🔬 NEW IN SOLEIL RESEARCH™
Teclistamab in High-Risk Smoldering Multiple Myeloma: What ImmunoPRISM Found
Can redirecting a patient’s own T cells against plasma cells, before symptomatic multiple myeloma develops, produce deeper disease control than conventional therapy?
A newly published randomized phase 2 trial in Nature Medicine provides an important—but still preliminary—answer. In ImmunoPRISM, investigators compared fixed-duration teclistamab, a BCMA×CD3 bispecific antibody, with lenalidomide plus dexamethasone (Rd) in adults with high-risk smoldering multiple myeloma (HR-SMM).
What the trial did
ImmunoPRISM was a multicenter phase 2 study conducted at U.S. academic centers. After a six-patient nonrandomized teclistamab safety run-in, participants were randomized 2:1 to teclistamab or Rd. The prespecified primary endpoint was complete response (CR) or better in the randomized population.
At the May 26, 2026 data cutoff, 59 treated participants were included in the report: 45 received teclistamab, including the six safety run-in participants, and 14 received Rd. The primary randomized efficacy analysis therefore included 39 teclistamab-treated participants and 14 controls.
Participants had HR-SMM defined by established clinical risk criteria and/or additional high-risk clinical or cytogenetic features. Baseline PET/CT or whole-body MRI was used to exclude active myeloma-defining bone disease.
What the study found
At a median follow-up of 24.5 months, 29 of 39 randomized participants receiving teclistamab (74%) achieved CR or better, compared with 0 of 14 receiving Rd.
When all 45 teclistamab-treated participants were considered, including the safety run-in cohort, 82.2% achieved minimal residual disease negativity at a sensitivity of 10−5. The estimated two-year progression-free survival rate was 92% with teclistamab versus 49% with Rd. Median PFS was not reached with teclistamab and was 20.3 months with Rd; the reported hazard ratio for progression or death was 0.15 (95% CI, 0.04–0.59).
These efficacy results are substantial for a phase 2 study, but the PFS analysis is based on a small trial with relatively few events. The estimated survival curves therefore carry meaningful uncertainty, especially in the 14-person control arm.
Safety matters differently in an asymptomatic precursor state
Teclistamab activates T cells against BCMA-expressing plasma cells, so immune toxicity and infection risk are central considerations—particularly when treating people who have not yet developed symptomatic myeloma.
Cytokine release syndrome occurred in 71.1% of teclistamab-treated participants, but all events were grade 1 or 2. No immune effector cell-associated neurotoxicity syndrome was observed. Grade 3 infections occurred in 20% of teclistamab-treated participants and 21% of the Rd group; all resolved, no grade 4 infections were reported, and no deaths occurred in either arm. Every teclistamab-treated participant received at least one dose of intravenous immunoglobulin.
The absence of deaths, severe CRS, or neurotoxicity is reassuring within this study, but a cohort of this size cannot establish the frequency of rare toxicities or long-term immune complications.
Plain-language summary
High-risk smoldering multiple myeloma is an asymptomatic plasma-cell disorder with a substantial risk of progressing to active multiple myeloma. In this small randomized phase 2 trial, teclistamab produced much deeper responses than lenalidomide plus dexamethasone: 74% of randomized teclistamab recipients reached complete response or better, compared with none in the control group. The study also showed a strong secondary signal for delayed progression.
However, this is not yet proof that teclistamab prevents multiple myeloma, improves overall survival, or should replace established management strategies. Longer follow-up and larger comparative trials are needed.
Methodological assessment
Overall assessment: strong phase 2 signal; moderate-to-high methodological quality for proof of concept, but not practice-definitive.
Key strengths include randomized active-comparator allocation, a prespecified primary endpoint, multicenter participation, objective disease-response criteria, next-generation sequencing for MRD assessment, baseline imaging to exclude overt myeloma, trial registration, a published protocol and statistical analysis plan, and concordance between response depth and progression-free survival.
Important limitations remain. The randomized sample was small (39 teclistamab vs 14 Rd), the trial was phase 2, the primary endpoint was response depth rather than overall survival or symptomatic progression, and the study was not designed to characterize rare safety outcomes. Treatment duration was amended after an emerging efficacy signal to reduce cumulative exposure, and some secondary teclistamab analyses pooled the nonrandomized safety run-in cohort with randomized participants. The trial was conducted at specialized U.S. centers, which may limit generalizability. HR-SMM itself is biologically heterogeneous, and longer follow-up is necessary to determine whether deep responses translate into durable prevention of symptomatic myeloma.
Comparator context is also evolving. The investigators describe Rd as the previous standard comparator, while daratumumab became the first approved therapy for high-risk smoldering multiple myeloma in 2025. That makes future head-to-head or contemporary comparative evidence especially important.
Funding and conflicts of interest
The clinical trial was supported by Johnson & Johnson; additional support was reported from the Miriam and Sheldon G. Adelson Medical Research Foundation and Menarini Silicon Biosystems. The authors disclosed multiple research, advisory, consulting, honoraria, and equity relationships with pharmaceutical and biotechnology companies, including relationships with Johnson & Johnson/Janssen among several investigators.
The paper states that the authors collected the data, performed the analyses, and interpreted the results. Its funding statement says the funders had no role in study design, data collection and analysis, the decision to publish, or manuscript preparation; the methods section separately states that the study was designed by the authors in collaboration with the sponsor. These disclosures do not invalidate the findings, but they reinforce the value of independent replication and longer-term follow-up.
🔎 Soleil Insight
A deep response before symptomatic disease is scientifically compelling—but interception is not the same as prevention.
ImmunoPRISM strengthens the biological case for testing BCMA-directed T-cell redirection earlier in the myeloma disease course. The randomized response difference is difficult to dismiss, and the PFS signal points in the same direction. But the scientific threshold should remain high when potent immunotherapy is moved into an asymptomatic population. The next questions are not only whether disease can be suppressed deeply, but whether that benefit persists, prevents clinically meaningful progression, improves survival or quality of life, and justifies the cumulative toxicity and treatment burden.
Bottom line
Teclistamab produced frequent deep responses and a strong progression-free survival signal compared with lenalidomide-dexamethasone in this randomized phase 2 study of high-risk smoldering multiple myeloma. The result deserves serious attention and further testing, but it should be interpreted as promising phase 2 evidence—not as proof of cure, disease eradication, or a definitive new treatment standard.
Original study: Nadeem O, Cordas dos Santos DM, Magidson S, et al. Teclistamab versus lenalidomide-dexamethasone in high-risk smoldering multiple myeloma: a randomized phase 2 trial. Nature Medicine. Published September 11, 2026. DOI: 10.1038/s41591-026-04642-w. ClinicalTrials.gov: NCT05469893.
Featured image credit: National Cancer Institute; original microscopy image credited by NCI to Case Reports in Oncological Medicine (2012), CC BY 3.0 US.
This article is for scientific and educational communication and does not constitute individual medical advice.
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