Ciltacabtagene Autoleucel in High-Risk Smoldering Multiple Myeloma: The CAR-PRISM Phase 2 Trial

In a single-center phase 2 study (CAR-PRISM; NCT05767359), researchers from the Dana Farber Cancer Institute have shown that a single infusion of BCMA-directed CAR T cell therapy with ciltacabtagene autoleucel (cilta-cel) produced rapid, sustained minimal residual disease (MRD)-negative remissions in 20 patients with high-risk smoldering multiple myeloma (HR-SMM). Published in Nature Medicine, PRISM is the first prospective evaluation of CAR T cell therapy in a precursor plasma cell disorder.

Patients with HR-SMM have a high risk of progression to symptomatic multiple myeloma with end-organ damage. As existing early-intervention strategies, including daratumumab monotherapy and multiagent regimens, have exhibited MRD negativity in approximately half of patients, the authors hypothesized that alternate approaches could improve outcomes. Specifically, they sought to determine if lower tumor burden, reduced genomic complexity, and preserved T cell fitness in HR-SMM would enhance the efficacy of BCMA-directed cellular therapy. To test this, patients received cilta-cel at doses of 0.3–0.5 × 10⁶ or >0.5 × 10⁶ viable CAR+ T cells per kilogram following lymphodepletion with fludarabine and cyclophosphamide.

Twenty patients were enrolled and treated (median age 58 years; 65% with high-risk cytogenetics). At a median follow-up of 15.3 months, all 20 patients (100%) achieved MRD negativity by month 2, with sustained negativity through the data collection cutoff. All 16 patients with at least 6 months of follow-up achieved stringent complete response or complete response (sCR/CR); no progressions or deaths were observed. Cytokine release syndrome occurred in all patients but was limited to grade 1–2 (100%). Non-ICANS neurologic toxicities (NINTs) occurred in 7 of 20 patients (35%), including 4 cranial nerve palsies that fully resolved and 3 patients with persistent grade 1 symptoms. Overall, this study establishes a foundation for the evaluation of future risk-adapted strategies in HR-SMM.

Reference:

Nadeem O, Cordas Dos Santos DM, Nikiforow S, et al. Ciltacabtagene autoleucel in high-risk smoldering multiple myeloma: the CAR-PRISM phase 2 trial. Nat Med. Published online April 20, 2026. http:doi.org/10.1038/s41591-026-04365-y