OA-08: GPRC5D-Targeted CAR-T Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma Progressing after or Refractory to BCMA CAR-T cell therapy: Updated Results from a Phase 2 Clinical Trial

Introduction: BCMA-targeted immunotherapy has shown unprecedented results in the treatment of R/RMM, but most patients (pts) eventually develop progressive disease (PD). Therefore, additional treatment options with novel therapeutic targets are warranted. Early results from the Phase 2 trial of autologous GPRC5D chimeric antigen receptor (CAR) -T cells in pts with R/R MM(ChiCTR2100048888) demonstrated an encouraging clinical efficacy and manageable safety profile, including pts with previous anti-BCMA CAR-T cell therapy. Here, we report updated clinical data on GPRC5D CAR-T cell therapy in R/R MM pts who have progressed or developed refractory disease after anti-BCMA CAR-T therapy.

Methods: This phase 2, single-arm study enrolled pts (18-70 years) with R/R MM. Eleven R/R MM pts with previous anti-BCMA CAR-T cell therapy were treated as part of the phase 2 study as previously reported. The primary endpoint was the proportion of pts who achieved an overall response. Safety was also assessed in eligible pts.

Results: Eleven R/R MM pts with previous anti-BCMA CAR-T cell therapy were enrolled and underwent apheresis between November 25, 2021 and November 8, 2022. Median age was 63 (range 46-70) years and pts received a median of 5 (range 2-12) lines of therapy. Of 11 pts, 6 (55%) had extramedullary diseases, 6 (55%) had a high tumor burden, 4 (36%) had R-ISS stage III disease, and 4 (36%) had high-risk cytogenetic abnormalities.
Median follow-up was 14.8 months (range 5.8-16.9). Eleven (100%) pts had an overall response, of whom 5 (45%) had a complete response (CR) or better. Two pts had received repeated anti-BCMA CAR-T cell infusions with no responses at the last time, of whom 1 patient achieved CR, and the other partial response after anti-GPRC5D CAR-T cell infusion. 8 (73%) of the 11 pts were minimal residual disease (MRD) negative in the bone marrow by multicolor flow cytometry (sensitivity: 10 -5). The median progression-free survival was 6.4 months (95% CI: 1.2 to 11.6 months). At the time of analysis, 5 (45%) pts are progression free and followed without additional therapy. We also noted robust GPRC5D-CAR expansion in the peripheral blood using qPCR with available data (peak expansion CAR DNA copies/μL, median: 22711; range: 2563- 75561).
Grade 3 or higher hematological toxicities were neutropenia (10[91%]), anemia (7[64%]), and thrombocytopenia (6[55%]). Cytokine release syndrome occurred in 10 (91%) of 11 pts (all were grade 1 or 2); 5 (45%) pts received tocilizumab and 3 (27%) received dexamethasone for the management of CRS. No neurological toxic effects were reported. One (9%) patient had a grade 1 nail change. One patient died of intracranial hemorrhage 29 days after CAR-T cell infusion, and no abnormal coagulation was observed.

Conclusions: Our study demonstrates anti-GPRC5D CAR T-cell therapy are clinical active with a favorable safety profile in pts who do not respond to or relapse after anti-BCMA CAR T-cell therapy.