Dexamethasone-Sparing Regimen Safe and Effective in Frail Patients with Multiple Myeloma

February 2023, Vol 14, No 1

Response to treatment with a regimen of daratumumab (Darzalex) plus lenalidomide (Revlimid; DR) was greater and minimal residual disease (MRD) was achieved more frequently compared with a regimen of lenalidomide plus dexamethasone (Rd) in the first randomized phase 3 clinical trial dedicated to frail, transplant-ineligible patients with newly diagnosed multiple myeloma.

Findings from the IFM2017-03 trial were presented by Salomon Manier, MD, PhD, Professor, Medicine, Université de Lille, France, at the 64th American Society of Hematology Annual Meeting and Exposition.

“These preliminary data on a dexamethasone-sparing strategy for frail patients is encouraging,” said Dr Manier. “The safety profile was favorable without increased infection or pneumonia rates with DR versus Rd and with similar rates of treatment discontinuation.”

Dexamethasone, a key agent in multiple myeloma induction regimens, is associated with side effects that disproportionately affect older patients, who have variable fitness levels and tolerance to treatment. The Rd regimen has been a standard treatment for transplant-ineligible patients with multiple myeloma based on results from the phase 3 FIRST trial. More recently, daratumumab plus lenalidomide plus dexamethasone (DRd) became the new standard of care for these patients based on findings from the phase 3 MAIA trial.

“We know that there is a higher rate of infection, especially pneumonia, in patients treated with DRd compared with Rd, especially in the frail population of patients,” Dr Manier said. “We made the hypothesis that a dexamethasone-sparing regimen will be effective with limited toxicity in a frail population of patients.”

Study Details

The IFM2017-03 study randomized 295 patients aged >65 years with newly diagnosed multiple myeloma and with a simplified Intergroupe Francophone du Myélome (IFM) frailty score ≥2 to receive Rd (N = 94) or DR (N = 199). Patients in the Rd arm received lenalidomide 25 mg daily on days 1 to 21 of each 28-day cycle and dexamethasone at 20 mg once a week. Patients in the DR arm received lenalidomide 25 mg daily on days 1 to 21, dexamethasone 20 mg weekly for 2 cycles, and daratumumab 1800 mg weekly for 8 weeks, every other week for 16 weeks, and every 4 weeks thereafter. Patients in both arms were treated until disease progression or unacceptable toxicity.

The median patient age was 81 years in both arms. The 2 arms were well-balanced for IFM frailty score as well as International Staging System disease stage. Approximately 80% of patients in both arms had standard-risk cytogenetics.

“The responses were deeper at all time points in the dexamethasone-sparing regimen, including at early time points,” said Dr Manier. The rates of very good partial response or better (≥VGPR) were 41% in the DR arm versus 26% in the Rd arm at 4 months; 68% versus 48%, respectively, at 8 months; and 71% versus 55%, respectively, at 12 months. Subgroup analysis showed superior rates of ≥VGPR in the DR arm for any frailty score (P = .87) and regardless of cytogenetic risk (P = .29).

MRD was assessed for patients with at least a ≥VGPR at 12 months. MRD status was missing or not assessable in 20.6% of the DR arm and 14.1% in the Rd arm. Patients with missing data were considered MRD-positive. In an intent-to-treat analysis, the rates of MRD at 10-5 by next-generation sequencing were 10% in the DR arm and 3% in the Rd arm.

Grade ≥3 adverse events were more frequent in the DR arm, “however, this was driven by hematological adverse events and mainly neutropenia that was higher in the DR group as compared to the Rd group,” Dr Manier said. “This didn’t translate into an increased rate of infection, with rates of 13% in the DR group versus 18% in the Rd group.” There was a trend toward a lower rate of grade ≥3 pneumonia in the DR arm (P = .06). The treatment discontinuation rates for adverse events were similar—14% in the DR arm versus 16% in the Rd arm.

When assessed by IFM frailty score, the rates of grade ≥3 adverse events in those with an IFM frailty score of 4 or 5 were 57% in the DR arm compared with 73% in the Rd arm, with rates of grade ≥3 pneumonia of 5% and 12%, respectively.

An analysis of progression-free survival is ongoing, Dr Manier noted.

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