Background: Frailty in Waldenström's Macroglobulinemia (WM) is poorly-defined and hard to assess objectively, despite its impact on treatment access, tolerability, and outcomes. In WM, commonly affecting elderly, comorbid patients (pts), first-line BTKi are EMA-approved only for pts ineligible to chemoimmunotherapy (CIT), though no standardized definition exists for ineligibility. Based on this, we evaluated weather an integrated geriatric- and quality of life (QoL)-based approach could better define pts fitness and guide treatment in WM.

Methods: in this ongoing prospective, multicenter, observational cohort study, consecutive adult patients with WM diagnosis, regardless of age, disease stage or treatment status, completed Practical Geriatric Assessment (PGA) (Dale et al., JCO, 2023) and EORTC QLQ-C30 (Aaronson et al., J Natl Cancer Inst, 1993) questionnaires at enrollment (baseline), 6, 12 and 18 months. PGA domains included: physical, functional, psychological, cognitive function, nutritional status, social support and comorbidities. Primary objective is to define frailty in WM using PGA metrics. Secondary include: PGA feasibility in clinical practice; relationship between clinical/disease characteristics and PGA domains; impact of PGA and EORTC QLQ-C30 on therapy choice, treatment management and outcomes, non-cancer-related survival. The study is conducted according to the Declaration of Helsinki. Here we report preliminary data from baseline assessment.

Results: From November 2024 to July 2025, 198 WM pts were enrolled: 78 on active treatment at any line (a-Tx); 62 previously treated and currently in watch and wait (t-ww); 58 untreated in watch and wait (u-ww). Median age for the whole population was 72 years (41-92), 66% were male, 14% had a high-IPSSWM, 17% neuropathy, 13% ECOG-PS>1. Median CIRS was 3 (0-19), with 17% having ≥1 major (grade 3-4) comorbidity (CIRS3+). 139/158 (88%) had MYD88 and 8/61(13%) CXCR4 mutations. When comparing the 3 groups, a-Tx pts were significantly older (median 74 vs 69 vs 69 y), had higher IgM levels, lower hemoglobin and more concomitant medications (conc-med). Among a-Tx, 73% were on targeted agents; 15% on CIT; 12% on clinical trials; median prior lines was 1 (range 0-7). All t-ww had prior CIT (median 1 prior line, range 1-2). Overall, 96% had ≥1 impaired PGA domain (median 3, range 0-6) with no significant differences across the 3 groups. In a range 0-100 (higher range score representing higher response level) median EORTC QLQ-C30 global health status (GHS) was 67 (67, 67 and 75 in a-Tx, t-ww, u-ww respectively, p=.628). Among 38 pts with CIRS >6 and/or CIRS3+, 97% perceived a significative impact of comorbidities on QoL on the PGA comorbidity domain. Notably, 90% of 145 pts without severe objective comorbidities also reported a significant impact at the PGA. At univariate analysis, conc-med, ECOG-PS and respiratory, neurologic and psychiatric CIRS items were associated with worse QLQ-C30 GHS, but not significant on multivariate. Independent PGA domains affecting QLQ-C30 GHS were: functional and psychological status (both p<.001) and lack of social support (p.002). Cumulative number of impaired domains was significantly higher at multivariate analysis in pts with neuropathy (p.052), presence of comorbidities (p.009), ECOG-PS≥1 (p.001) and vascular CIRS item (p .023). Analyzing individual PGA domains, prior CIT was detrimental on cognitive function only (p.018). Age and conc-med were the baseline pts characteristics most frequently affecting single PGA domains. When stratifying pts by traditional CIT fitness criteria (CIRS >6 and/or CrCl <70 mL/min), “unfit” had higher median number of impaired PGA domains than “fit” (4.0 vs 3.0; p.023) and were older (median age 77.4 vs 65.9 years; p<.001). A median of 3 altered domains still persisted in the “fit” group, highlighting the PGA's added value beyond conventional indices. Median time needed to complete PGA + QLQ-C30 was 20 minutes for pts and 5 minutes for physicians.

Conclusion: Preliminary data suggest this approach is feasible, time-efficient, and may improve fitness stratification. Despite the small sample, baseline PGA and EORTC-QLQC30 GSH were comparable across the 3 groups. Impaired functional and psychological status and lack of social support emerged as major detrimental factors for QoL. Ongoing enrollment aims to identify key PGA-based fitness determinants, track longitudinal changes, and assess therapeutic implications.

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2025
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