the most effective way to do this would be to lie on my couch with my feet high up on the back. Or maybe lying in bed let your head dangle off the bed. Or is it better to run around to raise the heart rate?  It probably would hurt to take an aspirin or two, thought this is going to take a while to 'thin' the blood. References for a heart blockage says getting to the hospital within even 3-5 hours after the attack can help minimize damage.

        In my TIA blindness incident I got out of bed then for a few seconds laid down flat again (no change). Since I had to go to the toilet and had no further idea what to do, I went and sat on the toilet. It was while sitting on the toilet (bent over a little) after a minute or so that my symptoms resolved and in 1-2 seconds my normal vision returned to my right eye. Does the blood pressure in the head go up a little sitting rather than standing because when sitting less pressure should be required to pump blood in the legs back up to the heart? Don't know. A review of the blood flow diagrams shows all the arteries going up the neck to the head branch right off the big aortic arteries coming out of the top of the heart. They should have the highest peak blood pressure in the entire circulatory system.

       So I started doing some research into arteries of the neck that supply blood to the head and brain. I soon found the answer to one question, where are the veins? Turns out the arteries and veins pair up in bundles (see image below left). This is true for the big carotid arteries in the front and the smaller arteries running in the holes in vertebrae. Note the outside holes in all the vertebrae have both an artery and vein in it.

         I soon realized I had a misconception.  I was aware from studying the cervical vertebrae that they all have outside holes (transverse foramen) for a blood vessel, and I had assumed this was the (big) carotid artery, the major supplier of blood to the head and brain. Wrong, well partially wrong! Images online show this artery, called the 'vertebral artery' and its paired vein, looks like it might supply 1/3rd of the blood. Wikipedia says this better protected artery/vein pair supplies (as the vertebrobasilar system) the upper spinal cord, brainstem, cerebellum, and posterior part of brain. The much larger artery/vein in the front of the neck and not in the vertebrae holes is called the 'carotid artery'. It is where you can feel your pulse. It goes about half way up the neck as without branching, this lower section called the 'common carotid'. About half way up the neck it divides into two equal branches called the 'internal carotid' and 'external carotid'.

Three sets of arteries (on each side)
        So the brain and head (on each side) get blood from three sets of artery/veins: 'vertebral artery' (in the vertebrae holes), 'internal carotid' and 'external carotid'. The latter two are the two major branches of the carotid artery. Some of these arteries actually join up in a loop, called the 'circle of willis'. The blood flow diagrams here are difficult to interpret, but it looks like the 'circle of willis' ties together arteries from both sides of the head, specifically the 'internal corotid arteries' and the combined 'vertebral arteries'. This allows blood flow up the neck to shift among the neck arteries if there are pressure differences. This is important because it means that if an artery blocks in the neck, the another arteries can at least partially  take over for it. I say partially because the connecting loops in the circle, called the 'communicating arteries', are rather small. This provides some redundancy for the brain/head blood flow. Wikipedia says this shift can sometimes supply enough blood to prevent symptoms of eschemia (restriction in a blood supply).

Internal carotid artery
        Which of these three sets of artery/veins supplies the eyes? Ans: 'Internal carotid artery' (see image below right).  This is the figure my eye doctor used and other references agree with it. This probably good news for testing for blockages that would affect the eye with ultrasound, because I suspect the vertebral artery enclosed as it in the hole of the vertebrae is very difficult (if not impossible) to image.

Video of carotid ultrasound test
        The youtube videos linked below are a good introduction to the carotid ultrasound test. The first has a lot of images taken in real time that would be useful for evaluating an ultrasound images or CD (if available). It shows clearly that the test follows the 'common carotid' up to where it splits, the operator looking especially for blockages in this region, and then following the two branches ('internal' and 'external') upward until they are obscured by the bones of the skull and jaw. The videos also show the 'vertebral corotid' can be "sampled", but since only the regions between the vertebrae can be seen only the blood flow direction is shown being measured.  Of course the imaging is done on both sides of the neck. The velocity of the blood is directly measured, as my technician told me, by use of the doppler technique.
                                    actual exam with commentary (8 min)              viewgraph lecture (29 min)

        I'm a little pissed, because the video shows a patient looking at the screen, while the operator explains the images. I was not given the option of looking at the screen.

(left image) -- arteries (red) and veins (blue) pair up including in vertebrae holes
(right image) -- arterial input to the eye is provided 'internal carotid artery' via the ophthalmic artery and its branches

carotid artery below the internal/external branch is knows as the 'common carotid'
Note  'internal carotid'  feeds brain and eye,
'external carotid' feeds face


End of my 2nd remission -- New Test Results (mar 2017)
(shortness of breath)

        Pom/carfilzomib/dex chemo started off strongly with a big drop in free light chain in the first cycle, but after 8.5 months my lambda free light chain was rising strongly as was M-spike and worse a little later a pet scan showed my 9th rib plasmacytoma had also brightened substantially in just the last 9 weeks, so clearly the cancer has evolved around this chemo. My 2nd remission has ended after just 8.5 months. Not only that by I appear to have acquired a lot of lung damage in the last few months, blamed on the carfilzomib as it has as a side effect that it has a toxic effect on the lungs. This lung damage is really affecting my quality of life as I now tire easily and have shortness of breath. This was confirmed by a lung test showing I am only taking in half the oxygen I should on each breath.

        Searching for a 3rd remission. Before going to a humanized antibody drug (daratumumab), I didn't want to bypass anther proteasome inhibitor, Ninlaro (equivalent to Velcade with a ten year good track record) that could easily be slotted in in place of carfilzomib, so that is the plan with a swap in of Ninlaro for carfilzomib beginning 4/3/17.

Photos from last day of carfilzomib infusion (3/21/17)
        Here are photos taken in the Lahey infusion room on the last day of my carfilzomib infusion showing me with my main infusion nurse, Marci. I found the large infusion room to be a friendly place, the four infusion nurses who attended me very skilled and a pleasure to be around. I got of lot reading done during the two hours of the carfilzomib infusion, and free WiFi too, so I sometimes brought in my android tablet to surf the web.

Here is my main infusion nurse, Marci.
Note the needle in my arm. The tubing was long enough so I could move the arm quite a bit, holding a book was no problem,
The drug is in the bag above, the pumping controlled by the programable controller next to me.

Bad news --- Free light chain is rising fast (3/6/17)
        At my meeting with my doctor to discuss these latest test results (heart and lung) because of my shortness of breath our working assumption had been that the pom/carfilzomib/dex chemo was continuing to work very well as it had for the last 8 months. New cancer tracking data from labs the day before was not yet available. However I  had noticed that the lambda free light chain had been slowly creeping up for a few months (from a low level) and had just recently exited the normal region at 2.83. Unfortunately when free light chain from the blood work the day before dribbled in after the meeting the upward climb of lanbda free light chain continued strongly reaching 4.55 mg/d (60% one cucle rise). This is nearly half way to free light chain disease progressing threshold of 10 mg/dL, where it was when pom/carfilzomib/dex chemo was begun. M-spike data is not yet available to me yet, but it should be in a day or two to my doctor.

        This free light chain rise in my opinion could strengthen the case for a one cycle test of Ninlaro swapping it in soon (maybe this cycle or next) for carfilzomib. Both are protease inhibitors, but they have different modes of action.

        Wed morning, day after out meeting, I messaged my doctor about possibly buyng Ninlaro this week, and swapping it in next week. This would give us a 1/3rd carfilzomib cycle and 2/rd Ninlaro cycle. I await her thoughts on this chemo swap test.
Overview (2/8/17) (3/6/17)
        Because my shortness of breath has been slowly getting worse for a few months (and a nasty cold for three weeks in feb 2017 exacerbated the problem) my consulting Dana Farber multiple myeloma specialist suggested tests be run on my heart and lungs. His concern is that one of my chemo drugs (carfilzomib) is known to damage the heart in some people and can have toxic effects on the lungs.

