Teclistamab versus lenalidomide-dexamethasone in high-risk smoldering multiple myeloma: a randomized phase 2 trial

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 . In the randomized phase 2 ImmunoPRISM trial, patients with high-risk smoldering multiple myeloma (MM) showed higher rates of complete clinical responses in response to treatment with teclistamab compared with lenalidomide–dexamethasone, although longer follow-up is required to determine durable prevention of progression to MM.