Findings from the phase 2 I-PRISM trial indicate that achieving deeper responses with ixazomib, lenalidomide, and dexamethasone (IxaRD) may predict better clinical outcomes in patients with high-risk smoldering multiple myeloma (HR-SMM). The study, published in Nature Communications, highlights the potential of IxaRD to prevent end-organ damage and limit toxicity in this patient population.
The I-PRISM trial enrolled 55 patients with HR-SMM without SLiM-CRAB criteria, treating them with nine cycles of induction therapy (ixazomib, lenalidomide, and dexamethasone) followed by 15 cycles of maintenance (ixazomib and lenalidomide). The primary endpoint was 2-year progression-free survival (PFS) per SLiM-CRAB criteria.
High Response Rates and Tolerability
The overall response rate (ORR) was 93%, with 31% achieving a complete response (CR), 15% a very good partial response (VGPR), and 47% a partial response (PR). According to Dr. Omar Nadeem, clinical director of the Center for Early Detection and Interception of Blood Cancers at Harvard Medical School, the all-oral regimen was well-tolerated overall. The most common adverse events included leukopenia (80%), neutropenia (78%), and fatigue (76%).
Impact of Response Depth on Outcomes
The median follow-up was 50 months. The primary endpoint of PFS was not reached (95% CI, 57.7-NR). 98% of patients remained progression-free without SLiM-CRAB criteria or death within 2 years of enrollment. The median biochemical PFS was 48.6 months (95% CI, 39.9-NR).
Patients who achieved VGPR or better had a longer median time to biochemical progression (58.2 months) compared to those with inferior responses (31.3 months; log-rank, p<0.001). Patients achieving a sustained CR experienced a significantly longer PFS compared to the non-CR group (log-rank, p=0.010).
Biomarkers and Disease Progression
Single-cell RNA sequencing was performed on samples from 22 patients to identify biological predictors of response and resistance to IxaRD. Higher expression levels of MHC class I genes were observed in tumor cells from non-progressors compared to progressors. Additionally, clonally expanded cytotoxic T cells from progressors appeared less mature and potentially less functional than those from non-progressors.
Implications for HR-SMM Management
These findings suggest that deeper responses to IxaRD are associated with improved outcomes in HR-SMM. Monitoring response depth and identifying biomarkers related to treatment response may help optimize management strategies for this patient population. The study supports the use of IxaRD as an effective and well-tolerated regimen for preventing progression to multiple myeloma in high-risk smoldering cases.
