Relapsed/Refractory Multiple Myeloma: Factors in Selecting Later-Line Therapy
Experts on multiple myeloma discuss how to select treatment options in later lines of therapy.
Transcript:
Thomas G. Martin, MD: Dr Nooka, we started with our first BCMA-targeted therapy, which was belantamab mafodotin, a BCMA ADC [antibody-drug conjugate]. That was taken off the market due to a failed phase 3 trial in relapsed/refractory multiple myeloma. Some places may still have access through an EAP [expanded access program], but we don’t at UCSF[University of California, San Francisco]. Ajay, when you think of triple-class refractory and a BCMA therapeutic, how are you doing it with the ADC vs the bispecific vs CAR [chimeric antigen receptor] T-cell therapy?
Ajay Nooka, MD: This is a great question. Right now, in post-CD38-antibody space was the previous lenalidomide- and bortezomib-refractory patients. For this group of patients, we don’t have a cookie-cutter approach for what needs to be happening. More data are pouring into the BCMA-targeted therapies. There are 3 options: antibody-drug conjugates, CAR T, and bispecific antibodies. If you look at antibody-drug conjugates, it’s not for lack of efficacy that the drug has been taken off the market. I have patients we have filed an individual compassionate use for. These are single-patient INDs [investigational new drugs],and we were able to get the drug available for these patients who are continuing to respond. The beauty of the drug is we have to give the dosing once every 3 weeks. It’s associated with… toxicities, as we’re all aware, and one-third of the patients respond. Those responses last for a durable amount of time beyond the 1-year mark. The patients who’ve been responding are the ones we’ve filed these single-patient INDs for.
Why has this has been taken off the market? Anything that comes with an accelerated approval based on a response rate needs to have a confirmative trial showing the benefit of the drug….Here, belantamab was compared against pomalidomide and dexamethasone in the DREAMM-3 trial. The PFS [progression-free survival] was significantly better for the belantamab arm, but it didn’t meet the statistical endpoint that was predesigned. It’s an active drug, but given the nuances of how the study designs are and what the confirmative trial should show, the drug has been taken off the market. There are ongoing confirmative trials. If they show the benefit of this drug in the long run compared with the standard of care, we’ll absolutely have the drug back in our armamentarium.
Moving on to the 2 areas of bispecific antibodies vs CAR T, how would you choose and whom would you give those to? My mantra in myeloma is very simple: give the best-available treatment for the patient at any given time. We have good CAR Ts that are clearly showing benefit. But if you want to prep a patient for a CAR T, it takes time. It takes time to evaluate whether this patient is the right candidate for a CAR T. Does the patient have organ functions good enough to sustain a CRS [cytokine release syndrome]? This is big CRS, as Dr Martin was mentioning. This isn’t mini CRS. If that’s the case, I’m lining up the patient for a CAR T, which means I should be able to control the disease for the next 2 months while the CAR Ts are collected and manufactured, and the patient should still have a well-controlled disease for me to move forward with that approach.
If things don’t fit this criteria, if I have doubt about controlling this patient for the next 2 weeks or this disease for the next 2 months, or if the heart functions are on the borderline, and I feel like I’m putting the patient in harm’s way more than the benefit I’m able to provide, then my go-to therapy is a bispecific antibody. Here, teclistamab helps in providing an immediately available off-the-shelf subcutaneous injection that potentially has a mini CRS, and the patient will be able to sustain and get the benefit of what we see for these triple-refractory patients.
Thomas G. Martin, MD: I completely agree. At our centers we’ve all have had lists of patients who were next up for CAR T-cell therapy. Patients would sit on the list for a while due to lack of manufacturing slots and lack of availability, and they’d relapse or progress. Having this very therapeutic and effective off-the-shelf drug has taken the pressure off that CAR T-cell list. I tell my other faculty, “Let’s pick the best patients for CAR T cell therapy.” In fact, patients who have slow relapse can wait for the CAR T slot, for the manufacturing, for the product to come back to be infused. That can include other things: can they stay in the city, can they be there for 4 weeks, do they have a caregiver. It’s taken the pressure off our CAR T slots, which has been great. In our practice, we probably treat the bispecific antibody with a rougher group of patients. It’s a more aggressive, more refractory patient population that potentially wouldn’t have made it to CAR T cell but now they can get the bispecific. We have to gauge response rates based on that. Jeremy, there’s another therapeutic available, and that’s selinexor. Where does that fit into your treatment paradigm ?Would you take a patient like this to a second autologous transplant?
Jeremy Larsen, MD: Utilization of second transplants has definitely declined in the era of the rise of CAR T. There’s still a subgroup of patients who have long, durable responses. I tend to think of second autologous a little earlier upfront. In my mind, once patients are triple-class refractory, I’m a little less enthusiastic about second autologous. [Regarding] the question about selinexor, I use it. A subset of patients can do really well with it. On the other hand, we can also knock some patients who are treading water and destabilize them with weight loss and cytopenias. But I like the combination. The BOSTON regimen is something I utilize, not infrequently: selinexor, bortezomib, and dexamethasone. I’ll often swap it for carfilzomib. In my mind, I’d usually utilize that a little beyond BCMA relapse.
Ajay Nooka, MD: I agree….Usage of selinexor probably has fallen significantly compared with what we were using before in this space. In some patients, if I’m prepping them for a CAR T and looking for a bridging therapy, that’s where it helps. Not in all patients, but at least in some patients for whom we feel the drug will be beneficial. At the same time, the FDA approved dosing for selinexor and dexamethasone. As a doublet, it’s probably way beyond what 1 individual can tolerate. That’s where the third agent will be able to help us lower the dosing and, at the same time, gain disease control until the patient will be able to receive the CAR T and the manufacturing product is available.
You asked about salvage autologous stem cell transplants. We used to do a fair number. When we start to look at the second relapses, the second autologous stem cell transplants, who were we doing in the past? Patients who got a good benefit from the first transplant—in other words, the melphalan-sensitive patients—got fairly good benefit and we were using it for them at the time of a relapse. Then we started to have a new problem. Patients who have CAR Ts would have cytopenias down the line. Historically we’ve collected stem cells for a couple of transplants, and I’d rather use the product available for the stem cells for a patien twith cytopenias down the line rather than for a second autologous stem cell transplant, where the benefits are not as well defined in triple-refractory, penta-refractory patients.
Transcript edited for clarity.
