Bispecific Antibodies Are Taking the Multiple Myeloma World by Storm

The expert panel.

The use of bispecific antibodies for patients with multiple myeloma was the latest topic of discussion during an Around the Practice® held during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

The conversation was moderated by Rafael Fonseca, MD, director for innovation and transformational relationships at Mayo Clinic in Phoenix, Arizona. He was joined by Samer A. Al’Hadidi, MD, MS, FACP, assistant professor of medicine at the University of Arkansas for Medical Sciences at Little Rock; Naresh Bumma, MD, a hematologist at The James Outpatient Care at The Ohio State University Comprehensive Cancer Center in Columbus; and Hans Lee, MD, associate professor in the Department of Lymphoma/Myeloma in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston. The panel discussed various trials with the use of bispecific antibodies, how they will fit into the multiple myeloma space, and where they are headed in the future.

Fonseca / What is the update on the phase 1 MonumenTAL-2 trial [NCT05050097] with talquetamab [Talvey]?¹

Lee / [Findings from] the MonumenTAL-2 study were presented last year at the [65th] American Society of Hematology Annual Meeting [and Exposition], and [the trial] was a combination of talquetamab plus pomalidomide [Pomalyst]. It was the first time data were presented with a bispecific plus pomalidomide. [They are] early data, but it was nice to show that talquetamab plus pomalidomide could be combined safely. There’s a potential biological rationale for combining an immunomodulatory drug [IMiD] with talquetamab or vice versa. That was encouraging to see.

These T-cell antibodies, including talquetamab, teclistamab-cqyv [Tecvayli], and elranatamab-bcmm [Elrexfio], are in clinical development, and many of these uses will be in combination. We saw data last year from the phase 1 TRiMM-2 trial [NCT04108195] of talquetamab plus daratumumab [Darzalex]. There have been further updates from the original phase 1/2 MonumenTAL-1 study [NCT03399799; NCT04634552] of single-agent talquetamab.² These have been important data that have been presented because the unmet need in multiple myeloma is the quadruplet refractory [disease]: not just IMiD, proteasome inhibitor [PI], [or] anti-CD30 refractory but BCMA-refractory multiple myeloma. One of the cohorts in the MonumenTAL-1 study, cohort C, included patients who had prior exposure to redirecting therapies. What we saw was that the responses were over 60%. This provides great data to support using talquetamab as a solid strategy for patients who have disease that’s refractory to some agents.

Fonseca / How do the updates from the phase 1/2 MajesTEC trial [NCT03145181; NCT04557098] compare?³

Al’Hadidi / Teclistamab was the first BCMA bispecific antibody that was approved [by the FDA] with the MajesTEC study [findings].⁴ At ASCO this year, we got a longer follow-up of this agent. The long-term duration of response is there with this agent, so many patients are responding for almost 2 years with teclistamab, despite doing a lower amount of dosing. Those patients are getting it now every other week, and some of them once a month. With such a strategy, we found that patients had less amount of infection and more tolerance to the treatment. The overall survival data were updated. Patients have been living for almost 2 years. That’s quite exciting because such patients with heavily pretreated multiple myeloma [in] the previous cohorts…didn’t use to live that long.

Fonseca / This is so important, because with a bispecific, like with a traditional drug, you can tell within 1 or 2 [months] if the patient is responding. For regulatory purposes, we need the comparisons, we need the P values. In the real world, we don’t care. If the patient responds, then your next step in the conversation with the patient will be the duration of the response. If you tell them, “It’s been a month; we’re moving in the right direction,” most people can get a couple of years of control. That’s powerful.

Dr Bumma, we are also seeing these ASCO data being presented with [the] MagnetisMM-30 trial [NCT06215118].⁵ Could you give us a little update on what to anticipate there?

Bumma / This segues nicely into what my colleagues mentioned. We have these great long-term data, and the next step is a combination [therapy]. This trial follows the blueprint of the trials that are going to be presented [at subsequent oncology meetings]. MagnestisMM-30 is a phase 1/2 trial with elranatamab, which is a BCMA/CD3 antibody. Phase 1 is to detect the dose-limiting toxicities. Phase 2 is dose optimization. Phase 1 will recruit about 27 patients, and phase 2 will be about 60 patients.

The thing to look into is that there will be PI and IMiD exposure. The one downside I see is that there’s no prior BCMA exposure. This will become the next wave of studies that we will do bispecifics, either BCMA engaging or GPRC5D engaging in combination, trying to find out what’s the best combination and when to do it to further improve those PFS [progression-free survival] data that we’re seeing. But I hope to get to the response faster and start spacing out the treatments or even thinking about treatment breaks down the line.

Fonseca / Dr Lee, the MagnestisMM-32 trial [NCT06152575] compared elranatamab with 3 standards of care, either with pomalidomide and dexamethasone; pomalidomide, bortezomib [Velcade], and dexamethasone; or carfilzomib [Kyprolis] and dexamethasone.6 What do these data show?

Lee / This is a trial in progress [with findings that were] presented at this year’s ASCO meeting. This is an important study because it is looking at elranatamab, a T-cell antibody in earlier lines of therapy. So [it’s] 1 to 4 lines of lenalidomide [Revlimid] and anti-CD30 exposure and looking at elranatamab vs 2 standard of care options. These trials will be critical to evaluate the role of these agents in earlier lines of therapy. We anticipate, given their effectiveness [in] later lines of therapy, that they’ll probably be effective in earlier relapsed/refractory multiple myeloma. We need to see the data when we see the [findings from] trials that demonstrate this. Optimizing the supportive care, infection prophylaxis, and things like that will be important as these agents move to earlier lines of therapy.

