Talquetamab in R/R MM: Managing GPRC5D-direced AEs, Prophylaxis, and New Safety Signals

EP: 1.Later R/R MM Treatment Landscape and Unmet Needs

EP: 2.ASCO 2025: MonumenTAL-1 Extended Follow-Up for Talquetamab in R/R MM

EP: 3.Insights From MonumenTAL-1: Impressions of Updated Efficacy Outcomes

EP: 4.MonumenTAL-1: Implications of Talquetamab, Prior TCR, and Sequencing for R/R MM

EP: 5.Safety Updates and Concluding Thoughts From Extended Follow-Up of MonumenTAL-1

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EP: 6.Talquetamab in R/R MM: Managing GPRC5D-direced AEs, Prophylaxis, and New Safety Signals

The sequencing of bispecific antibodies and CAR T-cell therapies represents a critical consideration in modern multiple myeloma treatment paradigms. Talquetamab demonstrates remarkable efficacy in patients with prior B-cell maturation antigen (BCMA) exposure, achieving response rates of 67% with a 19.2-month median duration of response in the T-cell redirecting therapy-exposed cohort. This performance nearly matches outcomes in treatment-naive patients, suggesting that switching targets from BCMA to GPRC5D can overcome resistance mechanisms and restore therapeutic sensitivity.

The timing and type of prior BCMA-directed therapy significantly influence subsequent treatment outcomes. Patients who relapse more than 1 year after CAR T-cell therapy may retain sensitivity to BCMA-directed approaches, while those with early relapse within months typically show reduced responsiveness to subsequent BCMA targeting. For patients receiving BCMA-directed bispecific antibodies, sequential BCMA bispecific therapy yields modest 40% to 50% response rates with 4- to 5-month median progression-free survival, highlighting the challenge of sequential bispecific administration even with target switching.

The optimal sequencing strategy increasingly favors target diversification rather than repeated BCMA targeting. Clinical data support using GPRC5D-directed therapy like talquetamab for patients with prior BCMA exposure, whether from CAR T cells, bispecific antibodies, or antibody-drug conjugates. However, sequencing from one bispecific to another remains challenging due to potential T-cell exhaustion affecting the CD3-engaging mechanism common to all bispecific platforms. Ongoing research focuses on determining optimal washout periods and strategies to restore T-cell fitness between bispecific therapies.