Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma

Abstract

Background B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T-cell therapy is an emerging treatment option for multiple myeloma. The aim of this systematic review and meta-analysis was to determine its safety and clinical activity and to identify factors influencing these outcomes. Methods We performed a database search using the terms “BCMA,” “CAR,” and “multiple myeloma” for clinical studies published between 01/01/2015 and 01/01/2020. The methodology is further detailed in PROSPERO (CRD42020125332). Results Twenty-three different CAR-T-cell products have been used so far in 640 patients. Cytokine release syndrome was observed in 80.3% (69.0–88.2); 10.5% (6.8–16.0) had neurotoxicity. A higher neurotoxicity rate was reported in studies that included more heavily pretreated patients: 19.1% (13.3–26.7; I2 = 45%) versus 2.8% (1.3–6.1; I2 = 0%) (p < 0.0001). The pooled overall response rate was 80.5% (73.5–85.9); complete responses (CR) were observed in 44.8% (35.3–54.6). A pooled CR rate of 71.9% (62.8–79.6; I2 = 0%) was noted in studies using alpaca/llama-based constructs, whereas it was only 18.0% (6.5–41.1; I2 = 67%) in studies that used retroviral vectors for CAR transduction. Median progression-free survival (PFS) was 12.2 (11.4–17.4) months, which compared favorably to the expected PFS of 1.9 (1.5–3.7) months (HR 0.14; p < 0.0001). Conclusions Although considerable toxicity was observed, BCMA-targeted CAR-T-cell therapy is highly efficacious even in advanced multiple myeloma. Subgroup analysis confirmed the anticipated inter-study heterogeneity and identified potential factors contributing to safety and efficacy. The results of this meta-analysis may assist the future design of CAR-T-cell studies and lead to optimized BCMA CAR-T-cell products.

CAR-T cell therapy: current limitations and potential strategies

“…Although CAR-T cell therapy has been a revolutionary cancer treatment tool, high rates of toxicities with some fatalities have prevented CAR-T cell therapy from becoming first-line treatment. Critical factors that likely determine the incidence and severity of CRS, HLH/MAS, and/or ICANS are the design of the CAR, the specific target, and the tumor type 81 . To date, the toxicities underlying CAR-T cell therapy have been most extensively characterized in patients receiving the first FDA approved CAR-T cell therapy, CD19-directed CARs 82 , 83 .…”

CAR T-cell therapy in multiple myeloma: more room for improvement

“…Despite being a plasma cell marker, BCMA is also co-expressed on normal B-lymphocytes, therefore, BCMA CAR T-cell therapy could also introduce on-target/off-tumor effects, where the common manifestations include B-cell aplasia, neutropenia, and immunosuppression that leads to increased infection risks. In the same aforementioned meta-analysis study, an average CRS and neurotoxicity prevalence of 80.3% and 10.5%, respectively, were reported 49 . While toxicities are frequent events, toxicity-related lethality in the patients are controllable.…”

“…Described in Table 2 are many more BMCA CAR T trials that are ongoing and recruiting, with different products demonstrating different levels of efficacy. A recent meta-analysis study on a total of 23 different BCMA-CAR T-cell products that have been used in a total of 640 patients, reported an average ORR of 80.5%, with 44.8% CR and 12.2 months median PFS 49 .…”

B-cell maturation antigen (BCMA) in multiple myeloma: the new frontier of targeted therapies

“…Recently published reviews as well as a meta-analysis provide a comprehensive summary of the efficacy and safety data of numerous CAR T-cell constructs currently in clinical trials. 7 , 8 , 45 Below, we highlight the most recent updates of the anti-BCMA CAR T-cell constructs bb2121, orvacabtagene autoleucel, and JNJ-68284528.…”