BCMA/GPRC5D bispecific CAR T-cell therapy for relapsed/refractory multiple myeloma with extramedullary disease: a single-center, single-arm, phase 1 trial

Abstract

Relapsed/refractory multiple myeloma (RRMM) with extramedullary disease (EMD) represents a challenging condition, with limited treatment options and poor prognosis. We conducted a phase 1 clinical trial to evaluate the safety and effectiveness of a novel bispecific chimeric antigen receptor (CAR) T-cell therapy targeting two antigens, B-cell maturation antigen and G protein-coupled receptor class C group 5 member D (BCMA/GPRC5D), in this high-risk population. A total of 12 patients were enrolled, of whom 3 were excluded due to disease progression or death before CAR T-cell infusion, despite meeting the inclusion criteria, leaving 9 for analysis. The median follow-up was 6.08 months (Interquartile Range [IQR]: 0.9-16.5). All patients received BCMA/GPRC5D bispecific CAR T-cell therapy after bridging therapy with localized radiotherapy or Elranatamab. Efficacy assessments revealed that 100% of patients achieved partial response (PR) or better, with 44.4% achieving complete response (CR). Common adverse events included hematological toxicities such as anemia, leukopenia, and thrombocytopenia. Cytokine release syndrome (CRS) occurred in 66.7% of patients, all of which were grade 1-2, and no neurotoxicity (ICANS) was observed. The 1-year overall survival (OS) and progression-free survival (PFS) rates were 60% and 63%, respectively. Median OS and PFS were not reached. Collectively, these findings highlight a potential therapeutic strategy involving BCMA/GPRC5D dual-targeted CAR T-cell therapy for patients with aggressive forms of multiple myeloma, particularly those with extramedullary disease, and support the need for further exploration and validation in larger, multi-center clinical studies.

Keywords: BCMA; CAR T-cell therapy; Extramedullary disease; GPRC5D; Immunotherapy; Relapsed/refractory multiple myeloma.

Fig. 1

Clinical Responses, CAR T-Cell Expansion, Survival, Adverse Events, and Inflammatory Markers in Patients Treated with BCMA/GPRC5D Dual Targeted CAR T-Cells. A Overall Response Rate (ORR) and Individual Patient Responses. The left bar chart shows the overall response rate (ORR), with 100% of patients (9/9) achieving clinical response (PR, VGPR, or CR). The right panel shows individual patient responses: each bar represents the duration of response (in days) for each patient, with different colors indicating the best response: Complete Response (CR) in green, Very Good Partial Response (VGPR) in pink, Partial Response (PR) in blue, and Progressive Disease (PD) in red. Data points indicate patient response status during the follow-up period. B CAR T-Cell Expansion in Peripheral Blood. The number of CAR T-Cells (cells/µL) in peripheral blood is shown for each patient across different time points post-infusion. Lines represent individual patient data, with each color corresponding to a different patient. C Overall Survival (OS) and Progression-Free Survival (PFS). Kaplan–Meier survival curves depicting the overall survival (OS, top) and progression-free survival (PFS, bottom) of patients following BCMA/GPRC5D dual-targeted CAR T-Cell infusion. D Adverse Events (AEs). A horizontal bar plot showing the incidence of various adverse events (AEs) observed in patients post-treatment, grouped by severity (Grade 1–2, blue and Grade 3–4, light blue). The left side represents CAR T-related AEs, and the right side represents all AEs, both collected from the same patient cohort. This mirrored design facilitates direct comparison between the two categories. The listed AEs include neutropenia, leukopenia, hypokalemia, anemia, hypocalcemia, lymphopenia, CRS, elevated AST/ALT, abdominal pain, infection, and others. Each bar represents the percentage of patients experiencing each event. Abbreviations: ORR = Overall Response Rate, CR = Complete Response, VGPR = Very Good Partial Response, PR = Partial Response, PD = Progressive Disease, OS = Overall Survival, PFS = Progression-Free Survival, AEs = Adverse Events, CRS = Cytokine Release Syndrome