        As I read the results of my recent tests (2/22/17) the 'explanation' for my shortness of breath is in my lungs. The diffusion of gases (in the test CO, but normally oxygen in and CO2 out) in the millions of alveoli across the alveolar-capillary membrane is only about half of what it should be (DLCO predicted = 44%). To me this result could be explained either by the areas of the membrane being destroyed or compromised (reversible?), or perhaps the problem is not in the lungs at all. It might be that my misshapen and sometimes immature red blood cells have limited oxygen carrying capacity, or maybe for some reason (cell  clumping or high viscosity) blood flow in my capilaries is reduced. I do have a blood cancer, my blood is not normal!

        My following blood test (3/6/17) show two signficant changes.
                    a) Hemoglobin popped up (12.3 => 14.1 g/dL) into the normal range (13.8 lower limit) for the first time since on carfilzomib. Maybe relevant
                                      here is I began taking an iron supplement pill (361% of FDA)  pill  2/15/17 three weeks before this blood test.
           b) Bilirubin (total) also showed a big jump (.9 => 1.6 mg/dL) taking it out of range (>1.3) for first time. Bilirubin should be cleared by liver
                               so may indicate a liver problem. Bilirubin reslts from the breakdown of red blood cells. Could it be related to the iron supplement pill?

        -- High bilirubin levels in adults usually means that there may be an underlying problem involving the red blood cells, liver, or gallbladder; however, other problems also may be found.

Heart tests (2/14/17)
        BNP (B-type Natriuretic Peptide) is a blood component test that relates to heart function.  This is the third time I have had this measured. Soon after beginning pom/carfilzomib/dex chemo the reading was 113 pg/ml, somewhat above normal. A second reading on oct 3, 2016 was normal at 23 pg/ml as is the latest reading (2/13/17) of 40 pg/ml.

BNP peptide is normal

Heart transthoracic echocardiogram (2/14/17)
        This is my second heart echocardiogram, my previous echocardiogram was in sept 2016. At that time no serious problems were found with my heart and my latest heart echocardiogram (2/14/17) shows the same, no significant change in my heart since the sept 2016 echocardiogram.

echocardiogram test 2/14/17

Echocardiogram Interpretation Summary

1. The left ventricle is normal in size and systolic function.
Estimated ejection fraction = 65%. Global longitudinal strain
(GLS) is normal (22%).

2. There is minimal thickening/calcification of the aortic
leaflets with mild aortic regurgitation.

3. Pulmonary artery systolic (peak) pressure is normal.

4. Compared to prior study of 9/2016, there is no significant
Right Ventricle
The right ventricle (pumps to lungs) is normal in size and function.

Left Ventricle
The left ventricle (pumps to body) is normal in size. Left ventricular systolic function is normal. Estimated ejection fraction = 65%. Global longitudinal strain (GLS) is normal (22%). No regional wall motion abnormalities noted.

The left atrial size is normal. Right atrial size is normal.

Tricuspid Valve
The tricuspid valve is normal. There is trace tricuspid regurgitation. Pulmonary artery systolic (peak) pressure is normal. (implies no deterioration of the capillary bed in the lung?)

Pulmonic Valve
The pulmonic valve is normal in structure and function.

Mitral Valve
Mitral leaflet thickness and mobility are normal. There is trace mitral regurgitation.

Aortic Valve
The aortic valve is trileaflet. There is minimal thickening/calcification of the aortic leaflets. No valvular aortic stenosis (narrowing of valve opening). Mild aortic regurgitation.

Great Vessels
The aortic root is normal size.

There is no pericardial effusion.

(source --- Wikipedia:  Diagram of the human heart)


Lung Tests
(2/22/17) (4/3/17)

        My moderate (to severe) shortness of breath that developed in early 2017 while on pom/carfilzomib/dex chemo prompted two tests of my lungs, a series of tests of lung capacity called 'pulmonary function tests' and a hires CT scan of the lungs. A related test given at the same time is a heart echocardiogram that allows a check of pulmonary hypertension. This is high blood pressure in the lungs, which I would think would rise if the capillary beds in the lung were being narrowed or obstructed.

Pulmonary function tests (2/22/17)
        The most significant result of this test is DLCO (Diffusing capacity of the lung for CO) is very low (off the charts low). This result combined with a test that ruled out mucus obstruction in air pathway to the lungs points to likely poor transfer of oxygen to the blood in the million of lung air chambers (alveoli).

        Below is how the results of my pulmonary function tests are posted on MyLaheyChart. Just a list of cryptic aberrations with no standard values (well 'Predicted' provide reference values, but it took me a while to realized this) and no analysis. Sweet, hey! Another example of no support for the patient! I was getting over a cold when this test was done, so had some wheezing gurgling in my lungs.  What triggered this test and associated heart flow test is moderate to severe shortness of breath I experience when doing even moderate exercise. It's been slowly getting worst over the last three months, but with my three week cold in feb 2017 it has increased more.

        It took quite a while online to make any sense of these pulmonary tests and numbers. Basically there are two tests here. The first (FVC, FVC1) measures lung capacity and flow rates, i.e. how much air you can take in an blow out in one second. 'Pred' stands for 'predicted' using a formula based on sex, age, height and corrected for hemoglobin (12.2 was my latest reading a couple of weeks earlier.) Here I am 80% of predicted in capacity and 75% of predicted for a one second exhale.

        In a youtube video of a doctor explaining the pulmonary function test he says an FVC below 80% of the reference value (based on population statistics of height, age, gender and race) is abnormal. I come in just at 80%. The video goes on to say the 'gold criteria' for obstruction is that you should be able to exhale in one second (FEV1/FVC) 70% (or more). I come in just slightly below at 68%, which I would think could be assigned to the gurgling in my lungs during the test.

        I question how the capacity test was conducted. My technician was clearly experienced, and she directed me exactly how to breath and I followed her instructions carefully. Online I see that the the patient is instructed (reasonably) to take in a deep breath to begin, which for me would take about two seconds, but my instructions were to take in a quick deep breath of one second. During the test I never felt that the lungs were at full capacity, because the breath in time was too short.
Methacholine Challenge --- asthma test
        I read about another pulmonary test that was not included in pulmonary function test I got. It is called the 'Methacholine Challenge' test and it typically used to diagnose asthma. It does the opposite of the inhaled test I got. Methacholine inhibits breathing. In asthma the airways tend to tighten (due to mucus) when you breathe, so this test is basically an asthma test. The test involves breathing in progressively higher levels of methacholine until FEV1 drops 20%, then an inhaled bronchodilator (usually albuterol or levalbuterol) is given to help reopen the airways. I don't have asthma (?)so this test would not benefit me. I learned from the test technician that exhaled volume increased only a tiny amount (3%) after breathing a bronodilator, indicating (to me) that the problem is in my lungs not the airways to the lungs.

DLCO test result (2/22/17)
       The second test (DLCO -- Diffusing capacity of the lung for CO) is a test that actually measure the gas transfer to the blood. This is far more important to me. This is test is done by breathing in a mixture of gases which includes a low concentration (0.3%?) of CO (carbon monoxide) and helium. The lung to blood transfer is assessed by looking at the exhale (vs inhale). CO is used because hemoglobin has a strong preference for carbon monoxide and will pick it up before oxygen. A 'corrected' DLCO (I think) corrects for hemoglobin, which in my case is below normal at 12.2 (on feb 6, but 14.1 march 6). The result is not marked corrected, but from discussions with the technician doing the test I suspect it is corrected. A repeat of the test after inhaling with a broncodilator mist showed basically no change which I read rules out asthma, which is blockage (due to mucus) in the tiny airways in the lungs to the millions of alveoli, where the diffusion of oxygen into blood cappilaries takes place..

        The most important result here is that DLCO is remarkably low (off the charts low) at 44% of the predicted value (my age and height). From the plot below my DLC my of 13.98 (same units as plot) is literally off the charts! Here are the results of Pulmonary function tests.

 FVC --- functional vital capacity (volume)                                                       DLCO standard chart (ml/min/mmHg)
 FVV1 --- exhale capacity in one second
DLCO --- Diffusing capacity of the lung for CO (carbon monoxide)
(my 13.98 reading is so low it is off the chart!)
 (source (right) --

        My capacity numbers are just at or slightly below the thresholds for a possible obstructive defect [FEV1/FVC = 70%  (my value 68%), FVC = 80%  (my value 80%)]

        --  An obstructive defect is indicated by a low forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio, which is defined as less than 70% or below the fifth percentile based on data from the Third National Health and Nutrition Examination Survey (NHANES III) in adults.

