What combination regimens including BiTEs are being evaluated for the treatment of RRMM?

The Multiple Myeloma Hub spoke with Ravi Vij, Washington University, St. Louis, US. We asked, What combination regimens including bispecific T-cell engagers (BiTEs) are being evaluated for the treatment of relapsed/refractory multiple myeloma (RRMM)?

During this interview, Ravi Vij discussed combination strategies involving BiTEs for the treatment of RRMM. Vij highlighted the movement of B-cell maturation antigen (BCMA)- and G-protein-coupled receptor family C group 5 member D (GPRC5D)-directed BiTEs into earlier lines of therapy and their integration into regimens with established agents such as daratumumab, pomalidomide, and lenalidomide. In addition, Vij noted that novel FcRH5-directed BiTEs such as cevostamab are being investigated in combination regimens, with early-phase studies reporting high response rates, including complete remissions. Vij concluded that while results are encouraging, concerns remain regarding increased risk of infections and the need for more mature data on durability of response and progression-free survival prior to regulatory approvals of new agents or combinations.

Key learnings

• BiTEs targeting BCMA and GPRC5D have been integrated into clinical practice for RRMM and are increasingly being studied in earlier lines of therapy.
• The rationale for combination regimens including BiTEs is to improve overall efficacy and disease control.
• Trials such as MajesTEC-2 (NCT04722146) and TRIMM-2 (NCT04108195) have demonstrated high response rates with teclistamab, a BCMA-directed BiTE, in combination with daratumumab and pomalidomide across both early and later relapsed MM.^1,2
• Post-autologous stem cell transplant maintenance with teclistamab + lenalidomide has also shown deep responses, as well as high rates of stringent complete response.³
• In newly diagnosed MM, teclistamab and elranatamab combinations with daratumumab, lenalidomide, and bortezomib have also shown promise.⁴
• There are several additional studies evaluating BCMA- and GPRC5D-directed BiTEs in combination with existing agents, with consistently high response rates.
• Novel FcRH5-directed bispecifics, such as cevostamab, are being evaluated in combinations, such as in the phase Ib CAMMA-1 (NCT04910568) study, which is investigating cevostamab + pomalidomide + dexamethasone and cevostamab + daratumumab + dexamethasone,⁵ which have shown encouraging response rates in early-phase trials.
• Combination regimens are associated with higher rates of adverse events, particularly infections, highlighting the need for longer follow-up and safety monitoring prior to regulatory approval.
• There is a shift in the use of bispecific antibodies, expanding beyond use in late relapse into earlier treatment settings, and combination strategies are likely to play a central role in the evolving treatment paradigm for multiple myeloma.