there was no significant evidence that baseline age, comorbidity, or frailty modified the efficacy of IIV-HD relative to IIV-SD.
4. Drug trials in patients with cancer
The EMN01 study was designed to compare the progression-free survival (PFS) of elderly newly diagnosed multiple myeloma patients treated with triplet vs. doublet induction regimens and the PFS following maintenance treatment with lenalidomide-prednisone vs. lenalidomide alone. Before treatment, a geriatric assessment to assess patients’ frailty status according to the International Myeloma Working Group (IMWG) Frailty Score was performed. In 2015, a frailty scoring system was developed by the (IMWG) that classifies patients into 3 frailty subgroups—fit, intermediate, and frail—based on age, comorbidities (Charlson comorbidity index, ≤1 vs. >1), Katz Activities of Daily Living (ADL) scale (>4 vs. ≤4), and Lawton Instrumental Activities of Daily Living (IADL) scale (>5 vs. ≤5). Participants were stratified into 3 groups according to their frailty status: fit (total score 0), intermediate-fit (total score 1), and frail (total score >=2). Post-hoc analysis according to frailty status in both induction and maintenance treatment arms showed thatfit patients benefit from a full-dose triplet regimen, while intermediate-fit and frail patients benefit from gentler regimens .  Frail patients had the highest rate of discontinuation due to adverse events; a trend towards a higher discontinuation due to adverse events was found in frail vs . fit patients.28
The ALCYONE was a phase 3 trial in 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression.29 The primary end point was progression-free survival. In the primary analysis of the study (median follow-up 16.5 months), adding daratumumab to bortezomib/melphalan/prednisone (D-VMP) significantly prolonged progression-free survival over bortezomib/melphalan/prednisone (VMP) and induced deep responses in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. After a median follow-up of 40.1 months, D-VMP continued to show significant progression-free survival benefit and significantly prolonged overall survival, even in patients aged ≥75 years.30 In 2021, Mateos and colleagues conducted subgroup analysis of ALCYONE participants comparing D-VMP versus VMP by frailty status.31 Frailty scores were calculated retrospectively for all participants based on age (≤75 years = 0 points; 76–80 years = 1 point, >80 years = 2 points), Charlson Comorbidity Index - CCI (≤1 = 0 points; > 1 = 1 point), and the Eastern Cooperative Oncology Group performance status (ECOG PS) score (0 = 0 points; 1 = 1 point; ≥2 = 2 points). The sum of scores was used to classify patients as fit (0), intermediate (1), or frail (≥2). When examining the impact of frailty on the intervention, frailty was treated as a binary variable: frail and non-frail. Those with a frailty status of fit (0) or intermediate (1) were collectively classified as non-frail. After a median follow-up of 40.1 months, the progression-free survival benefit of D-VMP versus VMP was maintained in all frailty subgroups: fit (HR 0.34, 95% CI 0.20-0.57), intermediate (HR 0.37, 95% CI 0.27-0.50), and frail (HR 0.51, 95% CI 0.39-0.68). The study confirmed the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status.
Auner and colleagues examined the effect of age and frailty on the efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in participants with previously treated multiple myeloma from the BOSTON trial.32 A recent FDA approval (December 18, 2020) was granted based on the phase 3 BOSTON trial in 402 patients with previously treated multiple myeloma, which demonstrated that the triplet combination of once-weekly selinexor with bortezomib and low dose dexamethasone (XVd) was superior to the standard twice-weekly combination of bortezomib and moderate dose dexamethasone (Vd). Among the 402 patients (195 on XVd, 207 on Vd) enrolled in the BOSTON study, 272 were non-frail (129 in the XVd arm and 143 in the Vd arm), 130 were considered frail with 66 in the XVd arm and 64 in the Vd arm. Frailty categories were assigned based on age, CCI, and ECOG PS. Frailty was treated as a binary variable: non-frail (0–1 points) or frail (≥2 points). The findings indicate that the combination of weekly selinexor with weekly bortezomib and dexamethasone was effective and safe in non-frail and frail patients . Median progression-free survival was prolonged with XVd compared with Vd, with non-frail patients having a significantly longer progression-free survival (median 13.24 months) on XVd as compared to Vd (median 9.43 months) (HR 0.66, 95% CI 0.47–0.93), and frail patients showing a trend towards improvement on the triplet (XVd, median 13.93 months vs. Vd, 9.46 months; HR 0.69, 95% CI 0.40–1.17)
In the phase 3 MAIA study of patients with newly diagnosed multiple myeloma (NDMM) who were not eligible for transplant, daratumumab plus lenalidomide/dexamethasone (D-Rd) improved progression-free survival versus lenalidomide/dexamethasone (Rd).33 Facon and colleagues conducted subgroup analysis of the MAIA study by frailty status.34 Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Frailty scores were used to classify patients into fit (0), intermediate (1), or frail (≥2) subgroups. Of the randomized patients (D-Rd, n = 368; Rd, n = 369), 396 patients were non-frail (D-Rd, 196 [53.3%]; Rd, 200 [54.2%]) and 341 patients were frail (172 [46.7%]; 169 [45.8%]). The analysis showed that the clinical benefit of D-Rd in transplant-ineligible NDMM patients enrolled in MAIA, regardless of frailty status. After a 36.4-month median follow-up, the progression-free survival benefit of D-Rd versus Rd was maintained across subgroups: HRs 0.41 (95% CI 0.22 - 0.75) in the fit group, 0.53 (95% CI 0.35 - 0.80) in the intermediate group, and 0.62 (95% CI 0.45 - 0.85) in the frail group. 34
5. Other drug trials
Rizka and colleagues aimed to determine the effect of alphacalcidol (a vitamin D analog) on inflammatory cytokines (IL-6, IL-10, g-IFN) and T cell subsets (CD4/CD8 ratio and CD8+ CD28-) of elderly people with various stages of frailty syndrome. This is a double blind RCT with allocation concealment, in 110 elderly participants, with an aim to examine the effect of 0.5 mcg alphacalcidol administration for 90 days on inflammatory cytokines (IL-6, IL-10, g-IFN) from PBMC culture supernatant, as well as CD4/CD8 and CD8+CD28- percentage using flow cytometry. Frailty was defined by Fried’s frailty criteria and in the analysis, frailty was categorized into 3 groups: fit, prefrail and frail. The study revealed that alphacalcidol improves immune senescence by acting as anti-inflammatory agent through increased IL-10 and decreased IL6/IL-10 ratio and also improves cellular immunity through increased CD4/CD8 ratio and decreased CD8+ CD28- subset in elderly, andthe effect is not influenced by frailty state .35
In a recent published study, Hanlon and colleagues use individual-level participant data (IPD from industry-sponsored clinical trials for three exemplar chronic conditions (type 2 diabetes mellitus, rheumatoid arthritis, and chronic obstructive pulmonary disease) to construct a frailty index. The authors then examined the prevalence of frailty in these clinical trial populations and examine whether frailty is associated with serious adverse events in the clinical trials studied. The prevalence of frailty in these trials were 7–21% in type 2 diabetes mellitus trials, 33–73% in rheumatoid arthritis trials, and 15–22% in chronic obstructive pulmonary disease trials. Across all trials, and after adjusting for age, sex, and disease severity,higher FI predicted increased risk of serious adverse events ; the pooled incidence rate ratios (per 0.1-point increase in FI scale) were 1.46 (95% CI 1.21–1.75), 1.45 (1.13–1.87), and 1.99 (1.43–2.76) for type 2 diabetes mellitus, rheumatoid arthritis, and chronic obstructive pulmonary disease, respectively.36