Table 2 Randomized controlled trial of therapeutic agents in multiple myeloma incorporating or reporting on frailty.
Study Name | Intervention arm | Control arm | Median age | Frailty definition | Frailty categories | Frailty prevalence | Outcomes for frail subgroup (intervention vs control arm)* | |
|---|---|---|---|---|---|---|---|---|
Newly-Diagnosed Multiple Myeloma | ||||||||
1 | Facon et al. (2022) MAIA [31] N = 737, Global Phase III | Dara/Len/Dex | Len/Dex | 73 | Simplified frailty score | Subgroup included: post-hoc, fit, intermediate fit, frail# | 341 (46.3%) | PFS (NR vs 30.4, HR 0.62, p = 0.003) OS: Not available ORR (87.2% vs 78.1%; p = 0.0265) Grade ≥ 3 TEAE (94.6% and 89.2%) |
2 | Larocca et al. (2021) N = 199, Europe Phase III [25] | Len/Dex X 9 followed by reduced Len | Len/Dex | 76 | IMWG | Study entry criteria: Intermediate fit | Not applicable | PFS (20.2 vs 18.3, HR, 0.78, p = 0.16) OS 3-yr (74% vs 63%, p = 0.06) ORR (78% vs 68%, p = 0.15) ≥ 1 non-hem Grade ≥ 3 AE (33% vs 43%; P = 0.14) |
3 | Jackson et al. (2021) Myeloma XI N = 1852, Europe Phase III [20] | Cyclo/Len/Dex X 6-8 followed by maintenance randomization | Cyclo/Thal/Dex X 6-8 followed by maintenance randomization | 74 | UK MM Research Alliance Risk Profile tested and validated | Subgroup included: Post-hoc, Low, medium, high risk | High risk: 617 (33.3%) | PFS (12 vs 12, HR 0.98, p = 0.830) OS (31 vs 24, HR 0.89, p = 0.224) ORR NA Toxicity NA |
4 | Mateos et al. (2021) ALCYONE N = 706, Global Phase III [32] | Dara/Bort/Mel/Pred X 9 followed by dara maintenance | Bort/Mel/Pred X 9 | 74 | Simplified frailty score | Subgroup included: Post-hoc: fit, intermediate fit, frail# | 315 (44.6%) | PFS (32.9 vs 19.5, HR 0.51, p < 0.0001) OS 36 m (71.4% vs 59.0%, HR 0.66, p = 0.0292) ORR (88.3% vs. 72.4%, p = 0.0003) Grade ≥ 3 TEAE (79.4% vs 81.5%, p = N/A) |
5 | Mina et al. (2021) EMN10 Unito | 1.Ixa/Cyclo/ex 2.Ixa/hal/dex 3.Ixa/benda/ex X 9 followed by Ixa maintenance | Ixa/dex X 9 followed by Ixa maintenance | 74 | IMWG | Subgroup included: Post hoc analysis, fit, intermediate fit, frail | 43 (25.1%) | Data for interventional vs control not available for frail subgroup |
6 | O’Donnell et al. (2021) Ongoing N = 188 target, USA AFT-41 Phase II [41] | Len/Ixa/Dara/Dex X 12 followed by Len | Len/Ixa/Dara/Dex X 12 followed by Len/Ixa/Dara | Ongoing | Alliance GA | Subgroup included: prospective, categories unknown | Not available | Not available |
7 | Cook et al. (2021) Ongoing, UKMRA FiTNEss (N-180/740), Europe, Phase III [27] | Adaptive (IMWG frailty adjusted dosing) Ixa/Len/Dex | Standard (reactive dosing) Ixa/Len/Dex | Ongoing, 77 | UK MM Research Alliance Risk Profile, IMWG | Frailty adapted design/longitudinal: Prospective, Fit, unfit, frail Or low, medium, high | IMWG frail 84/180 (46.7%) UK MM risk profile 75/180 (41.7%) | Not available |
