Ciltacabtagene Autoleucel in High-Risk Smoldering Myeloma

Key Takeaways

• Rapid MRD clearance was accompanied by deepening responses across follow-up in the treated cohort.
• The single-center phase 2 study enrolled 23 adults and treated 20 with cilta-cel after lymphodepletion, without induction or bridging therapy.
• No dose-limiting toxicities were observed, cytokine release syndrome remained grade 1 or 2, and neurologic toxicities affected seven patients.

In high-risk smoldering multiple myeloma, all treated patients reached MRD negativity at 10^-6 within 2 months of a single ciltacabtagene autoleucel infusion, with no progression events or deaths recorded at the data cutoff. Treatment followed lymphodepleting chemotherapy without induction or bridging therapy, as reported in the phase 2 CAR-PRISM report in Nature Medicine.

The CAR-PRISM trial was a single-center phase 2 study in adults with high-risk smoldering multiple myeloma. Primary endpoints were dose-limiting toxicities and treatment-emergent adverse events, and secondary endpoints included response and MRD negativity. Investigators enrolled 23 patients and treated 20, excluding those with more than 40% marrow involvement. Patients received fludarabine and cyclophosphamide before infusion. After a safety run-in and dose expansion, a protocol amendment lowered dosing to 0.3 × 10^6 viable CAR-positive T cells/kg for the final seven patients; no dose-limiting toxicities occurred.

At a median follow-up of 15.3 months, all treated patients achieved an objective response and became MRD negative at a sensitivity of 10^-6 by 2 months. The median time to first MRD negativity was 1 month, and MRD negativity at 10^-6 was sustained at months 3, 6, 12, and 24 through cutoff assessments. Eighteen of 20 treated patients had complete or stringent complete response as best response, and all 16 with more than 6 months of follow-up reached that depth. No progression or deaths were observed at the data cutoff.

Cytokine release syndrome occurred in all treated patients and remained limited to low-grade events, with 17 grade 1 cases and 3 grade 2 cases. Tocilizumab was given to 17 patients and dexamethasone to 13. Neurologic toxicities affected seven patients, including cranial nerve palsies that fully resolved in some patients, while others had persistent grade 1 symptoms at cutoff. Transient cytopenias were common, including grade 4 neutropenia in 11 patients and grade 3 neutropenia in 7 additional patients. Infectious adverse events were grade 1-2, all patients received IVIG prophylaxis, and investigators said the overall safety pattern was consistent with known cilta-cel experience.

The findings are limited by the trial's single-arm, single-center design and small sample, without a randomized comparator. Follow-up also remains limited for a precursor plasma cell disorder despite ongoing MRD assessments through the reporting cutoff. Investigators noted that longer observation is needed to assess durability and progression to symptomatic myeloma. Within the available follow-up, earlier BCMA-directed CAR T-cell therapy was associated with deep remissions in this high-risk smoldering cohort.