Updated Results of Fumanba-1: A Phase 1b/2 Study of a Novel Fully Human B-Cell Maturation Antigen-Specific CAR T Cells (CT103A) in Patients with Relapsed and/or Refractory Multiple Myeloma

Background： CT103A, is a fully human BCMA-specific chimeric antigen receptor (CAR) T-cell therapy product. Our previous results demonstrated that CT103A leads to early, deep and durable responses and a favorable safety profile in heavily pretreated relapsed and refractory multiple myeloma (RRMM) subjects. Besides, initial results showed that these subjects also experienced low host anti-CAR immunogenicity, which was probably due to the unique fully human single-chain variable fragments (scFvs). Here, we report updated data on more subjects from the FUMANBA-1 study with a longer duration of follow-up.

Methods： FUMANBA-1 (NCT05066646) is a phase 1b/2 study of CT103A that is conducted in 14 centers in China. This study enrolled RRMM subjects who received ≥ 3 lines of prior therapies containing at least a proteasome inhibitor and an immunomodulatory agent and were refractory to their last line of treatment. Subjects who have progressed on previous BCMA-CAR T-cell therapy were also included. Fludarabine (30 mg/m²) and cyclophosphamide (500 mg/m²) were used for 3 consecutive days as the lymphodepletion regimen. All subjects received a single infusion of CT103A at the dose of 1.0 x 10⁶ CAR⁺ T cells/Kg. The objective of this study is to evaluate the efficacy, safety and pharmacokinetics. CRS and ICANS were graded according to ASTCT criteria, and other adverse events (AEs) were graded by CTCAE v5.0. The response was evaluated conforming to the IMWG 2016 consensus criteria. MRD negativity was evaluated in bone marrow aspirate by standardized Euroflow flow cytometry with a minimum sensitivity of 10^-5 nucleated cells. Immunogenicity was assessed by MSD-based antidrug antibody (ADA) assay.

Results: As of the July 22, 2022, 103 subjects [53.4% male; median age 58.0 years (range 39-70)] with RRMM received CT103A (17 in phase 1b; 86 in phase 2) with a median follow-up time of 12.2 months (range 0.2 to 25.6). The treated subjects had received a median of 4 (range 3-23) lines of prior therapy. 27.2% and 18.4% of subjects were previously treated with auto-HSCT and anti-CD38 antibody respectively. Notably, 11.7% had previously received CAR T-cell therapy. Moreover, 9.7% of the subjects had extramedullary plasmacytoma at baseline, and 48.5% had high-risk cytogenetics.

100 subjects were evaluable for efficacy assessment. The median time to first response was 16 days (range 11-123). A 95% ORR was observed, with 74% ≥ CR, 17% VGPR, and 4% PR. Among them, 91 subjects who have completed 3-month follow-up achieved 96.7% ORR, with 76.9% ≥ CR, 15.4% VGPR, and 4.4% PR. Median DOR and median PFS have not reached. For 12 subjects who have previously been treated with CAR T-cell therapy, ORR was 75%, with ≥CR rate of 41.7%, VGPR of 8.3%, and PR of 25%. Notably, among the subjects who achieved sCR, 4/5 (80%) still sustained sCR over one year post infusion. Of the 100 subjects with evaluable samples, 95% achieved MRD-negativity with a median time to MRD-negative of 15 days (range 14-186), and all subjects with CR/sCR were MRD-negative. Furthermore, 80.0% (95%CI 67.6-88.6%) achieved sustained MRD negativity over 12 months.

The most common ≥ grade 3 treatment-related AE was expected hematological toxicity. 93.2% of the subjects experienced CRS, which was mostly ≤grade 2. There was only one≥ grade 3 CRS which was grade 4. All CRS cases were manageable using conventional CRS intervention, including tocilizumab and steroids. The median time to CRS onset was six days (range 1-13) with a median duration of 5 days (range 2-30). Only 2 (1.9%) subjects experienced ICANS, which were ≤grade 2 and manifested as a transiently decreased level of consciousness and soon recovered without intervention.

The expansion of CT103A reached the median peak level of 86376.5 copies/μg gDNA at a median of 12 days. CT103A was still detectable in 51.1% (23/45) subjects at 12 months and 45.5% (10/22) subjects at 15 months after infusion.

In addition, only 13 of 98 subjects (13.3%) with evaluable samples were detected to be positive for the anti-drug antibody. By months 3 and 6 after infusion, 2/78 (2.6%) and 5/61 (8.2%) of the subjects were ADA-positive.

Conclusion: The updated data from FUMANBA-1 demonstrated the sustained clinical benefit of CT103A, especially for those who previously received CAR T-cell treatment. The depth and durability of responses achieved with CT103A were consistent with their robust and prolonged persistence.

Xu:Nanjing IASO Biotherapeutics Ltd: Current Employment. Cai:Nanjing IASO Biotherapeutics Ltd: Current Employment. Zeng:Nanjing IASO Biotherapeutics Ltd: Current Employment. Guo:Nanjing IASO Biotherapeutics Ltd: Current Employment. Gui:Nanjing IASO Biotherapeutics Ltd: Current Employment. Wang:Nanjing IASO Biotherapeutics Ltd: Current Employment.