        -- Physician should determine if the disease is reversible based on the increase in FEV1 or FVC after bronchodilator treatment (i.e., increase of more than 12% in patients five to 18 years of age, or more than 12% and more than 200 mL in adults). Asthma is typically reversible, whereas chronic obstructive pulmonary disease is not.

Good reference for pulmonary function test interpretation ---

'Moderate' gas exchange abnormality
       What to make of these numbers? I found (below) the following examples online. The first (left) is a normal 65 year old man. Note his DLCO is 26.14 ml/min/mmHg (84% of predicted 31.28), whereas my DLCO is much lower at 13.98 ml/min/mmHg (44% of predicted). If we divide my 13.98/0.44 = 31.8, pretty close to the predicted in the 65 year old example. My predicted FVC [3.42/0.80 = 4.28] also agrees quite nicely with the 65 year old man example of 4.32. The youtube video describes the DLCO as a measure of the surface area of the (millions) of avolea and capillaries within the lung. (This surface area is the size of a tennis court.) Emphezima destroys this area. DLCO can read (falsely) low not due to a lung problem, but if the input breath is not large because air won't get down into the avolea.

        The commentary on right from a patient with a DLCO of 43% (very close to my 44%) is that she has a 'moderate' gas exchange abnormality. This low DLCO (44%) vs predicted I think is the most important result of my test. I have a 'moderate' abnormality in gas exchange which probably goes a long way to 'explaining' my shortness of breath. I suppose this could be a lung effect (maybe due to carfilzomib) or a blood circulation effect. I wish now that my lungs were clearer of the cold residue when this test was done. The youtube video gives the normal threshold for DLCO vs predicted at 80%, so I am clearly quite low.

        In other words one interpretation of this (very) low DLCO is that it is saying the lungs are being damaged (is it reversible?) that I have lost about half of my expected surface transfer area for gas exchange. However, this is for normal people. I have weird blood, both weird red blood cells and maybe abnormal viscosity. The gas exchange rate could be low because the either the number of normal red blood cells is low (blood test often note a lot of immature red blood cells) or maybe the viscosity is high so the flow through the capillaries is low.

(left --- normal 65 year old man)
(right --- low DLCO of 43%)
(source --

Carfilzomib lung toxicity
        Obviously my concern is with the low DLCO predicted of 44% in the functional lung test.

        ** Carfilzomib literature says if lung toxicity is occurring (without saying how this is determined) carfilzomib should be discontinued. (check the prescribing sheet for this)

        Three lung side effects of carfilzomib are given. Two are sudden, one of being a liquid build up in the lungs. Neither apply to me. The third is called 'Interstitial lung disease' and basically this is scarring of the lungs (generally irreversible). Wikipedia has a page on this.

        -- "But in interstitial lung disease, the repair process goes awry and the tissue around the air sacs (alveoli) becomes scarred and thickened. This makes it more difficult for oxygen to pass into the bloodstream."

        -- (Diagnosis) Chest radiography is usually the first test to detect interstitial lung diseases, but the chest radiograph can be normal in up to 10% of patients, especially early on the disease process]

Lung diagnostic test
        ** -- High resolution CT of the chest is the preferred modality, and differs from routine CT of the chest. Conventional (regular) CT chest examines 7–10 mm slices obtained at 10 mm intervals; high resolution CT examines 1-1.5 mm slices at 10 mm intervals using a high spatial frequency reconstruction algorithm. The HRCT therefore provides approximately 10 times more resolution than the conventional CT chest, allowing the HRCT to elicit details that cannot otherwise be visualized.  Radiologic appearance alone however is not adequate and should be interpreted in the clinical context, keeping in mind the temporal profile of the disease process.

What can be done to ease shortness of breath?
        -- Pulmonary rehabilitation (Note the answer below I think is basically for asthma suffers who have airway restrictions)
               -- Exercise is a cornerstone of this. There is someting called 'pursed lip breathing' (also called 'diaphragmatic breathing') that is taught to patients to ease shortness of breath. (Has its own Wikipedia page). It consist of inhaling through nose (two seconds) and breathing out through pursed lips (4 seconds). The purpose is to create back-pressure inside airways to splint them open; moving air thus takes less work. I've tried this, it might work a little. I am beginning to suspect this trick is more for asmatics in that it helps open the passagways into the lung.

Possible further tests
       * Exercise (walking only) oxygen/CO2 transfer test. (Does Lahey have this?m yes)
       * Measue oxgen content of blood --- Use my oximeter to read blood oxygen saturation levels, so climging my hill. Resting reading are nearly always normal (95% to 100%). I four times recently calibrated my oximeter to the oximeter used to get vitals (each hospital trip) and they  agreed exactly. A more exact test is measuring the partial pressure of oxygen in arterial blood (have no idea is this is a standard, or practical test)/
        * Note I found playing at home with my oximeter that if resting and getting very low oxygen saturation readings (91) I can raise the level 5-6 points with one minute of rapid breathing. For about a minute nothing happens, then in a few seconds it shoots up. Obvious some of this delay (7 to 10 seconds from power on) is built into the procssing algorithm of the oximeter, the rest must be due to the circulation time to the finger tip. (yup)

Check -- takes blood about one minute to circulate through the body
        -- The volume of blood in a human body is about 5 liters. The heart pumps about 70 mL of blood on each stroke  (1.4% of the total), so at resting heart rate of 70 beats/min it takes about one minute for blood to make the round trip to the heart.
Red blood cell tutorial
        Red bloods cells are essentially just bags of hemoglobin wrapped in a cell membrane. They have no nucleus, by dry weight 96% of a red blood cell is hemoglobin. They live 120 days, so every four months all red blood cells are replaced. Red blood cells outnumber white blood cells by 1,000:1, and platelet cells 25:1. Old red blood cells are captured by macrophages which takes them to the spleen where the iron atoms in the hemoglobin protein are recycled. Circulation of a red blood cell through the body takes about one minute.

        In a blood test red blood cells count (RBC) is determined by machine, but shape and color manually by an operator using a microscope. Red bloods technically are known as erythrocytes.

red blood cells (disk shaped) under microscope
red blood cells outnumber white blood cells (purple cell in center) by 1,000 to 1
(souse --

        My red blood cells are typically described (RBC morphology) as having  'variation in size or shape', sometimes as they don't look fully developed, immature. like they were released too soon by the marrow.

Pulse Oximeter
        I did a little research on the pulse oximeter and was surprised. It know it is used by the hospital on every visit to measure oxygen saturation. I bought one on Amazon (20 bucks) and cross checked across the hospital oximeter three times and it agreed exactly each time. Turns out this little device has a long history, and as a simple non-invasive way to measure oxygen saturation it has proved to be very effective clinically. For example Wikipedia says it revolutionized anaesthesia making it much safer, it also has proven to be very useful in the monitoring of premature newborns who need an adequate supply of oxygen, but too much oxygen leads to vision problems as blood vessels grow in the eye. Visiting my lung doctor the one test he did (aside from listening to my lungs with a stethoscope) was called 'Taking a walk', and it was just a walk down the corridor (fast and slow) with a trailing technician continuously monitoring oxygen level with the basic fingertip oximeter.

        What a modern oximeter does is measure the percent of hemoglobin (red blood cells) in arterial circulation that are oxygenated. It does this by using two LEDs of different frequencies (visible and infrared) that alternate and a single photodiode that shine through the finger tip, the ratio processed by a microprocessor. Typical result is 95% to 100%, meaning this is the fraction of hemoglobin (red blood cells are basically just bags of hemoglobin) that has picked up an oxygen atom in the lung. Wikipedia article on COPD says supplemental oxygen is needed if oxygen saturation is less than 88%.

