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First phase 3 trial of dexamethasone-sparing regimen in frail older patients with myeloma.

IFM2017-03 reports that lenalidomide plus daratumumab improved progression-free survival versus lenalidomide plus dexamethasone in this frailty-specific population, without increased infection risk; the strategy is now part of EHA–EMN myeloma guidelines.

  • Salomon Manier, MD PhD; Jérôme Lambert, MD PhD; Cyrille Hulin, MD; Margaret Macro, MD; Kamel Laribi, MD; Carla Araujo, MD; et al.

  • October 1, 2025

  • The Lancet Oncology
  • The Lancet Oncology, Volume 26, Issue 10, Pages 1323–1333
  • 10.1016/S1470-2045(25)00280-3

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Evidence before this study

We searched PubMed on Feb 23, 2025, using the keywords “myeloma” and “frail” to identify studies focused on patients with frailty who had newly diagnosed multiple myeloma. The majority of relevant literature emerged after the publication of the International Myeloma Working Group (IMWG) frailty score in 2015, which provided a standardised approach for assessing frailty in myeloma. Several phase 2 trials have explored treatment strategies for patients with frailty and newly diagnosed multiple myeloma, including low-dose intensity bortezomib-based regimens and ixazomib, daratumumab, and dexamethasone in the HOVON 143 trial, both showing favourable efficacy and safety profiles. In addition, retrospective subgroup analyses of patients with frailty in phase 3 trials, such as ALCYONE (daratumumab plus bortezomib, melphalan, and prednisone vs bortezomib, melphalan, and prednisone) and MAIA (daratumumab, lenalidomide, and dexamethasone vs lenalidomide plus dexamethasone), have provided further insights into the outcomes in these patients. However, we identified no randomised phase 3 trials conducted in older patients with frailty and newly diagnosed multiple myeloma, highlighting an unmet need for frailty-adapted treatment strategies.

Added value of this study

To our knowledge, the IFM2017-03 trial is the first phase 3 randomised trial focused specifically on older patients with frailty and newly diagnosed multiple myeloma. The study shows the superiority of a dexamethasone-sparing strategy with lenalidomide plus daratumumab compared with lenalidomide plus dexamethasone, with a notable median progression free survival for this population with frailty. Importantly, in the context of prolonged removal of dexamethasone, the addition of daratumumab did not lead to an increased risk of infections, including pneumonia. These results suggest that a dexamethasone-sparing strategy can mitigate toxicity risks while maintaining the benefits of anti-CD38 antibody therapy.

Implications of all the available evidence

The IFM2017-03 trial supports the integration of a dexamethasone-sparing regimen into clinical practice for older patients with frailty and newly diagnosed multiple myeloma. The strategy has been included in the European Hematology Association–European Myeloma Network evidence-based guidelines for diagnosis, tratment and follow-up of patients with multiple myeloma.

Source: The Lancet Oncology

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