Phase 1b sirolimus mTOR inhibitor pre-conditioning plus BCMA×CD3 or GPRC5D×CD3 bispecifics in relapsed/refractory myeloma.

This single-center, single-arm Phase 1b study with an expansion cohort tests whether short-course sirolimus (an mTOR pathway inhibitor that can reshape T-cell activation/exhaustion programs) can “pre-condition” the immune system before a commercial T-cell–engaging bispecific antibody in relapsed/refractory multiple myeloma previously exposed to prior T-cell engager therapy. Patients receive sirolimus followed by either teclistamab (Johnson & Johnson/Janssen; BCMA×CD3 bispecific antibody that redirects T cells to BCMA-positive plasma cells) or talquetamab (Johnson & Johnson/Janssen; GPRC5D×CD3 bispecific antibody that redirects T cells to GPRC5D-positive myeloma cells). Key endpoints include safety/tolerability plus physiologic immune readouts (changes in immune cell populations), with preliminary anti-myeloma activity explored in expansion. The practical angle is whether a low-cost, immunology-forward “primer” can improve depth/durability after bispecific exposure, where T-cell fitness and antigen escape are common constraints. Today’s care for heavily pretreated myeloma typically cycles through proteasome inhibitors, IMiDs, anti-CD38 antibodies, and then BCMA-directed CAR-T and/or bispecifics, with newer non-BCMA bispecifics like talquetamab used to manage BCMA resistance or post-BCMA relapse.