Phase 1 Study of CART-ddBCMA for the treatment of subjects with relapsed and refractory multiple myeloma.

Relapsed and refractory multiple myeloma (RRMM) is a plasma cell neoplasm defined by progressively refractory disease necessitating chronic and increasingly intensive therapy. Despite recent advances, limited treatment options exist for RRMM. This single-arm, open label phase 1 study (NCT04155749) aimed to evaluate the safety of novel BCMA-targeting CAR T construct that leverages a completely synthetic antigen binding domain (CART-ddBCMA), which was specifically engineered to reduce immunogenicity and improve CAR cell surface stability. Thirteen RRMM patients with age ≥18 years who received at least 3 prior regimens of systemic therapy were enrolled in the study. Patients received a single dose of 100x106 CART-ddBCMA (DL1) or 300x106 CART-ddBCMA (DL2) following standard lymphodepleting chemotherapy. The primary endpoints of the study were to evaluate the incidence of treatment emergent adverse events, including dose limiting toxicities, and establish a recommended phase 2 dose (RP2D). Results showed that CART-ddBCMA was well tolerated and demonstrated a favorable toxicity profile. Only 1 case of grade ≥3 CRS and ICANS were reported, which were both at DL2 and were manageable with standard treatment. No atypical neurological toxicities and Parkinson's disease-like movement disorders were observed. The maximum tolerated dose was not reached. All infused patients responded to CART-ddBCMA and 9/12 (75%) patients achieved CR/sCR. Responses deepened over time and at the time of last data-cut (median follow-up 56 weeks), 8/9 (89%) of evaluable patients achieved minimal residual disease negativity. In conclusion, the findings demonstrate the safety of CART-ddBCMA cells and document durable responses to CART-ddBCMA in RRMM patients.