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.