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 and Irene M. Ghobrial ()
Additional contact information
Omar Nadeem: Dana-Farber Cancer Institute
Michelle P. Aranha: Dana-Farber Cancer Institute
Robert Redd: Dana-Farber Cancer Institute
Michael Timonian: Dana-Farber Cancer Institute
Sophie Magidson: Dana-Farber Cancer Institute
Elizabeth D. Lightbody: Dana-Farber Cancer Institute
Jean-Baptiste Alberge: Dana-Farber Cancer Institute
Luca Bertamini: Dana-Farber Cancer Institute
Ankit K. Dutta: Dana-Farber Cancer Institute
Habib El-Khoury: Dana-Farber Cancer Institute
Mark Bustoros: Dana-Farber Cancer Institute
Jacob P. Laubach: Dana-Farber Cancer Institute
Giada Bianchi: Brigham and Women’s Hospital and Dana Farber Cancer Institute
Elizabeth O’Donnell: Dana-Farber Cancer Institute
Ting Wu: Broad Institute of MIT and Harvard
Junko Tsuji: Broad Institute of MIT and Harvard
Kenneth C. Anderson: Dana-Farber Cancer Institute
Gad Getz: Harvard Medical School
Lorenzo Trippa: Dana-Farber Cancer Institute
Paul G. Richardson: Dana-Farber Cancer Institute
Romanos Sklavenitis-Pistofidis: Dana-Farber Cancer Institute
Irene M. Ghobrial: Dana-Farber Cancer Institute

Nature Communications, 2025, vol. 16, issue 1, 1-17

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.

Date: 2025
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DOI: 10.1038/s41467-024-55308-5

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