GPRC5D (G Protein-Coupled Receptor Class C Group 5 Member D)

The potent and selective antitumor activity of ramantamig, with a clonal depleting ability in vitro, ex vivo, and in vivo warrants clinical evaluation of its ability to induce durable responses in myeloma. Phase 1 clinical trials are ongoing for patients with relapsed/refractory MM (NCT05652335, NCT06768489).

As GPRC5D-targeted agents advance through clinical development, large-scale prospective trials will be essential to define their therapeutic positioning and improve patient outcomes. GPRC5D is poised to become a leading next-generation target in MM immunotherapy following B-cell maturation antigen.

Adverse events were manageable and led to few treatment discontinuations. This review reports on talquetamab safety in MonumenTAL-1, with an additional pharmacy focus on strategies related to drug dispensing and clinical management.

P1, N=18, Recruiting, Chunrui Li | Trial completion date: Mar 2024 --> Oct 2025 | Trial primary completion date: Dec 2022 --> Sep 2025

The GPRC5D positivity rate in the plasma cells of patients with NDMM is associated with 1q21 gain and immune status. High GPRC5D expression at diagnosis may predict poor response to induction therapy and an unfavorable prognosis.

P1, N=12, Recruiting, Nanjing IASO Biotechnology Co., Ltd. | Trial completion date: Mar 2025 --> Oct 2026 | Trial primary completion date: Mar 2024 --> Sep 2025

Furthermore, azacitidine treatment induced GPRC5D mRNA and protein expression in hypermethylated MM cell lines. Our findings highlight that biallelic genetic inactivation and hypermethylation-driven epigenetic silencing are key mechanisms contributing to GPRC5D loss and treatment resistance.

GPRC5D is an active and safe target that shows promising results in the treatment of relapsed and/or refractory (R/R) MM and heavily pretreated patients.

P1, N=24, Recruiting, Dapartment of Hematology, West China Hospital, Sichuan University; West China Hospital of Sichuan University

Our findings underscore the importance of evaluating surface protein expression in HMCLs when modeling MM. The observed variations in expression levels emphasize the need for a strategic selection of cell lines based on the study's objectives.

Moreover, G protein-coupled receptor class C Group 5 member D (GPRC5D) is highly expressed in MM cells independently of B cell maturation antigen (BCMA) and is a highly promising target following BCMA. Aside from emphasizing the therapeutic efficacy and safety of targeting GPRC5D for the treatment of MM, this study also provides a prospective view on the mechanisms of drug resistance and relapse associated with GPRC5D-targeted therapies, as well as the timing of sequential or combined treatment strategies involving the dual targeting of both GPRC5D and BCMA.

Similar results for tumor inhibition were observed, as human GPRC5D-specific T cells and antibodies were induced by DNA vaccines. Taken together, these findings underscore the potential of GPRC5D-targeted DNA vaccines as versatile platforms for the treatment and prevention of MM.