8 | Zweegman et al. (2020) HOVON 126 N = 143, Europe, Phase II [33] | Ixa/Thal/Dex x 9 followed by Ixa maintenance | Ixa/Thal/Dex x 9 followed by placebo maintenance | 73 | Simplified frailty score^ | Subgroups included: fit, intermediate fit, frail | 63 (44.8%) | Not available |
9 | Facon et al. (2020) FIRST N = 1623, Global, Phase III [10] | 1. Len/Dex X 18 2. Len/Dex | Mel-Thal-Pred X 12 | 73 | Simplified frailty score derived and validated using this cohort | Subgroup included: Post-hoc, Nonfrail vs frail | 790 (48.6%) | Len/Dex vs Mel/Thal/pred PFS (19.4 vs 19.0, HR 0.75, p = 0.005) OS (44.3 vs 38.5, HR = 0.84; P = 0.11) ORR Not available Grade ≥ 3 TEAE (HR 1.03, p = 0.796) |
10 | Bringhen et al. (2020) MM4 N = 706, Global, Phase III [28] | Induction-Ixa maintenance | Induction-placebo maintenance | 73 | IMWG | Subgroup included: fit, unfit, or frail | 170 (24.1%) | PFS (15.4 vs 11.1, HR 0.733, p = 0.147) OS Not available ORR Not available Grade ≥ 3 TEAE (19% vs 9%, p = not available) |
11 | Brioli et al. (2020) GERMAIN N = 85, Europe, halted poor accrual Phase IIB [51] | Bort-Mel-Pred X 9 followed by Len maintenance | Bort-Mel-Pred followed by observation | 75 | Modified IMWG (EQ5D used to estimate ADLs and IADLs) | Subgroup included: retrospective fit, intermediate fit, or frail | 45 (54.0%) | Data for interventional vs control not available for frail subgroup specifically |
12 | Bringhen et al. (2020) EMN01 N = 662, Europe Phase III [29] | 1. Mel/Len/Pred 2. Cyclo/Len/Pred X 9 Followed by randomization to Len or Len/Pred | Len/Dex X 9 followed by randomization to Len or Len/Pred | 73 | IMWG | Subgroup included: post-hoc analysis fit, intermediate fit or frail | 165 (24.9%) | Induction: PFS (21.5/13.8 MPR/CPR vs 18.2 Rd, p=NS) OS (44.7/40.5 MPR/CPR vs 48.2 Rd, p=NS) Grade 3 Non heme (all induction): 42% Maintenance: PFS (RP vs R HR 0.90, p = 0.67) OS (RP vs R, HR 1.04, p = 0.89) Grade ≥ 3 Non-heme (all maintenance): 13% |
13 | FRAIL-M; Spencer, Andre (2019), ongoing, N = 69/300 enrolled, Australia and New Zealand, Phase II [60] | 1.Bort/Len/Dex 2. Bort/Dex | Len/Dex | Not available | Unknown | Subgroup included: primary outcome defined by frailty including ORR, toxicity fit, intermediate fit, frail | Not available | Not available |
14 | PI: Facon (2019) IFM 2017-03 N = 294 target, active not recruiting, Europe, Phase III [30] | Len/Dara subq | Len/Dex | Not available | IMWG, Simplified Frailty score | Study entry inclusion criteria: frail (score ≥ 2) | Not applicable | Not available |
15 | PI: Larocca (2017), ongoing, target N = 350, Europe, Phase IV [42] | Bort/Mel/Pred X 9 | Len/Dex | Not available | A frailty score based on age, comorbidities, physical and cognitive functioning | Subgroups included: planned secondary outcome, fit, intermediate fit, frail | Not available | Not available |
