Clinical remissions and limited toxicity in a first-in-human multicenter study of bb2121, a novel anti-BCMA CAR T cell therapy for relapsed/refractory multiple myeloma

Introduction: Chimeric antigen receptor (CAR) T cell therapies have demonstrated robust and sustained clinical responses in several hematologic malignancies. However, outside of CD19. clinical data supporting the promise of CAR T cells have been limited. We are testing the potential for CAR T cell safety and efficacy in relapsed/refractory multiple myeloma (MM), a patient population with limited treatment options. To redirect T cells to MM we have targeted B cell maturation antigen (BCMA), a member of the tumor necrosis factor superfamily that is near-uniformly expressed only by malignant myeloma cells, plasma cells, and some mature B cells. Initial proof of anti-BCMA activity has recently been demonstrated using T cells transduced with a gamma-retroviral vector encoding an anti-BCMA CAR with a CD28 costimulatory domain, but significant cytokine release syndrome occurred in patients with high disease burden (Ali et al., Blood 2016). Here we investigate bb2121, which consists of autologous T cells transduced with a lentiviral vector that encodes a novel CAR incorporating an anti-BCMA single-chain variable fragment, a 4-1BB costimulatory motif and a CD3-zeta T cell activation domain. We now report initial safety and efficacy results from a first-in...human Phase 1 multi-center clinical trial of bb2121. Methods: CRB-401 is a multi-center phase 1 dose escalation trial of bb2121 in patients with relapsed and/or refractory BCMA-positive MM who have received at least 3 prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory. Peripheral blood mononuclear cells are collected via leukapheresis and transferred to a centralized manufacturing facility for transduction and expansion. Patients undergo lymphodepletion with cyclophosphamide 300mg/m2 and fludarabine 30 mg/m2 on study Days -5, -4 and -3 then receive a single infusion of bb2121 on Day 0. The dose escalation portion of the study follows a standard 3+3 design with planned dose levels of 5.0 x107, 15.0xt07,45.0x107,80.0x107 and 120x107 CAR+T cells. Median age at enrollment for the 9 infused subjects was 58 years (43-68) and 67% were male. The median time from diagnosis was 6 years (1.3-8.6). The median number of prior lines of therapy was 6 (4-10); 100% of patients received at least 1 prior autologous stem cell transplant; 67% received prior daratumumab or CD38 mab; 89% received prior lenalidomide; 78% received prior pomalidomide; 100% received prior bortezomi