A Dexamethasone Sparing-Regimen with Daratumumab and Lenalidomide in Frail Patients with Newly-Diagnosed Multiple Myeloma: Efficacy and Safety Analysis of the Phase 3 IFM2017-03 Trial

Background. Two-third of patients with newly diagnosed multiple myeloma (NDMM) are over the age of 65. Those patients have heterogeneous fitness and disparate tolerance to treatment. Frailty scoring systems have informed the stratification of elderly patients and treatment guidance. The use of long term dexamethasone is associated with multiple side effects specifically in elderly patients. Here we present the response rates and safety analysis of the randomized phase 3 IFM2017-03 trial, comparing daratumumab lenalidomide (DR) without long term dexamethasone to lenalidomide dexamethasone (Rd) in a frail population of patients with NDMM.

Methods. Patients with NDMM over the age of 65 and with an ECOG proxy frailty score ≥ 2 were randomized 1:2 to receive 28-day cycles of lenalidomide (25mg/day, 21/28) and dexamethasone (20mg QW) or daratumumab (1800mg SC QW for 8 weeks, Q2W for 16 weeks and Q4W thereafter), lenalidomide (25mg/day, 21/28) and 2 cycles of dexamethasone (20mg QW for 8 weeks), until progression or unacceptable toxicity. Randomization was stratified on ISS and age. MRD by NGS at 10^-5 was performed at 12 months for all patients. Interim analysis endpoints were overall response rate, VGPR or better rate, MRD rate and occurrence of grade 3 or more side effects. The present analysis was done at 12-months-therapy data cut.

Results. In total, 295 patients were randomized (95 in Rd arm and 200 in DR arm). Median age was 81 years (68-92) with 84% of patients over the age of 75 years and 61% over the age of 80 years. Baseline demographics and disease characteristics were well balanced between arms.

Overall response rates were 77% in Rd arm and 89% in DR arm (p=0.025). 12-months rates of VGPR or better were 42% and 58% in Rd and DR arms, respectively (p=0.013). Depth of response improved during treatment and the median time to reach VGPR was 11 months in Rd group and 5 months in DR group. Treatment benefit for DR was homogeneous across all subgroups defined by age, ECOG, Charlson, ISS, cytogenetics and creatinine clearance. Among patients with VGPR or better at 12 months, 63 were evaluable for MRD at 10^-5 by NGS. MRD status at 12 months was negative in 18% of patients in Rd arm and 33% in DR arm (p=0.36).

During the first year of treatment, at least one AE (grade ≥ 3) occurred in 64% and 76% of patients in Rd and DR arms, respectively (p=0.052). Patients in DR group had more grade ≥ 3 hematologic AE with neutropenia (Rd 15%, DR 44%, p<0.001) and anemia (Rd 2%, DR 11%, p=0.01) but similar grade ≥ 3 infections, with 17% in Rd and 13% in DR arms (p=0.38). Among patients with infections, 13 had COVID-19 (3 in Rd and 10 in DR). Discontinuations for AEs were similar in both arms (16% in Rd and 13% in DR, p=0.64).

Conclusion. In this phase 3 trial dedicated for frail patients with NDMM, a dexamethasone-sparing regimen combining daratumumab and lenalidomide demonstrates deep and rapid responses and a favorable safety profile.

Manier:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees. Hulin:Sanofi: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; GSK: Honoraria; Amgen: Honoraria. Karlin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial Support travel & scientific meetings; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial Support travel & scientific meetings; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Macro:Janssen: Honoraria, Other: Travel/accommodation, Research Funding; Sanofi: Honoraria; GSK: Honoraria; Takeda: Honoraria, Other: Travel/accommodation, Research Funding. Perrot:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria. Moreau:AbbVie, Janssen, Celgene, Amgen, and Sanofi: Honoraria. Leleu:Janssen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Amgen, Merck, BMS, GSK, Janssen, Oncopeptide, Takeda, Roche, Novartis, AbbVie, Sanofi, Gilead, Pfizer, Harpoon Therapeutic, Regeneron, Iteos: Consultancy, Honoraria; Amgen, BMS/Celgene, Janssen, Takeda, Novartis, Sanofi, Merck, Oncopeptide, Karyopharm, Roche, Abbvie, Carsgen, GSK, and Harpoon Therapeutics: Honoraria.