BCMA-directed CAR T-cell Therapy May Be Effective Against High-risk Smoldering Multiple Myeloma

All patients were negative for minimal residual disease, and no patients experienced progression to active multiple myeloma during the median 15.3 months of follow-up

SAN DIEGO – A single infusion of ciltacabtagene autoleucel (Carvykti) led to a 100% minimal residual disease (MRD)-negativity rate in patients with high-risk smoldering multiple myeloma, according to results from CAR-PRISM, a phase II clinical trial, presented at the American Association for Cancer Research (AACR) Annual Meeting 2026, held April 17-22.

Smoldering multiple myeloma (SMM) is a precursor condition to the more advanced, symptomatic form of active multiple myeloma. A subset of patients with SMM have a high risk of progression, as determined by several criteria that include greater accumulation of plasma cells in the bone marrow and higher levels of certain plasma-cell protein products.

“Almost half of patients with high-risk SMM will experience progression to active multiple myeloma within two years, developing bone lesions and debilitating symptoms such as kidney failure, anemia, pain, and frailty,” said presenter Omar Nadeem, MD, a medical oncologist at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School.

Until recently, the only option available to patients with SMM was active monitoring through regular lab tests, imaging, and/or bone marrow assessments to check for signs of progression. “Typically, patients with SMM would begin therapy only after they had already developed organ damage or other symptoms of active multiple myeloma,” Nadeem said, adding that while some patients could receive experimental treatments by enrolling in a clinical trial, such trials were less accessible to the majority of patients treated outside of a major cancer center.

In November 2025, the U.S. Food and Drug Administration (FDA) approved daratumumab and hyaluronidase (Darzalex Faspro), a CD38-targeted monoclonal antibody, for the treatment of high-risk SMM, marking the first approved therapeutic for patients with SMM. The treatment, which is administered regularly for up to three years, reduced progression to active multiple myeloma by 51% in a clinical trial, but Nadeem noted that the trial did not evaluate whether patients had MRD, which can increase a patient’s long-term risk of disease progression.

Nadeem and colleagues conducted the phase II CAR-PRISM trial to evaluate the safety and efficacy of a different treatment approach—chimeric antigen receptor (CAR) T-cell therapy—for patients with high-risk SMM. The treatment, ciltacabtagene autoleucel, is approved by the FDA as a one-time infusion for relapsed or refractory multiple myeloma and targets the BCMA protein that is found on the surface of abnormal plasma cells, such as those that comprise SMM and active multiple myeloma.

“Due to its efficacy in relapsed multiple myeloma, and the fact that it is given as a single infusion, we reasoned that ciltacabtagene autoleucel could be a practical and effective approach for patients with high-risk SMM to intercept the disease before the patient develops any symptoms,” said Nadeem. “The other rationale was that the T cells are fitter during this early disease state, and so the efficacy of CAR T-cell therapy may be even greater when administered during SMM, when the immune system is more robust.”

The CAR-PRISM trial enrolled 20 patients with high-risk SMM, as defined by the 20/2/20 model, which evaluates the proportion of plasma cells in the patient’s bone marrow and the amount of plasma-cell protein products in the blood. In this model, patients are considered to have high-risk SMM if plasma cells account for more than 20% of the cells in their bone marrow, blood levels of the M-protein exceed 2 g/dL, and the ratio of involved-to-uninvolved free light-chain proteins in their blood is greater than 20. Patients were also eligible if plasma cells accounted for more than 10% of their bone marrow and they had additional high-risk biomarkers. Patients were excluded from the trial if plasma cells comprised more than 40% of their bone marrow, since there was no induction or bridging therapy administered in this study and these patients may be more likely to experience toxicities.

All patients treated with ciltacabtagene autoleucel experienced low-grade cytokine release syndrome (CRS), and no patients had grade 3 or higher CRS. The most common adverse events were transient hematologic toxicities, including grade 3 or 4 neutropenia. Non-immune effector cell-associated neurotoxicity syndrome (non-ICANS) neurologic toxicities (NINTs) occurred in seven patients: facial nerve palsy in four patients that resolved completely, and residual, but improved, mild motor symptoms in three patients.

Within two months of treatment, all 20 patients had experienced MRD negativity, which was sustained at a median follow-up of 15.3 months. Six patients who were followed for longer than 18 months continued to experience MRD negativity. No disease progression or deaths were observed during follow-up.

“In this pilot study, a one-time infusion of ciltacabtagene autoleucel—without any induction or bridging therapy—led to universal MRD negativity,” said Nadeem. “No instances of disease progression have been observed after a median follow-up of 15.3 months, far exceeding the progression-free survival we would expect with active monitoring.

“These results support our hypothesis that administering CAR T-cell therapy earlier—before the onset of active multiple myeloma—can lead to deep responses,” he added. “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.”

“One of the most interesting questions now is whether CAR T-cell therapy works differently in high-risk SMM than it does in relapsed disease,” said David Cordas dos Santos, MD, who is a co-author on the study and an instructor of medicine at Dana-Farber Cancer Institute. “Studying these differences may help us understand why responses appeared so deep and rapid in the SMM setting.”

“This study raises the question of whether early interception with immunotherapy can lead to a cure for patients with multiple myeloma,” said senior author Irene Ghobrial, MD, a professor of medicine at Dana-Farber Cancer Institute. “This is especially important to explore given the high tumor burden, genomic complexity, and T-cell exhaustion that occurs in later stages of the disease.”

Limitations of the study include its single-arm, single-institution design; the small sample size; the short follow up; and the exclusion of patients with SMM with plasma-cell infiltration exceeding 40%.

The study was supported by Johnson & Johnson. Nadeem reports participation on the advisory boards of Johnson & Johnson, Bristol Myers Squibb, Sanofi, GPCR Therapeutics, Kite Pharma, and AstraZeneca; and the receipt of research funding from Johnson & Johnson and Bristol Myers Squibb. Cordas dos Santos has received research funding from Regeneron. Ghobrial is a founder and executive board member of and holds private equity in Predicta Biosciences, and her spouse is the chief medical officer of and holds private equity in Disc Medicine. Ghobrial also reports consulting roles for AbbVie, Adaptive, Amgen, Aptitude Health, Arcellx, AstraZeneca, BioSkryb Genomics, Bristol Myers Squibb, Civala Inc., Clinical Care Options, Clinical Education Alliance, ENGAGE, Feromics Inc., Genentech, GSK, Janssen, Kite Pharma, Menarini, ONK Therapeutics, Pfizer, Regeneron, Sanofi, Silicon Biosystems, Takeda, TG Therapeutics, and Window Therapeutics; and honoraria from Amgen, Curio Science, Janssen, MD Education, MJH Life Sciences, Physicians’ Education Resource, Regeneron, Standard BioTools, Takeda, ThermoFisher/Binding Site, Veeva, and Vor Biopharma.

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