Omar Nadeem, David M Cordas Dos Santos, Sophie Magidson, Jeffrey Matous, Eva Medvedova, Elizabeth O'Donnell, Robert A Redd, Yuxin Liu, Shonali Midha, Adam S Sperling, Frances Arters, Christine Davie, Caroline Ricciardi, Rosa Toenges, Nayda Bidikian, Subear Hussein, Jean-Baptiste Alberge, Sungjae Kim, Lorena Pantano-Rubino, Francesco Corrado, Hannah Ashton, Daniel Addonizio, Siham Mohamed, Ashlee Sturtevant, Marjorie Marto, Amy Bergeron, Francesco Malfona, Kevin Panaro, Paul G Richardson, Jerome Ritz, Lorenzo Trippa, Irene M Ghobrial
Teclistamab, a B cell maturation antigen-targeting bispecific antibody, has demonstrated substantial activity in relapsed multiple myeloma (MM), particularly in earlier lines of therapy, and may have higher efficacy in high-risk smoldering MM (HR-SMM) with a more functional immune system. In the randomized phase 2 ImmunoPRISM trial, we compared fixed-duration teclistamab with lenalidomide-dexamethasone (Rd) in HR-SMM. After a six-patient safety run-in, patients were randomized 2:1 to teclistamab or Rd. The primary endpoint was complete response (CR) rate. As of 26 May 2026, 59 patients were treated-45 received teclistamab and 14 received Rd. Teclistamab treatment induced a CR in 77.8% patients versus 0% with Rd, and minimal residual disease negativity at 10-5 in 82.2% patients. At a median follow-up of 24.5 months, 2-year progression-free survival was 92% with teclistamab versus 49% with Rd. Overall, response rates, duration of response and time to progression (TTP) were significantly improved in teclistamab compared to Rd. Toxicities in the teclistamab arm included grades 1-2 cytokine release syndrome, no neurotoxicity and no increase in grade 3 infections compared to Rd (20% versus 21%). No deaths occurred in either arm. Teclistamab represents a highly active immune-interception strategy for HR-SMM. ClinicalTrials.gov registration: NCT05469893 .