Clinical Summary:

• Design/Population: The phase 2 ImmunoPRISM trial randomized 59 patients with high-risk smoldering multiple myeloma to receive teclistamab or lenalidomide plus dexamethasone following a safety run-in cohort. Eligible patients met established high-risk criteria, including the 20/2/20 model, IMWG risk score ≥9, or other high-risk clinical and cytogenetic features.
• Key Outcomes: Teclistamab produced substantially higher complete response and MRD negativity rates than lenalidomide plus dexamethasone while significantly improving progression-free survival. The safety profile was favorable, with no grade ≥3 cytokine release syndrome or ICANS and infection rates comparable to the control arm.
• Clinical Relevance: These findings support earlier use of BCMA-directed bispecific antibody therapy in high-risk smoldering multiple myeloma and suggest that deep molecular responses may be achievable before progression to symptomatic disease.

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 European Hematology Association (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 is looking 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% chance of progression to multiple myeloma within 2 years. Historically, patients were placed on observation until more recently, when we had our first approval with daratumumab based on the results from the AQUILA trial. While this was tremendous progress, there is room for improvement, as about 40% of patients on the AQUILA trial still developed disease progression at 5 years, and rates of complete response were less than 10%.

Teclistamab is a BCMA bispecific antibody that is currently approved for patients with relapsed or refractory myeloma. There are more recent data based on the results from the MajesTEC-9 and MajesTEC-3 trials showing that if you use teclistamab in an earlier relapse setting, after 1 to 3 prior lines of therapy, it substantially improves outcomes compared to standard-of-care regimens. The MRD negativity rate that was observed with single-agent teclistamab in the relapsed setting in the MajesTEC-9 trial was about 38%.

Again, the question is, if you move these T-cell therapies even earlier into the newly diagnosed setting, and especially into the high-risk smoldering myeloma space, can you improve upon some of these deep responses that are seen?

That was the background and the hypothesis of our immunoPRISM trial—to see if we could use these T-cell engagers to induce a deep response while minimizing toxicity at a time when the tumor burden is lower and the immune system is less altered. We hypothesized that the efficacy may be more enhanced and the safety profile may be better.

This was a phase 2 randomized trial that started with a safety run-in cohort of 6 patients. This was the first trial that looked at a bispecific antibody in high-risk smoldering myeloma. The first 3 patients were treated at a lower dose of teclistamab, 720 micrograms/kg weekly, just in cycle 1. The dose was then escalated to the standard dose of 1.5 mg/kg weekly going forward. After the 6 patient safety run-in, the trial design had a 2:1 randomization to either teclistamab or lenalidomide and dexamethasone. The treatment duration was 24 cycles, or two years, for both arms. 

However, in the middle of the study, we amended the protocol to reduce the duration of treatment in the teclistamab arm from 24 cycles to 12 cycles because we were seeing a strong efficacy signal and wanted to optimize the risk-benefit ratio. The primary end point of the study was complete response rate. 

In terms of pertinent inclusion criteria, patients who met high-risk criteria per the 20 to 20 model were included, along with patients who had an IMWG risk score of 9 or greater. We also included several other published high-risk smoldering myeloma criteria, including the evolving pattern, PETHEMA criteria, and high-risk cytogenetic abnormalities.

Ultimately, 59 patients were enrolled in this study. The median age was 65 years. Approximately half the patients had high-risk cytogenetic abnormalities, and 2/3 of patients met high-risk criteria according to the 20 to 20 model. The total number of patients treated with teclistamab in this study was 45, including the 6 safety run-in patients, and lenalidomide plus dexamethasone was administered to 14 patients. The baseline demographics were well balanced between the 2 arms. 

In terms of safety, no dose-limiting toxicities occurred in the safety run-in cohort. Cytokine release syndrome was seen in about 71.1% of patients in the teclistamab arm, and there were no grade ≥3 CRS events noted. Notably, there were no ICANS or any neurologic toxicity seen in this trial. Infections were seen in both arms, but the rates of grade ≥ 3 infections were actually the same. In the teclistamab arm, the rate was 20%, and in the lenalidomide plus dexamethasone arm it was 21%. All teclistamab-treated patients received IVIG prophylaxis. 

In terms of responses, 75.6% of patients achieved a complete response in the teclistamab arm, whereas no patients treated with lenalidomide and dexamethasone achieved a complete response. The rates of VGPR or better were also higher with teclistamab, at 87% versus approximately 14% in the lenalidomide and dexamethasone arm. 

In the teclistamab arm, there were 3 primary nonresponders. Three additional patients had a partial response and remained on therapy, and 2  patients achieved a complete response but remained MRD positive. In terms of MRD negativity, in the intention-to-treat analysis, 82% patients achieved MRD negativity at the 10^-5 level. At the 10^-6 level, the MRD negativity rate with teclistamab was 78%. No patients treated with lenalidomide and dexamethasone developed MRD negativity.

Among patients who achieved MRD negativity, all subsequent assessments remained MRD negative, so MRD negativity was sustained in 100% of patients. In terms of progression-free survival, at a median follow-up of 23.4 months, progression-free survival was significantly improved with teclistamab versus lenalidomide and dexamethasone, with a two-year estimated progression-free survival rate of 92% versus 51%. Median progression-free survival was not reached, and there were no deaths on study, so overall survival is currently 100%. Eight patients in the study developed either SLiM-CRAB or biochemical progression. Progression occurred in 7% of patients in the teclistamab arm and 36% of patients in the lenalidomide and dexamethasone arm. Five patients developed CRAB progression, all with bone lesions. Four percent of these were in the teclistamab arm and 21% in the lenalidomide and dexamethasone arm. 

We also looked at the three primary teclistamab nonresponders. Interestingly, there were no BCMA mutations, BCMA loss, or structural alterations identified in these patients, suggesting a different mechanism of potential resistance.

In conclusion, this is the first randomized trial of a BCMA 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 improved progression-free survival compared with lenalidomide and dexamethasone. The MRD negativity rate was very high with single-agent teclistamab in the high-risk smoldering myeloma population, at 82%, and remained sustained in all patients. The safety profile was generally favorable compared with the data we've seen with the same agent in the relapsed/refractory setting. There were no high-grade CRS events. Infection rates were generally lower in this trial, and grade 3 infections were approximately 20% in both arms.

Longer follow-up is now needed to determine the durability of these MRD-negative responses and to better understand the risk-benefit ratio 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.