Syed Abbas Ali, MBBS, an assistant professor of oncology at Johns Hopkins School of Medicine and Sidney Kimmel Comprehensive Cancer Center

Dr Ali on Choosing Between CAR T-Cell Therapy and Bispecific Antibodies in R/R Multiple Myeloma

"By and large, for patients who are able to receive CAR T-cell therapy, [oncologists should] go with CAR T-cell therapy first. If you can’t go with CAR T-cell therapy and have to go with another anti-BCMA agent, then [you should] see if there is an alternative." 

Syed Abbas Ali, MBBS, an assistant professor of oncology at Johns Hopkins School of Medicine and Sidney Kimmel Comprehensive Cancer Center, discusses factors the influence his choice between CAR T-cell therapy and bispecific antibodies for the treatment of patients with relapsed/refractory multiple myeloma who are eligible for both classes of agents. 

Recent studies have examined the efficacy of T-cell–engaging therapies in patients with relapsed/refractory multiple myeloma, particularly those with prior exposure to BCMA-targeted therapies, Ali begins. Both CAR T-cell therapies that are FDA approved for patients with relapsed/refractory multiple myeloma target BCMA, as do most bispecific antibodies, he says. Prior exposure to BCMA-directed agents—including antibody-drug conjugates, CAR T-cell therapy, or bispecific antibodies—may influence the effectiveness of subsequent BCMA-targeted treatments, he notes. 

Clinical data suggest that the sequencing of BCMA-targeted therapies is critical, Ali emphasizes. When using CAR T-cell therapy and BCMA-directed bispecific antibodies sequentially, the preferred approach is to administer CAR T-cell therapy first, followed by a BCMA-targeting T-cell engager or bispecific antibody, he states. This sequence generally results in better therapeutic outcomes, according to Ali. Conversely, patients who receive an anti-BCMA therapy before CAR T-cell therapy may experience reduced CAR T-cell efficacy, particularly if they had prolonged or recent exposure to a BCMA-targeted agent, he reports.

To optimize outcomes when sequencing BCMA-directed therapies, a treatment-free interval of at least 3 to 6 months between agentsis advisable, Ali recommends. Additionally, patients who previously had a robust response to an anti-BCMA therapy and subsequently received a non-BCMA therapy before initiating another BCMA-targeted treatment may have a higher likelihood of benefiting from the latter, he explains.

If CAR T-cell therapy is not feasible, alternative treatment strategies should be considered, such as bispecific antibodies in clinical trials or therapies targeting alternative antigens like GPRC5D, he notes. For example, the FDA-approved GPRC5D-targeted bispecific antibody talquetamab-tgvs (Talvey) is available for patients with relapsed/refractory multiple myeloma who have received at least 4 prior lines of therapy. As additional therapies receive regulatory approval, treatment sequencing will become more flexible, allowing oncologists to tailor therapy to individual patient responses and preserve options for future anti-BCMA treatments, he concludes.

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Syed Abbas Ali, MBBS, discusses treatment decisions for patients with R/R myeloma for whom CAR T-cell therapy and bispecific antibodies are both options.

Dr Ali on the Need for Novel Targets Beyond BCMA in Multiple Myeloma

“[BCMA and GPRC5D] are great [targets], but we need to increase the repertoire. The challenge is finding targets [that are] often expressed on myeloma cells, are expressed in a high density, and don’t disappear when you put them under pressure with treatment. Numerous [novel] targets are being studied, and we’ll have to see how the early- and later-phase trials pan out with those.”

Syed Abbas Ali, MBBS, medical oncologist, assistant professor, oncology, Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, discusses how the identification of targets beyond BCMA may address treatment sequencing challenges in patients with multiple myeloma who have progressed on BCMA-targeted agents.

BCMA has proven to be a highly effective target in multiple myeloma due to its nearly universal expression on plasma cells and its restricted expression profile, making it less likely to cause off-tumor effects, Ali begins. BCMA-targeted therapies deliver a robust on-target therapeutic effect without significant off-tumor toxicity, a common challenge with other therapeutic targets, he says.

GPRC5D is another key target that is highly expressed on myeloma cells, Ali continues. However, GPRC5D is also present in nonmalignant tissue cells, such as mucosal cells, leading to adverse effects like taste alterations and changes in skin and nails when targeted by therapy, Ali explains.

Although both BCMA and GPRC5D are pivotal targets in myeloma management, expanding the repertoire of viable targets is critical to overcoming resistance and enhancing therapeutic efficacy in this disease, Ali emphasizes. The key challenge lies in identifying novel targets that are highly and consistently expressed on myeloma cells, maintain expression under treatment pressure, and are minimally expressed in other tissues to avoid off-tumor toxicity, he says.

Numerous novel targets are under investigation in early- and late-phase clinical trials, though identifying targets exclusive to myeloma cells remains complex, Ali notes. He adds that the inherent redundancy of biological systems complicates the development of therapies aimed at single-tissue specificity. Continued research is needed to uncover and validate new targets that meet these stringent criteria to advance myeloma management, Ali concludes.

Syed Abbas Ali, MBBS, discusses the identification of novel targets for patients with multiple myeloma who previously progressed on BCMA-targeted agents.
 

Syed Abbas Ali, MBBS

Articles

Dr Ali on Choosing Between CAR T-Cell Therapy and Bispecific Antibodies in R/R Multiple Myeloma

Dr Ali on the Need for Novel Targets Beyond BCMA in Multiple Myeloma