Cilta-Cel Yields 100% MRD Negativity in High-Risk Smoldering Myeloma

A single infusion of ciltacabtagene autoleucel (cilta-cel; Carvykti) resulted in 100% minimal residual disease (MRD) negativity at a sensitivity threshold of 10⁻⁶ in all 20 patients with high-risk smoldering multiple myeloma (HR-SMM) treated in the phase 2 CAR-PRISM trial (NCT05767359), according to the primary analysis published in Nature Medicine.¹

At a median follow-up of 15.3 months, no disease progression or deaths were observed. Among 16 patients with at least 6 months of follow-up, all achieved a complete or stringent complete response (sCR/CR). The findings represent the first prospective evaluation of chimeric antigen receptor (CAR) T-cell therapy in a precursor plasma cell disorder, creating the potential for single-dose treatment that prevents progression to multiple myeloma.

Current Standard of Care and Unmet Need

HR-SMM carries a substantial risk of progression to symptomatic multiple myeloma with end-organ damage, and early intervention has increasingly been a subject of clinical investigation. Single-agent daratumumab (Darzalex) was the first therapy to be approved for HR-SMM, based data from the phase 3 AQUILA trial (NCT03301220) comparing it with active monitoring.² However, other regimens using multiple agents adapted from symptomatic myeloma, including triplet and quadruplet combinations, have achieved MRD negativity in only approximately half of patients, leaving a clear therapeutic gap for approaches capable of producing deeper, more durable remissions.

Trial Design and Patient Population

CAR-PRISM enrolled adults with HR-SMM defined by the 20–2–20 criteria or equivalent validated risk models. Patients with bone marrow plasma cell involvement exceeding 40% were excluded and bridging or induction therapy was prohibited to solely assess cilta-cel's therapeutic effect. Between April 2023 and July 2025, 23 patients were enrolled, 20 of whom underwent leukapheresis and received a single cilta-cel infusion following lymphodepleting chemotherapy with fludarabine and cyclophosphamide.

The primary end points were dose-limiting toxicities and treatment-emergent adverse events, with secondary end points including response and MRD negativity. The median patient age was 58 years; 65% harbored high-risk cytogenetic abnormalities, and the median time from diagnosis to enrollment was 16.1 months.

Initially, patients received 0.3 × 10⁶ viable CAR⁺ T cells/kg. After a safety signal involving nonimmune effector cell-associated neurotoxicity syndrome (NINT) was observed in the higher-dose cohort, and in light of associations between peak absolute lymphocyte count and neurotoxicity, the protocol was amended: the final 7 patients received a reduced dose of 0.3 × 10⁶ viable CAR⁺ T cells/kg with prophylactic dexamethasone triggered by absolute lymphocyte count above 3,000/μL.

Efficacy Outcomes

All patients achieved MRD negativity at 10⁻⁵ by month 1 and at 10⁻⁶ by month 2. MRD negativity was sustained at all subsequent assessments through the data cutoff. Notably, the reduced dose of 0.3 × 10⁶ cells/kg achieved response kinetics comparable to higher dose levels. No difference in response or durability was observed between high-risk and standard-risk cytogenetic subgroups.

Compared with the GEM-CESAR trial (NCT02415413) of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone followed by autologous transplantation, which achieved 60% MRD negativity with sustained MRD negativity at 4 years in 31% of patients with HR-SMM, the uniformity of responses observed with cilta-cel is notable, though longer follow-up will be required to assess durability.

Safety Profile

Cytokine release syndrome occurred in all 20 patients but was limited to grade 1 (85%) or grade 2 (15%), with no grade 3 or higher events. NINTs occurred in 7 patients (35%): 4 comprising cranial nerve palsies that fully resolved within 4 to 8 weeks, and 3 with ongoing grade 1 symptoms at data cutoff. No dose-limiting toxicities, immune effector cell-associated hemophagocytic lymphohistiocytosis–like syndrome, or secondary malignancies were observed. Transient cytopenias of grade 3 or 4 occurred at a 90% rate, but prolonged cytopenias and severe infections were not prominent, which investigators attributed to limited prior treatment.

Biomarker analyses indicated that NINT events were associated with greater postinfusion lymphocyte expansion and a higher CD4:CD8 ratio, suggesting elevated absolute lymphocyte count may serve as an early correlate of neurotoxicity risk, but these findings were exploratory and need validation.

Implications

The investigators characterized these findings as the first evidence that early BCMA-directed cellular therapy can achieve uniformly deep, treatment-free remissions in a precursor plasma cell disorder. Longer follow-up is needed to determine whether these responses translate into durable freedom from progression to symptomatic myeloma. The authors noted that results cannot be extrapolated to newly diagnosed or relapsed populations given differences in disease burden, immune fitness, and prior therapy.

REFERENCES

1. Nadeem O, Cordas dos Santos DM, Nikiforow S, et al. Ciltacabtagene autoleucel in high-risk smoldering multiple myeloma: the CAR-PRISM phase 2 trial. Nature Medicine. Published April 20, 2026. doi: 10.1038/s41591-026-04365-y

2. FDA approves daratumumab and hyaluronidase-fihj for high-risk smoldering multiple myeloma. US FDA. November 6, 2025. Accessed May 1, 2026. https://tinyurl.com/2vb674jn

3. Mateos MV, Martínez-López J, Rodriguez Otero P, et al. Curative strategy for high-risk smoldering myeloma: carfilzomib, lenalidomide, and dexamethasone (KRd) followed by transplant, KRd consolidation, and Rd maintenance. J Clin Oncol. 2024;42(27):3247-3256. doi:10.1200/JCO.23.02771