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. Video Summary.

Fig. 1. Structure of G protein–coupled receptor class C group 5 member D (GPRC5D).

Graphical representation of GPRC5D showing the transmembrane region, which crosses the lipid bilayer seven times, and short extracellular N-terminal domain.

Fig. 2. Expressionof G protein–coupled receptor class C group 5 member D (GPRC5D) in healthy tissues and in multiplemyeloma (MM) versus other cancer types.

The first panel (A) shows mRNA expression levels of GPRC5D across a range of healthy tissues. The second panel (B) shows mRNA expression levels of GPRC5D in multiple myeloma compared with expression levels observed across a range of hematological and solid tumor malignancies. ALL acute lymphoblastic leukemia, AML acute myeloid leukemia, CML chronic myelogenous leukemia, DLBCL diffuse large B- cellly mphoma, NSC non-small cell. Reproduced from Smith EL, et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med. 2019;11(485):eaau7746.

Fig. 3. Structure of bispecific antibodies and GPRC5D-targeting CAR-T therapies.

The first panel (A) shows a generalized structure ofGPRC5D-targeting bispecific antibodies with the Fc region and CD3 and antigen-binding regions depicted. The second panel (B) shows the structure of CAR-T therapies with the target scFv and spacer regions and costimulatory and CD3 signaling domains depicted.