Playing with my oximeter
        Normally my oxygen level is in the range of 96 to 98 (normal), and that was the result when the 'taking a walk'. However, one day at home sitting quietly with heart rate low (60 beats/min) I measured (for the first time) very low readings of 90-91 saturation. Running a little test while watching the oximeter I began consciously to breath more rapidly and deeply while continuing to sit quietly. What I found was interesting.

Breathing hard increases my oxygen saturation
       After about a minute of this deep breathing, I found my oximeter oxygen saturation level rose substantially (5 to 7 points) up into the normal region. In other words if my respiration rate is low, which may cause my oxygen saturation level to be low, I found I can pull my oxygen saturation level into the normal region by breathing hard. I think the reason I have not noticed this before it that when climbing a hill (or on the 'walk') breathlessness naturally leads to an increase in both heart rate and more rapid and deep breathing. This is all consistent with my very low the DLCO pulmonary test (13.98, 44%) which showed I am taking in only half the oxygen I should be on each breath.

Hill climbing test (4/17/17)
        I perfumed a more extreme version of the 'take a walk' test that was done on my first visit with my lung doctor. The 'take a walk' test turned out to be a short walk around the corridors of the hospital with a technician trailing reading out blood saturation with an oximeter connected via a wire. Clearly this was a test to see how oxygen saturation changed with moderate levels of exercise.

        With my own oximeter I saw I could easily do a controlled and more extreme version of this test since I live up a steep hill, 150 (to 200) yards up that takes about 2.0 minutes to climb. Just take a reading at the bottom and a reading at the top. Walking up this hill now at a moderate (to slow) pace leaves me breathless even wondering if I can make it without stopping to catch my breath. Here's the result

Baseline hill climb test  -- prior to use of any inhaler
            bottom of hill           96% oxygen saturation       heart rate not recorded (est 70 to 90 beat/min)
            top of hill                 98% oxygen saturation       heart rate 130 beat/min

        The result of the baseline test is clear cut.  Oxygen saturation remains in the normal region (shows a tiny rise) with the moderate level of work required to climb the steep hill on which I live. At the top I was breathing hard, my heart rate was 130 beat/min.  According to the table below this is consistent with chronic bronchitis (blue bloater), not emphysema (pink puffer).

Repeat hill climb test  -- after 10 days use of Spiriva HandiHaler inhaler (5/3/17)
            bottom of hill           98% oxygen saturation       heart rate 69 beat/min
            top of hill                 98% oxygen saturation       heart rate 116 beat/min

        After 10 days daily use of Spiriva HandiHaler my climb up my hill felt much easier than it has in recent months. I didn't feel exhausted before reaching the top as I had earlier. My heart rate at the top was a lot less (116 vs 130 beats/min). I think the inhaler is working for me in the sense that my peak energy output is higher.

Repeat hill climb test  -- after 4 weeks use of Incruse inhaler (6/18/17)
            bottom of hill           xx% oxygen saturation       heart rate xx beat/min
            top of hill                90% oxygen saturation       heart rate 123 beat/min

      As with the Spiriva HandiHaler my climb up my hill after using the Incruse inhaler felt much easier than it had before I started using any inhaler. I didn't feel exhausted before reaching the top as I had previously. This is good. What to make of these numbers I don't know. I didn't record the oxygen saturation at the bottom of the hill. I don't know if the very low oxygen saturation reading of 90% at the top of the hill is due to a shift in my body or is an issue with my oximeter. Low oximeter readings are now fairly frequent, whereas months ago they were very infrequent. The first order of business should be to change the battery in the oximeter and repeat the test.

COPD -- Pink Puffer and Blue Bloaters
        In reading about COPD (Chronic Obstructive Pulmonary Disease) I find there are two classic types: Pink Puffer (Emphysema) and Blue Bloaters (Chronic Bronchitis). One involves the destruction of the capillary bed, which means increased pulmonary pressure and consequent strain on the heart trying to force the blood through damaged (and reduced) capillaries, and one does not. It is emphysema (pink puffer) that gradually damages the pulmonary capillary bed.

        A "blue bloater" is a person where the primary underlying lung pathology is chronic bronchitis. Bronchitis is an inflammation of the lining of your bronchial tubes, which carry air to and from your lungs. (not me) Chronic bronchitis is caused by excessive mucus production with airway obstruction resulting from hyperplasia of mucus-producing glands, goblet cell metaplasia, and chronic inflammation around bronchi.  Unlike emphysema, the pulmonary capillary bed is undamaged. (In other words in a blue bloater the problem is not in the lung, it is in the pathway to the lung.)

        I don't seem to fit into either category. A pink puffer has a reduced DLCO, which is me, but is also described as having severe oxygen desaturation (as measured with an oximeter) with exercise, and this is not me. I have noticed for the first time ever some swelling in my ankles and feet.  A quick test showed my resting oxygen saturation to be 93. I kept the oximeter on and immediately followed with a minute or two of a simple exercise (rising to the balls of the feet). The exercise caused my oxygen saturation to rise to 99 along with a rise in heart rate. This is exactly the opposite of what happens to emphysema patients. (3/19/17)

dyspnea is shortness of breath
(source --

Lung CT scan (3/2217)
        Here is the result of the hires CT scan of my lungs. The question posed to the lung specialist was the drug carfilzomib damaging my lungs. The most common symptoms of interstitial lung disease are a dry cough and shortness of breath.  Whle I have shortness of breath,  I do not have a dry cough. The expert reading of the CT scan shows "no evidence of interstitial lung disease".

        -- The interstitium is a thin layer of tissue that is normally appears as a fine lace on X-rays or imaging studies (best visualized as the appearance of a sponge).

Key results (searchable text) of expert read of 3/22/17 hi-res CT scan of the lungs and chest with my translation of clinical jargon
            no CT evidence interstitial lung disease
                                -- All forms of interstitial lung disease cause thickening of the interstitium, the supporting tissues between the air sacs of the lung.
                                           The thickening can be due to inflammation, scarring, exposure to inhaled irritants (like asbestos) or extra fluid (edema).
                                           Some forms of interstitial lung disease are short-lived; others are chronic and irreversible.
            no lung infiltrates
                                -- Pulmonary infiltrate is a substance denser than air, such as pus, blood, or protein, which lingers within the parenchyma
                                           of the lungs. Pulmonary infiltrates are associated with pneumonia, tuberculosis, and nocardiosis.
            no pulmnary edema
                           -- Pulmonary edema is a condition caused by excess fluid in the lungs. This fluid collects in the numerous air sacs in the lungs,
                                      making it difficult to breathe.
            no significant bronchial wall thickening
                                     bronchi (with the tracea) are part of the upper air way with cartilaginous walls
            no pneumothorax or significant emphysema
                            -- pneumothorax is an abnormal collection of air in the pleural space that causes an uncoupling of the lung from the chest wall,
                                       sometimes called a collapsed lung
            no obvious suspicious hilar nodes (with caveat)
                                'hilar nodes' are lymph nodes in the lung high up in the broncial airways near the branching to the right and left lung (of clinical interest)
            subcentimeter axillary, mediastinal nodes
                               these appear to be lymph nodes in the lung below the high branching of the airway to the right and left lung
            no pleural or pericardial effusions
                            -- Normal pericardium is a fibroelastic sac surrounding the heart that contains a thin layer of fluid. A pericardial effusion is considered
                                        to be present when accumulated fluid within the sac exceeds the small amount that is normally present.
            mild vascular calcifications
                            -- Vascular calcification is a common complication in chronic kidney disease. It is a leading cause of death in patients with chronic
                                        kidney disease. (As best as i can tell, it is sort of a mineralized plaque tumor that grows on vessels walls.)

My strange collection of lung symptoms (3/21/17)
        After 8.5 months on carfilzomib I developed moderate (to severe) shortness of breath. A pulmonary function lung test shows a very low gas exchange rate per breath (DLCO = 44% predicted), a little less than half of normal. In a sense this 'explains' my shortness of breath. Yet readings of blood oxygen, taken every time I go the hospital always are normal (95% -99% saturated). Same readings I normally get with my own oximeter, except one day resting I got readings as low as 91/90%. Here I found if I only increased my breathing rate for a minute, I could raise my oxygen reading 5-6 points to well within the normal region.

