Omar Nadeem, David M. Cordas dos Santos, Sarah Nikiforow, Anna Bosch, Elizabeth O’Donnell, Robert Redd, Kevin C. DeBraganca, Adam S. Sperling, Yuxin Liu, Caleb McEntire, Frances Arters, Colin O’Donnell, Brendan Kineavy, Marjorie Marto, Amy Bergeron, Emilie Swenson, Kristin McHugh, Abigail Caron, Quentin Berry, Hope Wei, Emily Durlacher, Elizabeth Grimm, Francesco Corrado, Nayda Bidikian, Rocío Montes de, Tamar Lengil, Denise De Wiest, Casey Gervais, Kevin M. Panaro, Eric L. Smith, Kenneth Anderson, Caron Jacobson, Nikhil C. Munshi, Paul Richardson, Deepu Madduri, Jordan M. Schecter, Craig Tendler, Mark Wildgust, Lorenzo Trippa, María‐Victoria Mateos, Jerome Ritz, Irene M. Ghobrial
High-risk smoldering multiple myeloma (HR-SMM) carries an increased risk of progression to multiple myeloma, making it an ideal setting to test whether chimeric antigen receptor (CAR) T cell therapy can achieve curative outcomes. Here in this phase 2 study, patients with HR-SMM received ciltacabtagene autoleucel (cilta-cel) at 0.3–0.5 × 106 or >0.5 × 106 viable CAR+ T cells per kilogram without induction or bridging therapy. Patients with >40% marrow involvement were excluded. Primary endpoints were dose-limiting toxicities (DLTs) and treatment-emergent adverse events; secondary endpoints included response and minimal residual disease (MRD) negativity. As of 11 February 2026, 20 patients had been treated. The trial met the prespecified endpoints. No DLTs occurred. Adverse events included transient cytopenias (90% grade 3/4) and cytokine release syndrome (100% grade 1/2). Non-immune effector cell-associated neurotoxicity syndrome neurologic toxicities (NINTs) occurred in seven patients, with four comprising cranial nerve palsies that completely resolved. Three patients had persistent grade 1 symptoms. At a median follow-up of 15.3 months, all patients achieved MRD negativity 10−6 by 2 months and have remained MRD negative. Sixteen patients with follow-up >6 months achieved a complete response; no progression or deaths were observed. Cilta-cel produced rapid, deep, sustained MRD-negative responses in HR-SMM without induction therapy. Toxicities were consistent with the safety profile of cilta-cel. ClinicalTrials.gov: NCT05767359 . As presented at the 2026 AACR Annual Meeting, in a phase 2 trial, treatment of patients with high-risk smoldering multiple myeloma with BCMA-targeting CAR T cell therapy ciltacabtagene autoleucel was safe and led to encouraging rates of clinical responses.