Dexamethasone-Sparing Regimen Offers Safer Option for Frail Patients With MM

Frail patients with multiple myeloma (MM) can quickly wean off dexamethasone without increasing infection risk, according to new study results. The data, published in Lancet Oncology, reveals that daratumumab (Darzalex; Johnson & Johnson) plus lenalidomide (Revlimid; Bristol Myers Squibb) had superior progression-free and overall survival (PFS; OS) to lenalidomide plus dexamethasone.¹

MM is the second most common hematologic malignancy characterized by the overproduction of B lymphocytes, leading to renal failure, anemia, and brittle bones. Treatment options have evolved substantially, but obstacles persist across patient subgroups. In older patients, frailty can be a significant challenge.¹

“Older patients with newly diagnosed multiple myeloma [NDMM] show variability in their fitness levels and tolerance to treatment, making their management more complex than younger patients,” the authors of the study wrote. “This heterogeneity necessitates the development of tailored approaches adapted to different patient subgroups. Patients with frailty have worse outcomes due to higher rates of non-hematological adverse events [AEs] and treatment discontinuations.”¹

Dexamethasone is a key component in MM treatment regimens, most notably in the standard-of-care combination of daratumumab and lenalidomide. However, prolonged use of dexamethasone is associated with increased risk of AEs, including infections, hypertension, or hyperglycemia. In frail patients, this can present a significant challenge in treatment adherence and success.¹

In the randomized, open-label, multi-center, controlled phase 3 IFM2017_03 trial (NCT03993912), researchers hypothesized that subcutaneous daratumumab in combination with lenalidomide will prolong PFS and likely induce less toxicity compared with lenalidomide and dexamethasone in elderly frail subjects with NDMM who are ineligible for high-dose chemotherapy and autologous stem cell transplantation. They assessed 295 patients (median age 81 years; 51% female; 49% male) who were randomized 2:1 to receive either daratumumab (1800 mg subcutaneously) plus oral lenalidomide (25 mg daily for 21 days of a 28-day cycle) and dexamethasone (20 mg weekly) for 2 cycles (n = 200; dexamethasone-sparing group) or lenalidomide (25 mg daily) and oral dexamethasone (20 mg weekly; n = 95; control group).^1,2

The primary end point was PFS, with efficacy assessed in the intention-to-treat population and safety in the entire population.¹

At the median follow-up of 46.3 months, patients in the dexamethasone-sparing group achieved a PFS of 53.4 months (95% CI 35.3-not reached) in the dexamethasone-sparing group compared with 22.5 months in the control group (HR 0.51; 95% CI 0.37-0.70; P < .0001).¹

Response rates were also favorable. The authors reported rates of very good partial response or better in both groups at 69% and 51% of patients in the dexamethasone-sparing and control groups, respectively. Patients in the dexamethasone-sparing group also achieved significant improvements in complete responses (34% vs 12%). The median OS was not reached in the dexamethasone-sparing group versus 47.3 months in the control group (HR 0.52; 95% CI 0.35-0.77; P = 0.0001).¹

“The results of the IFM2017-03 trial show a substantial reduction in risk of disease progression or death with lenalidomide plus daratumumab compared with lenalidomide plus dexamethasone, with a consistent benefit across subgroups, including those defined by age, disease stage, and cytogenetic risk,” the authors wrote.¹

Regarding safety, the most common grade 3 to 5 AEs were neutropenia (55% in the dexamethasone-sparing group vs 24% of patients in the control group) and infection (19% vs 21%, respectively). A total of 126 patients in the dexamethasone-sparing group experienced serious adverse events compared with 66 patients in the control group. AEs leading to death occurred in 23 patients (12%) in the dexamethasone-sparing group and 12 patients (13%) in the control group, with 4 (2%) and 2 (2%) grade 5 treatment-emergent adverse events, respectively.¹

By demonstrating that dexamethasone can be minimized without compromising efficacy or increasing infection risk, the IFM2017-03 trial supports a new standard of care centered on individualized, steroid-sparing approaches. As the population of older patients with MM continues to grow, such regimens may improve both longevity and quality of life while reducing the burden of treatment-related toxicity.

REFERENCES

1. Salomon M, 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 Oncology. October 2025. 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). Updated September 11, 2025. Accessed October 7, 2025. https://clinicaltrials.gov/study/NCT03993912