              Shortness of breath (dyspnea)         moderate (to severe)
              DLCO (diffusion lung for CO)       44% predicted  (less than half of normal gas exchange per breath)
              Oxygen saturation of blood            95% to 99% (normal range) Very occasionally I will measure a very low resting oxygen saturation
                                                                             of 90/91% (with my oximeter) that I can raise into the normal region with faster breathing for 1 min.
              Pink puffer or Blue bloater             don't fit into either category.
                                                                             a) Pink puffer is emphysema (smokers), inflammation of the lung with degradation of the capillary bed.
                                                                                     (Pink puffers show a big drop in oxygen saturation with exercise. I don't see this, my oxygen levels
                                                                                     however, do drop a little (93%) with exercise.
                                                                            b) Blue bloater is asthma which is airways obstruction (due to mucus). Capillary bed is not damaged.
                                                                                      (Asthma airways obstruction is in the lung. The airways that obstruct with mucus are the
                                                                                      millions of tiny branch air channels that feed clusters of alveoli, which is where the capillary
                                                                                       beds are that allow air oxygen to diffuxe across a thin membrane into the blood.
              FEV1/FEV                                      68%  (one standard says FEV1/FEV < 70%  "confirms the presence of persistent airflow limitation
                                                                                and thus COPD (chronic obstructive pulmonary disease)"
              FEV after bronco dilator inhale      3% increase (negligible). Indicates that obstruction is NOT in the lung airways, so not like asthma.
              Pulmonary hypertension                  No -- heart electrocardiogram (2/14/17) reading, "Pulmonary artery systolic (peak) pressure is normal"
                                                                                (I would think a degraded  capillary bed would be expected to lead to high pulmonary arterial pressure)
              CT lung scan (hires)                        No interstitial lung disease or any other finding suggestive of pulmonary side effect of carfilzomib.
              Hill climbing test                             Oxgyen saturation remains in rhe normal region (shows tiny rise) with the moderate level of work required
                                                                              to climb the steep hill on which I live. Heart rate rises to 130 beat/min.

        Note one way a drug could lower the DLCO reading is by filling the alveoli (air sacs with capillary beds) with fluid. (I would think this might be reversible, but I go no confirmation of this from my lung doctor.)

Raw motes
moderate to severe shortness of breath --- DLCO of 13.98 (44% predicted)
oxygen saturation --- normal (95 to 99), some drop (93) with exercise in one test
My lung capacity numbers are just at or slightly below the thresholds for a possible obstructive defect
         [FEV1/FVC = 70%  (my value 68%), FVC = 80%  (my value 80%)]
Increase of only 3% in FEV1 or FVC in bronchodilator part of pulmonary function tests
my blood oxygen carrying capacity due to chemo is about 20% low
       [hemoglobin 12.6 g/dL,   hematocrit 38.5%]
interstitial lung disease --- negative (hires CT scan)
pulmonary hypertension --- negative (heart echocardiogram)

Lung doctor meeting (4/21/17)
        Since my hi-res CT scan of my lungs was absolutely clear and pressures in my heart are normal, my lung doctor nnow wants to check to see if I might have a blood clot in my lungs. There is a fancy test for that involving radiation called 'lung perfusion ventilation imaging', and it is scheduled for next week (4/27/17).

        To try and live better with my COPD that has developed in the last 3-4 months, presumably due to a toxic effect of the chemo drug carfilzomib on my lungs (now stopped), my doctor is prescribing an asthma type medicine, a broncodialator, a once a day inhaler called Spiriva. This is an experiment. Since both of these are new to me, I set out to do some research.

Pulmonary ventilation/perfusion scan (4/28/17)
        -- A pulmonary ventilation/perfusion scan involves two nuclear scan tests to measure breathing (ventilation) and circulation (perfusion) in all areas of the lungs. A pulmonary ventilation/perfusion scan is actually two tests. They may be done separately or together. I had both.

         For the ventilation scan, you first breathe in radioactive gas for 10 min. This leaves a radioactive coating in the lungs that is then checked with a radioactive scanner that takes three images: straight on and +/- 45 degrees. After this, is the perfusion scan. Here a radioactive albumin (blood protein) is injected into your vein, then the radioactive scanner again takes three images The machine scans your lungs as blood flows through them to find the location of the radioactive particles. I asked for a CD with the images and filled out the form and waited for an hour or so, only to be told none of the CD burners were working (really?). The CD is to be mailed to me.

        Here's the doctor's report. "Ventilation images show symmetric deposition of aerosol. No ventilation defects. Perfusion images show bilateral symmetric perfusion with no segmental or subsegmental perfusion defects." In other words no air flow obstruction and no blood clots.

Nothing found in 4/28/17 lung perfusion tests. Air flow uniform and symmetric, no air flow blockage and no sign of a blood clot.

Perfusion images (4/28/17)
        I waited after the scans for a CD of the scan images, but the CD was not ready, however, it did arrive promptly in the mail just a couple of days later. Here are my images and a similar reference set I pulled off the internet.

        My first minor mystery was I found 16 different images on the CD, but during the test I saw the 'camera' (radiation detector) repositioned only 6 times: three (straight on and +/- 45 degrees) after radioactive air inhalation (vent = ventilation) and three (straight on and +/- 45 degrees) after radioactive blood tracer injection (perf = perfusion). What were the other ten images? Well it turns out that even though all the lung scans were taken from the front (ant = anterior), a rear view (post = posterior) has been calculated. This doubles the number of images to 12. The other four are labeled right and left LAT (RLAT, LLAT) for ventilation and perfusion. As I write this, I don't know what these four images represent. (LAT =  lateral)

Comparing my perfusion images to reference perfusion images
        The simplest comparison is just to look at the straight on views (ant and post). Directly below are my lung perfusion images and below them a similar set of reference images I found online. In the two strips below the outside views line up, but the inside views are crossed.


my strainght on lung perfusion scans

reference strainght on lung perfusion scans
(source --

        As I eyeball above, my ventilation images are a little different from the reference images. The reference images are quite uniform across the lungs (top to bot, right to left), whereas my ventilation images have somewhat more output in the lower part of both lungs and somewhat less in the upper part. The blood perfusion images match up quite well to the reference images. Since one of the purposes of the test was to look for a blood clot (embolism) in the lungs, I don't see any hint of that in the perfusion images, where the outlines of both lungs are fully shown. This is the conclustion of the specialist who read the scans. (However, my (LAT=lateral) views do show some conceentration variations across the perfusion images.)

        To complete the story below are all my 16 images (right) and the for comparison the 12 reference images My four extra LAT images I soon found are 'lateral' projections, so RLAT and LLAT are right and left laterial views. My lateral (blood) perfusion views do show a concentration variation across the lungs, a hot spot in the front of one (or both) lungs.

(left --- reference images from (
(right --- my perfusion scans (ant =  front), (post = rear), (vent =  ventilation (gas)), (perf = perfusion (blood))
(Note the sequence right and left is not the same)
Data taken 4/28/17

        Here's a lung ventilation sketch with numbers. .It looks idealized. Notice  the blood coming out of the lungs is 100% oxygen saturated, but saturation has decline to 84% after circulating around the body. My guess is the standard finger oxygen saturation location would see about half the max oxygen saturation drop as blood circulates around the body to the legs. (Note, this image is from an anesthesia site so who knows how relevant it is to normal living.)

(source --

Spiriva mist vs powder inhalers
        I have messaged my lung doctor's nurse to clarify whether I am supposed to buy (from Spiriva) a mist inhaler, which the nurse spent 10 min showing me how to use, or a powder device (also from Spiriva) that I find has been added to my medications list on MyLaheyChart. The have the same active ingredient, but physically they are completely different, so which one do I buy? (Turns out the mist inhaler demo was a mistake. The drug prescribed in a Spiriva powder based device called the Spiriva HandiHaler (see below). My part D provider is Cigna Insurance, and while some of their plans cover the Spiriva HandiHaler, my plan does not, so it cost me out of pocket 390 for a one month supply (30 capsules.)

