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FAQs on BCMA SLAMF7 in MM
Experts Answer Questions About Therapies Targeting BCMA and SLAMF7 in Multiple Myeloma

Released: July 20, 2023

Shaji K. Kumar
Shaji K. Kumar, MD
Joseph Mikhael
Joseph Mikhael, MD, MEd, FRCPC, FACP
Noopur Raje
Noopur Raje, MD
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Key Takeaways
  • Patients with peripheral neuropathy but otherwise normal organ function are candidates for BCMA-targeted CAR T-cell therapy. 
  • Current studies are addressing time limited therapy strategies for some patients to reduce the need for indefinite treatment.
  • There is no difference in response to CAR T-cell therapy between men and women with multiple myeloma, but preliminary results suggest potential differences by race and ethnicity.
  • Antiviral prophylaxis is recommended for everyone receiving BCMA-targeted therapy in multiple myeloma.

In this question-and-answer session from the program “Exploring the Progress and Evolving Therapeutic Paradigm in Multiple Myeloma,” experts Joseph Mikhael, MD, Shaji Kumar, MD, and Noopur Raje, MD, discuss their clinical experience with CAR T-cell therapy, a potential role for targeting SLAMF7, and access to bispecific antibodies for treating multiple myeloma (MM).

Will there be a potential need for maintenance therapy to sustain progression-free survival (PFS) with CAR T-cell therapy?

Shaji Kumar, MD:
This is an important question right now. There have been several evaluations of CAR T-cell therapy in earlier lines of treatment. The data from the phase III KarMMa-3 trial of idecabtagene vicleucel vs standard of care alone are insufficient to draw definitive conclusions on long-term PFS. Other data from the original LEGEND trials and the phase III CARTITUDE-4 trial with ciltacabtagene autoleucel have demonstrated impressive improved PFS. It is too early to conclude whether there is an improvement in PFS by moving CAR T-cell therapy to earlier lines of treatment—more research is needed. However, it may be premature to conclude that PFS is shorter with CAR T-cell therapy compared with continued therapy until progression. For example, when looking at the potential for 3 years of PFS with CAR T-cell therapy in patients who are newly diagnosed, the benchmark for PFS is 6 years in the same setting with continuous lenalidomide maintenance after transplant. I think more than likely there will be a subgroup of patients with high-risk disease for whom introducing maintenance after CAR T-cell therapy will be necessary, whereas patients with less aggressive disease possibly could have a treatment‑free interval following CAR T-cell therapy.

Joseph Mikhael, MD:
The answer to this question also might affect treatment decisions in MM overall. There is a need to develop rules for when treatment can be stopped. Right now, the best evidence we have is for indefinite lenalidomide maintenance after transplant. Studies have demonstrated the continued benefit of maintenance at 3 years, 4 years, and even up to 5 years, but I would love to give my patients the option of not having treatment. Ideally, we would like to avoid treatment when we can, and there may be an opportunity to determine when that is possible.

Noopur Raje, MD:
There is potential benefit to patients of the one‑and‑done approach using CAR T-cell therapy. Patients who receive CAR T-cell therapy appreciate it so much because for the past 6 years, they have been receiving continuous therapy. If they can achieve 1.5 years of PFS, they often wish they had tried CAR T-cell therapy sooner. I agree that there will be a subset of patients who are going to need maintenance.

Would a patient with peripheral neuropathy but otherwise normal organ function be eligible for CAR T-cell therapy?

Noopur Raje, MD:
Absolutely. Most of our patients with MM have some level of peripheral neuropathy by the time they begin CAR T-cell therapy because of all the treatments they already have received. We have been able to successfully administer CAR T-cell therapy to these patients.

Is B-cell aplasia a concern with anti‑BCMA CAR T-cell therapy, similar to what has been observed with CD19‑targeting CAR T-cell therapy?

Noopur Raje, MD:
BCMA targeting in MM is a little different from CD19-targeting therapy in lymphoma, in which there is not as much loss of CD19 B-cells. In MM, we have observed downregulation of BCMA and some B-cell aplasia with BCMA-targeted CAR T-cell therapy, which partly explains the resulting immunoparesis and is a reason for administering IV immunoglobulin (IVIG). However, B-cell aplasia also could simply be a reflection of treatment efficacy. It is important to manage it and other potential CAR T-cell therapy adverse events with supportive care measures.

