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.

Keywords: BCMA; CAR-T; Multiple myeloma.

Fig. 1

Overview of BCMA CAR-T-cell therapies used to date in multiple myeloma (MM) patients. Twenty-three different BCMA CAR-T-cell products involving 640 patients were identified. All products were derived from autologous T cells collected by apheresis (1), and enriched and activated ex vivo by anti-CD3/CD28 stimulation ± interleukin (IL)-2 or by single anti-CD3 stimulation ± IL-2 (2). The CAR gene was introduced in the T cells by lentiviral or retroviral transduction, or using a transposon (3). The resultant CAR-T cells were then further expanded (4) and administered to the patient by intravenous infusion, usually after lymphodepleting conditioning with cyclophosphamide (CP) ± fludarabine (Flu) (5). The BCMA CAR-T-cell products used to date can be divided into three groups based on the origin of the extracellular antigen-recognition domain: murine, human(ized), or alpaca/llama. The murine and human(ized) CAR constructs are usually based on the antigen-binding domain of a monoclonal antibody (mAb) in single-chain fragment variable (scFv) format with the variable regions of the heavy (V_H) and light chains (V_L) linked together in a single chain. Alpaca/llama BCMA CAR constructs are based on the structure of a camelid nanobody containing one or more V_HH domains. In addition, the intracellular co-stimulatory domain allows a further subdivision in 4-1BB-based and CD28-based BCMA CAR-T-cell products. Age = studies in whom the median patient age was ≥ or < 60 years. CO+ = co-stimulatory domain. HR = studies with a median of ≥ or < 50% high-risk myeloma patients (based on cytogenetics and/or International Staging System [ISS] score). n = number of patients. PLT = studies in which the median number of prior lines of therapy was ≥ or < 5. TM = transmembrane domain.

Fig. 2

Search strategy and study selection. ASCO = American Society of Clinical Oncology. ASH =American Society of Hematology. BCMA = B-cell maturation antigen. CAR = chimeric antigen receptor. EBMT = European Group for Blood and Marrow Transplantation. EHA = European Hematology Association

Fig. 3

Kaplan–Meier progression-free survival curves