Twenty patients with high-risk smoldering multiple myeloma (SMM) remained negative for minimal residual disease (MRD) for more than 15 months after a single infusion of the CAR-T cell therapy ciltacabtagene autoleucel, according to a phase 2 study at the Dana-Farber Cancer Institute in Boston.

It’s the first time a CAR-T has been tested for SMM and the first report of universal MRD negativity in an SMM trial.

Eighteen patients had a stringent complete response, and the remaining two are expected to convert with longer follow-up, lead investigator Omar Nadeem, MD, reported at the American Association for Cancer Research Annual Meeting 2026.

“Our hope is that these responses continue to be durable to the point where we can say that patients are cured,” Nadeem said, adding that longer follow-up is needed to see if durability lasts beyond 5 years.

The findings were simultaneously published in Nature Medicine.

“This is just phenomenal data,” said study discussant Krina Patel, MD, a myeloma/lymphoma specialist at the University of Texas MD Anderson Cancer Center, in Houston.

“MRD negativity, sustained off therapy, hasn’t been demonstrated with any of our prior treatments,” Patel said. “Is cure possible before having significant symptoms from myeloma? Is 5 years functional cure enough for our smoldering patients? Or do we want 10 years? We’re finally able to talk about these things because we have data like this.”

Ciltacabtagene autoleucel (Carvykti), also known as cilta-cel, is a B-cell maturation antigen-directed CAR T-cell therapy already approved by the FDA for relapsed or refractory multiple myeloma after at least one prior line of therapy. However, it doesn’t work as well for that indication as it appears to for SMM, Nadeem said.

He suspects that’s because T cells are more robust and plasma cells are less genomically complex in earlier-stage disease, leading to a stronger therapeutic effect with cilta-cel.

That also means exposing patients with SMM to potential harms. Toxicities in the pilot study, dubbed CAR-PRISM, were common. All 20 patients developed grade 1/2 cytokine release syndrome, and most had transient hematologic adverse events, including grade 3/4 neutropenia. Infections were rare, mild, and mostly limited to the upper airways.

Seven patients developed non-immune effector cell-associated neurotoxicity syndrome neurologic toxicities, including four patients with facial nerve palsies that resolved, two with persistent grade 1 movement and neurocognitive symptoms, and one with grade 1 intention tremors.

Debate continues over whether and when to offer patients with SMM aggressive therapy that puts them at risk for serious side effects with uncertain benefit. At present, the only treatment for high-risk SMM on the US market is the CD38-targeted monoclonal antibody daratumumab/hyaluronidase (Darzalex Faspro), approved by FDA in November.

In a trial comparing 3 years of treatment with daratumumab against active monitoring, fewer than 10% of patients had a complete response, and almost 40% progressed to multiple myeloma by 5 years.

The hope with cilta-cel, Nadeem said, is that it will offer patients a “one-and-done” treatment for myeloma prevention.

With the bispecific antibodies linvoseltamab and teclistamab also showing promise for high-risk SMM, Nadeem said he anticipates the field will shift toward immunotherapy — but agents like daratumumab will still have a role, particularly for older patients and those unwilling to risk the side effects of immunotherapy.

In CAR-PRISM, patients were considered high-risk if they met the International Myeloma Working Group 2/20/20 criteria, had a total IMWG score of 9, or if plasma cells accounted for more than 10% of their bone marrow and they had additional high-risk biomarkers. Patients were excluded if plasma cells made up more than 40% of their marrow due to the increased risk for CAR-T toxicity.

All patients received lymphodepleting chemotherapy prior to infusion without bridging or induction therapy.

Doses were 0.5 × 10⁶ CAR+ T cells/kg in the first few patients, then raised to > 0.5-1.0 × 10⁶ after a safety review. However, doses were subsequently reduced to 0.3 × 10⁶ CAR+ T cells/kg after larger doses were linked to higher absolute lymphocyte counts and neurologic toxicities.

The median time to MRD negativity was 1 month. Six patients who have been followed longer than 18 months remained MRD-negative. There has been no disease progression and no deaths.

The work was funded by cilta-cel maker Johnson & Johnson. Nadeem reported being an advisor and disclosed receiving research funding from the company. Patel reported being a consultant.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@medscape.net.