CAR-PRISM phase II: Cilta-cel for high-risk smoldering MM

Results from CAR-PRISM (NCT05767359), a single-center phase II study evaluating ciltacabtagene autoleucel (cilta-cel) for the treatment of patients with high-risk smoldering multiple myeloma (HR-SMM; N = 20), were published in Nature Medicine by Nadeem et al. Patients received 0.3–0.5 × 10⁶ (n = 12) or >0.5 × 10⁶ (n = 8) viable chimeric antigen receptor (CAR)+ T-cells/kg without induction or bridging therapy. Patients with >40% bone marrow involvement were excluded. The primary endpoints were dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs).

Key data: No DLTs were observed; however, all patients experienced ≥1 TEAE. Cytokine release syndrome (CRS) occurred in 100% of patients (all Grade 1/2), while Grade 3/4 neutropenia and leukopenia occurred in 90% of patients. Non-immune effector cell-associated neurotoxicities (NINTs) occurred in 35% of patients, with no immune effector cell-associated neurotoxicity syndrome (ICANS) or fatal neurotoxic events reported. Infections were all Grade 1/2. At a median follow-up of 15.3 months, measurable residual disease (MRD) negativity at a sensitivity of 10⁻⁶ was achieved in all patients by Month 2, and was sustained through data cutoff. The best overall response was stringent complete response / complete response (sCR/CR) in 90%, with sCR/CR in 100% with ≥6 months’ follow-up (n = 16). No disease progression or deaths occurred.

Key learning: Cilta-cel induced rapid, deep, and sustained MRD-negative responses in HR-SMM without induction or bridging therapy, with no DLTs, disease progression or deaths reported during follow-up, supporting further evaluation of B-cell maturation antigen (BCMA)-directed CAR T-cell therapy in this earlier disease setting.