Identification of CD320, SLC44A1 and TNFRSF13B as potential novel therapeutic targets for CAR T-cell therapy in multiple myeloma.

Introduction: Multiple myeloma (MM) remains incurable despite effective therapies, with most patients eventually relapsing. Chimeric antigen receptor (CAR) T-cell therapy has improved treatment options but is limited by antigen escape and lack of durable responses. To expand the spectrum of actionable antigens, we sought to identify novel CAR-T actionable targets. Methods: We analyzed 11 publicly available single-cell RNA sequencing datasets from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), MM, relapsed/refractory MM (RRMM) and healthy donors. Plasma cell-specific surface proteins were identified via bioinformatic filtering and validated on external bulk transcriptomic database of ~2,000 patients and by flow cytometry on MM cell lines and primary bone marrow samples. Results: We identified 15 plasma cell-associated surface proteins, including BCMA, CD138, CD38, and SLAMF7. Five molecules-TNFRSF13B (TACI), CD59, FCGR2B (CD32B), SLC44A1 (CD92), and CD320-were prioritized for further study. CD320 and SLC44A1 were upregulated with disease stage and associated with poor survival, while TNFRSF13B, CD59, and FCGR2B were enriched in advanced disease and linked to better outcomes. Cytogenetic clustering linked these molecules to specific genetic backgrounds, suggesting subtyperelated expression patterns. Flow cytometry confirmed the surface expression of CD59, SLC44A1, TNFRSF13B and CD320. Discussion: CD320, SLC44A1, and TNFRSF13B are promising, clinically relevant targets for CAR T-cell therapy in MM. Their stage-specific expression and prognostic significance support their potential to enhance existing immunotherapeutic strategies.