In an ongoing phase I trial, 57 patients with relapsed/refractory multiple myeloma were treated with LCAR-B38M, a high-avidity CAR T cell therapy targeting two epitopes of the B cell maturation antigen. All patients experienced adverse events, with 90% reporting cytokine release syndrome (mostly grades 1 and 2); 65% had grade ≥ 3 adverse events. At data cutoff, overall response rate was 88% (68% CR, 5% very good PR, 14% PR), which was independent of BCMA expression levels. Median progression-free survival was 15 months; median overall survival was not reached. 20% of the initial responders progressed by the data cutoff date.

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM). METHODS: This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m(2). LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 x 10(6) cells/kg [range, 0.07 to 2.1 x 10(6)]) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group. RESULTS: At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced >/= 1 adverse events (AEs). Grade >/= 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade >/= 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval [CI], 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached. CONCLUSIONS: LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03090659 ; Registered on March 27, 2017, retrospectively registered.

Author Info: (1) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (2) Department of Hematology, The

Author Info: (1) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (2) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (3) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (4) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (5) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (6) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (7) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (8) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (9) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (10) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (11) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (12) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (13) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (14) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (15) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (16) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (17) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (18) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (19) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (20) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (21) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. (22) National-Local Joint Engineering Research Center of Biodiagnostics & Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, ShaanXi, China. (23) National-Local Joint Engineering Research Center of Biodiagnostics & Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, ShaanXi, China. (24) Department of Clinical Laboratory, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, ShaanXi, China. (25) Department of Clinical Laboratory, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, ShaanXi, China. (26) Nanjing Legend Biotech Inc., Nanjing, 210000, Jiangsu, China. (27) Nanjing Legend Biotech Inc., Nanjing, 210000, Jiangsu, China. (28) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. National-Local Joint Engineering Research Center of Biodiagnostics & Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, ShaanXi, China. (29) Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, ShaanXi, China. zhangwanggang2003@yahoo.com.

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