A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma

Abstract

BackgroundChimeric 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).MethodsThis 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/m2. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 106 cells/kg [range, 0.07 to 2.1 × 106]) 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.ResultsAt 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.ConclusionsLCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM.Trial registrationClinicalTrials.gov, NCT03090659; Registered on March 27, 2017, retrospectively registeredElectronic supplementary materialThe online version of this article (10.1186/s13045-018-0681-6) contains supplementary material, which is available to authorized users.

B cell maturation antigen‐specific chimeric antigen receptor T cells for relapsed or refractory multiple myeloma: A meta‐analysis

“…The baseline characteristics of the included studies are listed in Table 1. A total of 314 patients were included in the 18 studies, [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] all of which were single-arm early phase studies that included only patients with RRMM (17 studies) or newly diagnosed myeloma (1 study). Patients included in RRMM studies were heavily pretreated and received a median of 6 prior lines of treatment (proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, 1-2 autologous stem cell transplants).…”

“…31,43 Two studies did not report on the costimulatory domain that was used for the CAR T product. 32,36 Most studies used fludarabine and cyclophosphamide for lymphodepletion while one study used busulfan and cyclophosphamide 46 and one study used cyclophosphamide only. 42 Most studies included patients who underwent autologous stem cell transplantation as part of prior treatment while transplant data were lacking in six studies.…”

“…Additionally, the risk of evidence imprecision F I G U R E 1 shows the PRISMA flow diagram of the study selection process. Out of 18 identified studies, [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] three were included only in the qualitative review because they evaluated CAR T products that, in addition to BCMA, targeted other antigens such as CD19 and CD38. [46][47][48] The remaining 15 studies were included in the quantitative systematic review and meta-analysis [Colour figure can be viewed at wileyonlinelibrary.com]…”

Updates on CAR T‐cell therapy in B‐cell malignancies

“…Fifty‐seven patients with a median of three prior therapies were enrolled and treated. Fifty (88%) had a response, and 39 had a complete remission (68%), with an MRD‐negative response in the bone marrow of 36 patients (63%) . No clear correlation was seen between the BCMA level as measured by flow cytometry, though the authors refer to percent positivity of cells and not to fluorescence intensity or site density .…”

Cellular therapy: Immune‐related complications

“…Recent efforts have been aimed at developing CAR‐T directed toward other antigens and in other indications. The most developed program is a B‐cell maturation antigen (BCMA) directed CAR‐T in clinical trials for relapsed/refractory multiple myeloma . Additional B‐cell targeted single antigen therapy CAR‐T directed at TSLPR and CD38 are under development, though these are in earlier stages of development as compared with BCMA directed CAR‐T .…”