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<p>Daratumumab is approved for patients with multiple myeloma (MM) and high-risk smoldering MM (HR-SMM). However, HR-SMM is often as genomically complex as MM, suggesting it may be too advanced for single-agent intervention. We report on a Phase II trial of single-agent daratumumab in patients with earlier-stage disease, including high-risk monoclonal gammopathy of undetermined significance and low-risk SMM, to test if earlier treatment can induce deep responses and prevent progression to MM (D-PRISM/NCT03236428, <i>n</i> = 41). As primary outcome, the rate of Very Good Partial Response or better is 17% (95% CI: 7–32), which is comparable to what was observed in HR-SMM and does not meet the study’s primary endpoint. The overall response rate is 54%, with two patients developing MM and 51% biochemical progression. Grade 3 or higher toxicities include hypertension (7%), diarrhea (2%), flu-like symptoms (2%), and headache (2%). Genomic and immune variables associated with biochemical progression are identified in exploratory analyses leveraging whole-genome and single-cell RNA-sequencing. This study demonstrates that, although less effective than expected, daratumumab is safe and can induce deep responses in certain early-stage patients, highlighting the importance of adopting genomic and immune profiling to improve patient selection and maximize the benefit/risk ratio in trials of early intervention.</p>

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Daratumumab in high-risk MGUS and low-risk smoldering myeloma: results of the Phase II D-PRISM study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月8日

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  • Omar Nadeem,
  • Michelle P. Aranha,
  • Robert A. Redd,
  • Michael Koontz,
  • Jeffrey V. Matous,
  • Andrew J. Yee,
  • Jeffrey A. Zonder,
  • Andrew Kin,
  • Sophie Magidson,
  • Elizabeth D. Lightbody,
  • Ting Wu,
  • Floris Chabrun,
  • Jean-Baptiste Alberge,
  • Ankit K. Dutta,
  • Jacqueline Perry,
  • Ashlee Sturtevant,
  • Mahshid Rahmat,
  • Junko Tsuji,
  • Christine Davie,
  • Caroline Ricciardi,
  • Frances Arters,
  • Marjorie Marto,
  • Amy Bergeron,
  • Jacalyn Rosenblatt,
  • Elizabeth K. O’Donnell,
  • Tarek H. Mouhieddine,
  • Lorena Pantano,
  • Jacob P. Laubach,
  • Paul G. Richardson,
  • Gad Getz,
  • Lorenzo Trippa,
  • Romanos Sklavenitis-Pistofidis,
  • Irene M. Ghobrial

摘要

Daratumumab is approved for patients with multiple myeloma (MM) and high-risk smoldering MM (HR-SMM). However, HR-SMM is often as genomically complex as MM, suggesting it may be too advanced for single-agent intervention. We report on a Phase II trial of single-agent daratumumab in patients with earlier-stage disease, including high-risk monoclonal gammopathy of undetermined significance and low-risk SMM, to test if earlier treatment can induce deep responses and prevent progression to MM (D-PRISM/NCT03236428, n = 41). As primary outcome, the rate of Very Good Partial Response or better is 17% (95% CI: 7–32), which is comparable to what was observed in HR-SMM and does not meet the study’s primary endpoint. The overall response rate is 54%, with two patients developing MM and 51% biochemical progression. Grade 3 or higher toxicities include hypertension (7%), diarrhea (2%), flu-like symptoms (2%), and headache (2%). Genomic and immune variables associated with biochemical progression are identified in exploratory analyses leveraging whole-genome and single-cell RNA-sequencing. This study demonstrates that, although less effective than expected, daratumumab is safe and can induce deep responses in certain early-stage patients, highlighting the importance of adopting genomic and immune profiling to improve patient selection and maximize the benefit/risk ratio in trials of early intervention.