The association of allostatic load (AL) with diagnosis of monoclonal gammopathy of undetermined significance (MGUS) and progression to multiple myeloma (MM)

Introduction: AL is a measure of the physiological burden of chronic stress. There is no direct measurement; rather, indices are created based on available biomarkers for endocrine dysfunction. This study aimed to determine whether increased AL was associated with a higher odds of having MGUS and if AL was associated with an increased risk of progression from MGUS to MM in the nationwide Veterans Health Administration (VHA). Methods: Diagnosis of MGUS from 2003-2024 and subsequent progression to MM were confirmed by a published natural language processing algorithm (doi 10.1200/CCI.23.00081). AL was calculated using six biomarkers: body mass index (BMI), alkaline phosphatase (ALP), albumin (ALB), creatinine (CR), creatinine clearance (CRCL), and white blood count (WBC). For each, patients who were in the “worst” quartile were awarded 1 point, with the exception of BMI, where all with a BMI > 25 was awarded 1 point. For Aim 1, patients were indexed at first BMI measurement following their 50 th birthday. MGUS cases we matched (1:1) to controls of the same age and index date (within 6 months). MGUS diagnosis was treated as a time-to-event analysis with death being a competing risk. For Aim 2, patients were indexed at time of MGUS diagnosis. Progression to MM was treated as a time-to-event analysis with death being a competing risk. Patients who progressed, died, or lost-to-follow-up within 6 months of diagnosis were excluded. Results: In Aim 1, 4855 cases of MGUS were matched to 4855 controls. The median age was 62 years, 94% were Male, and 60% were non-Hispanic White (NHW), 24% were non-Hispanic Black (NHB), and 16% were another race/ethnicity or were unclassified. The median AL score was 2. For each 1-unit increase in AL score, the risk of being diagnosed with MGUS increased by 14% (aHR 1.14; 95% CI 1.11-1.18); p < 0.001). In Aim 2, 42683 cases of MGUS were identified. The median age was 73 years, 96% were Male, and 61% were non-Hispanic White (NHW), 26% were non-Hispanic Black (NHB), and 13% were another race/ethnicity or were unclassified. The median AL score was 2. In total, 3194 (7%) of cases progressed to MM and 21104 (49%) died without progression after a median follow-up of 46 months. For each 1-unit increase in AL score, the risk progression to MM decreased by 10% (aHR 0.91; 95% CI 0.89-0.94); p < 0.001). In post-hoc analyses, we determined that four components of the AL score, ALP, CR, CRCL, and WBC were associated with lower risk (all p < 0.001), while BMI and ALB were associated with higher risk. Patients with a BMI > 25 had a 21% increased risk in progression (HR 1.21; 95% CI 1.14-1.32; p < 0.001) and patients in the lowest quartile of albumin ( < 3.5g/dL) had a 17% increased risk in progression (HR 1.17; 95% CI 1.05-1.30; p = 0.003). Conclusions: AL score is a potential biomarker to determine who is at higher risk for MGUS, but its association with risk of progression to MM is unclear.