Geriatrician, Assistant Professor VA Boston Healthcare System and Brigham and Women's Hospital/Harvard Medical School, Massachusetts, United States
Introduction: Randomized controlled trial data suggest that initiation of the more intensive triplet bortezomib-lenalidomide-dexamethasone (VRd) versus the less intensive doublet lenalidomide-dexamethasone (Rd) in patients newly diagnosed with multiple myeloma (MM) confers superior survival, but it is uncertain whether this survival benefit generalizes to frail patients treated in practice.
Methods: We identified all patients newly diagnosed with MM who were initiated on either VRd or Rd in the national U.S. Veterans Affairs Healthcare System. We measured frailty using the electronic Veterans Affairs Frailty Index (VA-FI), which has been validated in veterans with and without cancer. Using established cutoffs, we identified patients who were moderate-severely frail (VA-FI ≥ 0.3), mildly frail (VA-FI 0.20-0.29), and nonfrail (VA-FI < 0.2). To reduce imbalance in potential confounding across treatment groups within frailty categories, we matched patients on MM stage and on a propensity score (1:1 nearest-neighbor with a caliper of 1%) that was modeled on the probability of being initially treated with VRd vs. Rd as a function of age, sociodemographics, comorbidity, and MM-specific covariates. We used Cox proportional hazards models to evaluate differences in mortality between veterans initiated on VRd and veterans initiated on Rd. Our secondary outcome was incidence of unplanned hospitalizations within one year of treatment initiation.
Results: We identified 2573 patients newly diagnosed with MM who were initiated either on VRd (990) or Rd (1583), spanning years 2004-2020. After matching, patients who were moderate-severely frail were older than non-frail patients (median age 71.1 years vs. 67.6 years), had a higher prevalence of stage III MM (32.9% vs. 19.5%), and had a higher prevalence of myeloma-related health deficits. VRd vs. Rd was associated with lower mortality (HR = 0.81, 95% CI = 0.70 - 0.94) in the overall population. Moderate-severely frail patients demonstrated the strongest association between VRd vs. Rd and lower mortality (HR 0.74, 95% CI 0.56 - 0.97), whereas the association was weaker in mildly frail (HR 0.80, 95% CI 0.61 - 1.05) and nonfrail patients (HR 0.86, 95% CI 0.67 - 1.10). Although there was a modestly higher incidence of hospitalizations associated with VRd vs. Rd (incidence rate ratio [IRR] 1.22, 95% CI 1.1 - 1.34) in the overall population, this association weakened in moderate-severely frail patients (IRR 1.14, 95% CI 0.96 - 1.36).
Conclusions: Our findings not only confirm the mortality benefit of VRd over Rd in U.S. veterans newly diagnosed with MM, but also suggest that this benefit is strongest in patients with the highest levels of frailty, countering historical recommendations to consider doublets in this population. These findings argue that a frail patient’s cancer should be considered as a treatable cause of their frailty wherein more intensive treatment may be more effective.
