New Data on BCMA-Directed Bispecifics in Multiple Myeloma

— Sarah Holstein leads a roundtable discussion on updates in the class


Promising data on new B-cell maturation antigen (BCMA)-directed bispecific antibodies were presented at the American Society of Clinical Oncology (ASCO) annual meeting.

These included results on two investigational products: the phase II LINKER-MM1 study, which showed that linvoseltamab elicited an objective response rate of 71% at the recommended dose of 200 mg for patients with relapsed/refractory multiple myeloma; and a pooled analysis of the MagnetisMM trials, which revealed that patients with relapsed/refractory multiple myeloma who had already undergone BCMA-directed therapy achieved responses from treatment with elranatamab monotherapy.

MedPage Today brought together three expert leaders in the field: Moderator Sarah A. Holstein, MD, PhD, from the University of Nebraska Medical Center in Omaha, is joined by Brea C. Lipe, MD, from the University of Rochester Medical Center in New York, and Monique Hartley-Brown, MD, from the Dana-Farber Cancer Institute in Boston, for a virtual roundtable discussion. This third of four exclusive episodes on multiple myeloma focuses on treatment with BCMA bispecific antibodies.

Following is a transcript of their remarks:

Holstein: So, as you all know, teclistamab [Tecvayli] of course is our only FDA approved BCMA-directed bispecific antibody. But there are many other BCMA bispecific antibodies under investigation at this time. And I thought there were a couple of interesting abstracts presented at ASCO recently that touched on new updates from these bispecific antibodies.

So first I wanted to discuss the LINKER-MM1 study, which involves a novel BCMA bispecific antibody called linvoseltamab. Dr. Lipe, could you provide a summary of that study please?

Lipe: Yeah, so this was a phase II trial that looked at a couple different dose cohorts -- 50 mg and 200 mg -- and these patients were receiving linvoseltamab. So this enrolled patients who had progressed on or after three lines of prior therapy. And the median in this trial, I believe, was five lines of prior therapy. And so largely these patients were triple-class refractory. And one of the things that happened in this trial was an amendment that allowed patients who had progressed during their 50-mg dose to [cross over to] the 200-mg dose, so they were allowed to cross over to the higher dose. So they also presented some data on the response rates for those patients who crossed over from the 50-mg to the 200-mg dose. So in this phase II trial, 179 patients had been treated, 75 patients at the 200-mg dose.

Some patients had some extramedullary plasmacytomas (about 12%), 12% had high-risk cytogenetics, which is different than what we've seen in some of these other trials. And so essentially what they showed was that the overall response rate was highest in the 200-mg cohort, and that was a 52% response rate versus 37% for the 50-mg dose. And those patients who had [a response], the median duration of response had not yet been reached, but the median follow-up is relatively short. It's only 2.3 months for the 200-mg dose and 4.7 months for the 50-mg dose. A lot of patients still had a response at 6 months, that was 89% in the 200-mg cohort. And of the eight patients who escalated their dose from the 50-mg to the 200-mg cohort, 75% were able to then recover a response.

So the adverse events are sort of similar to what we would expect, and we saw some cytokine release syndrome [CRS], 37% in the 200-mg cohort, with only 1% having grade 3 CRS. They had some fatigue, some anemia. There was some grade 3 ICANS [immune effector cell-associated neurotoxicity syndrome] in about 2% of patients. And then there was a risk of infection, 43% in this 200-mg cohort, and 26% of those were grade 3 or higher.

So basically what we're again seeing is that there is reasonably decent response rates. The durability, again, is something that we haven't seen yet, and it looks like we're doing a better job here of trying to find the dose.

Holstein: Thank you. And before we kind of open up the discussion to where these BCMA bispecifics might play a role in the future, Dr. Hartley-Brown, could you discuss the pooled analysis of elranatamab that was conducted, specifically looking at patients who'd previously received BCMA-directed therapy?

Hartley-Brown: Sure. So as a quick reminder, the MagnetisMM program includes MagnetisMM-1, -3, and -9. And all these patients had received prior BCMA-directed therapies within this pool analysis. We looked at these studies evaluating the efficacy and safety of elra [elranatamab] in patients with refractory disease and prior exposure to anti-BCMA therapy. And so this is a smaller pool. Previously we're talking about some bigger numbers here, but there are only 13 patients from the MM-1 data. And those patients, that was probably the second smallest cohort. The MM-9 we had nine patients. And then the MM-3 we had 64 patients.

The doses of elranatamab -- I'll say elra because I'm going to get tongue-tied -- of elra in the 13 who were in the MM-1 ranged from 215 mg/kg to 1,000 mg/kg. And this is given subcutaneously. The subcutaneous dosing for the other two cohorts, MM-3 and MM-9, was somewhat different with 76 mg [once]-weekly dosing. We were looking at safety signals -- looking at CRS, looking at ICANS -- and so overall it was 86 patients. Typical age range, I would say. About a half of them being male and most of them having good performance status. The high-risk cytogenetics were about a quarter of the patients, and a little over half had extramedullary disease. And the median prior lines of therapy was about seven. So very heavily pretreated patients.

When you looked at what type of BCMA-directed therapy they had received, we see the predominant amount had received antibody-drug conjugate [ADC] therapy, and that was about 68%, 67%, sorry. CAR [chimeric antigen receptor] T cells, about 42% had received prior CAR-T, and about 9% had received both. In regards to the refractoriness of the patient population, when we're talking about triple-class refractory, penta-drug refractory, it's about 96% triple-class refractory and about 55% were penta-refractory.

So now I'm going to go right into the response rates. We were seeing for this population, at about a median follow-up of 10 months, the duration of treatment was about 3 months, and about a quarter of the patients were still on treatment. Most commonly they discontinued because of progression of disease, but we still had some overall response rates of about 45% with some patients actually receiving CR [complete response] or better. And that was about 17% of the patients.

