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October 2013 Archives : Myeloma Voices

BrianGMDurieblog.pngThere are two important news items to report this week.  First, an article in Blood reports that current MRD testing for myeloma in the US is producing quite erratic results.

This disturbing assessment is made based upon a survey of 26 major institutions across the US. Key findings include variations in the number of cells checked after treatment, to see if myeloma cells are present, as well as wide variations in the methods used in the assessment of cells present.


So, if a patient goes to one center the test might show MRD negative, while to another--MRD positive! We know that the importance of this test is huge, and we need to clarify what it really means. New standardized criteria for MRD testing are definitely required.

The second news item is thus especially important as it is the breaking news from the first Black Swan Research Initiative Investigators Meeting that was held on October 25, 2013. I'm pleased to report that we are well on the way to consensus on how to assess MRD-Zero. Professors Alberto Orfao and Bruno Paiva from the University of Salamanca presented results of the new fully automated, sensitive, and standardized technique for MRD testing in myeloma as part of BSRI.
  The technique is flow cytometry, a method that truly provides a new way forward.

What this means is that a reliable test is now available to determine MRD-Zero, using the new flow methodology. This test will be the new response reference standard within many upcoming trials.

What does this mean for patients?

First, it means that a key first step in the Black Swan Research Initiative has been accomplished--and ahead of schedule.  However, it does not mean that all patients should rush to get MRD testing yet! A battery of tests is under evaluation to determine the indicators of MRD status. They are:
 

  • DNA testing is being assessed as another specific and very sensitive myeloma disease marker, and cross correlations between the flow and DNA tests are ongoing.

  • In addition, imaging (PET/CT or whole body low-dose CT) is important to determine if low levels of disease are being missed, especially in soft tissue or any sites outside the bone marrow.

  • The new Hevylite test is being studied as a more precise replacement for standard immunofixation (IFE) to determine if low levels of myeloma protein (M-protein) persist.

  • Large database analyses are also underway to establish the meaning of achieving an MRD-Zero disease status.  Correlations with patients who have been in complete remission for over 4 years (as long as > 25 years) have been carried out.

It will take time to standardize and validate MRD testing in myeloma in order to monitor response to treatment and push to achieve cure. The next step is integrating the agreed upon MRD testing protocol into upcoming trials.

This overview is just a glimpse of what is to come. There will be a full report from the Black Swan team very soon about the details of the new MRD flow test, followed by details about planned further studies and trials. Stay tuned!

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Questions are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate. To contact the IMF Hotline, call  800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Friday summer hours are 9 am to 3 pm PDT. Thank you.

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The University of Texas MD Anderson Cancer Center has announced that it will partner with IBM's Watson supercomputer to fight cancer - specifically leukemia. But myeloma patients may well ask:  "What can Big Data do for me?" The answer is: "A lot." 
 
The IMF has been conducting studies with Big Data analyses for a number of years now.  But let's credit the MD Anderson-Watson alliance with spotlighting the very important role Big Data can and should play in seeking cures for cancer, including myeloma.

The idea is that Watson, the same computer that was a winner on "Jeopardy," can review data related to the 100,000 or so patients cared for each year at MD Anderson and spot trends. When you're dealing with sample sizes that big, insights and patterns - relationships between treatments and recovery - that might otherwise be missed can make sense, as long as you've got immense cognitive computing power comparing each patient to the next. 

The IMF approach--through the efforts of its research arm, the International Myeloma Working Group (IMWG)--has been utilizing Big Data somewhat differently. A 2008 study and a follow-up 2010 study on the impact of age on myeloma recovery used data from 10,549 patients, all having myeloma. That's about 10% of the sample Watson will have access to annually - but the IMWG sample comprised myeloma patients, all of whom were carefully evaluated, treated, and monitored within clinical trials. They were, in other words, not randomly selected, as are referrals to a particular medical center such as MD Anderson.

That difference makes the aging study far more robust than sheer sample size might suggest, and the conclusions can have a profound impact on treatment.

Similarly, in 2005, the same patient sample was used for the development of the International Staging System for myeloma, which has added greatly to our understanding of how to categorize patients and apply different treatments based on those categories. 

With a random sample such as that used in the  Watson program, there are many variables and unknowns that make it really difficult to fully interpret outcomes no matter how much you "crunch the data" with a super computer.  Connecting genetic information to random outcomes can highlight trends, but that doesn't necessarily give enough targeted information to immediately advance research and provide a path to a cure.

