The Evolving Role of BCMA-Targeting Bispecifics in Multiple Myeloma
Expert panelists reflect on other clinical trials aimed at defining the role for BCMA-targeting bispecifics in multiple myeloma and consider how they would utilize this class of agents in real-world practice.
Transcript:
Amrita Krishnan, MD: Let’s turn to a discussion about some of the data we saw and some practical questions. Let me start with the first 1. Philippe showed some very impressive data about MajesTEC-2: teclistamab, daratumumab, and lenalidomide in the frontline setting [for multiple myeloma]. Josh, are you going to use teclistamab in the up-front setting?
Joshua Richter, MD: This is a great question. Obviously, teclistamab is extremely efficacious. It wouldn’t surprise me if, in 5 to 10 years, there’s a combination of something like teclistamab and iberdomide—the cell mod—in the up-front setting. The 1 thing that’s still out there is that there aren’t any data that I’ve seen about what it looks like collecting stem cells after a T-cell redirection agent. I may be old school because I still believe that stem cell transplant is a vital part of some patients’ induction therapy. My only hesitancy to move this very efficacious drug up front is that if I want to then collect stem cells, will I be able to?
Amrita Krishnan, MD: Josh raised some concerns about stem cell collection. Al, what about using it in the nontransplant-eligible population? Is this going to become your go-to regimen?
Alfred Garfall, MD: There’s real potential there. I’m glad those studies are ongoing. It could be a highly effective first-line therapy for patients. We’ll have to see. With the infection signal, the patients will be expected to be on teclistamab for a very long time if they’re using it as part of first-line therapy. We’ll see if those infections become a problem with cumulative immunosuppression over a long period of time. But it’s such a highly active agent in the first line of therapy, I wonder if there’s an opportunity for a more limited-duration therapy. It will take clinical trials to figure this out. That might be the best balance: redirecting T cells when they’re healthier in an early line of therapy but for a fixed duration that allows some immune reconstitution to mitigate the long-term infection risk.
Amrita Krishnan, MD: Philippe, you’ve presented teclistamab in every space of myeloma: front line, early relapse, later relapse. Where do you think it’s going to be positioned?
Philippe Moreau, MD: Because the data from MajesTEC-1 are so promising—so good, in fact—we’d like to use teclistamab in earlier lines. I’m very interested by the data that will be generated by the MajesTEC-4 study. This is a phase 3 study that will look at lenalidomide alone as maintenance after stem cell transplantation vs lenalidomide plus teclistamab. I’m old school like Joshua. I strongly believe we need stem cell transplantation up front for young patients. We need to improve on this strategy. We can probably do better than lenalidomide alone as maintenance. It will be very interesting to look at the combination of teclistamab plus lenalidomide.
We have other phase 3 trials ongoing for early relapse with the comparison of lenalidomide plus daratumumab or teclistamab plus daratumumab or teclistamab plus lenalidomide-daratumumab vs conventional combinations. But those studies are ongoing with the primary end point of PFS [progression-free survival]. We need to see the results. For sure we’ll use teclistamab at earlier lines for many patients in the future.
Amrita Krishnan, MD: Correct me if I’m wrong, but MajesTEC-4 the teclistamab is also going to be fixed duration, to Al’s point.
Philippe Moreau, MD: Yes, this is a very important point. We’re using teclistamab until progression in very advanced patients; maybe we shouldn’t. We should create and stop because the long-term toxicity could be an issue. It’s good to have a fixed duration of teclistamab. Maybe the weekly subcutaneous could be changed when we’re achieving a response to a subcutaneous every 2 weeks probably, and we have some PK-PD [pharmacokinetic-pharmacodynamic] data suggesting we can use the administration every 2 weeks for teclistamab, as we’re doing with elranatamab.
