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Getting Closer to CURE . . . Minimal Residual Disease (MRD)

| Jim Omel

Myeloma treatment has changed dramatically since my diagnosis 18 years ago. Prior to 2000, complete response (CR) used to be defined as a 75% reduction in M-protein, and stringent complete response (sCR) was a non-issue because it just didn’t happen. Now, however, therapies often take us beyond sCR to amazingly low levels of only one myeloma cell hiding in one million normal cells!  How do we define and how do we measure this tiny point of remaining minimal residual disease (MRD)?

The Black Swan Research Initiative® is tantalizingly close to reliably defining cure with Next Generation Flow (NGF)—a key laboratory test. Along with diagnostic imaging, the BSRI® team can identify 30% to 50% of high-risk smoldering multiple myeloma patients who might eventually prove be cured.  Dr. Durie identified over 20 ASH abstracts addressing MRD. At ASH, we support group leaders heard these oral presentations and talked to abstract authors at poster sessions.

At the IMF Global Advances symposium, Dr. Antonio Palumbo explained that MRD predicts outcome, but it is not a marker of cure. MRD does not evaluate progenitor cells, and are there progenitor cells hiding in niches even at MRD-zero? We need a valid biomarker of cure, and the clinical trials associated with Black Swan Research Initiative® will hopefully lead to these answers.

Oral abstract #367 explains how EuroFlow-IMF NGF-MRD provides a sensitive, accurate approach for assessing MRD in marrow samples from myeloma patients. The abstract indicates that preliminary results show higher sensitivity than next generation sequencing (NGS) and that next generation flow (NGF) overcomes the current limitations of first and second generation flow-MRD techniques. It is important to realize that a negative result (MRD-Zero) does not automatically mean a patient is cured. We will always be limited by the ability and validity of the test itself. Having said that, a detection level of just one cancerous cell in a million normal cells is extremely close to cure. When that remarkably low level is combined with sustained sCR plus negative imaging results, cure has to be close! The BSRI® will help us determine just how close.

Oral abstract #19 was presented by Dr. Bruno Paiva of Pamplona, Spain. He gave an interesting technical explanation of how identifiable cell surface phenotype markers (CD38, CD138, CD27, CD45, and so forth) provide reliable prognostic information about myeloma plasma cells. A phenotypic profile determined by combined CD45-CD56-CD117 expression, which was present in 39% of patients in his study, showed particular enrichment in high-risk cytogenetic abnormalities such as t(4;14) and del(17p). He concluded by saying that because surface marker expression is stable over time, MRD monitoring by multiparameter flow cytometry (MFC) can offer prognostic information based on the phenotypic profile of the drug-resistant myeloma clone. In other words, a simple flow cytometry lab test can give patients significant predictive value of their remaining clonal cells.

I found oral abstract #23, another presentation by Bruno Paiva, to be one of the most fascinating of ASH! Dr. Paiva explains the “Prognostic Relevance of Circulating Tumor Cells (CTCs) in Multiple Myeloma”. As a patient, this abstract has special importance because all of the cellular characterization being described is done on cells from peripheral blood(PB . . . not bone marrow! He said, “CTCs can be readily detected in the majority of MM patients”. He also explained the main point of his study is that these cells have a significant inter-predictability with similar myeloma cells derived from bone marrow. Wouldn’t it be wonderful if we patients could give our blood, instead of our marrow, and get the same useful needed information which is now only obtained from marrow cells! I will copy his exact ending conclusion with the reminder that “noninvasive” means bone marrow not needed.

Conclusion: This study defines a new role for Circulating Tumor Cells (CTCs) in the prognostic and molecular profiling of MM patients, and provides the rational for an integrated flow-molecular algorithm to detect CTCs in peripheral blood (PB) and identify candidate patients for noninvasive genomic characterization to predict outcomes. I talked to Dr. Paiva following his presentation, and he confirmed that examining PB will eventually have that diagnostic capability but we are not there yet.

Oral abstract #368 explained the importance of circulating tumor DNA . . . not tumor cells, but tumor DNA. It is a very technical paper/presentation, but the main take-away is that this cancerous genetic material is present in the blood, and can be readily measured.

Oral abstract #721 explained MRD from another point: prognostic significance of immune profiling in myeloma patients who do not reach MRD. Dr. Paiva explained that measurable characteristics can “identify patients that albeit being MRD-positive can still experience prolonged survival due to a unique immune signature”. He also reiterated that ongoing trials are needed to determine the approximate duration of maintenance therapy. MRD positivity may mean reversion to a monoclonal gammopathy of undetermined significance (MGUS) state, leading to long life with or without cure definition.

To summarize, MRD is a very valuable predictor for long-term outcomes. It is an important goal to be reached, and though not perfect, it should be a Primary Endpoint in newly designed myeloma clinical trials. How do we change treatment strategies based upon MRD test results? How long should maintenance therapy be continued if sustained MRD-Zero is achieved, and what is the chronologic definition of ‘sustained’ ? Those of us on National Cancer Institute’s Myeloma Steering Committee are wrestling with these very questions as we try to incorporate MRD into important new myeloma clinical trials.

by Jim Omel

Follow Jim on Twitter: @IMFjimMYELOMA
http://www.grandisland.support.myeloma.org
The Central Nebraska Myeloma Support Group
Grand Island, NE

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