16 | Stege et al. (2017), HOVON-87, N = 637, Europe, Phase III [34] | Mel/Len/Pred X 9 followed by Len maintenance | Mel/Thal/Pred X 9 followed by Thal maintenance | 73 | Simplified frailty score^ | Subgroup included: fit, intermediate fit, or frail | 259 (40.7%) | Not available |
Relapsed/Refractory | ||||||||
17 | Rocafiguera et al. (2022) OPTIMISMM (N = 559), Global, Phase III [48] | Pom/Bort/Dex | Bort/Dex | 68 | Simplified frailty score | Subgroup included: post hoc analysis non-frail or frail | 186 (33.2%) | PFS (9.7 vs 5.1, p = 0.006) OS Not available ORR (79.6% vs 41.9%, p < 0.001) Grade ≥ 3 TEAE (96.8 vs 87.9%, p = not available) |
18 | Quach et al. (2022) CANDOR (N = 446), Global, Phase III [47] | Dara/Car/Dex | Car/Dex | 64 | Simplified frailty score^ | Subgroup included: post hoc analysis fit, intermediate fit or frail | 118 (26.5%) | PFS (18.5 vs 9.3, HR 0.66, 95% CI 0.38–1.14) OS ORR 75% vs 54% (OR 2.39, 95% CI 1.09–5.22) Grade ≥ 3 TEAE 91% and 90%, p = not available) |
19 | Auner et al. (2022) Muk eight N = 112, Europe, Phase II [19] | Ixa/Cyclo/Dex | Cyclo/Dex | 70 | Simplified frailty score | Subgroup included: post-hoc analysis non-frail, frail | 81 (73.6)% | PFS (6.7 vs 5.6, HR 1.05, 80% CI 0.78-1.40) OS (14.1 vs 18.0, HR 1.49, 80% CI 0.99-2.23 |
20 | Auner et al. (2021) BOSTON N = 402, Global, Phase III [44] | Seli/Bort/Dex | Bort/Dex | 66 | Simplified frailty score | Subgroup included: post-hoc analysis non-frail, frail | 130 (32.3%) | PFS (13.93 vs 9.46, HR 0.69, p = 0.081) OS (NR vs 23.49, HR 0.62, p = 0.061) ORR (69.7% vs 60.9%, p = 0.148) Serious TEAE (59.1 % vs 48.4%) |
21 | Schjesvold et al. (2021) ICARIA N = 307, Global, Phase III [45] | Isa/Pom/Dex | Pom/Dex | 70 | Simplified frailty score | Subgroup included: post-hoc analysis Fit/intermediate fit vs frail | 86 (28.0%) | PFS (9.0 vs 4.5, HR 0.81, pvalue=0.493) OS 1 yr (66.9% vs 58.5%) ORR (52.1% vs 34.2%, p = 0.048) Grade [31] 3 TEAE (91.7% vs 80.6%) |
22 | Facon et al. (2020) ASPIRE N = 792, Global, Phase III [46] | Carf/Len/Dex | Len/Dex | 64 | Simplified frailty score^ | Subgroup included: post-hoc analysis fit, intermediate fit, frail | 196 (24.7%) | PFS (24.1 vs 15.9, HR 0.78, p = 0.085) OS (36.4 vs 26.2, HR 0.79, p = 0.070) ORR (84% vs 64%, p = N/A) Grade ≥ 3 TEAE (93% vs 94%) |
23 | Facon et al. (2020) ENDEAVOR N = 929, Global Phase III [46] | Carf/Dex | Bort/Dex | 65 | Simplified frailty score^ | Subgroup included: post-hoc analysis fit, intermediate fit, frail | 330 (35.5%) | PFS (18.7 vs 6.6, HR 0.50, p = < 0.01) OS (33.6 vs 21.8, HR 0.75, p = 0.026) ORR (76% vs 54%, p = N/A) Grade ≥ 3 TEAE (85% vs 79%) |
24 | Facon et al. (2020) ARROW N = 478, Global, Phase III [46] | Carf/Dex 70 mg/m2 | Carf/Dex 27 mg/m2 | 66 | Simplified frailty score^ | Subgroup included: post-hoc analysis fit, intermediate fit, frail | 141 (29.5%) | PFS (10.3 vs 6.6, HR 0.76, p = 0.098) OS not available ORR (56% vs 41%, p = N/A) Grade ≥ 3 TEAE (81% vs 70%) |
