Phase 1 Study of CART-Ddbcma for the Treatment of Subjects with Relapsed and /or Refractory Multiple Myeloma

Introduction: B-cell maturation antigen (BCMA) targeting chimeric Antigen Receptor (CAR) T cell therapies have shown compelling clinical activity and manageable safety in subjects with relapsed and/or refractory Multiple Myeloma (RRMM). CART-ddBCMA is an autologous anti-BCMA CAR T cell therapy with a unique, synthetic binding domain targeting BCMA, instead of the typical scFv approach, a 4-1BB costimulatory motif, and CD3-zeta activation domain. The binding domain is a small stable protein, called a D-Domain, comprising 73 amino acids. CART-ddBCMA is being studied in a first-in-human clinical study.

Methods: This Phase 1, multi-center, open label, dose escalation trial enrolling subjects with RRMM who have received ≥3 prior regimens, including a proteasome inhibitor, an Immune-modulatory agent, and a CD38 antibody, or are triple-refractory. Lymphodepletion is administered (fludarabine (30 mg/m2/day) and cyclophosphamide (300 mg/m2/day)) daily on days -5 to -3, then CART-ddBCMA is given as a single infusion on day 0. Dose escalation was performed at 100 (DL1) and 300 (DL2) x 10⁶ (+/- 20%) CAR+T cells and enrollment was continued at DL1 to further assess safety, efficacy, and pharmaco-kinetics and -dynamics. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures are quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria for MM, evaluation of minimal residual disease (MRD), progression-free and overall survival, and quantification of CAR+ cells in blood. MRD negative results were obtained by next-generation sequencing (Adaptive clonoSEQ).

Results: At the last data-cut performed on May 3, 2022, 37 patients (pts, median age 66 (range: 44-76)) were enrolled, 33 received CART-ddBCMA and 31 were evaluable for initial safety and clinical response. Median follow-up after CART-ddBCMA infusion was 12.1 months. 27 subjects received DL1 (6 in dose escalation and 21 in dose expansion, 25 evaluable) and 6 received DL2 (all evaluable). CAR+ cells comprised median 72% (48-87%) of total CD3+ T cells; median VCN was 2.2 copies/cell (1.1-3.5); median cell viability was 99% (91-100%), and median cell manufacturing yield was 1159 million cells (470-1626). Subjects had a median of 5 (3-16) prior lines of therapy. Twenty-four pts (77%) were “triple-refractory,” and 21 (68%) were “penta-refractory”; 12 pts (39%) had high tumor burden with ≥ 50% bone marrow plasma cells; and 12 (39%) pts (50%) had extramedullary disease at baseline. CRS was seen in 28/31 (90%) pts but only 1 subject (in DL2) had grade (G) 3 CRS and all other cases were G≤2. ICANS was seen in 7 subjects (5, G≤2; 2, G3), with 1 G3 case in each DL. All cases resolved without sequalae with standard management. No cases of off-tumor cell mediated toxicity, no delayed neurotoxicity events (i.e., occurring after day 28), and no Parkinsonian-like symptoms. All 31 evaluable subjects demonstrated clinical response per IMWG criteria (ORR, 100%) with 22 sCR/CR (≥CR rate, 71%), 7 VGPR (≥VGPR rate, 94%), and 2 PR. Responses deepened over time and conversion to CR/sCR was observed with longer follow-up (as late as month 12). Of those evaluable for MRD testing to date (n=22), 19 (86%) were MRD-neg at 10^-5 or lower. Median duration of response, PFS & OS were not evaluable at the time of data-cut because 22 of 31 evaluable subjects (71%) had ongoing response. In the patients with ≥12 months follow-up (n=16), which included 8 (50%) patients with EMD, ORR was 100%, ≥CR rate was 81% (13/16) and ≥VGPR rate was 88% (14/16). CART-ddBCMA product characteristics were consistent with the specifications in all the lots and there were no manufacturing failures.

Conclusions: Adverse events including CRS and ICANS were manageable and no off-tumor tissue-targeted toxicity, delayed neurotoxicity, or Parkinsonian-like events were observed in the entire cohort. Ongoing efficacy results are encouraging, with 100% ORR, including 29 (94%) demonstrating deep clinical responses of ≥VGPR and 22 (71%) with CR/sCR. At the time of the meeting, updated data will be presented.