A response rate of nearly 90% was achieved in an exploratory clinical study of a chimeric antigen receptor (CAR) T-cell (CAR-T) therapy targeted against 2 epitopes of the same B-cell antigen in patients with relapsed/refractory multiple myeloma (R/R MM).

R/R MM is associated with a poor prognosis. Treatment options are limited for these patients, and other therapeutic approaches are urgently needed.

Several previously conducted small trials of CAR-T therapy targeted against the B-cell maturation antigen (BCMA) have shown promising results in the setting of R/R MM. These studies have included a CAR-T preparation called LCAR-B38M that is targeted against 2 distinct epitopes on BCMA. This exploratory trial was conducted to investigate the kinetics of the investigational therapy, as well to further optimize the drug delivery schedule and the management of adverse events.

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Of the 17 patients with R/R MM treated with LCAR-B38M at 3 clinical centers in China between April 2017 and November 22, 2017, 12 individuals had received 3 or more lines of prior therapy, 8 had previously undergone autologous hematopoietic stem cell transplantation (HSCT), and 5 had extramedullary disease.

Prior lymphodepletion with either cyclophosphamide/fludarabine followed by 3 separate CAR-T infusions or cyclophosphamide followed by 1 CAR-T infusion was administered to 8 patients and 9 patients, respectively.  

Kinetic studies showed peak values of CAR-T cells were reached at 5 days to 30 days, with T cells persisting up to 9 months. Similar treatment efficacy, safety, and CAR-T cell peak values (P =.313) were noted with the 2 delivery schedules; hence, results for these 2 patient groups were combined.

An overall response rate of 88.2% (13 stringent complete responses [sCRs] and 2 very good partial responses [VGPRs]) was achieved in this patient cohort. Furthermore, 7 patients with sCRs and 1 patient with a VGPR had ongoing responses at 11 months following CAR-T infusion.

“In a number of patients the initial therapeutic effect was a PR, followed by VGPR, and then CR,” the study authors noted.

Although age, gender, cytogenetic markers, conditioning regimen, CAR-T therapy delivery schedule, or initial CR or VGFR did not correlate with likelihood of achieving a sustained response, there was evidence that patients receiving prior autologous HSCT and those with extramedullary lesions were more and less likely to experience a sustained response, respectively.

In addition, the presence of anti–CAR-T antibody was identified as a risk factor for relapse following administration of LCAR-B38M.

Cytokine release syndrome (CRS) was experienced by all 17 patients in the study, with 6 patients experiencing grade 3 CRS, and 1 case of CRS-related death. All patients with severe CRS, and 3 with mild CRS (grade 1/2) required treatment with the anti-interleukin 6 receptor blocker, tocilizumab, with symptoms typically resolving within 7 days following administration. Tumor lysis syndrome was experienced by 3 patients, necessitating rapid administration of supportive care.

“Biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable,” the study authors concluded.

Disclosure: Some of the study authors are employees of Nanjing Legend Biotech.

Reference

Xu J, Chen LJ, Yang SS, Sun Y, et al. Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma [published online April 15, 2019]. Proc Natl Acad Sci U S A. doi: 10.1073/pnas.1819745116