The IFM2017-03 Phase 3 Trial: A Dexamethasone Sparing-Regimen with Daratumumab and Lenalidomide for Frail Patients with Newly-Diagnosed Multiple Myeloma

Background. Elderly patients with newly diagnosed multiple myeloma (NDMM) have heterogeneous fitness and disparate tolerance to treatment. Frail patients develop more adverse events leading to higher rates of treatment discontinuation. The use of long term dexamethasone is associated with multiple side effects specially in elderly frail patients. In the phase 3 IFM2017-03 trial (NCT03993912) we investigate the efficacy and safety of daratumumab lenalidomide (DR) without long term dexamethasone to lenalidomide dexamethasone (Rd) in a frail population of patients with NDMM. Methods. The IFM2017-03 trial is a prospective, randomized, open-label study done at 90 IFM centers. 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) - Rd arm - 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) - DR arm - until progression or unacceptable toxicity. Randomization was stratified on ISS and age. The primary endpoint was progression free survival (PFS). Secondary endpoints were overall response rate, VGPR or better rate, overall survival (OS) and occurrence of grade 3 or more side effects. Results. In total, 295 patients were randomized (200 in DR arm and 95 in Rd arm). Median age was 81 years (range 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. At data cut-of, with a median follow-up time of 40 months (95%CI, 38.5 - 41.7), 79 (42%) and 16 (17%) patients in DR and Rd arms were still on treatment, respectively. Median treatment duration was 34.5 months (95%CI, 28.3 - 40.9) in arm DR and 14.3 months (95%CI, 10.8 - 20.6) in arm Rd. Overall best response rates were 92% in DR and 85% in Rd arms (p=0.025). Median PFS was 48.5 months (95%CI, 35,1-NR) in DR arm vs. 21.5 months (95%CI, 16.2-36.0) in Rd arm, HR 0.51 (95%CI, 0.37-0.71), log-rank p<0.0001 (Figure 1). PFS benefit was consistent across all subgroups defined by age, ECOG, Charlson, ISS, cytogenetics and creatinine clearance. Median OS was not reached in DR (95%CI, 53.4-NR) vs. 36.0 months in Rd, HR 0.46 (95%CI, 0.31-0.69), log-rank p=0.0001. At least one AE (grade ≥ 3) occurred in 88% and 77% of patients in DR and Rd arms, respectively. Patients in DR group had more grade ≥ 3 hematologic AE with neutropenia (DR 62%, Rd 33%) but similar grade ≥ 3 infections, with 18% in DR and 19% in Rd arms. Among patients with infections, 5% in DR and 7% in Rd had a pneumonia. Discontinuations due to AEs were similar in both arms (28% in DR and 34% in Rd). Baseline health-related quality of life (HRQoL) were well balanced between the 2 arms. The DR group had significantly shorter times to clinically meaningful improvement than Rd group in all QLQ-C30 domains. Conclusion. The IFM2017-03 trial is the first phase 3 study dedicated to frail patients. It shows a significant reduced risk of progression or death by 49% in DR (dexamethasone-sparing regimen) vs. Rd, with a favorable safety profile and an improved HRQoL.