Alfred Garfall, MD: Another nice aspect of the MajesTEC-4 study is that—correct me if I’m wrong—there’s also a teclistamab monotherapy arm after transplant. At some point, there was a leap of faith, and we got away from using the cytotoxic chemotherapies earlier in place of the novel agents. We have to see where teclistamab combines with traditional myeloma therapies but also where it can replace some of our traditional therapies. Long-term lenalidomide maintenance after transplant can be a big quality-of-life barrier for patients. I like the idea of studying the replacement of long-term lenalidomide maintenance with novel therapies like teclistamab. We’ll see how that pans out in results of studies like MajesTEC-4.
Philippe Moreau, MD:You’re right, Alfred. That’s a 3-arm randomized study of lenalidomide, lenalidomide plus teclistamab, and teclistamab alone.
Sandy Wong, MD: The other thing we should also think about—I’m also old fashioned because I’m a big believer in stem cell transplant—is the CARTITUDE-6 study, which is underway. We’re looking to see if CAR [chimeric antigen receptor] T-cell therapy can replace stem cell transplant. What if that’s a positive study, and CAR T can replace some cell transplant? We’re talking about much later down the line. It will take a long time for that trial to read out. But what happens to these T-cell engagers? The question you raise is if you can get stem cells from patients who’ve been exposed to these agents. My other question is can you make CAR T cells in patients who’ve been exposed to these agents? What’s the help?
That gets to the crux of the question: what’s the T-cell health of the patient after being exposed to these agents? We’re studying this obviously in the newly transplanted space, in the maintenance phase, especially over long periods of time. What’s the T-cell health of a patient? Can those T cells be used to make CAR Ts? Even before the CARTITUDE-6 readout comes out, you wind up having teclistamab in maintenance, for example. If someone is progressing through teclistamab maintenance, what does that mean in terms of the ability to make T cells? After that, would a BCMA CAR T cell work in those patients? Are we then sacrificing potentially some efficacy? That gets to the question of sequencing. Now that we have so many BCMA-targeted agents, how do we sequence this strategically for our patients?
Amrita Krishnan, MD: You’ve brought up the next questions.… As you said, there are many BCMA-targeting agents. I saw at ASH [American Society of Hematology Annual Meeting] you were the alnuctamab queen. You presented the MagnetisMM-3 data. Magnetis has an 11.8-month PFS; teclistamab, 11.3 month. Elranatamab is probably going to get approved later this year. How would one choose?
Sandy Wong, MD: That’s a good question. All things being equal, looking at the CRS [cytokine release syndrome] between these 2 drugs, my hunch is that there’s probably going to be a REMS [Risk Evaluation and Mitigation Strategies] program for elranatamab. They’re very similar in terms of their toxicity. Practically speaking, teclistamab is the first 1. Individuals are slowly onboarding in terms of getting lenalidomide certified in the community. Whether individuals do REMS for elranatamab hinges on using teclistamab and then elranatamab. That’s 1 question. In terms of efficacy and safety, they seem very similar. If you have a REMS program already set up for teclistamab, you’re going to want to use teclistamab based on safety and efficacy. I’ll be curious to hear what my colleagues say.
Joshua Richter, MD: I completely agree with you. There are going to be 2 factors. There’s the additional time where they’re just monotherapies. If they’re just monotherapies with no huge distinguishing factors at the moment, it will be what’s on our formulary or what our local institution is using. The future is going to be combinations. Let’s say teclistamab is approved with daratumumab, and elranatamab is approved with pomalidomide. Figuring out which combo may be better for an individual patient will likely be driven by which combinations are approved.
Alfred Garfall, MD: At the last IMS [International Myeloma Society Annual Meeting], there was a finding that BCMA point mutations were at the binding sites for 1 of the anti-BCMA agents. I forget the details, but we may have to get more sophisticated with the testing we can do on patients, both to identify whether BCMA is persisting on relapsed disease after receiving anti-BCMA therapy and perhaps to understand whether there have been mutations in BCMA at the binding sites for different agents. We’d be borrowing from our lung cancer colleagues in terms of sequencing and identifying the specific resistance mutations. That’s very appealing if we could get that sophisticated with our treatment selection. We need help from our pathology colleagues to develop the test to integrate these questions in our clinical samples.
