In a phase I clinical trial, 17 patients with relapsed/refractory multiple myeloma were treated with lymphodepleting chemotherapy followed by CAR T cells that simultaneously targeted two epitopes of the B cell maturation antigen (BCMA). The ORR was 88.2% (13 stringent CRs, 2 very good PRs), with 8 ongoing responses 11 months after therapy. All patients experienced cytokine release syndrome (CRS; 10 mild, 7 severe), and 3 had tumor lysis syndrome (TLS); one patient died from severe CRS and TLS. Prior auto-HSCT was associated with sustained response, while the presence of anti-CAR T antibodies was a risk factor for relapse or progressive disease.
Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.
Author Info: (1) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao T
Author Info: (1) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (2) Department of Hematology, Jiangsu Province Hospital, First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, China. (3) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (4) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (5) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (6) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (7) Department of Hematology, Jiangsu Province Hospital, First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, China. (8) Department of Hematology, Changzheng Hospital, The Second Military Medical University, 200003 Shanghai, China. (9) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (10) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (11) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (12) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (13) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (14) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (15) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (16) Department of Hematology, Changzheng Hospital, The Second Military Medical University, 200003 Shanghai, China. (17) Department of Hematology, Changzheng Hospital, The Second Military Medical University, 200003 Shanghai, China. (18) Department of Radiology and Nuclear Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (19) Department of Radiology and Nuclear Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (20) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (21) Department of Hematology, Changzheng Hospital, The Second Military Medical University, 200003 Shanghai, China. (22) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (23) Nanjing Legend Biotech, 210008 Nanjing, China. (24) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China; zchen@stn.sh.cn frank.fan@legendbiotech.com houjian@medmail.com.cn lijianyonglm@medmail.com.cn jianqingmi@shsmu.edu.cn sjchen@stn.sh.cn. (25) Nanjing Legend Biotech, 210008 Nanjing, China zchen@stn.sh.cn frank.fan@legendbiotech.com houjian@medmail.com.cn lijianyonglm@medmail.com.cn jianqingmi@shsmu.edu.cn sjchen@stn.sh.cn. (26) Department of Hematology, Changzheng Hospital, The Second Military Medical University, 200003 Shanghai, China; zchen@stn.sh.cn frank.fan@legendbiotech.com houjian@medmail.com.cn lijianyonglm@medmail.com.cn jianqingmi@shsmu.edu.cn sjchen@stn.sh.cn. (27) Department of Hematology, Jiangsu Province Hospital, First Affiliated Hospital of Nanjing Medical University, 210029 Nanjing, China; zchen@stn.sh.cn frank.fan@legendbiotech.com houjian@medmail.com.cn lijianyonglm@medmail.com.cn jianqingmi@shsmu.edu.cn sjchen@stn.sh.cn. (28) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China; zchen@stn.sh.cn frank.fan@legendbiotech.com houjian@medmail.com.cn lijianyonglm@medmail.com.cn jianqingmi@shsmu.edu.cn sjchen@stn.sh.cn. (29) State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China; zchen@stn.sh.cn frank.fan@legendbiotech.com houjian@medmail.com.cn lijianyonglm@medmail.com.cn jianqingmi@shsmu.edu.cn sjchen@stn.sh.cn.
