Strategic Use of BCMA- and GPRC5D-Directed Bispecifics in R/R MM

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Bispecific antibodies have transformed the relapsed/refractory multiple myeloma treatment landscape, with therapeutic options now available across the entire spectrum of myeloma care, from posttransplant maintenance through late-line salvage therapy. Treatment selection depends heavily on CAR T-cell candidacy status, with GPRC5D-targeted bispecifics (such as talquetamab) preferred for CAR T–eligible patients to avoid sequential BCMA targeting. This strategy preserves BCMA-directed CAR T-cell efficacy while providing effective bridging therapy or definitive treatment options.

For patients who are not CAR T-cell candidates, both BCMA-directed and GPRC5D-directed bispecifics represent viable options, with BCMA bispecifics generally offering better long-term tolerability when proper infection prophylaxis protocols are implemented. The choice between these agents depends on individual patient factors, including infection risk profiles, B-cell aplasia concerns, and overall treatment goals. Clinical experience suggests that BCMA bispecifics may be preferred as initial therapy for most non-CAR T candidates due to their established efficacy and manageable toxicity profiles.

Earlier-line bispecific integration presents complex decision-making challenges, particularly given the superior overall survival benefits demonstrated with CAR T-cell therapy in trials such as CARTITUDE-4. The ethical considerations surrounding clinical trial enrollment when effective CAR T-cell therapy is available require individualized discussions incorporating patient preferences, toxicity concerns, and long-term treatment goals. Treatment decisions must balance immediate disease control needs with preservation of future therapeutic options.