Daratumumab/Lenalidomide With Limited Dexamethasone Displays Feasibility in Older/Frail Newly Diagnosed Myeloma

Treatment with the combination of daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro), lenalidomide (Revlimid), and dexamethasone—with dexamethasone exposure limited to the first 2 cycles—led to an improvement in progression-free survival (PFS) compared with lenalidomide plus continuous dexamethasone in older and frail patients with newly diagnosed multiple myeloma, according to data from the phase 3 IFM2017-03 trial (NCT03993912).1

Findings published in Lancet Oncology demonstrated that at a median follow-up of 46.3 months (interquartile range, 46.0-52.7), patients treated in the dexamethasone-sparing group (n = 200) experienced a median progression-free survival (PFS) of 53.4 months (95% CI, 35.3-not reached [NR]) compared with 22.5 months (95% CI, 16.5-39.0) for patients treated with standard dexamethasone plus lenalidomide (n = 95; HR, 0.51; 95% CI, 0.37-0.70; P < .0001). This PFS benefit was consistent across most subgroups, including age, ECOG performance status, International Staging System (ISS) disease stage, and cytogenetic risk group.

“Although lenalidomide plus dexamethasone represents a previous standard of care [SOC], it remains commonly used globally for patients with frailty as an all-oral regimen,” lead study author Salomon Manier, MD PhD, and colleagues wrote in the publication. “Although using a regimen of the combination of daratumumab, lenalidomide, and dexamethasone as the control group would have provided a direct comparison to lenalidomide plus daratumumab, it was not the SOC at the time the protocol for this trial was developed. Despite this, the trial clearly showed the superiority of lenalidomide plus daratumumab over lenalidomide plus dexamethasone in older patients with frailty, along with the absence of higher toxicity when adding the anti-CD38 antibody daratumumab to lenalidomide.”

Manier is an associate professor in the Department of Hematology at the University Hospital of Lille in France.

What Was the Rationale for and Design of the IFM2017-03 Trial?

Manier and colleagues noted that older patients with multiple myeloma have varying levels of fitness and treatment tolerance, translating to more complex management decisions compared with younger patients. Of note, they explained that patients with higher frailty scored tend to experience higher rates of non-hematologic adverse effects (AEs) and treatment discontinuation.

Dexamethasone serves as part of the backbone in several combination regimens for the treatment of patients with multiple myeloma, and this agent has been associated with a risk of AEs such as infections, hypertension, and hyperglycemia. As such, investigators sought to reduce the risk of these AEs by limiting dexamethasone exposure in this study.

IFM2017-03 was a randomized, open-label, active-controlled phase 3 study that enrolled patients at least 65 years of age with newly diagnosed multiple myeloma who were not candidates for high-dose chemotherapy and autologous stem cell transplant.2 Patients were required to have a frailty score of at least 2. Other key inclusion criteria comprised adequate laboratory values and measurable ISS with β2-microglobulin and albumin values.

Patients were randomly assigned in a 2:1 fashion.1 Those in the experimental arm were administered subcutaneous daratumumab at 1800 mg once per week in cycles 1 and 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter, until disease progression or unacceptable toxicity, in combination with lenalidomide at 25 mg on days 1 to 21 of each 28-day cycle until disease progression or unacceptable toxicity and dexamethasone at 20 mg on days 1, 8, 15, and 22 cycles 1 and 2. In cycle 3 and beyond, patients could receive prednisone at 1 mg/kg as an alternative premedication, if clinically indicated.

Those in the control arm received the same schedule of lenalidomide plus dexamethasone at 20 mg on days 1, 8, 15, and 22 of each cycle until disease progression or unacceptable toxicity. In both arms, lenalidomide could be given at a reduced dose of 10 mg for patients with creatinine clearance between 30 and 60 mL/min.

PFS served as the trial’s primary end point. Secondary end points included time to treatment failure, time to next treatment, time to second progression, overall survival (OS), complete remission rate, very good partial response (VGPR) or better rate, overall response rate (ORR), and safety.

What Were the Additional Efficacy and Safety Findings?

Data also showed that patients in the dexamethasone-sparing group achieved an ORR of 92% compared with 85% in the control arm. The rates of VGPR or better were 69% (95% CI, 62%-75%) and 51% (95% CI, 40%-61%), respectively (P = .0050).

The median OS was NR in the dexamethasone-sparing group vs 47.3 months (95% CI, 36-NR) in the lenalidomide/dexamethasone arm (HR, 0.52; 95% CI, 0.35-0.77; P = .0001).

Regarding safety, the rates of any-grade AEs were 98% in the dexamethasone-sparing group and 98% in the control group (relative risk [RR], 1.01; 95% CI, 0.97-1.04). The rates of serious AEs were 63% and 69%, respectively (RR, 0.91; 95% CI 0.76-1.08), and the respective rates of grade 3 or higher AEs were 89% vs 79% (RR, 1.13; 95% CI, 1.01-1.26).

AEs led to discontinuation of at least 1 study drug in 30% of patients in the experimental arm vs 34% of patients in the control arm; AEs led to discontinuation of all drugs in 18% and 24% of patients, respectively (RR, 0.74; 95% CI, 0.47-1.18).

“The proportion of patients who had infections, including pneumonia, was similar between groups, although among patients with an IFM frailty score of 4 or 5, pneumonia was more common in the control group than in the dexamethasone-sparing group,” study authors noted.

AEs led to death in 12% of patients in the dexamethasone-sparing group compared with 13% of patients in the control arm (RR, 0.91; 95% CI, 0.47-1.75).

References

1. Manier S, Lambert J, Hulin C, et al. 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;26(10):1323-1333. doi:10.1016/S1470-2045(25)00280-3
2. Compare lenalidomide and subcutaneous daratumumab vs lenalidomide and dexamethasone in frail subjects with previously untreated multiple myeloma who are ineligible for high dose therapy (IFM2017_03). ClinicalTrials.gov. Updated September 11, 2025. Accessed October 9, 2025. https://clinicaltrials.gov/study/NCT03993912