GPRC5D (G protein-coupled receptor class C group 5 member D) is a cell-surface protein that serves as a major therapeutic target for multiple myeloma.
Key Facts About GPRC5DExpression: It is highly expressed on the surface of multiple myeloma cells, with very limited expression in healthy human tissues outside of hard keratinized structures like hair follicles.
GPRC5D is highly expressed on plasma cells from patients with multiple myeloma, including smoldering disease, and generally shows little or no expression in normal B cells, T cells, NK cells, myeloid cells, or marrow progenitors.
This makes it a useful target for T-cell–redirecting therapies, particularly as an alternative or sequential target after BCMA-directed therapy.
GPRC5D-G protein–coupled receptor, class C, group 5, member D is an orphan, seven-transmembrane GPCR encoded on chromosome 12p13.
Because of its restricted expression profile, it is an ideal target for immunotherapies, offering a vital alternative for patients whose cancer has progressed after BCMA-targeted treatments.
It had become an important immunotherapy antigen in multiple myeloma because of strong expression on malignant plasma cells and relatively restricted normal-tissue expression.
Approved Therapies: Talquetamab is a first-in-class, FDA-approved bispecific T-cell engager antibody that binds to both CD3 on T cells and GPRC5D on myeloma cells to trigger an immune attack against the tumor.
Targeting GPRC5D can lead to unique on-target, off-tumor toxicities affecting hard keratinized tissues, which commonly include skin peeling, nail changes, and taste alterations (dysgeusia).
The narrow normal-tissue profile predicts a toxicity pattern distinct from BCMA targeting.
In addition to plasma cells, GPRC5D expression has been identified in:
Keratinized tissue and hair follicles Skin adnexal structures, including eccrine glands The tongue—especially the base of filiform papillae / keratinizing epithelium.
Accordingly, GPRC5D-directed treatment—especially talquetama can cause characteristic on-target, off-tumor epithelial toxicities, such as dysgeusia or hypogeusia, dry mouth, oral mucosal changes, skin rash or desquamation, nail disorders, and alopecia.
Cytokine-release syndrome and infection risk are also relevant, as with other T-cell–engaging strategies.
CD3 bispecific antibody
Talquetamab-Bridges GPRC5D-positive myeloma cells to CD3-positive T cells.
The first approved GPRC5D-directed agent for heavily pretreated, triple-class–exposed relapsed/refractory myeloma.
Autologous CAR-T cells directed against GPRC5D ha demonstrated activity in relapsed/refractory myeloma, including patients previously treated with BCMA-directed therapy.
Clinical positioning
GPRC5D is particularly relevant in relapsed/refractory myeloma because it offers antigenic diversification beyond BCMA.
Practical uses include:
Treating disease after prior BCMA CAR-T, BCMA bispecific, or BCMA ADC exposure.
Considering sequential or potentially combination immunotherapy approaches, while balancing cumulative T-cell dysfunction, cytopenias, infection risk, and antigen escape.
Providing an “off-the-shelf” option with talquetamab when CAR-T manufacturing time, eligibility, access, or prior BCMA exposure affects treatment selection.
GPRC5D attractiveness derives more from its plasma-cell–restricted surface expression and druggability than from a known essential signaling function in malignant plasma cells.
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