Abstract
Background: ARI0002h (cesnicabtagene autoleucel) is a BCMA-CART developed at Hospital Clinic de Barcelona (HCB). Approval was granted by the Spanish Medicines Agency (AEMPS) under the hospital exemption clause in August 2024, based on the results of the multicenter CARTBCMA-HCB-01 trial for patients (pts) with relapsed/refractory multiple myeloma (RRMM). The trial was designed with a point-of-care (PoC) network strategy, including 2 manufacturing sites and 7 treatment centers around the country. In the last update (December 2023), overall response rate (ORR) was 95%, with 58% complete responses (CR). With a median follow-up of 24 months (m), progression-free survival (PFS) was 20m, with an overall survival (OS) rate of 63% at 24m. Cytokine release syndrome (CRS) occurred in 90% (5% grade ≥3) and immune effector cell-associated neurotoxicity syndrome (ICANS) in 3% (no grade ≥3). Immune effector cell-associated HLH-like syndrome (IEC-HS) occurred in 10% (Oliver-Caldés, Lancet Onc. 2023; Fernández de Larrea, ASCO, 2024).
The trial completed enrolment in October 2022. Due to the unavailability of commercial products for RRMM and while waiting for ARI002h national approval, a compassionate use program (CUP) was established. Here we present results of RRMM treated in this real-world scenario.
Methods: RRMM pts were eligible after ≥2 prior lines, including a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 antibody. All cases required individualized approval by the institutional CART committee and by the AEMPS, after which CAR-T manufacturing was performed at PoC or in the closest facility. Prior to infusion, lymphodepletion (LD) with cyclophosphamide and fludarabine was administered. The target dose of ARI0002h (3x106 CAR+cells/kg) was administered in a fractionated manner (10%/30%/60%), with at least 24h between infusions. A booster dose of up to 3x106 CAR+ cells/kg was administered at least 3 months after the first dose in responders with no limiting side effects.
Results: As of February 2025, 123 pts with RRMM had undergone apheresis and 113 had received ARI0002h. Here we present results of 99 infused pts with a minimum follow-up of 3m.
Median age was 62 (range 39-76) and 45% were female. Mean serum M protein was 8 g/L (0-39.5) and median bone marrow plasma cell count was 8% (0-96). Median prior lines was 3 (2-7), with prior autologous stem cell transplantation (SCT) in 78%. ISS stage was 3 at diagnosis in 42% of pts, 18% with extramedullary plasmacytomas at baseline and 79% presented at least one high-risk genetic alteration, including 45% del(17p).
Median CAR-T cell production and turnaround times were 9 (IQR 8-9) and 30 days (IQR 26-36), respectively. Median vein-to-vein time was 42 days (IQR 34-55); 77% received bridging therapy. The ORR in the first 3m was 92% [≥ very good partial response (VGPR) in 72%]. MRD-negative rates on evaluable bone marrow samples on day 100 were 90%. Responses deepened over time, with an ORR of 94%, including 60% ≥ CR, 28% VGPR, 6% partial response, 2.5% stable disease and 2.5% refractoriness; 1 patient died prior to evaluation. With a median follow-up of 7.3m (95%CI 5.2-9.4), median PFS and OS were not reached. PFS and OS rates at 12m were 77% and 83%. Patients with extramedullary plasmacytomas had a shorter PFS [9.6m (95%CI 6.9-12.3) vs not reached; p=0.009].
CRS was observed in 66% (97% grades 1-2). Median time to CRS was 7 days, with a median duration of 3 days. Grade 1-2 ICANS were reported in only 5 pts (5%), with no late neurologic events. Eight pts (8%) developed IEC-HS. Tocilizumab and steroids were administered to 80% and 39% of pts, respectively. Fourteen pts (14%) died, mainly due to disease progression (n=10) and infection (n=3).
Fifty-seven (58%) pts received the booster dose at a median time of 4.3m, with none developing relevant toxicities; 19% received a second LD according to loss of CART persistence. Response after booster was evaluable in 54 pts; 28% (n=15) were already in CR, 35% (n=19) maintained the response and 26% (n=14) improved the response; six patients (11%) progressed within 6m. Additional information regarding correlative studies and longer follow-up will be updated at the meeting.
Conclusion: ARI0002h demonstrated notable efficacy and manageable toxicity in patients with RRMM, very close to the data reported in the pivotal clinical trial. These findings support the feasibility of a PoC CAR-T network strategy with real-world evidence.
