Clinical Summary:

• Design/Population: In the phase 2 ImmunoPRISM trial researchers evaluated teclistamab versus lenalidomide and dexamethasone in patients with high-risk smoldering multiple myeloma.
• Key Outcomes: Teclistamab achieved a complete response rate of 75.6%, an MRD negativity rate of 82%, and a 2-year progression-free survival rate of 92%  No grade ≥3 cytokine release syndrome or neurotoxicity events were observed.
• Clinical Relevance: These findings suggest that early intervention with BCMA-directed bispecific therapy may substantially deepen responses and delay progression in high-risk smoldering myeloma.

Omar Nadeem, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, discusses results from the phase 2 ImmunoPRISM trial evaluating teclistamab in patients with high-risk smoldering multiple myeloma. The study represents the first randomized trial of a BCMA-directed bispecific antibody in this patient population and was designed to determine whether earlier use of T-cell–redirecting therapy could improve outcomes compared with standard approaches.

Teclistamab produced markedly higher complete response and MRD negativity rates than lenalidomide and dexamethasone, with sustained MRD negativity observed in all responding patients and significantly improved progression-free survival. These findings suggest that BCMA-targeted bispecific therapy may redefine treatment goals in high-risk smoldering myeloma by inducing deep and durable remissions before progression to active disease.

Dr Nadeem presented these results at the EHA Congress in Stockholm, Sweden. 

Transcript:

Hi, my name is Omar Nadeem from the Dana-Farber Cancer Institute. It’s my pleasure to share results from the phase 2 ImmunoPRISM trial, which looked at teclistamab versus lenalidomide and dexamethasone in patients with high-risk smoldering myeloma. These data were presented as a late-breaking abstract at the EHA Congress in Stockholm.

High-risk smoldering myeloma is a precursor plasma cell disorder that carries approximately a 50% risk of progression to multiple myeloma within 2 years. Historically, patients were observed until progression, although more recently we had our first approval in this space with daratumumab based on the AQUILA trial. While that represented tremendous progress, there is still room for improvement, as approximately 40% of patients on the AQUILA trial developed disease progression by 5 years, and complete response rates were low, at less than 10%.

Teclistamab is a BCMA-directed bispecific antibody that is currently approved for patients with relapsed/refractory multiple myeloma. More recent data from studies such as MajesTEC-9 and MajesTEC-3 have shown that if teclistamab is used earlier, in patients with 1 to 3 prior lines of therapy, outcomes are substantially improved compared with standard-of-care regimens. In the MajesTEC-9 trial, the MRD negativity rate observed with single-agent teclistamab in the relapsed setting was approximately 38%.

So the question became: if you move these T-cell–engaging therapies even earlier, particularly into the high-risk smoldering myeloma setting, can you improve upon these deep responses? That was the background and hypothesis behind the ImmunoPRISM trial—to determine whether T-cell engagers could induce deep responses while minimizing toxicity at a time when tumor burden is lower and the immune system is less altered.

This was a phase 2 randomized trial that began with a 6 patient safety run-in cohort. It was the first study to evaluate a bispecific antibody in high-risk smoldering myeloma. The first 3 patients received a lower dose of teclistamab, 720 μg/kg weekly during cycle 1, and then the dose was escalated to the standard dose of 1.5 mg/kg weekly moving forward. After the 6 patient safety run-in, patients were randomized in a 2:1 fashion to receive either teclistamab or lenalidomide plus dexamethasone. Treatment duration was initially 24 cycles, or 2 years, for both arms. However, during the study, the protocol was amended to reduce teclistamab treatment duration from 24 cycles to 12 cycles because we were seeing strong efficacy signals and wanted to optimize the risk-benefit ratio. The primary end point was complete response rate.

Key eligibility criteria included patients meeting high-risk smoldering myeloma definitions by the 20/2/20 model, patients with an IMWG risk score of 9 or greater, and selected additional high-risk features including evolving disease patterns, PETHEMA criteria, and high-risk cytogenetic abnormalities.

Ultimately, 59 patients were enrolled. The median age was 65 years. Approximately half had high-risk cytogenetic abnormalities, and about 2/3 met high-risk criteria by the 20/2/20 model. A total of 45 patients received teclistamab, including the 6 safety run-in patients, and 14 received lenalidomide plus dexamethasone. Baseline characteristics were well balanced between the 2 groups.

In terms of safety, no dose-limiting toxicities occurred during the safety run-in. Cytokine release syndrome occurred in approximately 71% of patients treated with teclistamab, but there were no grade ≥ 3 CRS events. Importantly, there were no cases of ICANS or other neurologic toxicities. Infections occurred in both treatment arms, but rates of grade ≥3 infections were similar—20% in the teclistamab arm and 21% in the lenalidomide/dexamethasone arm. All patients treated with teclistamab received IVIG prophylaxis.

In terms of efficacy, 75.6% of patients treated with teclistamab achieved a complete response, whereas no patients receiving lenalidomide and dexamethasone achieved a complete response. Rates of VGPR or better were also substantially higher with teclistamab, at 87%, compared with approximately 14% in the lenalidomide/dexamethasone arm.

Within the teclistamab arm, 3 patients were primary nonresponders. Three additional patients achieved partial responses and remained on therapy, and two patients achieved complete responses but remained MRD positive. Looking at MRD negativity, in the intention-to-treat population, 37 of 45 patients—or 82%—achieved MRD negativity at a sensitivity of 10⁻⁵. At 10⁻⁶ sensitivity, the MRD negativity rate was 78%. No patients treated with lenalidomide and dexamethasone achieved MRD negativity. Among patients who achieved MRD negativity, all subsequent MRD assessments remained negative, resulting in a sustained MRD negativity rate of 100%. 

At a median follow-up of 23.4 months, progression-free survival was significantly improved with teclistamab compared with lenalidomide and dexamethasone. The estimated two-year PFS rate was 92% versus 51%, respectively. Median progression-free survival was not reached, and there were no deaths on study, resulting in an overall survival rate of 100%. 

Eight patients developed either SLiM-CRAB progression or biochemical progression. Seven percent of patients in the teclistamab arm experienced progression compared with 36% in the lenalidomide/dexamethasone arm. Five patients developed CRAB progression, all due to bone lesions. Four percent were in the teclistamab arm versus 21% in the lenalidomide/dexamethasone arm.

We also evaluated the 3 primary teclistamab nonresponders and found no BCMA mutations, BCMA loss, or structural alterations, suggesting alternative mechanisms of resistance.

In conclusion, this is the first randomized trial of a BCMA-directed bispecific T-cell engager, teclistamab, compared with a control arm of lenalidomide and dexamethasone in high-risk smoldering myeloma. Teclistamab demonstrated a superior complete response rate of 75.6% versus 0% and significantly improved progression-free survival compared with lenalidomide and dexamethasone. MRD negativity rates were remarkably high at 82%, and those responses have remained sustained in all patients evaluated.

The safety profile was generally favorable compared with what has been reported in the relapsed/refractory setting. There were no high-grade CRS events, infection rates were lower than expected, and rates of grade 3 infections were approximately 20% in both arms.

Longer follow-up will be needed to determine the durability of these MRD-negative responses and to better understand the risk-benefit profile of teclistamab in high-risk smoldering myeloma.

Source:

Nadeem O, Santos DC, Magidson S, et al. Teclistamab improves depth of response and PFS versus lenalidomide-dexamethasone in high-risk smoldering multiple-myeloma: Results from the phase 2 IMMUNOPRISM trial. Presented at EHA Congress. June 11 - June 14, 2026. Stockholm, Sweden. Abstract EHA-7181.