Fonseca / Should we begin use with BCMA, or is there an argument to use GPRC5D first?

Al’Hadidi / I usually go with the BCMA first. That has to do with how those were developed but also has to do with the longer follow-up data we have with the BCMA-based therapies in general. We know more about how patients are doing, and we know more about how patients are responding. More importantly, we know more about [adverse] effects. We tend to know how to deal with cytopenias better than other [adverse] effects when it comes to bispecifics.

When it comes to the GPRC5D talquetamab bispecific, there is a learning curve on how to deal with the [adverse] effects that we are encountering nowadays compared with what we see with the BCMA. I prefer to start with a BCMA-targeted therapy before going to GPRC5D. The other way around is also possible. A few cohorts of patients were presented where they started with GPRC5D, and then they went to BCMA-based therapy, and they still responded well. That is another possible way of sequencing.

Fonseca / Dr Bumma, with the bispecifics, all the trials have the step-up dosing. How are you doing that, and how do you work around those aspects with patients? Has this been challenging? Is this becoming mainstream? One of the things that our audience knows is bispecifics are coming for other disease types like lymphoma.

Bumma / My experience has been [extensive] in clinical trials. The step-up dosing has been inpatient, in the hospital on a cellular therapy service, with providers who are very well versed with ICANS [immune effector cell–associated neurotoxicity syndrome] and CRS [cytokine release syndrome] mostly out of an abundance of caution now that some of these molecules are not available commercially. At our institution, we hope to start these as an outpatient [procedure]. However, as of now, out of an abundance of caution, it’s mostly been inpatient.

Some of the patients are not super excited about being in the hospital, but most of them are grateful that they’re being monitored. There’s also somebody there to keep an eye on them, somebody who knows what they’re doing. It ends up being an interesting discussion with the patient as to what they want to do. More importantly, from a step-up perspective, we have to have shared decision-making with the patient and, if they have [one], a community oncologist…as well just to make sure that everybody feels comfortable with the plan.

Fonseca / Dr Lee, what has your experience been with step-up dosing?

Lee / In general, there’s probably a lot of variation between centers [on] how step-up dosing is done inpatient vs outpatient. Even how CRS is managed, whether we’re giving prophylactic tocilizumab [Actemra] at first fever or grade 1 CRS or waiting to give the tocilizumab or perhaps dexamethasone in the first line as well as management for CRS. At MD Anderson [Cancer Center, what] what we are doing is more accelerated step-up dosing. For instance, with teclistamab on days, 1, 3, and 5, we’re still doing inpatient [dosing]. The plan is to transition soon to outpatient dosing. In general, these agents are new. We’re going to learn a lot more and become much more efficient giving these [treatments].

Think back to when daratumumab was first approved back in 2015. It gave people a lot of concern about all the infusion-related reactions, and people were doing split dosing over 2 days and things like that. Fast-forward 10 years, and we have simultaneous anti-CD3 monoclonal antibodies [approved]. My prediction is in 3 to 5 years we’ll be looking backward. You remember those days when we used to give bispecifics, right? Then it’d be “Well, it’s much easier now [to administer].” The ultimate thing is [that] we want to improve access to these drugs. Ultimately, if we improve how we administer the drugs, more patients, particularly [in] the community, will be getting these drugs. That will be a win for our patients, as they don’t have to travel to the major academic centers to get these drugs.

References

1. Matous J, Biran N, Perrot A, et al. Talquetamab + pomalidomide in patients with relapsed/refractory multiple myeloma: safety and preliminary efficacy results from the phase 1b MonumenTAL-2 study. Blood. 2023;142(suppl 1):1014. doi:10.1182/blood-2023-187706
2. Schinke CD, Touzeau C, Minnema MC, et al. Pivotal phase 2 MonumenTAL-1 results of talquetamab (tal), a GPRC5DxCD3 bispecific antibody (BsAb), for relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2023;41(suppl 16):8036. doi:10.1200/JCO.2023.41.16_suppl.8036
3. Garfall AL, Nooka AK, van de Donkk NWCJ, et al. Long-term follow-up from the phase 1/2 MajesTEC-1 trial of teclistamab in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2024;42(suppl 16):7540. doi:10.1200/JCO.2024.42.16_suppl.7540
4. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed July 10, 2024. https://shorturl.at/muzWb
5. Lesokhin AM, Raza MS, Acosta J, et al. MagnetisMM-30: a phase 1b, open-label study of elranatamab in combination with iberdomide in patients with relapsed or refractory multiple myeloma (RRMM). J Clin Oncol. 2024;42(suppl 16):TPS7577. doi:10.1200/JCO.2024.42.16_suppl.TPS7577
6. Schuster SR, Ito S, Hoyle M, Yver A, Hong F, Finn G. Evaluation of elranatamab vs EPd, PVd, or Kd in patients with relapsed or refractory multiple myeloma and prior anti-CD38–directed therapy: MagnetisMM-32. J Clin Oncol. 2024;42(suppl 16):TPS7576. doi:10.1200/JCO.2024.42.16_suppl.TPS7576