Friday, February 28, 2014

Dr. Rajkumar, and my "Grand Unified Theory" on the curability of Myeloma

I participated in a very interesting conference call / panel hosted by the good people at Cure Talk this week.  Our guest this time was Dr. Rajkumar from Mayo, MN. 
 
Dr. Rajkumar was the lead author of the paper on secondary MGUS that helped assuage my concerns when I noticed this in my blood last year.  As such, he is one of few people qualified to directly speak to the topic so I was sure to ask him about it.  He didn't tell me too much more than I'd already read in his paper, but there were a couple of new insights and it was quite interesting overall:
 
* A significant number of post-transplant patients have been seen to have a secondary monoclonal signature in their blood that typically disappears after about six months.  They have observed it in about 30% of patients that they've seen at Mayo post-transplant, and it is likely underreported since not all patients commit to regular follow-up and it only shows up on detailed IFE blood tests, not in standard SPEP blood tests.
 
* In cases of secondary MGUS (as opposed to disease recurrence), the monoclonal protein that appears does not come from the same clone that presented at baseline.  In many cases, it will come back in a different region of the immunglobulin spectrum (e.g., if somebody had IgG Lamba myeloma, the secondary MGUS might be IgA Kappa).  In my case, it was in the same part of the spectrum -- IgG Lamba -- so it wasn't as clear that it wasn't disease return.  But it was a faint light chain only, no heavy chain, and ultimately it went away so it was simply a different manifestation in the gamma globulin spectrum.
 
* Patients that exhibit this transient protein -- provided it is eliminated without treatment -- have an overall survival twice as long as those who do not exhibit this condition.  That's a good sign for me...now that it's gone away of course.  : )
 
* He posited that appearance and elimination of the protein was a good sign because it was reflective of an immune system that was able to eliminate the clone.  The clone is there in the first place because the immune system is manufacturing immunoglobulin to repopulate itself after treatment, and when there isn't enough normal immunoglobulin to fill up the "cup" that represents the system, benign monoclonal proteins can emerge unchallenged.  However, even if benign, the clone is superfluous to immune function and if the immune system is able to get rid of it, it's not just a sign of an immune system rebuilding: it's a sign of an immune system functioning effectively.
 
* He did note that in the majority of cases, this phenomenon is seen within the first year of transplant.  He didn't assign any particular importance to the fact that mine showed up four years after transplant, although he said it was very unusual.  However, UAMS uses a lot more medicine than Mayo and it's simply possible that it took longer for my immune system to recover than would be the case were I treated less aggressively (this is my guess -- he did not opine).  I was still on Velcade up to a couple of months prior to the disappearance of the protein.
 
My question came late in the panel.  The rest of his talk was primarily about the main topic for the conversation: cure versus control.  It's a topic covered increasingly on these calls, and certainly one that I continue to address in these pages.  You can listen to the entire call by clicking on the link here, below the picture of Dr. Rajkumar, but the highlights were as follows:
 
* He believes that some patients are being cured today.  In fact, he believes in very rare cases people were being cured 20 years ago.
 
* He noted that approximately 40% of Total Therapy patients remain in complete remission after five years and acknowledged that if the data holds, many or most of them are likely cured.  He basically said that we have to wait to see what the future has in store.  Recall, however, the 40% includes the subgroup of high risk patients who do not respond to any current treatment.  Remove them and the 40% becomes 50% -- which is consistent with what UAMS has said of late with respect to "low risk" patients.  Also, the published data is old as all published data is because of the demands of third party oversight, peer review, etc. that slow down the publication process.  The newest data confirms the curve does plateau -- which indicates cure in the same way that the plateaued curves for certain other blood cancers do.
 
* He noted that "we do not need to cure MGUS -- we need to cure Myeloma" and that many people could experience long-term remission even if they have trace levels of monoclonal protein in their blood, as it might be a benign clone unrelated to the Myeloma.  This is consistent with UAMS' assertions that there are those who are functionally "cured" with an ongoing MGUS signature.
 
