What combination regimens containing BCMA-directed bispecific antibodies are being evaluated for MM?

The Multiple Myeloma Hub spoke with Alexander Lesokhin, Memorial Sloan Kettering Cancer Center, New York, US. We asked, What combination regimens containing B-cell maturation antigen (BCMA)-directed bispecific antibodies are being evaluated for multiple myeloma (MM)?

In this interview, Lesokhin discussed the range of combination regimens featuring a BCMA-directed bispecific antibody for MM, outlining the rationale for these strategies and noting that while BCMA bispecifics have shown high response rates in the relapsed/refractory setting outcomes can be further improved. Lesokhin reviewed combinations with other bispecific antibodies, established MM therapies, and other novel agents including checkpoint inhibitors and those that can enhance BCMA expression on malignant cells.

Key learnings

• BCMA-directed bispecific T-cell engagers have demonstrated single-agent activity in relapsed/refractory MM; however, there is potential to improve efficacy through combination strategies.
• One strategy under evaluation involves combining BCMA-directed bispecific antibodies with other T-cell engagers that target different antigens, such as GPRC5D or FcRH5, to broaden immune engagement and potentially overcome mechanisms of resistance.
• The combination of teclistamab, a BCMA-directed bispecific antibody, with talquetamab, a GPRC5D-directed bispecific antibody, has shown activity in ongoing studies, including RedirecTT-1, as well as in patients with extramedullary disease, which is a historically challenging population to treat.
• FcRH5-targeting bispecific antibodies, such as cevostamab, are also being assessed in combination with BCMA-directed bispecifics; these combinations are in early-phase trials, and data have not yet been fully reported.
• Combinations of elranatamab, a BCMA-directed bispecific antibody, with established myeloma agents, such as the anti-CD38 antibody daratumumab and the immunomodulatory drug lenalidomide, are currently under investigation as part of the phase II MagnetisMM-6 trial and have demonstrated MRD rates approaching 100% in patients with newly diagnosed MM.
• Cereblon E3 ligase modulators, including iberdomide and mezigdomide, are also in evaluation with BCMA-directed bispecific antibodies.
• Proteasome inhibitors, such as carfilzomib, have demonstrated early signs of activity in combination with BCMA-directed bispecific antibodies in patients with one to three prior lines of therapy.
• Exploratory combinations include BCMA-directed bispecific antibodies with immune checkpoint inhibitors, as well as other immune agonists, though these remain in early investigation with limited available data.
• Approved BCMA-directed bispecific antibodies, including elranatamab and teclistamab, are being investigated in combination with both approved and investigational agents for multiple myeloma; emerging data from these studies may help to refine future treatment strategies.