Health Related Quality of Life (HRQoL) in Relapsed/Refractory Multiple Myeloma (RRMM): A Systematic Literature Review (SLR) and Meta-Analysis

Background: While narrative SLRs of HRQoL in RRMM have been conducted recently (Ojo et al, 2024), these have not accounted for the recent rise of cellular therapies. The objective of this study was to provide specific baseline EORTC QLQ-C30 or QLQ-MY20 scores for use as benchmarks in future research.

Methods: MEDLINE, EMBASE, CENTRAL and pertinent conferences were systematically searched for publications (January 2012 to March 2024) of clinical trials or observational real-world evidence (RWE) studies of patients with RRMM in the context of any pharmacological intervention. To generate benchmark values on the QLQ-C30 and the QLQ-MY20 module, inverse variance meta-analyses of baseline or pre-treatment observations were conducted to quantify HRQoL burden and facilitate comparisons across populations. Study and patient characteristics were explored to identify trends and drivers of differences in HRQoL. QLQ-C30 observations were compared to age- and sex-adjusted population norms and these differences were compared to published minimally important differences (MID).

Results: We identified 35 unique studies reporting baseline outcomes for QLQ-C30 (n=34) and QLQ-MY20 (n=19). Benchmark pre-treatment values for the QLQ-C30 and comparisons to population norms (all statistically significant) include: Global Health Status (60.0 vs 66.4 for MM and population norms, respectively; MID=4); Physical Functioning (71.6 vs 82.9, MID=5); Cognitive Functioning (82.9 vs 86.8, MID=3); Role Functioning (67.5 vs 83.6, MID=6); Social Functioning (74.3 vs 88.4, MID=5); Appetite Loss (15.7 vs 7.3, MID=5); Fatigue (37.6 vs 26.0, MID=5); Pain (34.8 vs 24.0, MID=6); and Financial Difficulties (17.3 vs 8.4, MID=3). For QLQ-MY20, in the scales where higher scores are more favorable, the average for Body Image was 78.9 (95% CI: 77.2, 80.5) and the average for Future Perspective was 59.0 (57.4, 60.6). Where higher scores reflect more impairment, the average for Disease Symptoms was 25.8 (24.5, 27.0) and the mean for Side Effects of Treatment was 17.8 (17.0, 18.5).

Comparisons by study design show that patients enrolled in RWE studies have statistically significantly lower HRQoL at baseline than patients enrolled in clinical trials including the QLQ-C30 domains, Global Health Status (-2.5; 95% CI: -4.5, -0.5 for RWE vs trials, respectively), Cognitive functioning (-3.7; -6.5, -0.9), Emotional functioning (-3.0; -5.7, -0.4), Role functioning (-9.2; -13.1, -5.4), Social functioning (-5.6; -9.8, -1.3), Constipation (5.3; 2.2, 8.4), Dyspnea (5.1; 1.6, 8.6), Fatigue (6.5; 4.3, 8.8), Nausea/Vomiting (2.3; 0.2, 4.5), and the QLQ-MY20 domain, Side effects of treatments (1.8; 0.2, 3.3). Within-study (n=4) comparisons of line of therapy (LOT) indicate that increasing LOT is associated with statistically significant decreases in Global Heath Status (Increase in LOT: -3.8; 95% CI: -6.4 -1.1) and Physical Functioning (-3.1; -5.9, -0.3), and statistically significant increases in Pain (3.9; 0.4, 7.4) and Fatigue (4.5; 1.5, 7.6).

Conclusions: Unsurprisingly, patients with RRMM had clinically meaningful impairments from population norms in several pre-treatment HRQoL domains. HRQoL worsened with increasing LOT as well. The novel finding of a difference between the real-world and clinical settings suggests that trials may underestimate RRMM-associated HRQoL burden. As such, HRQoL improvements in clinical trials may be amplified in real-world settings, supporting the HRQoL endpoint as a powerful tool to assess the impact of novel therapies. By quantifying pre-treatment HRQoL burden in both trial and real-world settings, our study provides a reference for contextualizing baseline patient burden as emerging therapies for RRMM continue to evolve.