Clinical Scorecard: Exploring GPRC5D as a New Therapeutic Target in Multiple Myeloma: A Comprehensive Review
At a Glance
Category
Detail
Condition
Multiple Myeloma (MM), a genetically complex hematologic malignancy
Key Mechanisms
GPRC5D is an orphan G-protein coupled receptor highly expressed on MM cells, enabling T-cell–redirecting immunotherapy with minimal off-target effects
Target Population
Patients with multiple myeloma, including those with relapsed/refractory disease and high-risk genetic profiles
Care Setting
Hematology/oncology clinical settings, including specialized centers administering immunotherapies
Key Highlights
GPRC5D is selectively expressed on malignant plasma cells in MM with limited expression in normal tissues, primarily hair follicles and plasma cells.
GPRC5D-targeting T-cell–redirecting agents offer a novel mechanism distinct from BCMA therapies, potentially overcoming resistance and relapse.
High GPRC5D expression correlates with increased tumor burden and poor prognosis but is independent of BCMA expression.
Guideline-Based Recommendations
Diagnosis
Assess GPRC5D expression on MM cells using complementary assays such as immunohistochemistry, in situ hybridization, RNA sequencing, or flow cytometry.
Management
Consider GPRC5D-targeting T-cell–redirecting therapies as a treatment option for MM, especially in patients with relapsed or refractory disease.
Combine GPRC5D-targeting agents with BCMA-targeting therapies to address tumor heterogeneity and reduce relapse risk.
Monitoring & Follow-up
Monitor disease progression and response to therapy through standard MM clinical and laboratory assessments.
Evaluate GPRC5D expression status during treatment to inform therapeutic decisions.
Risks
Potential off-tumor effects may be limited due to restricted GPRC5D expression, but vigilance for skin and epithelial-related adverse events is warranted given expression in hair follicles and skin.
Patient & Prescribing Data
Patients with multiple myeloma, including those with high-risk genetic aberrations and relapsed/refractory disease
GPRC5D-targeting therapies may provide effective cytotoxicity with reduced antigen shedding and could be used alone or in combination with BCMA-targeting agents to improve outcomes.
Clinical Best Practices
Utilize multi-modal assays to accurately determine GPRC5D expression in MM cells prior to therapy initiation.
Incorporate GPRC5D-targeting agents in treatment regimens for patients who have exhausted BCMA-directed therapies or exhibit BCMA loss.
Monitor for and manage potential adverse effects related to GPRC5D expression in skin and epithelial tissues.
Consider patient-specific tumor heterogeneity and genetic risk factors when selecting immunotherapy targets.
by Paula Rodriguez-Otero, Niels W. C. J. van de Donk, Kodandaram Pillarisetti, Ingrid Cornax, Deeksha Vishwamitra, Kathleen Gray, Brandi Hilder, Jaszianne Tolbert, Thomas Renaud, Tara Masterson, Christoph Heuck, Colleen Kane, Raluca Verona, Philippe Moreau, Nizar Bahlis, Ajai Chari
