Emerging Therapies in Relapsed or Refractory Multiple Myeloma - Episode 3


Kenneth Shain, MD, PhD reviews phase 3 OCEAN study design and safety and efficacy data from patients with RRMM treated with melphalan flufenamide + dexamethasone doublet or pomalidomide + dexamethasone.

Kenneth Shain, MD, PhD: One thing we want to think about is targeting myeloma cells in a unique way, enriching for that target as a population of cells. We learn it’s approved and successful in late relapse patients. They created the OCEAN study, which is a randomized study looking at doublet vs doublet. It’s a nice randomization, the first 1 we’ve seen in a long time where it’s 2 drugs vs 2 drugs: melphalan flufenamide plus dexamethasone vs pomalidomide vs dexamethasone. This is in a relapsed patient population—2 to 4 prior lines of therapy in that window between the late-earlys and the early-late relapses. It’s a patient population mostly based on the study itself, based mostly in Europe and where doublet therapy remains the standard of care. What’s interesting about this study is that it’s head-to-head vs doublet: a well-established doublet in pomalidomide and dexamethasone vs melphalan flufenamide and dexamethasone. They showed that melphalan flufenamide had a superior progression-free survival [PFS]. The overall survivals weren’t all that dissimilar.

What was done in an intelligent way is that before randomization they were stratified by age, by prior lines of therapy, and other subgroup analyses that wanted to parse out where these things were going to be most beneficial and what subgroups were most beneficial. The data showed that in those patients who are over 75 years old, their stratification of age had a greater benefit for melphalan flufenamide over pomalidomide than vice versa. It was a very interesting observation. Maybe older patients are benefiting. They took in data looking at prior autologous stem cell transplant as well, so you could envision that older patients probably weren’t eligible or less likely to be eligible for transplant.

What they identified later on is the big differences and the big benefit from melphalan flufenamide and dexamethasone over pomalidomide, in terms of progression-free survival, was in patients who had not received prior autologous stem cell transplant. That means high-dose melphalan, a high dose of an alkylator, and stem cell transplantation. If you look at those patients, the benefit was marked and proven for those who did not receive prior stem cell transplant. We want to make sure we’re thinking about that as we develop new therapies and new therapeutics, whether alone or in combination: what subgroups are going to benefit these patients the most? That’s important for us to think about both in terms of progression-free survival and overall survival.

Those are the things I wanted to touch on with melphalan flufenamide. It’s a new drug to most of us, but it has a novel mechanism of action and can be specific for your myeloma cells. It’s a smarter therapy. Then we think about who can gain the most benefit from this. From phase 3 data looking at doublet therapy—melphalan flufenamide and dexamethasone vs pomalidomide-dexamethasone—there’s a subgroup of patients, which appears to be the right group: those who are older or did not have prior stem cell transplant.

Obviously, a number of questions remain open-ended. These are still hypothesis-generating statements, but is there a time frame between transplant and when it becomes more beneficial? Is it ever seeing an alkylator before? These are all things we need to continue to learn and grow with. But we’ve identified a therapy that was very successful, which led to its approval. From randomized data…there are subpopulations that may benefit 1 set of therapeutics better than another. These are exciting data for melphalan flufenamide and for our patients, but also thinking about how we want to target our own patients in different management strategies.

Whenever we talk about any new therapy to us and utilization—we have direct evidence of melphalan flufenamide and dexamethasone vs pomalidomide and dexamethasone with doublet therapy—there are good things like improvement in maximum response rates, PFS, some populations benefiting more than others. We have to think about the potential emergent, adverse events that occur with the utilization of this therapy.

If you compare the arms—the reasons for discontinuation, the progression—all these things tend to be very similar. There’s not 1 significant set of toxicities driving discontinuation in 1 vs the other or more harm than 1 vs the other. But there are definitely some differences in terms of the toxicities that we have to think about when looking at melphalan flufenamide. Although we think of it as being a smarter therapeutic in terms of targeting myeloma cells vs nonmyeloma cells, because of this immune-peptidase as a requirement for metabolism to the act of therapy, we still see that is going to be some toxicity associated with marrow toxicity. There were significant increases in thrombocytopenia with melphalan flufenamide vs the pomalidomide and dexamethasone. With neutropenia, we think about marrow suppression. With infection, we think about marrow toxicities like anemia. All the lines you’re thinking about are the ones we most want to contribute and we’re thinking about along the lines of toxicities.

What else is along those lines? There’s not a lot that’s terribly different, but these are things we have to make sure we’re thinking about. This is a new drug with a more mild suppression. You’re going to require some more dose delays. It’s given differently. It’s going to be something that’s given on a 4-week basis vs an oral-monthly basis. These are all things you want to address up front with yourself and then with our patients so they know what they’re looking for. They know what to help us find out so we can better care for them.

When we think about myelomas, especially in this context, there are certain expectations in terms of the therapies that we use and in terms of the toxicity they have. When we’re talking about the treatment of relapsed and refractory patients and marrow suppression, these things aren’t unexpected when we talk about doublet or triplet agents in these patients. When you think about the adverse events we see with melphalan flufenamide, it may be higher than pomalidomide and dexamethasone. They aren’t things that were unexpected. These are things we all can handle and manage. They aren’t that dissimilar from those things that we knew. There was no new adverse event that we aren’t used to dealing with, that we aren’t used to supporting our patients through and making decisions about. In the end, although head-to-head, it was maybe more toxic from a myelosuppression perspective. It wasn’t outside our normal expectations of what might happen to individuals in that late-early relapsed setting.

Transcript edited for clarity.