Dr Parrondo on the Investigation of GPRC5D-Targeted CAR T-Cell Therapy in Multiple Myeloma

Ricardo D. Parrondo, MD, hematologist/oncologist, assistant professor, Mayo Clinic, discusses the exploration of the non-BCMA CAR T-cell target GPRC5D in multiple myeloma.

GPRC5D has emerged as a new target of interest within multiple myeloma, sparking interest in the development of novel CAR T-cell products and bispecific antibodies targeting this antigen, Parrondo begins.

A phase 1 dose-escalation study (NCT04555551) of MCARH109, a first-in-GPRC5D-targeted CAR T-cell therapy, is being conducted in patients with relapsed/refractory myeloma, Parrondo continues. The study enrolled heavily pretreated patients, as well as those with high-risk cytogenetics, and patients who received prior anti-BCMA CAR T-cell therapy, he details.

Previously reported results showed that MCARH109 demonstrated a manageable safety profile and achieved high rates of initial clinical responses and minimal residual disease negativity across multiple dose levels, Parrondo says. The ongoing dose escalation study aims to further evaluate the efficacy of MCARH109, with additional patients planned for treatment at higher doses.

The development of GPRC5D-targeted therapies extends beyond CAR T cell therapy, with various companies pursuing other agents targeting this antigen as well as BMCA/GPRC5D–targeted combination regimens, Parrondo notes.

Furthermore, the FDA approved the GPRC5D-targeting bispecific antibody talquetamab (Talvey) for relapsed/refractory multiple myeloma in August 2023, marking a significant milestone in this field, Parrondo states. The regulatory decision was supported by data from the phase 1/2 MonumenTAL-1 studies (NCT03399799/NCT04634552), in which talquetamab demonstrated notable objective response rates (ORRs), leading to FDA approval of both the 0.8 mg/kg and 0.4 mg/kg biweekly doses.

These findings indicate the potential of GPRC5D-targeted therapies, highlighting CAR T-cell therapy and bispecific antibodies, as promising treatment options for patients with multiple myeloma, Parrondo says. Continued research could elucidate and potentially allow for sequencing of BCMA-targeted CAR T-cell therapy with GPRC5D-targeted CAR T-cell products, as well as the development of combination approaches targeting these different antigens, Parrondo concludes.