Early CAR T-Cell Intervention Shows Disease-Eradication Potential in High-Risk Smoldering Myeloma

Results from the single-center CAR-PRISM trial, presented at the AACR Annual Meeting 2026 in San Diego and published in Nature Medicine, showed that all 20 treated patients became minimal residual disease, MRD, negative within two months after receiving ciltacabtagene autoleucel, or cilta-cel. At a median follow-up of 15.3 months, every patient remained MRD-negative, with no disease progression or deaths observed.

“Within two months, all patients were MRD-negative at the deepest level we can measure, and at 15 months or so of follow up, everyone remains MRD-negative,” said presenter Dr. Omar Nadeem, clinical director of the Myeloma Immune Effector Cell Therapy Program at Dana-Farber Cancer Institute. “This is the first time this kind of result has been reported in any spectrum of myeloma and really shows the efficacy of CAR T-cells in earlier disease state.”

Testing CAR T Cells Before Active Myeloma Develops

Smoldering multiple myeloma is an asymptomatic precursor to multiple myeloma, a plasma cell malignancy of the bone marrow. When the disease becomes active, patients may develop bone lesions or fractures, anemia, renal impairment and pain. About half of patients with high-risk smoldering multiple myeloma progress to active multiple myeloma within two years.

Cilta-cel is a BCMA-directed CAR T-cell therapy that targets B-cell maturation antigen on abnormal plasma cells. It was approved by the U.S. Food and Drug Administration in 2024 as a second-line treatment for relapsed multiple myeloma. The CAR-PRISM study tested whether this immune cellular therapy could be more effective earlier, before patients receive multiple therapies and before immune dysfunction becomes more established.

“The hypothesis was that CAR T-cell therapy might work better when patients have a lower tumor burden and the immune system is still able to work well against cancer cells,” said Dr. Irene M. Ghobrial, principal investigator and director of the Center for Early Detection and Interception of Blood Cancers at Dana-Farber. “We wanted to learn if it can provide deep remissions that last a very long time.”

Trial Design and Patient Selection

The CAR-PRISM trial enrolled patients with high-risk smoldering multiple myeloma, mainly defined by the 20/2/20 risk criteria: more than 20% bone marrow plasma cells, M-protein greater than 2 g/dL, and an involved-to-uninvolved serum free light-chain ratio above 20. Patients with additional high-risk biomarkers and at least 10% marrow plasma cells could also be enrolled.

To reduce safety risk, patients with more than 40% marrow plasma cell involvement were excluded, based on evidence that this subgroup may be more prone to treatment-related toxicities.

Twenty patients received a single infusion of cilta-cel after lymphodepleting conditioning chemotherapy. No induction chemotherapy and no bridging therapy were used. According to the abstract, cilta-cel was administered at 0.3 to 0.5 × 10⁶, or more than 0.5 × 10⁶, viable CAR-positive T cells per kilogram. The trial met its prespecified endpoints. No dose-limiting toxicities occurred.

Universal MRD Negativity and No Progression

The depth of response was striking. All 20 patients achieved MRD negativity at a sensitivity threshold of 10⁻⁶ by two months. At the median follow-up of 15.3 months, all remained MRD-negative. Sixteen patients with more than six months of follow-up achieved a complete response, and six patients followed for more than 18 months continued to have complete responses with maintained MRD negativity.

“Our hope is that these responses continue to be durable in the long term to the point where we can say that patients are cured,” Nadeem said.

Safety Profile: No High-Grade CRS, but Neurologic Events Require Attention

Safety findings were broadly consistent with the known profile of cilta-cel. All patients developed low-grade cytokine release syndrome, CRS, but there were no grade 3 or higher CRS events. The most common adverse events were transient cytopenias, with grade 3 or 4 cytopenias reported in 90% of patients in the abstract.

Non-ICANS neurologic toxicities occurred in seven patients. Four cases were cranial nerve palsies that completely resolved. Three patients had persistent grade 1 symptoms, described as mild and improved. Importantly, no high-grade side effects and no dose-limiting toxicities were observed, supporting the feasibility of this approach in a carefully selected high-risk smoldering myeloma population.

A Potential Shift in Early Myeloma Intervention

Historically, most patients with smoldering multiple myeloma have been monitored until progression to active disease. That landscape has begun to change. In November 2025, the FDA approved daratumumab, a CD38-targeted monoclonal antibody, for high-risk smoldering multiple myeloma, the first approved therapeutic option for this disorder.

The CAR-PRISM results now raise a more ambitious question: whether a single CAR T-cell infusion, delivered before symptomatic myeloma emerges, could eradicate disease in some patients.

“One question is whether CAR T-cell therapy works differently in high-risk smoldering myeloma than it does in relapsed multiple myeloma,” said co-first author Dr. David Cordas dos Santos, instructor of medicine at Dana-Farber. “Studying these differences may help us understand why responses appear so deep and rapid in these patients.”

Longer follow-up will be essential to determine whether MRD negativity translates into sustained progression-free survival or potential cure. For now, the data provide the first clinical evidence that BCMA-directed CAR T-cell therapy can induce rapid, universal and sustained MRD-negative responses in high-risk smoldering multiple myeloma without induction therapy.

“The results of the CAR-PRISM study really set the stage for what is possible with CAR T-cell therapy for patients with high-risk smoldering multiple myeloma,” Nadeem said. “CAR T-cell therapy has the potential to be a one-time treatment that offers disease eradication.”