Multicenter phase 1 study of anitocabtagene autoleucel for refractory of recurrent multiple myeloma

Anitocabtagene autoleucel (anito-cel) is a BCMA-directed CAR T-cell therapy with a synthetic D-domain binder (ddBCMA). A multicenter phase 1 trial in the USA evaluated anito-cel in patients with relapsed or refractory multiple myeloma (R/R MM) who had received three or more lines of therapy or had triple-class refractory disease. Patients received anito-cel at 100 x 10⁶ CAR+ T cells (dose level 1) or 300 x 10⁶ CAR+ T cells (dose level 2). Primary endpoints were adverse events during the treatment period and establishment of the recommended phase 2 dose (RP2D). Thirty-eight patients received anito-cel. All patients had an adverse event, and 37 patients (97%) had an adverse event of grade 3 or higher. Among patients receiving dose level 1 (RP2D), 94% had cytokine release syndrome of grade 1 or 2, with no events of grade 3 or higher, and 16% had immune-effector cell-associated neurotoxicity syndrome of grade 1 or 2, while one patient (3%) had a grade 3 event. No non-ICANS or delayed neurotoxic effects occurred. At a median follow-up of 38.1 months, all patients had a response, with 79% having complete response. The 24-month progression-free survival rate was 57%, with a median PFS of 30.2 months an a 36-month overall survival rate of 65%. In complementary in vitro studies, the ddBCMA binder had a faster off-rate compared to the dual variable heavy-chain domain of a heavy chain-only antibody (dual-VHH) binder corresponding to the published sequence for ciltacabtagene autoleucel; although cytotoxicity was similar with the two therapies, ddBCMA CAR T cells led to less cytokine release and did not results in activation without antigen or in off-target cytotoxic effects. The authors conclude that anito-cel led to a high incidence of response among patients with heavily pretreated R/R MM. CRS and ICANS of grade 3 or higher were rare.