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