BCMA-Targeting Bispecifics in Multiple Myeloma: Elranatamab
Key opinion leaders in the field of multiple myeloma review clinical data behind BCMA-targeting bispecific antibody elranatamab, followed by other T-cell engagers in the pipeline.
Transcript:
Sandy Wong, MD: Now we’re going to talk about elranatamab, another bispecific T-cell engager, also targeting BCMA. The MagentisMM-1 trial was the first-in-human phase 1 trial looking at this in patients with relapsed/refractory myeloma, and multiple phase 3 trials are ongoing, looking at this agent in monotherapy and in combination with other already approved myeloma agents.
First, let’s go over the MagentisMM-1 study. This is a phase 1 study, like I’ve talked about. This drug is given subcutaneously, and the doses investigated ranged from 215 to 1000 μg/kg in patients with late relapsed myeloma, and the analysis included 55 patients at these doses. Notably, 29% of patients had high-risk cytogenetics, and these patients were heavily pretreated with a median of 5 prior lines of therapy, and 91% of patients were triple-class refractory. In terms of safety, you can see the high-grade AEs [adverse events] were primarily hematologic. Specifically, you can see that 75% of patients had neutropenia, and if you look at the grade 3 and 4, you can see a high percentage of them had high-grade neutropenia. In terms of nonhematologic toxicities and patients getting CRS [cytokine release syndrome], that was around 87%. Luckily, all of them were limited to grade 1 or 2 CRS. And notably with the 44-mg step-up priming dose, the overall incidence was then reduced to 67%. The CRS was further mitigated by further changes in the primary dose by the 12- and 32-mg primary dose in the phase 1 study.
In terms of efficacy, the response rate was 64%, and almost 40% of patients had a CR [complete response] or better. For the patients who responded, the median duration of response was 17 months, and the median PFS [progression-free survival] was 11.8 months. All evaluable patients achieved MRD [minimal residual disease] negativity, and 62% of patients were MRD negative for more than 6 months. Now, MagentisMM-3 is a study in patients who are triple-class refractory. They had 2 cohorts. One was cohort A, which included 123 patients, and there was also cohort B. Notably, cohort A did not allow prior BCMA-directed treatment, whereas cohort B did allow prior BCMA-directed ADC [antibody-drug conjugate] or CAR [chimeric antigen receptor] T-cell therapy. What was presented was the results of cohort A, and essentially the response rate for cohort A was around 60%, very similar to teclistamab. In terms of the PFS, the PFS was not reached.
MagentisMM-5 is a combination study in patients with relapsed/refractory myeloma. This study is divided into part 1 and part 2. For part 1, patients were enrolled who had at least 3 prior lines of therapy, including lenalidomide, a proteasome inhibitor, or elranatamab was initiated in the beginning, and then daratumumab was added on cycle 1, day 15. Part 2 is a randomized study. This is including patients with earlier lines of therapy, so now we’re talking about patients who had 1 to 4 prior lines of therapy, including lenalidomide, a proteasome inhibitor, and then patients who randomized 1:1:1 to elranatamab as monotherapy versus elranatamab plus daratumumab versus daratumumab, pomalidomide, dexamethasone, which is the standard of care.
As of last year in April, 28 patients were enrolled and treated, so it’s still very early in terms of this study right now. We have a limited number of patients, but what we can see is that patients had a median of 5 prior lines of therapy, 18% of patients were triple-class refractory, and 71% of patients had a prior stem cell transplant. Now in terms of high-grade TEAEs [treatment emergent adverse events], 46% of patients experienced grade 3 or higher TEAEs. The most common included CRS, which was 50%. This is not surprising. We know these types of agents have patients who experience CRS, but luckily all were confined to grade 1 or 2. Other common TEAEs included neutropenia and pyrexia, and notably no patients experienced ICANS [immune effector cell-associated neurotoxicity syndrome]. When you look at the CRS events, the majority of them occurred after the first dose, and because these events were grade 1 or 2, no patients discontinued the study because of CRS. A very small percentage of patients needed an elranatamab dose interruption. It only occurred in 7.1% of patients. And most importantly, no DLTs [dose-limiting toxicities] were observed. That’s obviously very important because this is a combination study, and it is exciting to see this is the safety profile.
In terms of responses, we have to be careful in terms of looking at these data, it’s really early and with a limited number of patients. But there were promising early responses, including deep responses that were observed. The median time to response was 1 month, so these responses did occur quickly. As a result of these early phase trials with monotherapy for these BCMA-targeting agents, both teclistamab and elranatamab are now being studied in phase 3 trials, in combination with different agents that are already FDA approved, as well as in earlier lines of therapy and in the maintenance setting. And of course, the transplant-ineligible setting is an area of interest in the newly diagnosed setting. Studies are being conducted in that space as well.
This presentation would not be complete without mentioning the other BCMA-targeted bispecifics. There are a number of other ones out there, and these are 3 other BCMA-targeting B-cell engagers. On the left, you see alnuctamab, a bispecific T-cell engager with a 2 plus 1 format. Initially, it was studied intravenously [IV], but then the study ran into very high-grade CRS, and they had to pivot to the subcutaneous administration. What was presented was an update about the IV cohort, and then new data on the subcutaneous [sub-Q] cohort. As you can see there, the overall response rate for the sub-Q cohort was 77%. In terms of AEs, you can see that CRS occurred in 53% of patients. In terms of HPN217, this is another T-cell engager, but this is a trispecific BCMA-targeted T-cell engager. It is given weekly intravenously, and 48 patients were presented. You can see that it’s also an active BCMA T-cell engager. On the right-hand side is linvoseltamab. This is another BCMA T-cell engager given weekly intravenously, and it is also quite active. In patients who received the 200-mg and higher dose, granted the numbers are small, only 24 patients, but the response rate was 75%.
Transcript edited for clarity.