Amrita Krishnan, MD: Is anyone looking for BCMA expression before treating with these agents? To your point, Al, is the mutation issue more worrisome? Is it adequate to see BCMA expression by IHC [Immunohistochemistry]? It may not be.
Alfred Garfall, MD: We’re not doing that routinely. At our institution [University of Pennsylvania], which is a pretty high-volume institution, it’s a send-out test to get the immunohistochemistry. We need a lot more data to understand the clinical importance of these tests. We’re going to be beating up on BCMA a lot, between the different CAR T-cell products and bispecifics, even if we get the elranatamab back. Real-world evidence is going to be important in figuring out the rules of the road, and how to use and predict sensitivity in patients who are receiving many of these agents in sequence.
Amrita Krishnan, MD: Before we speak about our non-BCMA agents, [I have 2 practical questions about] the REMS program. Is everyone giving teclistamab in patient for the priming doses? How long are you keeping patients in the hospital?
Philippe Moreau, MD: It may be different in the United States, but in France it’s mandatory that the patient stays in the hospital during the first week—during the step-up doses—to be sure we aren’t harming patients with CRS. That’s outpatient immediately after the first full dose. That’s something that we have to do.
Amrita Krishnan, MD: Is everyone else also admitting patients for a week?
Joshua Richter, MD: We’re giving the first dose as an outpatient, so it doesn’t get sucked up in the NDRG, and admitting them directly. For what it’s worth, the step-up was originally planned for 72 hours…. You can give it at 48 hours if they don’t have higher-grade CRS. We have a number of patients getting it on days 1, 3, and 5. If they cruise through it, they get out a little earlier, but otherwise they’re being admitted for the rest of that step-up.
Alfred Garfall, MD: We’re admitting all our patients and trying to dose 48 hours apart in rapid succession. I’m hearing from some other sites about rubrics for outpatient administration. With the right infrastructure and ability to quickly get patients into the emergency department, it could be possible to do this as an outpatient for select patients. We’re investigating that. I imagine we’re going to hear more reports of paradigms for outpatient dosing. It would be nice if it could be demonstrated that it’s safe.
Sandy Wong, MD: What we’re doing is similar to what everybody else is doing. We’re admitting all our patients, but they get dosed on phase 1, 3, and 5 and then discharged on day 7. We’re very fast when it comes to using tocilizumab, even though it’s not on the US package insert for mitigation of CRS. We give tocilizumab and Tylenol with the first fever, and we’ve had good experience with lack of CRS in subsequent doses. Everybody is still playing around with the right way to manage these patients. We hope it will eventually open the eye toward an outpatient administration. I agree with Alfred that sometimes it might be institution specific. The right resources and workflow have to be in place, and geographical resources have to be in place. In San Francisco we’re connected by a lot of bridges, so it can be difficult if someone were to be given at this as an outpatient who lived in the East Bay, across the bridge…from UCSF [University of California San Francisco]. That’s a very different scenario. We’re interested to see how this plays out down the line as we experiment with these ways of giving this drug.
Amrita Krishnan, MD: The other interesting thing is that there’s a cohort ongoing with tocilizumab premedication. That may add to our cost even further, but at least we can avoid using tocilizumab very liberally.
Philippe Moreau, MD: That’s very interesting, Amrita. You’re right. At ASH, Suzanne Trudel presented tocilizumab preemptively with cevostamab, which is another bispecific antibody with pretty good results. That’s something we’ll do in the future.
Sandy Wong, MD: We’ve discussed that, but the issue is that tocilizumab cost prohibitive. It’s a rather expensive drug. I’ve learned a lot about the pricing aspects of these drugs, and you’re basically using it off-label because there’s no indication…. That’s where things become very cost prohibitive. You need that study to show that it provides that added benefit to get a label change. It’s hard to give a cost-prohibitive drug in the outpatient setting.
Transcript edited for clarity.