       Next morning I got a reply message. I considered this whole thing a screw up. The nurse's reply characterized it as a "miscommunication" (blaming it on the doctor), but telling me the device I should buy was the powder version (Spiriva HANDIHALER), not the mist version I had been taught to use. Why? No explanation given. On the same day (4/24/17) I went to my local CVS pharmacy and was surprised that they had on file for me a prescription for the Spiriva HandiHaler (they had not called me as they usually do), so avoiding the insurance approval hassle I determined to buy it with cash sans insurance using one of my discount card (MA card, 398, inhaler plus 30 cartridges for a 30 day supply). The 398 he quoted agrees exactly with pricing shown on the MA drug card site for my local CVS. The pharmacist said he could do a little better on price and put me in with a drug insurance discount plan they have that lowered the cost to 390, which I paid out of pocket.

Spiriva HandiHaler powder inhaler (4/24/17)
        Here I have photographed my Spiriva powder inhaler.

Spiriva HandiHaler --- photo by Twinkle Toes Engineering .Spiriva HandiHaler cap opened--- photo by Twinkle Toes Engineering
...Spiriva HandiHaler fully opened--- photo by Twinkle Toes Engineering
(top left) Spiriva powder inhaler closed
(top right) Spiriva powder inhaler opened showing mouthpiece
(lower) Spiriva powder inhaler with mouthpiece raised showing hole for capsule (left).
Pressing the green button pierces the capsule with a large needle.

Using the Spiriva powder inhaler
       Using it is not difficult.  I got it right the first time. Open up inhaler and put in a capsule. (Cautioned that capusles should not be exposed to air very long, so take from bubble pack just before putting into the inhaler.) Close it up and push the green button (once). This forces a large needle to pierce the capsule. Breath out all the way, put mouthpiece in mouth while holding device hor, your head upright, and breath in deeply. "Should hear the inhaler rattling, an indication you breathed in correctly" (I do). Hold breath for 5-10 sec, then removed mouthpice and begin breathing normally Open  the inhaler and dump  the used cartridge into the trash. When needed, the inhaler can be cleaned by rinsing it under warm running water.

        This is for one inhalation, which is what my doctor calls for. Once a day (in the morning). There is enough active ingredient in the 18 microgram capsule for a second inhalation, which the manuf calls the standard dose. The nurse advised me after to gargle with some water, apparently to flush excess powder out of the mouth area, where she said it could cause a nasty 'thrush' fungal infection. (Curiously I can find no estimate of the dose that would typically be inhaled. It mut be less than 9 micrograms because the 18 microgram cartridge is good for two inhalations.)

        So while easy to use, it is expensive, about 400 a month, and presription must be refilled monthly. It/s been 12 hours since my first inhalation, and I feel no side effects, a good sign.

        The mist device (Spiriva Respimat) is a combination of a plastic inhaler into which a cartridge with about the drug is inserted. A single press of a button injects a fixed dose into your lungs. My instructions are a single dose each morning. I find the  cartridge has about 60 doses, so it would last me about two months.

Full prescribing information for both Spiriva powder and mist devices

        -- SPIRIVA® RESPIMAT® (tiotropium bromide) inhalation spray, for oral inhalation. A cartridge is used with SPIRIVA RESPIMAT inhaler. The RESPIMAT inhaler is a hand held, pocket sized oral inhalation device that uses mechanical energy to generate a slow moving aerosol cloud of medication from a metered volume of the drug solution. When used with the SPIRIVA RESPIMAT inhaler, each cartridge containing 4 grams of sterile aqueous solution delivers the labeled number of metered actuations after preparation for use

        -- SPIRIVA RESPIMAT, 1.25 mcg (single inhalation), is a long-term, once-daily, prescription maintenance treatment of asthma for people 12 years and older. (The prescribing documents says two inhalations (2.5 = 2  x 1.25 mcg) is the standard dose, but I was advised by the nurse to use one inhalation daily.)

        It looks like the manuf sells two different forms of this inhaler that differ only in the dose. The inhaler for COPD delivers 2.5 mcg per mist, whereas the inhaler for asthma is half the dose (1.25 mcg per mist). (I have yet to see my prescription to find out which I will get).

        On MyLaheyChart I find the entry below for the prescribed drug:
                    "tiotropium 18 mcg inhalation capsule, Commonly known as: SPIRIVA WITH HANDIHALER"
                    "Instructions: Place 1 capsule (18 mcg total) into inhaler and inhale daily".  (not clear, once?)
                    "Prescribed quantity: 30 capsules"  (without  insurance discount price of this quantity is close to 400)

        Copy of my prescription (obtained from CVS pharmacy) says
                  Durg:                tiotropium  (Spiriva with HandiHaler) 18 mcg inhalation capsule
                  Qty:                 30 capsule
                  Sig:                   Place 1 capsule (18 mcg total) into inhaler and inhale daily                    (does this mean ONE inhale?)
                  Date written:     4/21/17
                  Refills:               5
                 Proscriber:       Dr. Villanueva, Andrew, MD
                                         41 Mall Rd. Burlington, MA 01805
                  Diagnosis         j432                       (Centrilobular emphysema)    -- Centrilobular  primarily the upper lobes  Occurs with loss of the respiratory bronchioles in the proximal portion
                                                                           of the acinus, with sparing of distal alveoli. This pattern is most typical for smokers.

HandiHaler prescribing document
        -- Spiriva HandiHaler is an anticholinergic indicated for the long term, once daily, maintenance treatment of bronchospam associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysem aand for reducing COPD exacerbations.

        -- Inhalation powder: SPIRIVA capsules contain 18 mcg tiotropium bromide powder for use with HANDIHALER device. Two inhalations of the powder contents of a single SPIRIVA capsule (18 mcg) once daily.

        -- Tiotropium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic. In the airways, it exhibits pharmacological effects through inhibition of M3-receptors at the smooth muscle leading to bronchodilation. The terminal half-life of tiotropium in COPD patients following once daily inhalation of 5 mcg tiotropium was approximately 25 hours.

        -- In these studies, SPIRIVA HANDIHALER, administered once-daily in the morning, provided improvement in lung function (FEV1), with peak effect occurring within 3 hours following the first dose. The mean peak improvement in FEV1, relative to baseline, was 0.28 to 0.31 liters (28%  to 31%), after 1 week of once-daily treatment. Improvement of lung function was maintained for 24 hours after a single dose and consistently maintained over the 1-year treatment period with no evidence of tolerance.

(.30 L increase in FEV1 for my 2.31 L measurement would be about a 13% increase)
(from Spiriva HandiHaler prescribing document)

Incruse Ellipta  --- another once daily powder inhaler (5/4/17) (6/28/17)
(6/28/17 update)
        I found in getting near the end of the first Incruse Ellipta inhaler there is a problem in knowing when it is empty. The package instructions say: 'Discard when  the counter reaches "0"'. But this is ambiguous! Does this mean "0" before you slide it down to open it or after you open it?  (I found out from two telephone calls to the manuf contact tel# that the answer is before.)

        When you pick it up with one dose remaining inside, before you open it the window counter will read "1" (there is also a thin red bar to the left of the 1), but after you open it in preparation for breathing, it will read "0", because each time you slide down the slider to expose the breathing hole, the count decrease by one. So while you are breathing in the last dose the counter will read "0". This is confusing. The package instructions say just 'Discard when the counter reaches "0", so when you have opened it and have not yet breathed in with the counter showing a "0", it is not clear whether you are going to get a dose or not! With this inhaler unlike the Spriva Handihaler, there is no audio feedback, or in fact no feedback of any kind to the user, that when you breath in you are breathing in the powder. The only indication you have that you are getting a dose of the drug is the counter reading, so the ambiguity in understanding what the counter reading means is very important.

        Here's what the counter window means --- The window count BEFORE you open the slider (to expose the inhale opening) indicates the remaining doses inside. Thus the window count for the last dose will read before you open it "1", and it will show "0" while you are breathing in.
        The Spiriva Handihaler is not in the formulary of my Part D provider (Cigna), but the formulary includes three or four other drugs in the same class. GoodRx says the Incruse Ellipta and Tudorza Pressair are similar drugs to the Spiriva and none of them have generics, so (surprise!) this is why they are all so expensive. From that list my lung doctor selected (Incruse, Ellipta) as an insurance covered replacement for the Spiriva HandiHaler. It is also a powder based inhaler taken once a day. Without insurance both drugs cost in the region of 350 to 400 per month. I expect that since by feb I am into Part D catastrophic coverage for my super expensive chemo pills, that should apply here too. Thus I expect my out of pocket costs for an inhaler with part D drug insurance coverage to be about 5% of 400, or 20 per month.