Is there a difference in response to CAR T-cell therapy between men and women with MM?

Joseph Mikhael, MD:
No, we have not seen a difference between men and women. Preliminary data from a retrospective study presented in 2022 suggested differential outcomes in response and toxicity based on a patient’s race and ethnicity. Although the patient numbers were small, an increased risk of higher-grade cytokine-release syndrome was observed in non-Hispanic Black patients, resulting in longer hospitalization periods. A lower rate of PFS in Hispanic and non-Hispanic Black patients receiving CAR T-cell therapy also was noted. No racial or ethnic differences were noted in overall survival. We do not yet know the full extent that differences in sex, race, and ethnicity may affect response and toxicity, but as additional data are collected and pooled, we hope to gain more insights.

Long‑term immunodeficiencies have been observed from earlier treatments such as rituximab. Would this also be anticipated to occur with CAR T-cell therapy?

Noopur Raje, MD:
It depends on the treatment. With idecabtagene vicleucel, we do see some level of immunoparesis when a response to treatment is being maintained. With ciltacabtagene autoleucel, we have seen recovery of immunoglobulin levels, so it has not been necessary to provide as much IVIG support compared with other treatments. With bispecific antibodies, our current approach is to use them continuously. We are still early in the development of bispecific antibodies. I think there will be a push for determining a fixed treatment duration by evaluating increased duration and timing between doses. Once we have a clearer idea on optimal duration and timing, we hopefully can avoid prolonged immunoparesis in these patients.

What are some of the barriers and drivers for bispecific antibody use in treating MM?

Joseph Mikhael, MD:
The biggest factor is access, which varies considerably between different healthcare centers. We hope that more patients can be offered bispecific antibodies as access to these treatments improves. No drug being used to treat MM right now is used exactly in the way it was released originally. Every drug regimen evolves in an attempt to increase its efficacy and reduce toxicity—for example, a twice-weekly regimen of bortezomib evolving to once weekly and IV daratumumab evolving to a SC bortezomib/daratumumab combination. Every drug has its learning curve, and I think bispecific antibodies are still in that curve. In terms of how we manage cytokine-release syndrome—how to predict it, when to intervene—we have become a little more aggressive now compared with 1 year ago. We also have been pooling information to determine when to introduce tocilizumab and when to introduce corticosteroids. We have not yet found the optimal strategies for treatments, but the hope is to eventually be able to offer bispecific antibodies to more patients.

How is teclistamab‑associated infection being prevented and managed in real-world clinical practice? Are you routinely using IVIG or other modes of prophylaxis?

Noopur Raje, MD:
We recommend administering IVIG when IgG is ≤400 mg/dL. In addition, everybody should receive antiviral prophylaxis. As we have observed atypical opportunistic infections, we recommend Pneumocystis jirovecii pneumonia prophylaxis, but we have not typically seen a need for antifungal prophylaxis.

Joseph Mikhael, MD:
For Pneumocystis jirovecii pneumonia prophylaxis, we typically would use the sulfamethoxazole and trimethoprim combination. However, because there have been challenges with this antibiotic combination, have you been using more atovaquone or a different drug?

Noopur Raje, MD:
We use either atovaquone or the sulfamethoxazole and trimethoprim combination. The challenge is really neutropenia and thrombocytopenia, but these occur early on and can be managed.

Considering recent data and the current treatment paradigm, what are your thoughts on the role of targeting SLAMF7 in the treatment of MM? 

Shaji Kumar, MD:
Right now, the only treatment available targeting SLAMF7 is elotuzumab. It also is being explored with some immunotherapy platforms, but results of these studies are still forthcoming. Recent presentation of results from a phase III trial demonstrated that the addition of elotuzumab to weekly carfilzomib/lenalidomide/dexamethasone in an upfront setting in MM showed a deep response. Other trials conducted in patients who were newly diagnosed did not show any meaningful improvement with the addition of elotuzumab, but I think the elotuzumab/pomalidomide/dexamethasone combination as a second-line option for patients who have experienced relapse is a reasonable regimen. To that end, there is certainly a role for SLAMF7-targeted therapy in MM, but more results from clinical trials are needed to clarify whether such treatments could be used as first-line therapy and in additional settings.

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