Dr Krishnan on the Potential Clinical Impact of Trispecific Antibodies in R/R Multiple Myeloma

"Trispecific antibodies have the theoretical advantage that if you're dual targeting, you can overcome some degree of clonal heterogeneity. Perhaps you will reduce resistance because you'll have less selective pressure on 1 antigen.”

Amrita Krishnan, MD, director of the Judy and Bernard Briskin Center for Multiple Myeloma Research at City of Hope, discussed the potential clinical impact of trispecific antibodies in the management of relapsed/refractory multiple myeloma, with a focus on preliminary findings from a first-in-human phase 1 study (NCT05652335) of JNJ-79635322 (JNJ-5322).

JNJ-5322 is a novel, next-generation trispecific antibody designed to engage CD3 on T cells and simultaneously target BCMA and GPRC5D. The rationale for this approach stems from the need to address clonal heterogeneity and antigen escape mechanisms that contribute to therapeutic resistance in relapsed/refractory multiple myeloma. By concurrently targeting 2 myeloma-associated antigens, trispecific antibodies could reduce selective pressure on a single antigen and potentially improve activity for patients with extramedullary disease, Krishnan said.

In early data presented at the 2025 ASCO Annual Meeting, JNJ-5322 generated an overall response rate (ORR) of 100% overall response rate (ORR) in patients naive to both BCMA- and GPRC5D-directed therapies. This 100% ORR was achieved in patients treated at the recommended phase 2 dose of 100 mg once every 4 weeks (n = 27) and in those treated at 300 mg once ever 4 weeks (n = 8). This represents a notable increase in ORR compared with what is typically observed with bispecific antibodies targeting a single antigen, Krishnan explained.

Despite these encouraging initial findings, Krishnan noted that the median follow-up remains relatively short, and progression-free survival (PFS) data are still immature. The long-term durability of responses and potential correlation with minimal residual disease (MRD) negativity remain critical unanswered questions. Additionally, whether trispecific antibodies can provide comparable or superior efficacy to CAR T-cell therapy—particularly in earlier lines of treatment or high-risk subsets—requires further investigation in ongoing and future studies, Krishnan concluded.