Optimizing Treatment in Frail Elderly with Newly Diagnosed Multiple Myeloma: Insights from the IFM2017-03 Trial on Dexamethasone-Sparing Daratumumab and Lenalidomide Regimen

Highlight

The IFM2017-03 trial investigated the safety and efficacy of a dexamethasone-sparing regimen integrating daratumumab with lenalidomide compared to standard lenalidomide-dexamethasone in frail elderly patients newly diagnosed with multiple myeloma. The study found that limiting dexamethasone to only the first two cycles, while maintaining daratumumab and lenalidomide, significantly prolonged progression-free survival (PFS) and showed a comparable safety profile. This regimen offers a promising treatment approach tailored to the unique needs of the frail elderly population.

Study Background

Multiple myeloma (MM) predominantly affects older adults, with a significant proportion of patients exhibiting frailty—characterized by decreased physiological reserves and increased vulnerability to adverse events. Frailty in newly diagnosed MM patients is associated with poorer outcomes due to increased toxicity, treatment discontinuation, and comorbidities. Standard regimens often include dexamethasone, a corticosteroid effective in MM but known for contributing to significant side effects such as immunosuppression, hyperglycemia, mood disturbances, and muscle weakness, which can be particularly detrimental in frail elderly patients.

Daratumumab, a monoclonal antibody targeting CD38, combined with lenalidomide, an immunomodulatory drug, represents an effective therapeutic strategy in newly diagnosed MM. However, the optimal dosing and combination, especially concerning corticosteroid exposure in frail patients, remained unclear prior to this study. The IFM2017-03 trial was designed to address this gap by testing whether a dexamethasone-sparing regimen could improve outcomes without compromising safety.

Study Design

This phase 3, open-label, multicentre, randomized controlled trial was conducted across 61 centers within the Intergroup Francophone of Myeloma network. Eligible patients were aged 65 or older with newly diagnosed multiple myeloma and a frailty score of 2 or higher using an Eastern Cooperative Oncology Group (ECOG) proxy measure.

Participants were randomized in a 2:1 ratio to either the dexamethasone-sparing group or control group. The dexamethasone-sparing group received daratumumab (1800 mg subcutaneously) plus oral lenalidomide (25 mg daily for 21 days of each 28-day cycle) along with dexamethasone 20 mg weekly only during the first two cycles. The control group was treated with oral lenalidomide (25 mg daily continuously) plus dexamethasone (20 mg weekly) throughout treatment. Randomization was stratified by International Staging System (ISS) stage, age, and center.

The primary endpoint was progression-free survival (PFS), defined as the time from randomization to disease progression or death. Secondary assessments included safety and tolerability across all patients exposed to at least one dose of study medication.

Key Findings

Between October 2019 and July 2021, 335 patients were screened and 295 enrolled and randomized (200 to the dexamethasone-sparing group; 95 to the control group). The median age was 81 years (IQR 77–84), with 61% aged over 80, reflecting a truly frail elderly cohort. Gender distribution was balanced.

After a median follow-up of 46.3 months, the dexamethasone-sparing regimen demonstrated a remarkable improvement in median PFS of 53.4 months (95% CI, 35.3 to not reached) compared to 22.5 months (95% CI, 16.5–39.0) in the control group. This equates to a hazard ratio (HR) of 0.51 (95% CI, 0.37–0.70; p < 0.0001), indicating a 49% reduction in the risk of progression or death.

Regarding safety, grade 3–5 adverse events (AEs) were noted in both groups, with neutropenia more frequent in the dexamethasone-sparing group (55% vs. 24%), likely reflecting daratumumab’s immunomodulatory effects. Infection rates were comparable between groups (19% vs. 21%). Serious AEs occurred in 63% of the dexamethasone group and 69% of controls. Deaths due to AEs were similar at 12% and 13%, respectively, with grade 5 treatment-emergent events equally low (2% each).

Notably, the reduction in dexamethasone exposure did not increase serious infection risk nor treatment-related mortality. The improved PFS combined with a manageable safety profile suggests superior tolerability and efficacy of the dexamethasone-sparing approach in frail elderly patients.

Expert Commentary

This trial provides compelling evidence to reconsider the traditional use of sustained corticosteroids in the treatment of frail elderly patients with newly diagnosed MM. Dexamethasone’s dose-dependent toxicity can worsen frailty and decrease treatment adherence. By limiting dexamethasone to two initial cycles, the IFM2017-03 regimen retains the anti-myeloma synergy of lenalidomide and daratumumab while mitigating steroid-associated harm.

Despite increased neutropenia in the experimental arm, infection rates did not rise significantly, highlighting effective supportive care and infection monitoring strategies. These findings align with growing data supporting dexamethasone minimization or elimination in certain MM treatment settings.

Limitations include the open-label design and potential selection bias inherent in enrolling patients with frailty, yet the trial’s pragmatic approach strengthens its clinical relevance. Results are potentially practice-changing, but real-world applicability requires confirmation across diverse populations and healthcare settings.

Conclusion

The IFM2017-03 trial establishes that a dexamethasone-sparing regimen of daratumumab plus lenalidomide significantly improves progression-free survival compared with continuous lenalidomide-dexamethasone in frail elderly patients with newly diagnosed multiple myeloma. This approach minimizes corticosteroid exposure, reducing toxicity without compromising efficacy or increasing mortality, thus addressing a critical unmet need in this vulnerable population.

Clinicians should consider lenalidomide plus daratumumab with limited dexamethasone as a frontline treatment option for older, frail patients, tailoring therapy to optimize balance between efficacy and tolerability. Further studies are warranted to evaluate long-term outcomes, quality of life, and integration with emerging myeloma therapeutics.

Funding and Registration

This study was funded by Johnson & Johnson. The clinical trial is registered at ClinicalTrials.gov under identifier NCT03993912.

Reference

Manier S, Lambert J, Hulin C, Macro M, Laribi K, Araujo C, Pica GM, Touzeau C, Godmer P, Slama B, Karlin L, Orsini Piocelle F, Dib M, Sanhes L, Morel P, El Yamani A, Tiab M, Tabrizi R, Richez V, Garderet L, Royer B, Bareau B, Mariette C, Fleck E, Robu D, Calmettes C, Rigaudeau S, Demarquette H, Frenzel L, Decaux O, Mohty M, Arnulf B, Bigot N, Perrot A, Corre J, Mary JY, Avet-Loiseau H, Moreau P, Leleu X, Facon T. Safety and efficacy of a dexamethasone-sparing regimen with daratumumab and lenalidomide in patients with frailty and newly diagnosed multiple myeloma (IFM2017-03): a phase 3, open-label, multicentre, randomised, controlled trial. Lancet Oncol. 2025 Oct;26(10):1323-1333. doi: 10.1016/S1470-2045(25)00280-3. PMID: 41038184.