Patients understand that improved treatment for myeloma can result in unprecedented depth of response, and myeloma treatment has changed dramatically in the last few years. Prior to 1997 when I was diagnosed, complete response (CR) was defined as a 75% reduction in M-protein. Stringent CR (sCR) did not exist because this deep level of control just didn’t happen. Now, however, therapies have taken us beyond sCR to amazingly low levels of detection. Eight-color Next Generation Flow (NGF) developed by Dr Paiva’s team in Spain can reliably find one myeloma cell hiding in one million normal cells!
How do we define and what is the best way to measure this small amount of remaining minimal residual disease (MRD)? The Black Swan Research Initiative® (BSRI) has designed two clinical trials to prove cure in high-risk myeloma: the CESAR trial in Spain and the ASCENT trial in USA. Just as last year, we support group leaders find many abstracts and posters at ASH16 featuring MRD in myeloma, and it is exciting to hear MRD mentioned at oral presentations.
In his November 3, 2016 blog, Dr. Durie explains that NCCN (National Comprehensive Cancer Network) has endorsed IMWG response criteria including MRD testing. Next Generation Flow (NGF) and Next Generation Sequencing (NGS) have equal sensitivity. Both methods are mentioned at ASH. Each method has its unique characteristic of tissue required, timing, cost, and sequential tracking ability.
At a special MRD meeting of the BMTCTN Myeloma Intergroup committee the evening before ASH, Dr. Bruno Paiva confirmed that NGF reveals 10-6 sensitivity in the vast majority of patients.
At an Oral Abstract session, Dr. Roger Owen explained (Abstract #245) how powerfully predictive MRD is for myeloma patients ineligible for transplant. Only 13.8% of patients in his analysis actually reached this low level plateau using flow cytometry, but they had significantly longer progression free survival (PFS) and even overall survival (OS) results than patients who achieved CR (once thought to be a very good endpoint). He concluded that MRD should serve as a primary endpoint and surrogate marker for survival in future clinical trials.
Abstract #246 presented by Dr. Herve Avet-Loiseau showed both the value of daratumumab in CASTOR and POLLUX trials, and also the significant predictive value of MRD(-). He said that patients who achieved MRD(-) status experienced fewer PFS events compared to MRD(+) patients.
MRD predicts outcome but is not currently a marker of “cure.” It does not evaluate progenitor cells which hide in bone marrow niches at MRD zero, so we need clinical trials to test MRD as a valid biomarker. Why do some patients remain persistently MRD (+) and how can we eliminate their disease? Actually, we must decide if it is worth the added toxicity cost to even try. Can patients safely stop taking expensive maintenance therapy when they have no measurable disease? Somehow we must bridge the gap from long term remission to cure.
MRD(-) status is now a primary and secondary endpoint for most new myeloma clinical trials. It will also become a basis for expedited FDA approval of new myeloma drugs. Does sustained MRD (-) mean that I am cured? Possibly. Does MRD (+) at a low rate such as 10-6 mean I need more treatment? Maybe, but then, maybe not. It could just represent harmless monoclonal gammopathy of undetermined significance (MGUS). The clinical trials associated with BSRI are designed to prove that we have cure in multiple myeloma if it is treated early and aggressively.
MRD is mentioned in some way at every myeloma presentation at ASH. To think of how far we’ve come, and to be able to even consider this deep response in myeloma, is truly exciting.