Incruse Ellipta powder based inhaler for COPD

        Incruse is a new drug only approved by the FDA in 2014. It has a different active ingredient (umeclidinium) than Spiriva. It comes with its own inhaler. The drug quantity for a daily single inhale is 62.5 micrograms. I note its two main side effects (increased eyeball pressure and worsening of uninary retension) are the same as Spiriva, so the two drugs must be quite similar. Its mechanism of action is described in its proscribing document this way:

        -- Umeclidinium is a long-acting antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. (Translation -- it is a bronchodilator. It relaxes the muscles that form the airways in the lungs)

        -- INCRUSE ELLIPTA is an anticholinergic medicine. Anticholinergic medicines help the muscles around the airways in your lungs stay relaxed to prevent symptoms such as wheezing, cough, chest tightness, and shortness of breath. These symptoms can happen when the muscles around the airways tighten. This makes it hard to breathe.

        The instructions for use are basically the same as for the Spiriva. Breath out deeply, then breath in deeply through the inhaler, hold your breath for a few seconds. I haven't had my hands on the Incruse yet, but it looks like it should be a little easier to use than the Spiriva. With the Spiriva each day you need to open a blister pack (a pain) to get a capsule to insert into the inhaler. With the Incruse it looks like all 30 doses for the month are inside, a new dose is available each time you open it, a counter displays on the front.
Breo Ellipta
       Just after I had finished writing up the Incruse Ellipta, I see an ad on TV for the Brio Ellipta inhaler. What? This can't be a coincidence. Sure enough looking at the Brio inhaler, it has same distinctive shape as the Incruse inhaler, they must be from the same company. Yes, GlaxoSmithKline. So what's the difference?  Both are once daily, powder inhalers for bronchodilation. The Brio comes in two different dosages, the lower dose marketed for COPD and asthma while the x2 higher dose is marketed for just asthma. The Brio has two active ingredients, both different from the Incruse, and one of the Brio active ingredients is a corticosteroid. The Brio seems to have a lot of side effects, perhaps because it includes a steroid.

        --BREO ELLIPTA is a combination of fluticasone furoate, an inhale corticosteroid (ICS), and vilanterol, a long-acting beta2-adrenergic.

90 day supply of Incruse Ellipta unexpectedly arrives in the mail ---another screw up on the inhaler (5/6/17)
       I found my first inhaler (Spiriva HandiHaler) was not in the formulary of my part D (drug) provider, so I checked a list of alternative inhalers provided by the hospital to see if any were covered. As  instructed, I called the hospital with this information and was told by the lung support person that my doctor would be changing my preseription to an inhaler covered by my Part D insurance (Incruse Ellipta), and that the prescription would be sent (electronically) to my local CVS pharmacy. When I tried to buy a 30  day supply of Incruse inhaler at CVS, I was told my insurance would not pay for it until after July 19, ten weeks from now. What? I said that can't be right, I will be out of inhalant capsules in about two weeks, so I left CVS very puzzled. When I arriced home, I found in my mail a package from Cigna Home Delivery Pharmacy that contained three Incruse Ellipta inhalers, a 90 days supply. The retail cost of each inhaler is about 340 dollars, so this is about  thousand dollars worth of drugs.

I did not authorize this purchase
       Here's the thing  I had no idea that my prescription had been sent to Cigna Home Delivery Pharmacy. Cigna pharmacy never called me for authorization. I did not authorized this purchase or the quantity, and I certainly did not authorize my my credit card to be charged. Cigna has my credit card number of file, because monthy I buy by super expensive (tier 5) chemo drugs from their seciality pharmacy. When I do buy my chemo drugs monthly, Cigna speciality pharmacy always calls and verifies the drug, quantity, and asked if they can charge my credit card.

         A little googling finds a site with 69 complaints about Cigna Home Delivery Pharmacy! Here's a poster on the site and what just happened to me happened to him in 2015.

-- "Cigna home delivery sent me $465 worth of medications I never ordered. They charged my credit card which they had on file. I immediately called them the day I received the shipment. I asked if I could mail it back to them but they refused. They said the doctor sent them the prescription so they assumed I needed it. I am now stuck with this charge for prescriptions I never ordered."
I call Cigna Home Delivery Pharmacy (5/8/17)
        Cigna tells me that when they receive a prescription, they routinely mail out the drugs without calling for authorization. This is their policy they tell me. They take the (electronic) receipt of the prescription as the patient authorization. I told them I consider this to be is an abusive billing practice perhaps bordering on fraud. I ask them to return the money as they had already charged my credit card. They refused.  When I ask about why Cignal always confirms my chemo drug order and confirms they can charge my credit card, they are less than clear but seem to say they have a different policy for super expensive tier 5 drugs.
Federal Trade Commission
        Q. Am I obligated to return or pay for merchandise I never ordered?
        A. No. If you receive merchandise that you didn’t order, you have a legal right to keep it as a free gift.
Messages to the hospital
        I sent the following message to the prescribing doctor about this unauthorized Incruse inhaler shipment" (5/8/17)
        I want to make you aware of what I consider to be a screw up by the lung support staff. You started me on Spiriva HandiHandiler about two weeks ago. I was handed a sheet of paper at that time with 18 other inhalers with instructions to see which of them are covered by my insurance. I did as instructed and called the tel # on the sheet giving the inhalers in my insurer's formulary. You were checked with, and I was told the inhaler prescription would be changed to the covered Incruse Ellipta and forwarded to my local CVS pharmacy. I said Ok. Later I verified that CVS had received the Incruse prescription. This was last week.

        Over the weekend  a package arrived in the mail (out of the blue) with a thousand dollars (retail) worth of drugs, specifically a 90 days supply of Incruse Ellipta (three inhalers) from Cigna Home Delivery Pharmacy. I knew nothing of this order. Neither the hospital nor the insurer called me about it. I did not authorize the shipment, I did not authorize my credit card be charged.

        The Federal Trade Commission says if merchandise is sent to you that you never ordered, you have a legal right to keep it as a free gift!

        I can only assume that some lung support person sent (electronically) my Incruse prescription to TWO pharmacies: CVS and Cigna Home Delivery Pharmacy. I was only told it was going to CVS. On a call to Cigna Home Delivery Pharmacy they tell me their position is when they receive a prescription they assume receipt of the prescription ALONE constitutes approval of the patient for shipment.

        Clearly this is an aggressive sales tactic (bordering on fraud). It has generated tons of complaints about them to be found online. I tried to get Cigna to refund my money since I had not ordered or in any way authorized this drug shipment. They refused.

        As a matter of principle and procedure I think this is a pretty bad screw up, however, in practical terms its effects are minor. The price was right (53 dollars, 5% of the thousand dollar retail cost, since I take very expensive chemo drugs and am in Part D catastrophic coverage). At CVS I would have bought a one month supply to see if if the new inhaler worked for me, now I have a 90 day supply, but other than that no problem.

2nd followup message to the hospital the next day (5/9/17)
        This is a supplement to yesterday's message. After talking with my brother about how Cigna Home Delivery Pharmacy came to receive my prescription for Incruse inhaler, which they obviously did, he suggested a possibility I had not considered, saying the point of contact between CVS pharmacy and Cigna Home Delivery Pharmacy is likely to be my medicare part B insurer, who (surprise!) happens to be Cigna Insurance.

        I read Cigna Insurance and Cigna Home Delivery operate as two separate companies, but clearly they are both under the Cigna umbrella. So it might very well be (even perhaps likely?) that when my local CVS contacted Cigna Insurance for approval, Cigna Insurance seeing a thousand dollar purchase on the line and my credit card on file forwarded the prescription to Cigna Home Delivery Pharmacy, who scooped the sale from under CVS's nose for themselves by immediately hustling the drugs out the door and getting paid by charging my credit card (all without my knowledge). This does fit all the known facts.

