GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review

Abstract

Multiple myeloma is a genetically complex and heterogenous malignancy with a 5-year survival rate of approximately 60%. Despite advances in therapy, patients experience cycles of remission and relapse, with each successive line of therapy associated with poorer outcomes; therefore, therapies with different mechanisms of action against new myeloma antigens are needed. G protein–coupled receptor class C group 5 member D (GPRC5D) has emerged as a novel therapeutic target for the treatment of multiple myeloma. We review the biology and target validation of GPRC5D, and clinical data from early phase trials of GPRC5D-targeting bispecific antibodies, talquetamab and forimtamig, and chimeric antigen receptor T cell (CAR-T) therapies, MCARH109, OriCAR-017, and BMS-986393. In addition to adverse events (AEs) associated with T-cell–redirection therapies irrespective of target, a consistent pattern of dermatologic and oral AEs has been reported across several trials of GPRC5D-targeting bispecific antibodies, as well as rare cerebellar events with CAR-T therapy. Additional studies are needed to understand the underlying mechanisms involved in the development of skin- and oral-related toxicities. We review the strategies that have been used to manage these GPRC5D-related toxicities. Preliminary efficacy data showed overall response rates for GPRC5D-targeting T-cell–redirecting therapies were ≥64%; most responders achieved a very good partial response or better. Pharmacokinetics/pharmacodynamics showed that these therapies led to cytokine release and T-cell activation. In conclusion, results from early phase trials of GPRC5D-targeting T-cell–redirecting agents have shown promising efficacy and manageable safety profiles, including lower infection rates compared with B-cell maturation antigen- and Fc receptor-like protein 5-targeting bispecific antibodies. Further clinical trials, including those investigating GPRC5D-targeting T-cell–redirecting agents in combination with other anti-myeloma therapies and with different treatment modalities, may help to elucidate the future optimal treatment regimen and sequence for patients with multiple myeloma and improve survival outcomes.

Leukemic Stem Cells and Hematological Malignancies

“…A recent study shows that GPRC5D is a G protein-coupled receptor and a target for multiple myeloma treatment. Talquetamab targets GPRC5D and has shown efficacy in refractory multiple myeloma patients [ 73 ].…”

Multiple Myeloma: The Role of Autologous Stem Cell Transplantation in the Era of Immunotherapy

“…Novel therapeutic anti-GPRC5D strategies, such as CAR-T cells and the first-in-class BsAb talquetamab, showed great efficacy with acceptable toxicity [82][83][84][85]. Regarding talquetamab, the updated results from the phase 1/2 MonumenTAL-1 trial (NCT03399799/ NCT04634552) showed a high and rapid ORR in the pivotal cohorts (74%, ≥VGPR: 59% at the dose of 405 µg/kg; 73%, ≥VGPR: 57% at the dose of 800 µg/kg), as well as in patients who had received prior T cell redirecting therapy (63%, ≥VGPR: 53%), without new safety concerns [83,86].…”