And so, this kind of leans in on the fact that prior BCMA-directed therapy and pivoting to another BCMA-directed therapy, or bispecific in this case, is not unforeseen -- and some patients will respond. And I think this is very important to note. We're still seeing overall response rates for the patients with prior ADC, about 41%, and about 52% for those with prior CAR-T.

So the duration of response, we're still not getting very long duration of response, but that's not unexpected. But we do see that at 9 months we had about 67% with the prior ADC therapy responding still, and prior CAR-T there was about 78% of patients. Short follow-up median PFS [progression-free survival] of 4.8 months.

But again, the take-home here is we're seeing similar toxicities when it comes to cytopenias. We're seeing a little bit of a GI [gastrointestinal] signal with some diarrhea in a third of the patients. ICANS similarly reported at about 5.8%. And the CRS signal was there as well, as expected. But we are still seeing fairly good responses, anywhere from 40% to 50% in the overall response rate. So elra is efficacious, it's well-tolerated. We're not seeing any new signals in regards to safety. And this speaks to the point that, maybe if you do have someone in the community that can't get to a center to get CAR-T therapy or bispecific therapy, maybe bridging them once or twice with another BCMA-directed therapy might be helpful for that patient.

Holstein: Thank you. So we of course have teclistamab now FDA approved. We have elranatamab, we have linvoseltamab, we have a few others ... Dr. Lipe, are we going to have a future where we have four or five BCMA bispecifics to choose from? And right now, do you think there's anything that distinguishes one from the other?

Lipe: You know, I don't know that we're seeing that now, and some of them, they have slight differences in their manufacturing, but we're seeing pretty similar response rates across the board. And I don't think that there's any that's really jumping out and yelling out that it is different. But I do think that there's a possibility that that could change over time.

So I think that maybe one of the things that may happen is that we'll have these different drugs targeted into these niche trials, and we have data. So now we have some data on elra and the BCMA-prior-therapy-exposed-patients. So if you have a patient who's already seen BCMAs, are you going to go with one that doesn't have as much data in that setting, or are you going to go with one that does? And I could see that I would go with the one that has the most data because, theoretically, there could be differences. And I think in this space maybe we'll just have to let the data speak for itself and go from there is what I see.

Holstein: Absolutely. It would make it a little bit easier to counsel somebody if you at least had some data with a specific agent to say, OK, for patients who received this agent and previously had CAR-T, this is the expected response rate. But I think it is going to be interesting to see how all these bispecifics end up and how we're going to be sequencing them and or using them. Is it just going to be one bispecific per patient? Or can we envision a future where you've gotten one in one context -- perhaps in combination like we're going to talk about a little bit later -- and then might have rationale to use a different one later on? Dr. Hartley-Brown, what are your thoughts?

Hartley-Brown: I agree with you both. I think the data is early yet we don't have all the information as of yet, but it's a great space to be in, to have these options. And if we think about it, I think some of these just depend on what pans out with their toxicity profile or the dosing schedule -- for example, the interval schedule coming in weekly versus every 2 weeks versus once a month -- it can be a big difference for patients. So a lot of this information, I look forward to how it's going to pan out and how we're going to incorporate the bispecifics in the treatment regime for our patients. Because I think we're still not sure exactly how to do it yet, but we're trying to figure it out. And with having this data and more and more patient data coming out in the sequencing situation, then we will be a little bit more informed as to how best to treat certain patients.

Holstein: Definitely a very fast-moving field right now. And for both of these abstracts as well as a few others that we're going to discuss, they did spend a lot of time talking about the various infections including grade 3/4 or higher infections, which in some cases were a quarter to almost 40% of patients experiencing grade 3 or grade 4. Some patients experiencing infections that we don't normally come across in the myeloma world too often, such as CMV [cytomegalovirus] or PJP [Pneumocystis jirovecii pneumonia].

Dr. Lipe, do you think that there's an important signal here for these BCMA bispecifics? Are you doing anything different in your practice because of these data?

Lipe: Yeah, so we've started routinely putting patients on PJP prophylaxis again. It's generally pretty well tolerated, and one of the issues we've had is then when you get the cytopenias, a drug like Bactrim [sulfamethoxazole and trimethoprim] can be challenging to give, but I do think it is something that we're paying attention to.

The data on IVIG [intravenous immunoglobulin] I think has always been a little bit shaky to me. And so I know people are using IVIG more -- and I don't know that it ever worked to begin with and I don't know that it's going to work now -- but it definitely feels, when you see these rates of infection, I feel compelled to do something. We have started checking CMV levels. I think that these are real concerns. And I think that it's also challenging when we talk about patients who aren't necessarily close, now it's not only us that has to remain vigilant for some of these unexpected toxicities -- which is probably easier at an academic center when we've been more exposed to the transplant setting -- but now we have to make sure that our community providers know how to start to recognize and treat CMV or other ... or who knows. So I think that that's something challenging.

And I think one of the things that I find interesting in this space is the role that insurance companies are going to take. We're having issues getting certain things paid for. Can we get growth factors for patients who get these prolonged neutropenias, post-some BCMA therapies. Can we get IVIG approved? Are insurance companies going to be telling us which one to use? I think that that's all evolving and it makes things more complicated, as if it's not complicated enough. And dealing with insurance is challenging on its own. And then you add these other things that we need to mitigate and the reluctance of some insurance providers to allow us to properly care for our patients.

Holstein: Excellent points. And I think as these data continue to accumulate, we're really going to need national guidelines, because sometimes insurance companies do pay attention to those in terms of best practices for keeping our patients safe.

Click here to watch the other episodes from this ASCO roundtable series on multiple myeloma.

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