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

• Published in: Blood advances Vol. 7; no. 5; pp. 768 - 777
• Main Authors: Frigault, Matthew J., Bishop, Michael R., Rosenblatt, Jacalyn, O’Donnell, Elizabeth K., Raje, Noopur, Cook, Daniella, Yee, Andrew J., Logan, Emma, Avigan, David E., Jakubowiak, Andrzej, Shaw, Kit, Daley, Heather, Nikiforow, Sarah, Griffin, Faith, Cornwell, Christine, Shen, Angela, Heery, Christopher, Maus, Marcela V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.03.2023; The American Society of Hematology
• Subjects: Clinical Trials and Observations; Humans; Lymphocytes; Multiple Myeloma - drug therapy; Neurotoxicity Syndromes; Receptors, Chimeric Antigen - therapeutic use
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2022007210

•CART-ddBCMAs are safe for use in patients with relapsed or refractory multiple myeloma.•CART-ddBCMAs produce deep and durable responses in patients with poor prognostic factors. [Display omitted] 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 aimed to evaluate the safety of novel B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (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 patients ≥18 years with RRMM who received at least 3 prior regimens of systemic therapy were enrolled in the study. Patients received a single dose of 100 × 106 CART-ddBCMA (DL1) or 300 × 106 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. Results showed that CART-ddBCMA was well tolerated and demonstrated a favorable toxicity profile. Only 1 case of grade ≥3 cytokine release syndrome and 1 case of immune effector cell–associated neurotoxicity were reported; both were at DL2 and were manageable with standard treatment. No atypical neurological toxicities and Parkinson 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 complete response/stringent complete response. Responses deepened over time, and at the time of last data-cut (median follow-up 56 weeks), 8/9 (89%) 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 patients with RRMM. This trial was registered at www.clinicaltrials.gov as #NCT04155749.