The IMF, as part of Bank on a Cure, identified genetic features linked to bone disease and the likelihood of myeloma. (2009)  However, even four years later it has proven challenging to apply this information directly to strategies for prevention of myeloma and/or to the development of new therapies. More recently (in 2012), we were able to use Big Data to generate genetic FISH information to enhance the ISS staging system

So, use of Big Data is not new to the IMF. We believe in Big Data and we want Watson to succeed. But Watson needs precise input to have clear output. Teaching Watson the nuances of all different cancers is no easy task. After all, Watson's a whiz at math, but he didn't go to medical school. Getting the most out of Big Data requires us to be smart about the data provided and to think ahead about the answers we need and want. So let's see how this works out, and hope Watson succeeds in medical school and an oncology fellowship. 

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Questions are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate. To contact the IMF Hotline, call  800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Friday summer hours are 9 am to 3 pm PDT. Thank  you.

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A recent article in the New York Times draws attention to how cancers survive and evade the immune system and highlights a new book, "The Compatibility Gene: How Our Bodies Fight Disease."  The key point for myeloma research is that inactivation of T-lymphocyte cells and natural killer cells--which should be killing myeloma cells--occurs through a mechanism called the PD-1/PD-L1 system.

The way it works is that the myeloma cells and many other types of tumor cells have many PD-L1 receptors on their surfaces. These receptors work as a protective shield because the PD-L1 triggers the surrounding immune cells to stop working - allowing, for example, myeloma cells to grow. Research in other cancers is much further along, and novel anti-PD antibodies have been developed which block this process and allow the immune cells to attack those cancers.  There has been great success with this in patients with melanoma, some of whom have had dramatic remissions.

What about myeloma? The research is not as far along, but one anti-PD1 antibody (CT-011) has been used in early testing and shows benefit.

This is exciting because it provides an entirely new approach to attack myeloma.  Dr. David Avigan and the research team at Beth Israel Deaconess Medical Center in Boston are exploring the use of the CT-011 anti-PD antibody therapy as part of a vaccine approach to myeloma therapy. Early results are promising.

So, a better understanding of what can be wrong with the immune system in myeloma patients is leading to ideas about how best to fix the problem! Stay tuned. I am sure further progress will be reported and next steps developed to improve responses and outcomes for myeloma.  

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Questions are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate. To contact the IMF Hotline, call  800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Friday summer hours are 9 am to 3 pm PDT. Thank  you.
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Two recent publications highlight the need to adapt guidelines to accommodate treatment that is truly available in different countries and regions of the world. Myeloma treatment guidelines for Asia appear in The Lancet, and those for Latin America appear in the Brazilian Journal of Hematology.

In setting guidelines, one needs to consider the four As: Availability, Approval Status, Affordability and Access--to everything from routine diagnostics, standard therapies, novel agents and clinical trials. These factors influence responses to therapy, toxicities/tolerance and cost efficiency.

Rather remarkably, the outcomes in Asia and Latin America are quite good, and have survival rates comparable to those in the US and Europe, despite much later diagnosis and considerably reduced access to the newer IMiDs and proteasome inhibitors. Revlimid is still not approved in Korea and Brazil, for example, and there is extremely limited access to Pomalidomide and Carfilzomib, both approved by the FDA in the US.

At the patient level it is difficult to cope with the knowledge that better options are available elsewhere in the world. But patients should also be reassured by the fact that options widely used outside the US, such as the CyBorD regimen (Cytoxan/Velcade/DEX), are perhaps not so inferior to a more common regimen in the US such as VRD (Velcade/Revlimid/DEX). The myeloma community is forced to look more closely at the "standards of care" and, in many instances, conclude that older more widely available approaches are actually no so bad in terms of overall outcomes. Formal, randomized studies are needed to compare available regimens with novel combinations not widely available.

But clearly, the big deficiency is at the level of access to newer agents in clinical trials. This type of access can definitely extend lives. With this in mind, the International Myeloma Foundation, through the International Myeloma Working Group, is committed to accelerating and enhancing access to newer agents. We support applications for new drug approvals whenever possible and we are now starting a new Novel Agent Access Program through the Asian Myeloma Network (AMN), which will allow access to drugs such as Pomalidomide in the years prior to approval in, for example, several countries in Asia. Companion programs for education of both physicians and patients are key in an effort to achieve best outcomes.

As a baseline it is very important and helpful to have these two publications summarizing basic, limited, enhanced and maximum options that are currently available. Within this framework the stage is set to attempt to provide equitable care to myeloma patients globally.

This is a difficult task, but will certainly not be achieved without aggressively setting forth! The myeloma community is strong and can work collectively to achieve the best for patients everywhere.

This is a difficult task, but will certainly not be achieved without aggressively setting forth! The myeloma community is strong and can work collectively to achieve the best for patients everywhere.

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Questions are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate. To contact the IMF Hotline, call  800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Friday summer hours are 9 am to 3 pm PDT. Thank  you.