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Deeper response predicts better outcomes in high-risk-smoldering-myeloma: results of the I-PRISM phase II clinical trial

Author

Listed:
  • Omar Nadeem

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Michelle P. Aranha

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Robert Redd

    (Dana-Farber Cancer Institute)

  • Michael Timonian

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Sophie Magidson

    (Dana-Farber Cancer Institute)

  • Elizabeth D. Lightbody

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Jean-Baptiste Alberge

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Luca Bertamini

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Ankit K. Dutta

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Habib El-Khoury

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Mark Bustoros

    (Dana-Farber Cancer Institute
    New York-Presbyterian Hospital)

  • 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
    Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Lorenzo Trippa

    (Dana-Farber Cancer Institute)

  • Paul G. Richardson

    (Dana-Farber Cancer Institute)

  • Romanos Sklavenitis-Pistofidis

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Irene M. Ghobrial

    (Dana-Farber Cancer Institute
    Harvard Medical School
    Broad Institute of MIT and Harvard)

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.

Suggested Citation

  • 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, 2025. "Deeper response predicts better outcomes in high-risk-smoldering-myeloma: results of the I-PRISM phase II clinical trial," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55308-5
    DOI: 10.1038/s41467-024-55308-5
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    References listed on IDEAS

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    1. Eileen M. Boyle & Shayu Deshpande & Ruslana Tytarenko & Cody Ashby & Yan Wang & Michael A. Bauer & Sarah K. Johnson & Christopher P. Wardell & Sharmilan Thanendrarajan & Maurizio Zangari & Thierry Fac, 2021. "The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
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