Relative mortality in elderly frail patients with newly diagnosed multiple myeloma: Ad-hoc analysis of the Phase 3 IFM 2017-03 trial compared to population-based data in France and implications for the functional cure concept

Abstract Background. Recent improvements in frontline treatments have led to remarkable outcomes in elderly patients with newly diagnosed multiple myeloma (NDMM), raising the question of a “functional cure”, defined by prolonged disease control, preserved quality of life, and near-normal life expectancy. The IFM2017-03 phase 3 trial, dedicated to frail patients with NDMM, randomized participants to receive either daratumumab-lenalidomide (DR) or lenalidomide-dexamethasone (Rd). This trial provides unique survival data for a largely underrepresented population. The median progression-free survival (PFS) was 53.4 months in the DR group, and the 4-years overall survival (OS) rate was 68%. Considering these improved outcomes, we sought to determine whether frail elderly patients now achieve survival trajectories approaching those of their age- and sex-matched peers in the general population.Methods. Patients included in this analysis were drawn from the IFM2017-03 trial and compared to the general French population using aggregated mortality data stratified by age, sex, and calendar year. OS was estimated using the Kaplan-Meier method within each treatment arm (DR and Rd). Treatment effect was expressed as a hazard ratio (HR) with corresponding two-sided 95% confidence intervals (CI), estimated using a stratified Cox proportional hazards model. Relative survival and its 95% CI were estimated for each treatment arm by comparing observed survival with expected survival from the general French population, adjusted for age, sex, and study entry year. Standardized mortality ratios (SMRs) and their 95% CIs were calculated for each group, defined as the ratio of observed to expected deaths in a population with matching demographics.Results. A total of 295 frail, transplant-ineligible patients with NDMM were randomized in the IFM2017-03 trial to receive either DR (n=200) or Rd (n=95), with enrollment occurring across 61 centers in France between October 2019 and July 2021. Median age was 81 years, and 61% of patients were aged ≥80 years. At 48 months, OS was 67.9% [95% CI: 61.2–75.4] in the DR arm and 47.8% [95% CI: 37.7–60.6] in the Rd arm with a HR of 0.52 [95% CI: 0.35–0.77], p=0.001; relative survival was 0.87 vs 0.63, and SMR was 1.61 [95% CI: 1.22–2.07, p=0.0003] vs 3.07 [95% CI: 2.24–4.11, p<0.0001], respectively.In patients aged ≥80 years (n=180), 48-month OS was 63.9% [95% CI: 55–74.1] in DR vs 37.1% [95% CI: 25.1–54.8] in Rd. Relative survival was 0.88 in DR vs 0.55 in Rd. The SMR for DR in this age group was 1.39 [95% CI: 1.00–1.90, p=0.043], compared to 2.93 [95% CI: 2.03–4.09, p<0.0001] in Rd.Among patients <80 years, (n=115), 48-month OS was 73.9% [95% CI: 64.2-85] in DR vs 66% [95% CI: 51.4-84.7] in Rd. Relative survival was 0.85 in DR vs 0.76 in Rd. The SMR for DR in this age group was 2.35 [95% CI: 1.42–3.68, p=0.002], compared to 3.64 [95% CI: 1.81–6.51, p=0.0007] in Rd. These results in patients <80 years should be interpreted with caution, as all patients included in the trial were classified as frail by inclusion criteria and may therefore not be directly comparable to the general population matched only on age and sex.Conclusion. In this ad-hoc analysis of the IFM2017-03 trial compared to population-based data, the SMR was significantly lower in the DR group across all age subgroups. While excess mortality persists in frail patients with NDMM overall, outcomes among patients aged ≥80 years treated with DR showed a markedly reduced SMR approaching that of the general population. These findings suggest that frail patients aged ≥80 years or older may now achieve survival trajectories consistent with a “functional cure”.