BCMA/GPRC5D Dual-Target CAR-T Cell Immunotherapy for Relapsed/Refractory Multiple Myeloma - NCT07927842

Sponsor: Liping Dou Conditions: Multiple Myeloma; Relapsed/Refractory Multiple Myeloma This is a single-center, open-label, single-arm, investigator-initiated clinical study to evaluate the safety, tolerability, and preliminary efficacy of SL4903, a BCMA/GPRC5D dual-target autologous CAR-T cell injection, in patients with relapsed or refractory multiple myeloma (R/R MM) whose clonal plasma cells are positive for BCMA and/or GPRC5D. After leukapheresis, participants receive lymphodepleting conditioning (fludarabine 30 mg/m\^2/day plus cyclophosphamide 500 mg/m\^2/day on Days -5 to -3), followed by a single intravenous infusion of SL4903 at a dose of 1×10\^6 CAR-positive cells/kg; bridging therapy (e.g., immunomodulatory drugs or anti-CD38 monoclonal antibody) is permitted between leukapheresis and conditioning at the investigator's discretion. Treatment-emergent adverse events, including cytokine release syndrome (CRS), neurotoxicity, hematologic toxicity, and organ toxicity, will be assessed within 3 months after infusion. Preliminary antitumor activity will be evaluated according to the 2016 International Myeloma Working Group (IMWG) criteria, including objective response rate (ORR), complete response rate (CRR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and measurable residual disease (MRD) negativity rate. Pharmacokinetics (Cmax, Tmax, persistence, and AUCd0-28 of CAR-T cells in peripheral blood by flow cytometry and qPCR) and pharmacodynamics (peripheral blood plasma cell proportion and cytokine levels) will also be evaluated. Participants will be followed for safety and efficacy for up to 2 years after cell therapy. This is a single-center, single-arm, open-label, investigator-initiated clinical study of SL4903 autologous T-cell injection in adults with R/R MM. SL4903 is an autologous CAR-T cell product in which the CAR comprises, in order, a GPRC5D-targeting nanobody (VHH1), a BCMA-targeting nanobody (VHH2), a CD8 hinge region, a CD8 transmembrane domain, a 4-1BB costimulatory domain, and a CD3-zeta signaling domain; autologous peripheral blood mononuclear cells are collected by leukapheresis (approximately 80-120 mL), transduced ex vivo with a lentiviral vector, and expanded over a manufacturing period of approximately 7-8 days. Participants receive lymphodepleting conditioning with fludarabine (30 mg/m\^2/day) and cyclophosphamide (500 mg/m\^2/day) on Days -5 to -3, which may be adjusted at the investigator's discretion, followed by a single intravenous infusion of SL4903 at 1×10\^6 CAR-positive cells/kg on Day 0. Planned enrollment is 20 participants; enrollment accounts for potential CAR-T manufacturing failure or rapid disease progression that may preclude infusion. Safety assessments include adverse events and serious adverse events graded per NCI CTCAE v5.0, with CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) graded per the ASTCT consensus criteria; infection, hematologic toxicity, organ toxicity, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), and tumor lysis syndrome (TLS) are also monitored. Disease response is assessed per the 2016 IMWG criteria at baseline, Day 28, and Months 2, 3, 6, 12, 18, and 24, including serum/urine M-protein studies, serum free light chains, bone marrow examination with flow cytometry/MRD, and imaging (preferably PET-CT) for extramedullary disease. Pharmacokinetic assessments include CAR-T cell expansion in peripheral blood by flow cytometry and qPCR (Cmax, Tmax, in vivo persistence, and AUCd0-28); pharmacodynamic assessments include peripheral blood plasma cell proportion/count and cytokine quantification (at least IL-6, IL-2, IL-10, IFN-gamma, and TNF-alpha).