Editor's Note: At the EHA 2026 conference, Professor Omar Nadeem from the Dana-Farber Cancer Institute (USA) announced the latest results of the Phase II ImmunoPRISM trial. This study compared the BCMA×CD3 bispecific antibody Teclistamab with the standard regimen of lenalidomide + dexamethasone (Rd) in patients with high-risk smoldering multiple myeloma (HRSMM), providing heavy evidence for early precision intervention in this field.01 Therapeutic Challenge: Intervention Dilemmas in High-Risk Smoldering Multiple Myeloma
Smoldering multiple myeloma (SMM) is the precursor stage of multiple myeloma (MM). Based on historical data, patients with high-risk smoldering multiple myeloma (HRSMM) have up to a 50% risk of progressing to active MM within two years of diagnosis. Historically, clinical management was mostly based on watchful waiting. It was not until 2019, based on the Aquila study, that the FDA approved Daratumumab for HRSMM, but its complete response (CR) rate was less than 10%. Professor Omar Nadeem pointed out that the core issue currently faced clinically is: how to achieve “disease eradication” through more potent and precise treatment regimens at a stage where the patient’s immune system is not yet compromised and the tumor burden is low. Teclistamab, as an anti-BCMA bispecific T-cell engager, has shown excellent efficacy in relapsed/refractory multiple myeloma (RRMM), and its application prospects in HRSMM are highly anticipated.
02 Study Design: Innovative Immune Strategy of the ImmunoPRISM Study
ImmunoPRISM (NCT04953897) is a randomized, open-label, Phase II clinical trial. Inclusion criteria strictly followed the 20/2/20 criteria or an IMWG score of ≥9 for HRSMM patients. The study randomized patients 2:1 to the Teclistamab group or the Rd control group. • Teclistamab group (n=45): After step-up dosing, 1.5 mg/kg weekly for Cycles 1-2; 3 mg/kg every two weeks for Cycles 3-6; and 3 mg/kg monthly from Cycle 7 onwards. Notably, based on the observed potent early response during the study, the treatment duration was shortened from the original 24 cycles to a fixed-duration treatment of 12 cycles. • Rd group (n=14): Received standard lenalidomide + dexamethasone treatment for two years. The primary endpoint was the complete response (CR) rate, and secondary endpoints included safety, progression-free survival (PFS), and minimal residual disease (MRD) negativity rate.
03 Efficacy Data: Unprecedented Response Depth and MRD Clearance
The results of the ImmunoPRISM study showed that Teclistamab demonstrated an overwhelming advantage in improving response depth. • Complete Response Rate (CR): The CR rate in the Teclistamab group reached 75% (34/45), while the CR rate in the Rd group was 0%. • Very Good Partial Response (VGPR) or better: 87% in the Teclistamab group, significantly higher than 14% in the Rd group. • MRD Negativity Rate (10⁻⁵): In the intention-to-treat (ITT) analysis, the MRD negativity rate in the Teclistamab group was as high as 82%, with 78% of patients achieving deep negativity at the 10⁻⁶ level. In contrast, no cases of MRD negativity were observed in the Rd group. Professor Omar Nadeem particularly emphasized that the median time to MRD negativity for Teclistamab was only 6 months, and in approximately two years of follow-up, all patients who achieved MRD negativity maintained this status, demonstrating the durability of immune intervention.
04 Survival Benefit: PFS Significantly Prolonged, Reduced Risk of Disease Progression
With a median follow-up of approximately 2 years, data showed that Teclistamab significantly improved long-term benefits for patients: • Estimated 2-year PFS rate: 92% for the Teclistamab group, significantly better than 51% for the Rd group. • Progression Event Analysis: A total of 8 progression events were recorded, with only 7% progressing in the Teclistamab group, mostly biochemical progression; while the proportion of progression in the Rd group was as high as 36%. • CRAB Criteria Progression: Only 4% of patients in the Teclistamab group developed CRAB symptoms such as bone lesions, compared to 21% in the Rd group. Currently, the median PFS and overall survival (OS) for both groups have not yet been reached.
05 Safety Profile: Predictable and Superior to the RRMM Stage
In terms of safety, Teclistamab’s performance in HRSMM patients was more advantageous due to their better immune background. • Cytokine Release Syndrome (CRS): The incidence was 71%, but all were grade 1-2 low-level events, and no grade 3 or higher CRS occurred. • Neurotoxicity: No ICANS or any form of neurotoxicity was observed in the entire group. • Infection Risk: The incidence of grade 3 or higher infection was basically the same in the Teclistamab group and the Rd group, at approximately 20%. This figure is significantly lower than the infection rate of Teclistamab in the relapsed/refractory stage (over 40% in the Majestic-1 study). The study effectively controlled the risk of infection through preventive use of intravenous immunoglobulin (IVIG). • Neutropenia: There was no statistically significant difference in grade 3 or higher events between the two groups.
06 Deep Reflection: Resistance Mechanisms and Future Clinical Practice
There were still 3 patients in the study who were primary non-responders to Teclistamab. Professor Nadeem’s team conducted whole-genome sequencing (WGS) on them and found no BCMA mutations, structural changes, or BCMA loss. Interestingly, after these resistant patients transitioned to subsequent myeloma therapies (such as Daratumumab + VRd combination and autologous stem cell transplantation), they all achieved deep responses. This suggests that resistance to Teclistamab may be more related to T-cell exhaustion or microenvironment dysfunction rather than loss of the target, and early use of bispecific antibodies does not affect the sensitivity of subsequent traditional treatments.
Conclusion and Outlook
The ImmunoPRISM study is the first randomized controlled trial to compare a BCMA bispecific antibody with the standard Rd regimen for HRSMM. Professor Omar Nadeem concluded: “Through 12 cycles of fixed-duration treatment, Teclistamab induced extremely high CR rates and durable MRD negativity in patients with high-risk smoldering multiple myeloma, and its safety profile is significantly better than that of patients with late-stage MM. This finding supports moving the threshold of immune intervention forward, laying the foundation for future curative exploration in HRSMM.” As follow-up time extends, future research will focus on the maintenance of long-term remission after 12 cycles of fixed-duration treatment, as well as how to use biomarkers to precisely screen the subgroups most likely to benefit from this immune strategy.
Expert Profile Omar Nadeem, MD Assistant Professor at Harvard Medical School and Associate Director of the Multiple Myeloma Clinical Research Program at Dana-Farber Cancer Institute. Focuses on immune therapy and new drug development for multiple myeloma and precursor plasma cell diseases.
