Dr. Martin: Improving Survival Rates in High-Risk Multiple Myeloma

Docwire News spoke with Thomas G. Martin, MD, Professor of Medicine and Associate Director of the Myeloma Program at the University of California, San Francisco, about exciting new data on improving treatment outcomes for patients with high-risk multiple myeloma.

This is part two of a four-part conversation with Dr. Martin. Watch part one, where he defines high-risk multiple myeloma.

DocWire: What is some promising new research regarding the treatment of high-risk multiple myeloma?

Dr. Martin: We all have followed survival curves over the last five and 10 years. If we look at the overall survival curve, there’s always unfortunately somewhere between 10, 15, 20% of patients that unfortunately don’t survive the first three years. And so our treatments are hopefully for the broad group of patients with myeloma, but also are going to help those patients that don’t make it in the first three years. So those are really the tough ones in my mind. And so a lot of the clinical trials that we’ve done have basically focused on frontline therapy or newly diagnosed myeloma patients and the frontline therapies have been for the broad group of patients with myeloma, but we always pull out the high-risk patients and see if there’s been a benefit in the high-risk patients.

I would say some of the things recently that have caught my eye are … one actually is a trial that was done in Italy. It was called the forte trial. This is a trial that was actually a three arm randomization at the start and the goal was to test a couple of things: one [was] carfilzomib, lenalidomide, and dexamethasone (KRd), that triplet, as frontline therapy versus carfilzomib cyclophosphamide [and dexamethasone (KCd)]. So KRd versus KCd, it was very easy. The first presentation was a few years ago. It was very easy to show that actually a proteasome inhibitor (PI) plus an immunomodulatory drug (IMiD) index is much better than a PI plus an [alkylating agent] and IMiD, so KRd won. But the other randomization was actually to KRd for 12 cycles and no transplant versus KRd four cycles, single transplant, and then KRd four cycles of consolidation. And over time we’ve seen that the KRd four cycles plus transplant plus four cycles of KRd consolidation was better for the majority of patients. And that included patients that had high risk disease. And that transplant [eligibility] is still a very important component.

Now a this year’s past American Society of Hematology (ASH) [2020 Annual Meeting], they actually updated data. There was another randomization at maintenance and the maintenance strategy was … all the patients in all the arms got randomized to either just [lenalidomide (R)] as maintenance or lenalidomide plus carfilzomib (KR) as maintenance, and the maintenance was meant to go on until progression or intolerance. And in fact, what they showed was that during maintenance with KR versus R, more than 40% of patients had a deepening of the response with KR, and there was only maybe 30% with R. So the deeper the remission, the better, and the doublet did better … Saying that [is] kind of no surprise, but what was really surprising is that [adding carfilzomib was not only] important for the high risk patients, but it also was important for the non-high risk patients and the non-high risk patients benefited too, in a subset analysis, which is kind of cool. So for me, for the high-risk [patients], I think it’s a great regimen.

The other regimen that was updated at ASH was the Griffin trial, which was a randomized study of lenalidomide, bortezomib, and dexamethasone (RVd) versus daratumumab a CD38 antibody plus RVd (D-RVd) so a quadruplet versus a triplet. I think everybody knows about this study, but that said, they updated it one year into the maintenance based therapy. So it was RVd four cycles, transplant, RVd consolidation, and then D-RVd maintenance versus RVd four cycles, transplant, RVd consolidation, and then just RV, for maintenance based therapy. There was no second randomization. Essentially they showed the progression free survival (PFS) at 24 months was 95% in the D-RVd arm— actually was quite good in the RVD arm too so we need longer follow-up—but in subset analysis at the 12 months post maintenance, there was a benefit again for all patients getting D-RVd, including the patients that had high-risk cytogenetics.

So I think that’s also a really good regimen for patients that have high-risk cytogenetics. Unfortunately, in the U.S.—in my mind, specifically in San Francisco, cause I’m in San Francisco—it is very difficult for me to get insurance approval of D-RVd, where I can definitely do carfilzomib (K)-RVd for patients who have high-risk disease.

Now these are data that have been presented in kind of non-presentations or what we don’t have data for yet, but the exciting trials in my mind, I think, are to use chimeric antigen receptor (CAR) T cells as consolidation therapy for these people. So there’s a number of trials going on right now—in fact, if you do clinical trials.gov search, you’ll get 10 or 20 trials ongoing in the U.S. and also China and other places outside of the U.S. But specifically Bristol Myers Squibb has a trial that is looking for patients that have these high risk cytogenetics and elevated beta-two microglobulin, so that’s revised ISS stage three disease at diagnosis, and they’re getting induction therapy followed by CAR T cell therapy. And I actually think that’ll be really interesting. The Penn Medicine Multiple Myeloma program is doing a study also—I think they’ve actually completed accrual on their study—so we’re all hoping to see data soon. And their study was also induction therapy followed by BCMA-targeted CAR T cell therapy. But their study actually was also in some patients to do dual CAR Ts, so it’s a BCMA-targeted CAR T, plus a CD19+ CAR T, with the thought that in these high risk patients, they may have more myeloma stem cells and the stemness might be defined as having CD19 on the cell surface. And so you do a CAR for BCMA, which is on the myeloma cell, but also to the CD19, which might be the myeloma stem cell. So we’re all looking really to those data. It will be really exciting. I do think that CAR T cell [therapy] is going to work, but we’ll just have to see when they’re presented. Hopefully we’ll see them in the next year or two.