Long-term follow-up of ARI0002h (cesnicabtagene autoleucel), an academic point-of-care B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell strategy: Activity and safety after fractionated initial therapy and booster dose in 60 patients with relapsed/refractory multiple myeloma (RRMM).
Authors: Fernandez de Larrea Carlos , Oliver-Caldés Aina , Gonzalez De La Calle Veronica , Cabañas Valentin , López-Muñoz Nieves , Rodríguez-Otero Paula , Reguera Juan Luis , Español-Rego Marta , Inogés Susana , Zabaleta Aintzane , Rodríguez-Lobato Luis Gerardo , Varea Sara , Sanchez-Pina Jose , Ortiz-Maldonado Valentín , Juan Manel , Martinez-Lopez Joaquin , Moraleda José María , Pascal Mariona , Mateos Maria-Victoria , Urbano-Ispizua Alvaro 
Published: June 2024

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Background: The activity and safety ofARI0002h, an academic autologous CAR T-cell product with a humanized single chain variable fragment targeting BCMA has been reported in a pilot multicenter clinical trial (CARTBCMA-HCB-01) treating 30 patients (pts) with RRMM (NCT04309981) (Oliver-Caldés, Lancet Onc 2023). Here, we describe results of the final cohort of 60 pts with longer follow-up. Methods: Patients aged 18-75 years old with RRMM were eligible if they had measurable disease, were refractory to the last line of treatment and received ≥2 prior regimens, including a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 antibody. The target dose (3x106/kg CAR+cells) was administered in a fractionated manner (10%/30%/60%). A second dose of up to 3x106 CAR+ cells/kg was planned at least 3 months after the first dose in pts with any kind of response and no limiting side effects. Primary endpoints were overall response rate (ORR) within the first 3 months and rate of cytokine release syndrome (CRS) and/or neurotoxicity in the first 30 days. Bone marrow minimal residual disease (MRD) was analyzed by next-generation flow at a sensitivity of 10-6. Results: As of December 18th 2023, 72 pts with RRMM were screened, 69 underwent apheresis and 61 received LD, with 60 pts finally receiving ARI0002h. The ORR in the first 3 months was 95% (≥ very good partial response (VGPR) in 77%). Median time to first response was one month. Responses deepened over time, achieving 58% complete response (CR) (55% stringent CR). MRD-negative rates on evaluable samples on days 28 and 100 were 98% and 96%, respectively. With a median follow-up of 24 months (95%CI 9.8-39.9), estimated median progression-free survival (PFS) was 20 months (95% CI 13.2-26.8). Median overall survival (OS) was not reached with OS rate at 24 months of 63%. CRS was observed in 90% with 5% grades ≥ 3. Median time to CRS was 7 days (1-14) with a median duration of 4.5 days. Mild acute neurotoxicity was reported in only 2 pts (3%) with no late neurologic events. 6 pts (10%) developed a macrophage activation syndrome (4 grades 1-2, 1 grade 3, 1 grade 5). Seven patients (11.7%) developed second primary malignancies after ARI0002h infusion, including 3 skin cancers (one in situ melanoma), 3 solid tumors and one acute myeloid leukemia. 80% (44 out of 5) eligible pts had already received the booster dose, with no relevant toxicities. Median time after first infusion was 4.4 months. Response was evaluable in 42 pts; 45% (n=19) were already in sCR, 29% (n=12) maintained the response and 26% (n=11) improved the response. Conclusions: Results from 60 pts and a longer follow-up confirm the safety profile and the deep and durable responses obtained after ARI0002h infusion. Clinical trial information: NCT04309981 .