Cesni-cel (ARI0002h) in ultra-high-risk multiple myeloma with plasma cell leukaemia or central nervous system involvement.

Ultra-high-risk multiple myeloma (uHRMM), defined by extra-medullary disease (EMD, including central nervous system [CNS] or plasma cell leukaemia [PCL]), remains as a predictor of early relapse after chimeric antigen receptor T cell (CAR-T) therapy. We analysed the characteristics, toxicities, response and survival of patients with PCL/CNS-multiple myeloma (MM) treated with cesnicabtagene autoleucel (ARI0002h) at three Spanish centres (2020-2025). PCL was defined as per International Myeloma Working Group (IMWG) 2021 criteria; CNS-MM by leptomeningeal and/or intraparenchymal involvement. Nineteen patients (68% female; median age 61) were included: 12 patients had PCL, 5 had CNS-MM, and 2 had dual involvement. Fifty per cent had primary PCL. In CNS-MM, all had leptomeningeal disease and one had also intraparenchymal lesions. Fifty-seven per cent received CNS-directed therapy. Seventy four per cent harboured high-risk cytogenetics. Median prior lines: 3; 74% had haematopoietic stem cell transplantation (HSCT); two had prior B-cell maturation antigen (BCMA) exposure. One patient died pre-apheresis and one during manufacturing; 17 (89%) received ARI0002h. Cytokine release syndrome (CRS) occurred in 76% (none ≥G3), G3 immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) occurred in one case (not CNS-MM) and IEC-associated haemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) occurred in 18% (one fatal). Overall response rate (ORR) was 88% at day +100, of which 87% achieved ≥ very good partial response (VGPR) and 80% complete CNS response. Median progression-free survival (PFS) and overall survival (OS) were 10.5 and 15.9 months respectively. ARI0002h induces deep responses in relapsed uHRMM, supporting inclusion of PCL and CNS-MM in clinical trials.