Investigational Agents in Relapsed/Refractory Myeloma

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Keith Stewart, MD, ChB, MBA: I want to close by moving beyond things that are available to the community today to things that are only on clinical trials—which are BCMA and other antigen targets on the cell surface. I’ll open this up to any of you who are feeling energetic at this stage. Tell us a bit of advice for the bispecifics.

Sagar Lonial, MD, FACP: I’m going to jump in and start by saying that following what we’ve been seeing with BCMA, there’s another means to target BCMA is with these bispecific antibodies, where they hook on to BCMA and to a local T cell. Without the need to collect T cells and go through the manufacturing process, the off-the-shelf concept of being able to engage the T cells. Looking at them in general, we’re going through this evolution, so they’re becoming safer and more effective. But we’re seeing a 60% to 70% response rate. That’s essentially double what we’ve seen with single agents in patients who were heavily pretreated. It’s exciting to see that, but also to see that we don’t target only BCMA. A couple of other targets are GPRC5D and FcRH5. Every time I see a license plate, I’ve got a new target for bispecific therapy. These different ones are upcoming, and we’re seeing a little consistency with less CRS [cytokine release syndrome] than we see with CAR [chimeric antigen receptor] T-cell therapy, albeit some, demanding in-patient delivery for probably at least the first 1 or 2 doses. But response rate is 60%, 70%, and it’s too early to know how sustainable they are. There are some unusual toxicities, but I’m going to let my colleagues jump in. It’s going to be an emerging class for which we’re going to see many therapies and great options for patients, especially those who aren’t going to be able to get to CAR T therapy.

Keith Stewart, MD, ChB, MBA: Cristina, what’s your feeling about these BiTEs [bispecific T-cell engagers] and bispecifics? Where are we going to end up by using these? Are these late-stage drugs? Are there going to be combinations earlier on? What do you think?

Cristina Gasparetto, MD: That’s a good question. They definitely look like they’re effective. The preliminary results are very encouraging. We don’t have long follow-ups because the toxicity profile is similar to the CAR T cell but not as profound. They’re convenient because they’re all switching to subcutaneous injection once a week or every 3 weeks. There are different schedules, but they still need to be given…. For example, the other BCMA, the conjugated antibodies, can be used in the community, but the CAR T cell and the BiTEs may need the academia.. We’re starting to see that some patients are not on teclistamab but on the other BiTEs I’ve run. That was part of the study from Pfizer, where some of the patients exposed to prior BCMA product were OK to go on trial. It will be very interesting, over the next year or so, to see how we can sequence these drugs. If we use only CAR T cells, for instance, in the high-risk patients, can we use some of these products or some of these agents later on and get some good responses? The responses are impressive as well.

Keith Stewart, MD, ChB, MBA: Sagar, they’re very impressive. They all have 60% to 70% response rate, and it’s hard to tell the difference among them. Many have been reported—at least 4 or 5 already. There’s a race the finish line. But if I was in the community, this is attractive. I could probably treat in my local hospital for a couple of days to watch for CRS and then manage these patients at home. Why on earth would I send them all the way to Atlanta, Georgia to get CAR-T therapy if I have these available?

Sagar Lonial, MD, FACP: That’s a fair question. The question I’ve asked in a couple of forums—I get dirty looks when I say it—is, if a bispecific can rescue a CAR T failure, then why give a CAR T? What we’re learning about bispecifics, at least in ALL [acute lymphoblastic leukemia], is that when you have low levels of MRD positivity in ALL, a bispecific can come in, clean that up, and perhaps give you a durable response. Maybe that’s how we need to think about these. If you give CAR and you have a short-term persistence, rather than giving more CAR 3 months, 6 months later, perhaps we come in with a bispecific, at 3 months, at 6 months, at 9 months, to try to prolong the duration and ultimately get to the curative end point with longer MRD negativity.

Keith Stewart, MD, ChB, MBA: Nina, I’m going to give you the last word. You know, 60% to 70% vs 98% PFS [progression-free survival] is a little less clear for the bispecifics, but I doubt it’s going to be a duration of response of 22 months. Would you still send your patients for CAR T therapy, or would you use a BiTE?

Nina Shah, MD: It’s patient dependent. The BiTEs are well tolerated in our older population, with a bit of renal insufficiency. Remember, you must have sufficient renal function fludarabine [Fludara], which is necessary for your lymphocyte-depleting chemotherapy. Not all myeloma patients are the same. As I always say, there’s enough myeloma to go around. If all things were equal among healthy patients, I probably would give the CAR T first because of the 1-and-done mentality. If they could get 22 months, which is the duration of response reported by Saad at ASCO [American Society of Clinical Oncology annual meeting] this past year, that would be great. If it’s not possible, then bispecifics are a reasonable option. Ultimately, all this is going to move to the second line, and maybe bispecifics consolidating CAR T. Who knows? We’ll see.

Keith Stewart, MD, ChB, MBA: Thank you, everybody. I hope we’ve conveyed to the audience that BCMA therapies are here to stay. They’re very exciting. They’re going to create a paradigm shift in how we treat myeloma. I wouldn’t be surprised if BiTEs targeting BCMA, for example, become part of our frontline regimens in the not-so-distant future. For now, these are still in clinical trials, but many academic centers will have these available. There are multiple BiTEs and bispecifics, not just against BCMA as referred; some other new targets have emerged. I’d like to thank the panel for their time and for the lively discussion. We’ll see you next time.

Transcript Edited for Clarity