Emerging Bispecifics and Trispecifics and Addressing Unmet Needs in R/R MM

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Trispecific antibodies represent the most promising emerging therapeutic development, with 2 leading candidates showing exceptional early clinical results. The B-cell maturation antigen (BCMA)/GPRC5D trispecific antibody demonstrated 100% overall response rates in BCMA-naive patients at recommended phase 2 dosing, with the majority achieving deep responses. A second trispecific targeting BCMA and CD38 (developed by Ichnos Sciences') has also shown highly encouraging preliminary data. These agents address the theoretical risk of antigen escape by simultaneously targeting multiple myeloma antigens within a single therapeutic construct.

Frontline combination strategies, particularly for transplant-ineligible patients, represent another area of active development. The MAGNETISMM-6 trial data presented at EHA 2025 demonstrates the potential for bispecific antibodies in earlier treatment lines. Novel constructs with attenuated CD3 binding designed to reduce cytokine release syndrome may offer improved safety profiles for older or frail patients who struggle with current immunomodulatory drug-based regimens. These developments could provide more tolerable first-line options for vulnerable patient populations.

Two critical unmet needs persist in multiple myeloma care: ultrahigh-risk disease and truly frail patients. Ultrahigh-risk patients, including those with extramedullary disease, require innovative combination approaches incorporating the best available immunotherapies with emerging agents such aa cellular modulators . Despite improvements with combination bispecific therapy, progression-free survival remains suboptimal compared with standard-risk patients. Frail patients who would never qualify for clinical trials need better-defined treatment strategies and potentially novel therapeutic approaches designed specifically for their unique needs and limitations.