* He noted -- appropriately, in my view -- that an issue with saying TT is a cure is that not everybody is eligible for it.  And that for a disease to be considered curable, it would have to be something that could be applied broadly across all patients.  I don't disagree with this -- although I do think he underestimates the eligibility for TT.  But there's no escaping the fact that the elderly will get less of an incremental benefit from TT versus less aggressive therapy, and those who are not healthy enough to undergo treatment or who can't afford to take 6-9 months off work (or who can't afford the treatments) or who are unable to go to Arkansas are not able to have the opportunity at this treatment, even if it is potentially curative.
 
* He acknowledged the importance of MRD testing but in discussing its use, he said (unintentionally) something slightly misleading when he referenced other UAMS data that suggested quick remissions were among the least durable.  This is true in the case of high risk disease reponse to Total Therapy -- remission is easily achieved but rarely meaningfully sustained.  In the case of the 85% of newly diagnosed patients with low risk disease, the speed of remission is not associated with a bad outcome.
 
* Importantly, he implied that the UAMS data shows a potential plateau while other doctors that have good survival durations do not show plateau.  In other words, a certain renowned anti-transplant doctor might say his patients survive for 7 years or what-not, but the mortality rate eventually turns up, whereas with UAMS the mortality rate (from Myeloma) may not.  This is consistent with BB's comment to me that "the curves for progression free survival and overall survival are essentially superimposable."  In other words: the people that are dying have no Myeloma when they die of something else.  When you have a median age of 71 at diagnosis, you are going to see deaths -- Father Time is, after all, undefeated.
 
This all leads me to an important crystalization of my own viewpoint on the curability of this disease, which has been refined through this conversation, discussions with several other patients with well-informed points of view on the subject, and discussions with BB and other experts.  By rephrasing my belief per the below, I'm hoping it makes room for those that don't support Total Therapy, or who don't think it's as broad a cure as is necessary to cause us to say "Myeloma is a curable disease."  The term Grand Unified Theory refers to a scientific concept in physics that attempts to reconcile three disparate theories under a unified banner that explains the physics of everything in the world.  That's a more messianic metaphor than appropriate for the following entry, but you get the idea.  Plus it was punchy as a headline for this post.  : )
 
I believe that Total Therapy represents a potentially curative option for a meaningful subset of newly diagnosed patients and can exceed a 50% cure rate for patients in the right population.  Patients who have (1) not undergone meaningful amounts of previous treatment for the disease, who are (2) young enough to benefit from the additional lifespan beyond the potential 5-10 years that less invasive therapy generally provides in a successful case, who are (3) healthy enough to receive multiple courses of chemotherapy including two high-dose courses of Melphalan, who are (4) psychologically prepared to embrace an aggressive treatment protiocol and who are (5) prepared for the logistics of an extended stay at a center of excellence for this treatment (whether Little Rock, Iowa, etc.) should consider that, if they are in the 85% of patients with "low risk" disease, they have a better than 50% chance of being cured.
 
Does this statement with all its qualifications mean that Total Therapy constitutes a cure for the disease?  Biologically, it probably constitutes a good shot at it for those that are otherwise healthy.  Psychologically, not all patients are prepared for it -- and I think that's in part because they have been led to be terrified by the concept of a transplant, which is a shame.  For the older diagnosed patient (Tom Brokaw comes to mind), the incremental few years of life in his late 80s may not be worth the added intensity of treatment versus the less invasive program he is receiving at Mayo.  For the high risk patient, unfortunately, few if any cases are cured through existing treatments.  But still -- for someone like me, diagnosed at 40, otherwise healthy, and prepared to fight like hell -- the chance of a cure is not some shot in the dark, 2% chance.  It's even money or better -- and once one achieves remission and maintains it for a period of time, it approaches certainty.  Whether that period of time is 6 years, as BB and team now maintain, or some longer timeframe as Rajkumar appears to suggest, it's out there.  Dr. Rajkumar agrees with that much, and notes that people were cured 20 years ago with Melphalan and Predisone -- just not very many.
 