        An inquiry to the Lahey lung support staff could clarify matters.  If they say they my new prescription for Incruse was ONLY sent to CVS, as I was told, then I will accept it, and I withdraw my (vague) allegation of yesterday that Lahey procedures seem to be screwed up.

        As a mere patient (an engineer) I don't have any inside knowledge as to how the murky pharmacy/insurance world works, so I can't figure out how Cigna Home Delivery Pharmacy got my prescription. Did it come directly from Lahey or via Lahey/CVS/Cigna insurance? All I can do is look at the known facts and speculate.

        From the invoice in the Incruse box --- Cigna Home Delivery Pharmacy, PO Box 382097, Pittsburgh PA 15250-8097,  Order #:10225915300, Account #: 95027751, Ship date 5/4/17.  Questions:  800-835-3784. Sold to Donald E. Fulton, Cost: $53.23 (This is 5% of retail cost since I am now in Part D catastrophic coverage), Payment received: $53.23. (Confirmed --- my bank checking account shows a 53.23 charge to my debit card the next day) My debit card # is not referenced on the invoice. Turns out that Cigna Speciality Pharmacy (800-351-3606), where I get my super expensive chemo drugs monthly, is probably just a division of Cigna Home Delivery Pharmacy both based South Dakota, and as a convenience for these expensive monthly purchases they keep my credit card # of file.

        From the pharmacy label on the Incruse box:
                 Rx 1397229569                                  (important, this is the reference to this particular prescription)
                 Address: 4901 N. 4th Ave, Sioux SD57104
                 (prescribing doctor) Dr. Vxxxxx
                 Dispense date:  5/4/17
                 Refills:  3

        So before I have even tried Incruse, the alternate inhaler to Spiriva, I am sitting on a 90 day supply of it In retail terms (sans insurance) this is more than a thousand dollars worth of drugs. Now for me the price is right, since my out of pocket charge for the 90  days supply is only 51 (about 17 per inhaler capsule). This is the correct price, because due to my super expensive chemo pills I am in Part D catastrophic coverage for 11 months of the year, hence I pay only 5% of the retail price.

What happened here? (5/7/17)
       Looking over the invoice and label on the thousand dollars of drugs I got in the mail I have a pretty good guess as to what happened. I think the hospital made a (minor) mistake in forwarding my new prescription to two pharmacies: CVS and Cigna Home Delivery Pharmacy. The told me only about CVS.  Cigna is where I get my chemo drugs, so for these monthly purchases they keep my credit card # on file, a convenience for me.

        The big screw up (if that is what it was, but I suspect it was deliberate!) was at Cigna pharmacy. My guess is to boost sales they take a prescription like mine with three refills and just send out all three, billing the customer since my credit card # is on file WITHOUT calling me to seek authorization either for the purchase or the quantity! If Cigna had called me for authorization, as of course they should have, I would have either denied it or changed the quantity to one, so the hospital's error would not have mattered.

        When I do some googling, I find others complaining that Cigna home delivery pharmacy has charged their credit cards without authorization. Another poster on the same site in 2015 writes "The pharmacy service with Cigna insurance forces you to have 90 day prescriptions written and delivered to your home regardless of whether your physician writes 90 day prescriptions or not," and his wife works for Cigna. (

Abusive billing practice
        Found a 2013 posting (below) of a patient similar to me who received an order from mail order pharmacy that she did not authorize. The expert opinion answer is the sounds like abusive, if not fraudulent, billing by the pharmacy. Apparently this is a far too common abusive billing practice, even local pharmacies were doing it at one point until Medicare ordered them to stop.  In general you have a legal right to keep for FREE anything sent to you that you did not order or authorize. You cannot be required to return the merchandise. There are hints in the posting that the pharmacy may rely on a patient authorization that is obtained by the prescriber.

HandiHaler  --- Now I am now totally confused. What I was shown by the nurse is called the SPIRIVA RESPIMAT inhaler by the manuf. The prescribing document describes the HANDIHALER as delivering a "powder" (18 mcg) not a mist!  The handihaler, which is on my drug list and presumable specified in the prescription, is clearly a different device from the SPIRIVA RESPIMAT inhaler that is shown in the video. GoodRx says 30 capsules are a 30 day supply, so even though each capsule contains 18 micrograms, only a tiny fraction of which is used for an inhalation, apparently a new capsule is needed every day.
Here's a video from the manuf boehringer-ingelheim showing how to setup and use the inhaler

GoodRX info (4/23/17)
        The GoodRx drug discount site has some good information about this inhaler.

Spiriva Tiotropium
        "Tiotropium (Spiriva) is an expensive drug used to treat chronic obstructive pulmonary disease (COPD), including emphysema and chronic bronchitis. This drug is more popular than comparable drugs. There are currently no generic alternatives for Spiriva. It is not covered by most Medicare and insurance plans, but manufacturer and pharmacy coupons can help offset the cost. The lowest GoodRx price for the most common version of Spiriva is around $385.02, 15% off the average retail price of $453.83." (GoodRx)
Side effects
        The three main side effects appear to be increased pressure in the eyes, which can cause blured vision because it raises the pressure in the eyeball, urine retention and sore throat.

         I was advised by the nurse showing me how to use it that these types of inhalers are particle based, so gargling is advised because accumulation of the particles in the throat can lead to 'thrush', described as nasty.

Price and dose
        From a sheet given to me at the hospital other COPD inhalers in the same general class as Spiriva include: Tudorza. Combivent, Incruse, Anoro, (Atrovant). GoodRx amazingly shows these drugs are about the same price, nearly 400 for a month's supply (smells like price fixing to me!). The active ingredient is different for each brand.

Insurance coverage
        I was handed at the hospital a sheet titled: 'Inhaler options to  review with your insurance' with 18  inhalers (in five unlabeled classes), and advised to call my insurance company to see what is covered and not covered, then to call a tel # (781-744-3365) at the hospital. (This tel # is close to Dr. Villeneuva's number)

Check of 2017 (and 2016) Cigna Insuranc Comprehensive Drug list (Formulary)
Jesus Christ --- Cigna has a bunch of formularies
                         Information below  is from 2017 HMO plans, but Spiriva is missing from 2017 formulary for Cigna-HealthSpring Rx Secure (PDP)
                         My plan is  Cigna-HealthSpring Rx Secure-Xtra   (note Xtra on the end)
Yikes   --- Cigna cusomer tel # printed everywhere is  totally wrong. I called it and it is another company, who told me Cigna printed the  wrong #. She read me the number, butI  didn't write it down.
                  Even when I log into my account the tel # is wrong. (Its the tel # I just called).

My part D insurer, Cigna Insurance, drives me up the wall
        How can one insurance company be so incompetent? I spent literally hours trying to find out if a prescription bronchodilotors was covered by my Part D Cigna plan.

Wrong contact tel # at Cigna
       For starters Cigna's main customer contact tel # on their online formulary documents is wrong. This is freaking unbelievable! Not just wrong on one document , but on multiple documents. I called the number, and it is another company who explained to me Cigna has put down their number. They told me the correct Cigna number (which I did not write down), and it is totally different. How can such an error not have been corrected almost immediately?  The only answer I can come up with is they don't give a shit.

No index into the multiple  formularies
        The root of the problem in checking for my new drug in the Cigna multiple formularies is finding the right formulary. Cigna has a lot of different plans with very similar, long, complex names. I now know (after a lot of time wasted searching) that these plans do not use the same formulary. Cigna has multiple formularies.  What's needed is an index tying Cigna's various plans to the formulary for that plan. If such an index exists, I can't find it and apparently neither can  google. Where it should be is in the beginning of each formulary. All you find now at the beginning of a Cigna formulary is the name of the plan it applies to.

        For example, the exact name of my Cigna medicare part D plan name is 'Cigna-HealthSpring Rx Secure-Xtra'. Look at this name, four qualifiers after Cigna! Do all these words matter in searching for a formulary. Turns out they do, but this is after wasting