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My related essay 'Medicare Part D and Medigap: What cancer patients on super expensive chemo need to know' is here
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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
Intro
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
Hypercalcemia
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)
           Repeated blood transfusions
       Health update (11/28/17)
           Super low platelets   (value 3)!

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

Appendix
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
plasmacytoma
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.
 

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)).

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).

 (10/28/15)
        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.

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.

 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.

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)

Worked
       ** 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).

Plot of my numbers (1 - 9 months)

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.

red: IgG production by cancerous plasma
blue: IgG serum concentration
SPE =  serum protein electrophoresis
(source -- http://www.wikilite.com/wikilite/index.php?title=File:18.15.jpg)

        Later I discovered a nearly identical plot (above). This is from the Freelite (Wikilite) people (www.wikilite.com and http://www.us.bindingsite.com/) 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.

        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.

        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.

Oligoclonal
        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.

       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.
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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.
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Intro
        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.)

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)
source: https://www.youtube.com/watch?v=BrItOoELlZg
https://www.youtube.com/watch?v=ajL8D9JIja8

        https://www.youtube.com/watch?v=YRBtisJhKlw

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.

(update)
        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.

        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.

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."

        "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.)

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)

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. "

        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.

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).

         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).

        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.

        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)
 

        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

Nephelometry
       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.

 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."

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.

        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.
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        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.

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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.

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.

        * 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.
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        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.)

        http://multiplemyelomablog.com/2015/05/tom-brokaws-program-about-his-multiple-myeloma-a-pleasant-surprise.html

        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.

        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.

        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?)

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.
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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.

        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!

        -- "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 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.

        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.
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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).
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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.

        https://www.themmrf.org/multiple-myeloma-knowledge-center/myeloma-treatments-guide/growth-factors/erythropeietin/

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.

            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)

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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.
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        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.)

        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.

Hypercalcemia
        "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."

CRAB
        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)

(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.

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.

Introduction
       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.

M-spike
       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.

        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 (MyLaheyChart.org) 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.

            "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.)

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.

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.

         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.

        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.

        Cancer.org 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." (http://www.myelomabeacon.com) 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.

        -- "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!)

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        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.

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
Pelvis
        -- several turmors in the pelvis, most notably within the ('iliac wings' are the large flaring surfaces of the pelvis)
Ribs
        -- 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.)
Arms
        -- several small tumors (well-defined lucent lesions) in both upper arm bones ("proximal humeri") (humeri is the plural of humerus)
Legs
        -- 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)

        -- 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.)
CT
        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.

IMPRESSION:
           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
metastases.

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

INDICATION:
        Acute pathologic fracture of C2

FINDINGS:
        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)

IMPRESSION:
        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.)

IMPRESSION:
        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).

IMPRESSION:
        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.

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.

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).

INDICATION:
        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.

FINDINGS:
        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).

IMPRESSION:
        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.

        A 2012 open source MM book, very technical, each chaptor by different authors.
         http://www.intechopen.com/books/multiple-myeloma-an-overview

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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
        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."

Revlimid
        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.

Pomalidomide
        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."

        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)
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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%).
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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.

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.

Details of C1,C2 fusion operation, which looks like my procedure, from International Spine Center, Berlin:
         http://www.kreuzschmerzen.org/en/precedures/microsurgery/spinal-fusion/c1-c2-fixation.html
         https://kulaga.wordpress.com/2012/10/17/cervical-spinal-fusion-of-c1-c2-vertebrae/
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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.
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        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.

        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).
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        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."
                      (http://investor.millennium.com/phoenix.zhtml?c=80159&p=irol-newsArticle&ID=2014902&highlight=)

"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

        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

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)

         http://www.mskcc.org/cancer-care/adult/multiple-myeloma/clinical-trials                                                                                27 MM trials
         https://www.dana-farber.org/Research/Clinical-Trials/Clinical-Trials-Search-Result.aspx?q=multiple%20myeloma             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.

         http://www.mskcc.org/cancer-care/adult/multiple-myeloma/clinical-trials/12-018

         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.)

         https://clinicaltrials.gov/ct2/show/record/NCT01191060

        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.

         http://www.mskcc.org/cancer-care/adult/multiple-myeloma/clinical-trials/08-121

        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.

         http://www.mskcc.org/cancer-care/adult/multiple-myeloma/clinical-trials/12-138

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Salt
             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)
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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.)

        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).

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.

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.

        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.

        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).

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]

        -- "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."

        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".

    CR --- Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and<5% plasma cells in bone marrow.

        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.

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.
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References
        Multiple myeloma overview arrticles
                This paper ('Multiple Myeloma: An Update', 2013) by a doctor from Oman has a very detailed overview of MM.
         http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3562980/

        2015 MM Patient Handook from International Multiple Myeloma Foundation (good technical reference)
         http://myeloma.org/pdfs/PHB_2015.pdf

        2013 Mayo clinic MM treatment recomendations (detailed paper, complete)
         http://www.mayoclinicproceedings.org/article/S0025-6196(13)00077-3/fulltext

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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)

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!)

        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)

         http://www.bloodjournal.org/content/bloodjournal/114/15/3139.full.pdf

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.)

        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?

Summarizing
        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]

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.

        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.
 

        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.)

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.

        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)

         http://myeloma.org/pdfs/U-PEP-Eng2012(P)_f1web.pdf

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

                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.

        http://myeloma.org/pdfs/U-Freelite-Eng2011_g2web.pdf

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.

