Ciltacabtagene Autoleucel CAR T Therapy for High-Risk Smoldering Multiple Myeloma

A phase 2 clinical trial has found that treatment with ciltacabtagene autoleucel, a BCMA-targeting chimeric antigen receptor (CAR) T cell therapy, is safe and associated with encouraging clinical response rates in patients with high-risk smoldering multiple myeloma, according to results presented at the 2026 American Association for Cancer Research (AACR) Annual Meeting and published online in Nature Medicine on April 20, 2026.

The trial, known as CAR-PRISM, evaluated ciltacabtagene autoleucel in 45 patients with high-risk smoldering multiple myeloma, a precursor condition characterized by an increased likelihood of progression to active multiple myeloma. Participants had a median age of 62 years and had not received prior antimyeloma therapy. All patients received a single intravenous infusion of the CAR T cell product following lymphodepleting chemotherapy.

At a median follow-up of 18 months, the overall response rate was 73%, with 44% of patients achieving a stringent complete response and 22% achieving a complete response. No dose-limiting toxicities were observed, and the most common adverse events included cytokine release syndrome (89% of patients, predominantly grade 1 or 2) and neutropenia (76%). Immune effector cell-associated neurotoxicity syndrome occurred in 13% of cases, all of which were grade 1 or 2 and resolved with supportive care.

“These results suggest that early intervention with BCMA-directed CAR T cell therapy may alter the disease trajectory in high-risk smoldering multiple myeloma,” said the study’s lead author, Dr. Elena Rodriguez, a hematologist at the Memorial Sloan Kettering Cancer Center in New York. “We are seeing deep and durable responses in a population that otherwise faces a high risk of progression, and the safety profile remains manageable with current supportive care strategies.”

Smoldering multiple myeloma is asymptomatic but carries a significant risk of progression to active myeloma, particularly in high-risk subgroups defined by biomarkers such as elevated involved-uninvolved serum free light chain ratio, bone marrow plasma cell percentage ≥20%, and abnormal serum free light chain kinetics. Current standard of care for high-risk smoldering multiple myeloma typically involves observation or participation in clinical trials, as no therapy has yet been approved specifically for this stage.

The CAR-PRISM trial builds on prior evidence of ciltacabtagene autoleucel’s efficacy in relapsed or refractory multiple myeloma, where it has demonstrated high response rates and is approved in several countries, including the United States and members of the European Union. By shifting the intervention earlier in the disease course, researchers aim to prevent or delay the onset of symptomatic myeloma and potentially improve long-term outcomes.

Study limitations noted by the investigators include the single-arm design, lack of a control group, and relatively short follow-up duration, which precludes definitive conclusions about progression-free survival or overall survival benefits. The researchers emphasized that longer-term data are needed to determine whether early CAR T cell therapy can delay or prevent progression to active myeloma and improve survival.

Ongoing and planned studies, including randomized phase 3 trials, are expected to further evaluate the role of CAR T cell therapies in earlier lines of treatment for plasma cell disorders. The trial was sponsored by Legend Biotech and Janssen Pharmaceuticals, the developers of ciltacabtagene autoleucel, which is marketed under the brand name Carvykti.