Results from a Pilot Study of ARI0002h, an Academic BCMA-Directed CAR-T Cell Therapy with Fractionated Initial Infusion and Booster Dose in Patients with Relapsed and/or Refractory Multiple Myeloma

Background: ARI0002h is an academic lentiviral autologous second-generation CAR T-cell product with a 4-1BB co-stimulatory domain and a humanized single chain variable fragment targeting BCMA. In pre-clinical studies, ARI0002h has demonstrated potent in vitro and in vivo activity. Here, we report the first safety and efficacy results of the CARTBCMA-HCB-01 multicenter clinical trial for patients with relapsed/refractory multiple myeloma (RRMM) (NCT04309981) who received ARI0002h in 5 Spanish centers.

Methods: Patients (pts) aged 18-75 years old with RRMM were eligible for this study if they had measurable disease, as assessed by M-protein or serum free light chain levels, received ≥2 prior regimens, including a proteasome inhibitor, an immunomodulatory drug (lenalidomide or pomalidomide) and an anti-CD38 antibody, and were refractory to the last line of treatment. Bridging therapy was allowed after apheresis. Cyclophosphamide (300 mg/m ²) and fludarabine (30 mg/m ²) on days -6 to -3 were used as lymphodepletion regimen. The targeted dose was 3x10 ⁶/kg CAR+cells (range 1.2-3x10 ⁶) and was administered in a fractionated manner (10%/30%/60%), with at least 24h between infusions. A second dose of 3x10 ⁶ CAR+ cells/kg was planned at least 4 months after the first dose in pts who had any response and had not presented MM progression or serious complications after the first administration, with or without repeated lymphodepletion depending on the persistence of CAR-T cells. Primary objectives were overall response rate (ORR; at less partial response -PR-) within 3 months of the first infusion and rate of cytokine release syndrome (CRS) and/or neurological toxicity in the first 30 days. Response was assessed as per IMWG criteria and bone marrow minimal residual disease (MRD) was analyzed by next-generation flow. Adverse events (AEs) were graded using CTCAE v5.0. CRS and neurotoxicity were graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) criteria.

Results: As of July 19 ^th, 35 pts (median age 61 years) with RRMM were included in the trial. Four pts could not receive ARI-0002h due to MM progression before apheresis (2 pts) or treatment (2 pts) and one pt died of a fungal infection. Therefore, 30 pts received ARI0002h cells (modified intention-to-treat population), of which 47% received bridging therapy. The main characteristics of these pts and previous treatments are described in Table 1. Median CAR-T cell production time was 11 days (range 9-14) with a 100% manufacture success.

Median follow-up after ARI0002h administration for surviving pts was 8 months (range 2-12). The ORR of 27 evaluable pts at 3 months was 96%, with a stringent complete remission (sCR) rate of 44.4% (Table 1) and very good partial response (VGPR) observed in 18.6% of pts. Median time to first response was one month. All pts achieved at least a PR and only one patient progressed after 4 months exclusively with extramedullary disease.

Of 25 MRD-evaluable pts at day +100, 92% were MRD-negative. Median progression-free survival (PFS) and overall survival (OS) were not reached and the 6-month PFS and OS rates were 92.1% (Figure 1) and 95.8%, respectively.

AEs reported in >70% of pts were CRS (87%; grade [gr] 3/4 0%; gr 1 73%), neutropenia (97%; gr 3/4 100%), anemia (85%; gr 3/4 43%), and thrombocytopenia (79%; gr 3/4 70%). Median duration of CRS was 4 days (range 1-12). No CAR-T cell-related neurotoxicity cases were reported. Tocilizumab and corticosteroids were administered in 76% (mainly for persistent grade 1 CRS) and 12% of pts, respectively. One death occurred due to unrelated causes (cranial traumatism).

ARI0002h cells demonstrated peak expansion on day 14 (range 7-100 days). Among the pts with 3 and 6 months follow-up, 54% and 24% had measurable CAR+ T cells in peripheral blood, respectively. 22 out of 27 eligible pts (81%) have already received the second dose (range 1.2-3x10 ⁶ CAR+ cells/kg). Median time after first infusion was 4 months; 36% received a second lymphodepletion. No relevant toxicities after second infusions were reported. Responses deepened over time and at 6 months, 5 pts who had reached PR achieved VGPR and one improved from VGPR to sCR.

Conclusion: ARI0002h is the first European academic CAR T-cell for RRMM that has demonstrated excellent feasibility in a clinical trial, with deep and durable responses and a favorable safety profile, including the absence of neurotoxicity.

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