        -- 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.

        http://szpiczak.org/index.php?lang=en&vol=szpiczak&part=3     (part 1)
        http://szpiczak.org/index.php?lang=en&vol=szpiczak&part=4     (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
         http://courses.washington.edu/conj/bess/bone/bone2.html

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.

        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)'.

        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.

        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". (http://www.myelomacanada.ca/docs/u-dex-eng_c1-web.pdf)

K_Shash
        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.

rafaelmsantiagomd
        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:

         http://mmfordummies.blogspot.com/2009/03/myeloma-mondays-archive-survivorpatient.html

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

Overview
        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.

Discussion
        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.

Lymphoma
        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
        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.

        -- 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.

M-spike
       -- 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.

Dental
        -- 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.
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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.

FISH
       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)

        --  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.

        ** 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)
           https://www.ebmt.org/Contents/Data-Management/Helpdesk/Documents/Myeloma%20-%20evaluating%20response%20to%20treatment%20and%20relapse.pdf

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.)

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

        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 (https://www.ncbi.nlm.nih.gov/pubmed/22763387)
                                                                         "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 Selleckchem.com pharmacy, The site also shows a lot of chemical information about each drug
         with links to literature and clinical trials.
           http://www.selleckchem.com/products/oprozomib-onx-0912.html?gclid=CI724Kya4dQCFRBMDQodUSUIsA

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
           http://www.nejm.org/doi/full/10.1056/NEJMoa1606038?rss=mostEmailed#t=article
                                                                            New England Journal of Medicine paper on Castor trial results Aug  2016 -- 'Daratumumab, Bortezomib,
                                                                                  and Dexamethasone for Multiple Myeloma'
           http://www.nejm.org/doi/pdf/10.1056/NEJMoa1606038
           Slide talk on the Castor trial
                                                                      New England Journal oct 2016 paper on Pollux trial, 'Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma'
           http://www.nejm.org/doi/full/10.1056/NEJMoa1607751#t=article
         http://www.nejm.org/doi/pdf/10.1056/NEJMoa1607751
                                                                ----------------------------
                                                            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.
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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.

        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.
        MDX-1097
        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
                                                          Pharmaceuticals.
                                                 “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
         https://www.themmrf.org/multiple-myeloma-knowledge-center/myeloma-drugs-guide/velcade/

        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.

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'.

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
              -- 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.

        -- “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
         http://mmrf.pub30.convio.net/living-with-multiple-myeloma/relapsed-refractory-patients/treatment-options/mln9708.html
        Carfilzomib --- based on
        ONX 0912
        NPI-0052 -- Marizomib, infusion
        CEP-18770
http://www.cancernetwork.com/oncology-journal/current-advances-novel-proteasome-inhibitor%E2%80%93based-approaches-treatment-relapsedrefractory-multiple
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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.

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Immunotherapy
        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.”

        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.
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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).

http://www.arraybiopharma.com/product-pipeline/filanesib/

21 slides    http://www.arraybiopharma.com/files/5913/9810/8038/PubAttachment592.pdf     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.

    800                       http://meetinglibrary.asco.org/content/150495-156
 

------------------------------
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.

                      Mar 2016 paper with 600 patients showed adding an alkylating agent to Revlimid did not improve progression time.
                                               (http://www.myelomabeacon.com/forum/revlimid-triplets-no-better-than-doublets-t6879.html)
                                               (http://www.bloodjournal.org/content/127/9/1102?sso-checked=true)

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)
         https://www.themmrf.org/multiple-myeloma-knowledge-center/myeloma-drugs-guide/kyprolis/kyprolis-side-effects/

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.)

       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:

         http://multiplemyelomablog.com/2015/11/ninlaro-should-be-a-great-drug-but-storm-clouds-on-the-horizon.html

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).

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)

Farydak
        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:

         http://www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/default.htm

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.

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.)

        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.

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 Medicare.gov 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."

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.

        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.
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        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.

Here's C1 rotating about the C2 dens

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 https://en.wikipedia.org/wiki/OsiriX
 

         http://unbeknownst.net/archives/466                       patient posting recommending Mango for Windows
         http://ric.uthscsa.edu/mango/                                   Mango   (big package, lots of options)

         https://beta.jackimaging.com/demo                        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!

         http://www.radiantviewer.com/

         http://rsbweb.nih.gov/ij/                                        ImageJ is an java/nih viewer  poster uses it with CT and MRI images (customer unfriendly)

         http://www.osirix-viewer.com/                             OsiriX is the standard, open source free (?) viewer. Powerful 3d viewer. Apple only.

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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
        http://www.bio-rad.com/webroot/web/pdf/lsr/literature/Bulletin_6040.pdf

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

         http://sciex.com/products/capillary-electrophoresis-instruments
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        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.)

        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".

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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.

Plot of my M-spike(s) numbers for 2016 (updated 12/12/16)

        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)

        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).
 

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.
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        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.

        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%,

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). https://www.ncbi.nlm.nih.gov/pubmed/?term=N+Engl+J+Med+372%3A142-152%2C+2015

        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).

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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.)

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.
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        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.
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(6/13/16)
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.

Dosing
        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.

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.

        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!

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).

            ECG (12 lead)                                     Borderline ECG   (same as EKG?)
                                                                        Sinus bradycardia    (pulse < 60 beats/min)
                                                                       Abnormal R-wave progression, early transition

            echocardiogram

        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.