Emerging GPRC5D-Targeted therapies for multiple myeloma: a comprehensive review

GPRC5D is a promising myeloma-associated antigen, and several GPRC5D-targeted therapies are under active investigation, including CAR T cells, bispecific and trispecific antibodies, and antibody-drug conjugates. This class of agents is poised to transform the landscape of multiple myeloma treatment.

Here, we review the biology of GPRC5D, the current and emerging uses of talquetamab in relapsed/refractory multiple myeloma, the landscape of investigational GPRC5D-targeted drugs, and how these agents are likely to be implemented into future clinical practice.

Talquetamab is currently the only approved GPRC5D-targeted therapy, primarily used for BCMA-refractory multiple myeloma, but there is no biological reason BCMA therapies must be exhausted before targeting GPRC5D; utilizing GPRC5D in innovative ways will be key to fully realizing its therapeutic potential. Newer trials are exploring more aggressive approaches combining multiple immunotherapy targets within a single line to prevent resistance and potentially achieve a cure. While GPRC5D-targeted therapies are highly effective, they also pose significant toxicity risks including oral, skin, nail, and cerebellar toxicity. In addition to improving efficacy, future research must also focus on optimizing dosing, identifying biomarkers for toxicity, and developing better strategies for managing adverse events to optimize the risk-benefit profile of these therapies.