Treatment Selection for Relapsed Multiple Myeloma: CAR-T Versus Bispecifics

A roundtable discussion, moderated by Thomas Martin, MD, Blood Cancers Today Associate Editor, of the University of California, San Francisco, focused on bispecific therapeutics for the treatment of multiple myeloma. Dr. Martin was joined by Ajay Nooka, MD, MPH, FACP; Ajai Chari, MD; and Angela Dispenzieri, MD.

In the next segment of the roundtable series, the panel provided insights on how they determine whether to give a patient with myeloma CAR T-cell therapy or a bispecific agent.

Watch the next segment in this series.

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Dr. Martin: Ajai, you had mentioned that there are other options in the space. Now we’re looking at post-fourth-line therapy, right? When you think about chimeric antigen receptor (CAR) T-cell therapy and bispecifics, how do you choose between the two?

Dr. Dispenzieri: It’s a tough one. It’s this whole new world that we’re entering in terms of what is really going to be the best sequencing? Again, where in the lines, we have fourth line, but is it going to come sooner? Then the other struggle is it’s hard sometimes to get to fourth line because a lot of people are being treated with quadruplets up front and maybe transplant and they’re maintained on one therapy. Then sort of getting to fourth line is really interesting and challenging.

As far as sequence, to me, I am imagining, but I don’t have data to back me up, probably CAR-Ts are going to be earlier and maybe replacing transplant as they are in lymphoma to some extent. Then later on, perhaps the bispecific, because again, as mentioned, CAR-T, you need to prepare. Relapse is not predictable. It’ll be interesting. But again, will bispecifics be some type of maintenance? There’s so many questions to answer and will they be in combination something to enhance T-cell performance?

Dr. Martin: Yeah, that’s going to be fun actually learning about all that and actually finding what is going to be the best sequence or the best combination. In your practice, Ajai, for now, if you see a patient and you talk to them about CARE versus BiTE, what do they usually choose?

Dr. Chari: The fact currently we should mention that all of these products, both bispecifics and CAR-Ts are approved for four or more lines of therapy and triple-class exposed. If you stick to that label, which currently we have to, thanks to the payers, then I think to me the single best therapy in myeloma to date has been ciltacabtagene autoleucel (cilta-cel), right? With the response rate approaching 100% and the PFS [progression-free survival] of almost three years, it’s hard for anybody to beat that—not only those efficacy but the treatment-free interval, which translates into tremendous quality of life benefit for patients. I would say if that’s my goal, if I can get a relapsed/refractory patient who meets the indication to cilta-cel, meaning they don’t have explosive disease, there’s a reasonable chance of getting a slot, then I would try to prioritize that and not do anything to jeopardize that.

I think that’s important because we do have some preliminary data that CARTITUDE-2, when you give prior BCMA-directed therapy, that PFS plummets to less than six months for bispecifics. I would not do teclistamab or elranatamab in somebody who I’m taking to cilta-cel. Whether GPRC-directed therapy affects it in the same way, I don’t think we completely know yet. I think part of the issue is when do you collect the T-cells? Because I think if you’re going to do cilta-cel, I think collect first before you do any bispecific, including GPRC. Because one of the limitations of bispecifics I would say as a group is we don’t really know a lot about the long-term dosing and schedule. I think we’re glad that we have accelerated approval for all of these, but I know that in myeloma we’re so busy getting things to our patients, then we also have to kind of catch up a little bit and be like, wait, how are these working? What’s the right long-term strategy?

I think for now, if I have a patient who I can get the cilta-cel, I would probably collect T-cells first before exposing them to even talquetamab and then do the cilta-cel. If they’ve already had cilta-cel, then I think what we’re also learning, there was a really cool paper in Nature Medicine that just came out about losses of expression, right? That 16p is where BCMA sits, 12p is where GPRC sits. We are understanding that there’s more mutations and losses of both of these targets. Those are going to be very important along with T-cell function to sequence thoughtfully and not just like do the kitchen, let’s just throw everything together. Then the last point I would say is if you do have prior T-cell redirection, this may be where we either need a gap in therapies or combination strategies to overcome some of those issues.

Dr. Martin: Ajay, Angela brings up a good point that CAR T-cells, it requires a whole commitment by the patient, the caregiver coming to the center, etc. As Ajai said, these bispecifics are off the shelf. Give me a real-world picture of Emory. How many patients really go to CAR versus those that go to bispecifics at the current time? What do you think? What would you estimate that would be?

Dr. Nooka: Absolutely. I think this is a very important discussion in the clinic that happens. The first thing that I lay out with the patients is these are not mutually exclusive treatments. If you get one, that doesn’t mean that you should not get the other one, which makes it easier for the patient to make a decision. I’m not losing one option by choosing the other one. Now the next question comes in here is what is the optimal treatment strategy to move on? In myeloma we’ve seen time and again, the most effective treatment is the one that we first go for. I go with probably what Ajai said before, going on with the CAR-T with the most effective treatment strategy. But when the patient is progressing, that’s where it becomes the biggest question, what is the next optimal solution?

Going back to the question that you asked about the bispecifics versus CAR-T, if I lay it out to the patients and if there’s a patient that is rapidly progressing, I probably don’t give an option in terms of, you should choose a CAR-T first because of the availability of the off-the-shelf agent. Me and the patient can decide, and the patient can get it next week. Similar to what your experience is, we had treated probably 51 patients as we speak with the bispecifics over the last seven months. We never treated so many patients in such a short timeframe without knowing what the long-term efficacy would be. But these are great times, and I always encourage the patients to go with the most optimal effective treatment that they have at that specific time that the disease would be amiable to respond to.

Dr. Martin: Yeah, I completely agree. I would say that I have an individual discussion with every patient, lay it out—a month in San Francisco versus coming back once a week or once every other week in San Francisco for the drive. It’s really, in my mind, it’s a different decision for each patient. One patient will say I want the one month and I’d be done with it, and then I get the free period for sure. The other patients will say I’d rather just come in once a week, drive in, get my therapy or once every other week and then go home. It’s actually the patients decide too. Sometimes like you say, the disease makes the decision for us. Sometimes that happens.