The impact of frailty on real world outcomes for multiple myeloma patients in England – a cohort study from the uncover study group and ukmra frailty group.

Abstract Introduction Evidence for disease outcomes in Multiple Myeloma (MM) is largely derived from clinical trials which often exclude frail patients. UNCOVER is a blood cancer health data research programme that utilises the National Cancer Registration Dataset (NCRD). NCRD includes information on all patients diagnosed with all types of cancer in NHS institutions in England (Int J Epidemiol 2020; 49(1):16–16h). Here, we report the demographics, incidence and survival of patients with myeloma in the UNCOVER dataset with particular emphasis on frailty. Methods Data was selected for patients diagnosed with MM (ICD-O-3: 97323, 97343, 97313) between Jan 2014 and Dec 2021 with follow-up until July 2023. International Myeloma Working Group (IMWG) modified frailty scores (non-frail 0-1, frail 2-5. Facon et al, 2019) could be assigned to patients who received systemic anti-cancer treatment (SACT). Crude and adjusted incidence rate ratios (IRRs) were estimated and compared between groups using Poisson regression, and calendar time trends were assessed. All-cause overall survival (OS) was assessed using KM methods and an adjusted Cox regression model. Cause-specific (Fine-Gray model) and relative (Pohar Perme method) survival were estimated. All models were adjusted for age at diagnosis, gender, index of multiple deprivation (IMD) quintile and government region, while Cox and Fine-Gray models were also adjusted for ethnicity and Charlson co-morbidity index (CCI). OS and net survival (NS) were estimated for frail and non-frail groups and a multivariable Cox model fitted that included frailty status. Results 39,521 MM patients were identified in total. 25.3% were >80 years of age, with the majority being <75 (58.5%). Frailty score was available for 23,674 patients [frail n=9,487 (40.1%); non-frail 14,187 (59.9%)]. 4,416 (11.2%) patients had a score >3 and would be considered ’ultra-frail’. In all MM patients, adjusted IRRs increased with age and were higher in males [1.62 (1.59-1.66, 95% CI), p<0.001], in most deprived IMD quintiles compared to the least deprived [IMD1 vs 5, 1.05 (1.01-1.08), p<0.001], and lower in all 8 provincial regions compared to London [North West 0.63 (0.61-0.66), p<0.001]. Adjusted IRRs were higher for Black people [1.45 (1.38-1.53), p<0.001] and lower for Asian people [0.44 (0.42-0.47), p<0.001] and those of mixed/other ethnicity [0.47 (0.43-0.50), p<0.001] compared to White people. Median follow-up was 33.7 (IQR: 14.3–58.7) months. 21,987 (55.6%) patients died with median OS 49.5 (48.5–50.5) months and NS 58.7% and 45.3% at 3 and 5 years. Hazard ratio (HR) for all-cause mortality was higher for males [1.06 (1.03–1.08)] and increased with age [10.2 (8.1–12.1) for 81–99 vs <40], deprivation [1.29 (1.22–1.34) for IMD1 vs 5], comorbidity [1.46 (1.41–1.50) for CCI>1 vs ≤1], and provincial regions vs London [1.21 (1.15–1.28) for North West]. HR was lower in all other ethnic groups compared to White [Black,0.77 (0.72-0.83); Asian, 0.80 (0.65, 0.98); p<0.001]. OS and NS increased for cohorts diagnosed in successive years until 2019 [HR 0.81 (0.77, 0.85) for 2019 vs 2014]. Compared to non-frail patients, frail patients had a shorter OS (median 31 vs 78 months; p<0.001), higher all-cause mortality [HR 1.75 (1.66-1.84), p<0.001] and shorter NS (44.5% vs 73.1% at 3 years, 26.0% vs 58.1% at 5 years). Patients aged 76-80 who were classified as frail had a shorter NS at 5 years compared to non-frail patients aged 76-80 (28.2% vs 39.1%). Deprivation was associated with lower NS at 5 years in both non-frail (51.6% vs 61.4% for IMD1 vs IMD5) and frail (23.9% vs 26.1%) patients. The same was true of region (NS at 5 years for North East vs London: 55.9% vs 61.4% in non-frail group; 22.6% vs 30.0% in frail group). Conclusion This national cohort study highlights variation in incidence, survival, and mortality outcomes within the English MM population. Deprivation and regional disparities in survival were evident in both frail and non-frail cohorts, suggesting a synergistic effect between frailty and socioeconomic disadvantage. Disparities persisted among patients categorised as frail by modified IMWG due to factors other than age (<80 years), suggesting that frailty plays a prognostic role independently of age. These findings highlight the need for tailored clinical approaches and policy interventions to improve outcomes in multiple myeloma.

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