BB and Total Therapy are curing a meaningful portion of patients that undergo Total Therapy.  Patient empowerment and a gradual broadening of the centers that offer Total Therapy as a choice should increase the reach of this alternative, and that's a good thing.
 
Patients that come across this blog likely already can figure out where to go to learn more about MIRT and UAMS.  But if you need a link, here it is.
 
Ultimately, this is another element of a movement in treatment towards care that is individualized, taking into account each person's biology and preferences.  Knowledge is power, and more options are better than fewer options.  I'm glad I had the option of choosing aggressive treatment in pursuit of a cure.  And I'm glad BB was iconoclastic and insisted on pursuing this approach instead of settling with mere control, where other options exist.
 
With that, I wish you all a great weekend!

8 comments:

  1. Excellent read Nick...thank you. This is the first time I've ever read, or heard, any explanation for why transient proteins are viewed as a good thing. As for cure vs controlled; or, aggressive tandem versus everything else, I look at it as risk vs reward. Those who undergo a protocol like TT, for whatever reason, take on more risk in hopes of greater returns. No different than any other investment opportunity. Since the tandem I received from Dr. Tricot is similar in many ways to TT, I like that 6 year number you're throwing around...especially since it's now in my rear view mirror. Again, excellent read...thank you.

    ReplyDelete
  2. Well said Nick, well said!!

    ReplyDelete
  3. Well done Nick. A Grand summation indeed.

    One thing to point out ... even though "cure" is not likely for high risk cases, TT is still the best option for patients who meet your criteria and are hoping for maximum periods of remission.

    ReplyDelete
  4. Glenn, you are correct -- the TT protocols for high risk patients are as good or better in terms of survival duration than other options. It is a lot of treatment, so the tradeoffs as they relate to patient preference is even more pronounced for high risk cases than for low risk.

    Barlogie told me that he wants to increasingly focus on high risk disease since if that can be cured, it will likely work on low risk disease. Here's hoping he or someone else gets there quickly!

    ReplyDelete
  5. Hi Nick, i was also in a modified total therapy protocol because of age. I was 73 years old when diagnosed. Now i am 76. I would like to ask you, in the total therapy 4 Lite the people that were older than 70, received in the transplant MEL35 X 4 instead of MEL50 X 4?

    Thanks Niki

    ReplyDelete
  6. Hi Nick,

    I really want to thank you for everything you write in your blog. You have kept me sane over the past 18 months, since my husband was diagnosed. I wish you all the best - keep writing for us - you have really helped,

    Ellen

    ReplyDelete
  7. Cà phê là loại thức uống được nhiều người ưa thích, tuy nhiên cà phê có những mặt có lợi và những mặt có không tốt cho sức khỏe. Vậy uống cà phê như thế nào cho tốt. Uống cà phê và ăn xôi mỗi buổi sáng là thói quen của nhiều người. Vậy liệu ăn xôi nhiều có tốt không. Khi mang thai vấn đề dinh dưỡng rất quan trọng, do vậy bà bầu có nên ăn xôi không.
    Ngày cá tháng tư sắp đến hãy cùng lựa chọn những tin nhắn trêu chọc ngày cá tháng tưtrò lừa hay cho ngày cá tháng tư để true chọc bạn bè nhé, sẽ rất thú vị đó.
    Cọc đi tìm trâu là điều mà hiện nay rất nhiều giới trẻ tìm đến cách tỏ tình với bạn trai. Vậy làm sao để tỏ tình hiệu quả, bạn cần nên có những câu chúc buổi sáng cho người yêu để có thể tiếp cận được bạn người bạn trai. tin nhắn hài hước chúc buổi sáng

    ReplyDelete