Deeper response predicts better outcomes in high-risk-smoldering-myeloma: results of the I-PRISM phase II clinical trial
Omar Nadeem, Michelle P. Aranha, Robert Redd, Michael Timonian, Sophie Magidson, Elizabeth D. Lightbody, Jean-Baptiste Alberge, Luca Bertamini, Ankit K. Dutta, Habib El‐Khoury, Mark Bustoros, Jacob P. Laubach, Giada Bianchi, Elizabeth O’Donnell, Ting Wu, Junko Tsuji, Kenneth C. Anderson, Gad Getz, Lorenzo Trippa, Paul G. Richardson, Romanos Sklavenitis‐Pistofidis, Irene M. Ghobrial
Abstract
Abstract Early therapeutic intervention in high-risk smoldering multiple myeloma (HR-SMM) has shown benefits, however, no studies have assessed whether biochemical progression or response depth predicts long-term outcomes. The single-arm I-PRISM phase II trial (NCT02916771) evaluated ixazomib, lenalidomide, and dexamethasone in 55 patients with HR-SMM. The primary endpoint, median progression-free survival (PFS), was not reached (NR) (95% CI: 57.7–NR, median follow-up 50 months). The secondary endpoint, biochemical PFS, was 48.6 months (95% CI: 39.9–NR) and coincided with or preceded SLiM-CRAB in eight patients. For additional secondary objectives, the overall response rate was 93% with 31% achieving complete response (CR) and 45% very good partial response (VGPR) or better. CR correlated strongly with the absence of SLiM-CRAB and biochemical progression. MRD-negativity (10 -5 sensitivity) predicted a 5-year biochemical PFS of 100% versus 40% in MRD-positive patients (p = 0.051), demonstrating that deep responses significantly improve time to progression. Exploratory single-cell RNA sequencing linked tumor MHC class I expression to proteasome inhibitor response, and a lower proportion of GZMB+ T cells within clonally expanded CD8+ T cells associated with suboptimal outcomes.