Summary

In a randomized phase 2 trial, teclistamab produced deeper responses and longer progression-free survival than lenalidomide-dexamethasone in people with high-risk smoldering multiple myeloma. The study found high rates of complete response and minimal residual disease negativity after fixed-duration treatment.

A randomized phase 2 trial found that single-agent teclistamab produced deeper responses and longer progression-free survival than lenalidomide-dexamethasone in people with high-risk smoldering multiple myeloma (HR-SMM), an asymptomatic plasma-cell cancer with a high risk of progressing to active myeloma.

The ImmunoPRISM trial enrolled 64 adults between April 2023 and July 2025. By the data cutoff on 26 May 2026, 59 participants had received at least one treatment cycle: 45 received teclistamab and 14 received lenalidomide-dexamethasone, or Rd. The results were published in Nature Medicine on 11 September 2026.

Contents

Trial design and primary result

After a six-person safety run-in, participants were randomized in a 2:1 ratio to teclistamab or Rd. The primary endpoint was the rate of complete response (CR) or better, assessed using International Myeloma Working Group criteria.

Teclistamab is a bispecific antibody that targets B-cell maturation antigen (BCMA) and redirects T cells toward BCMA-expressing plasma cells. The researchers tested whether using this immune-based treatment earlier, when disease burden is lower and immune function is relatively better preserved, could produce deeper remissions than less intensive therapy.

The teclistamab schedule was changed during the study after an early efficacy signal. The original plan allowed 24 cycles, but the amended protocol limited treatment to a maximum of 12 cycles, or 15 months. Rd was given for up to 24 cycles.

In the randomized population, 29 of 39 participants assigned to teclistamab achieved CR or better, compared with none of the participants assigned to Rd. When the six safety run-in participants were included in the broader teclistamab-treated group, 35 of 45 participants, or 77.8%, achieved CR or better.

Molecular responses and disease control

Teclistamab also produced a high rate of very good partial response or better: 39 of 45 treated participants, or 86.7%, reached that level. The overall response rate was 93.3%.

Minimal residual disease (MRD) was measured in bone-marrow samples using next-generation sequencing. At a sensitivity threshold of 10⁻⁵, 37 of 45 teclistamab-treated participants, or 82.2%, became MRD-negative during treatment. At the more sensitive 10⁻⁶ threshold, the rate was 77.8%. Thirty-three participants achieved both CR or stringent CR and MRD negativity.

The median time to MRD negativity was 6.2 months. Among 28 participants with serial assessments who were MRD-negative at their first assessment, that status was maintained through their latest available assessment.

Disease control also differed between the groups. Median progression-free survival was not reached in the teclistamab arm, compared with 20.3 months with Rd. The estimated two-year progression-free survival rate was 92% with teclistamab and 49% with Rd. In the study analysis, teclistamab was associated with a lower risk of progression or death than Rd, with a hazard ratio of 0.15 (95% confidence interval 0.04–0.59; P = 0.007).

At the data cutoff, nine participants had progressed: three in the teclistamab group and six in the Rd group. No deaths occurred in either arm.

Safety and what the study means

The main immune-related adverse event associated with teclistamab was cytokine release syndrome (CRS), an inflammatory reaction caused by immune-cell activation. CRS occurred in 32 of 45 teclistamab-treated participants, or 71.1%. Twenty-nine cases were grade 1 and three were grade 2; no grade 3 or higher CRS occurred.

No immune effector cell-associated neurotoxicity syndrome or other treatment-emergent neurotoxicity was reported. Grade 3 infections occurred in 20% of teclistamab-treated participants and 21% of those receiving Rd. All reported grade 3 infections resolved, and no grade 4 infections occurred. Every participant in the teclistamab arm received at least one dose of intravenous immunoglobulin under the study protocol.

The findings support early BCMA-directed immune therapy as an active approach in HR-SMM, producing deep molecular responses with a fixed treatment period. However, this was a small phase 2 study. The primary CR analysis excluded the nonrandomized safety run-in, while the 77.8% CR-or-better figure includes those participants in a descriptive analysis. Longer follow-up is needed to establish whether these responses prevent progression to symptomatic myeloma over time; the current follow-up cannot determine an overall-survival benefit or disease eradication.

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