Evaluating MRD-Guided Therapy in Patients with NDMM


Dr Cindy Varga explains the design and results of the MASTER study presented at ASH [American Society of Hematology Annual Meeting] 2021.

Peter Voorhees, MD: Cindy, Luciano Costa and colleagues recently published their data from the MASTER trial, which was interesting on a couple of different fronts. Do you want to tell us about that trial?

Cindy Varga, MD: The trial had a very interesting design. This was a phase 2 trial, single arm study, multi-center trial. Where patients with newly diagnosed multiple myeloma were enrolled. There were 3 groupings. Patients with standard risk disease, patients who did not have any high-risk cytogenetics. Then there was the high-risk group that had one high risk cytogenetic mutation. And then the ultra-high risk, patients who had a double hit, so 2 or more cytogenetic mutations. And the primary endpoint for this study was MRD negativity at 10 to the negative 5. And other endpoints were MRD negativity 10 to the negative 6 and the loss of MRD negativity, conversion from MRD negative state to a positive state. And these patients were enrolled and received dara-KRd, so a quadruplet therapy. This time instead of bortezomib, with carfilzomib. They had 4 cycles. They went on to get transplanted. And then after transplant, basically their treatment was dictated based on MRD status. They had MRD testing after transplant. If they were positive, then they went on to get 4 cycles of consolidation therapy with dara-KRd. If they were still MRD positive, they went on to get another 4 cycles, for a maximum of 8 consolidation cycles after transplant. And if they were still positive after 8, then they went on to get len maintenance. But if at any point they were MRD negative consecutively, then they achieved this MRD-sure state or phase and they could get off therapy and just be monitored off therapy. And the results were interesting. Patients did very well from a MRD negative standpoint. I believe 80% of patients achieved a MRD negative state at 10 to the negative five, and that included the ultra-high-risk grouping. I believe 65% of the patients achieved 10 to the negative six. And then the MRD-sure phase, achieving two MRD negative states, was achieved 70% of the patients, including the ultra-high risk. We could see that this was a very good and effective treatment regimen for even the ultra-high risk. They achieved good responses. And where things started to get interesting was at a 2 year mark, looking at PFS. The standard risk and the high risk did quite well, over 90% were still in a disease-free state. But the ultra-high risk was at, I believe, 60%, we see a loss of response already. And then if they looked at 12 months after stopping therapy, when patients were in that MRD-sure phase, the standard risk and high-risk patients, they didn't relapse, they didn't have progression of disease. But about 30% of the ultra-high risk group did. In conclusion, in this study, the dara-KRd is a very good and effective treatment regimen, but for the ultra-high risk, it raises the question whether we should be stopping therapy in these patients, even if they're achieving MRD negative state, because they are seroconverting to MRD positivity.

Peter Voorhees, MD: I completely agree with that. One of the other things that I thought was quite impressive with this particular trial was the depth of MRD responses. In the GRIFFIN trial, R rates of MRD negativity at 10 to the minus six, intent to treat analysis was on the order of just over 30%. And in this trial it was approximately 60 - 65% or somewhere along those lines. MRD results that have never been reported to that extent, which I thought was really quite impressive. Sascha, based on the data that have been published at this point and presented, if you had a revised diastasis stage one patient, hyperdiploid, no high-risk cytogenetic markers, is MRD negative at the end of induction and after recovery from stem cell transplant, would you use this data to stop therapy?

Sascha Tuchman, MD: If you had 10 myeloma experts in a room, you'd get 10 different answers on this question. It's a great one. A few years from now we will be much wiser in terms of our answers to this question. Personally, I do not MRD guided decisions at this point. It's extremely promising. We know that MRD is an incredibly powerful prognostic tool. It tells us patients are likely to do better or worse with time, but we really have zero data at this point, even from MASTER, I would argue, to tell us whether we should be using MRD data for decision-making. Meaning we need a study that looks at patients who are MRD positive, let's say, and says that intensifying therapy is better for those patients for long-term outcomes rather than continuing them on what they're doing. Or for this situation, we need a separate study that looks at patients who have achieved MRD negativity after, let's say as you propose, induction followed by transplant, and they are not hurt by stopping therapy. Because we have decades of therapy telling us that maintenance therapy is effective and prolongs overall survival. These studies, again, extremely promising but very early and no mature overall survival data. Most of them, like MASTER, are not comparative. And it's too early to be doing decision-making based on MRD status. But I do think that that's why it's incredibly important to enroll to studies like S1803, which is the, as you know, post-transplant maintenance study being run by SWOG, where patients are randomized to either - they're post-transplant/MRD positive - and they're randomized to lenalidomide or lenalidomide daratumumab, with overall survival as the primary endpoint.

Peter Voorhees, MD: No, I couldn't agree more. The data are very provocative. They're hypothesis-generating. But it clearly tells us that for patients who have none or one high-risk cytogenetic marker, that de-escalation of therapy is potentially feasible. We need longer follow-up. And, to your point, we need a randomized trial to prove that that's an appropriate way to go. Particularly with the determination results really speaking to the use of lenalidomide maintenance until disease progression.

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