Proskuriakova, Ekaterina

Importance Obesity is a risk factor associated with multiple myeloma (MM) and its precursor, monoclonal gammopathy of unknown significance (MGUS). However, it is unclear how cumulative exposure to obesity affects the risk of MGUS progression to MM. Objective To determine the association of cumulative exposure to excess body mass index (EBMI), defined as BMI (calculated as weight in kilograms divided by height in meters squared) greater than 25, with risk of MGUS progression to MM. Design, Setting, and Participants This cohort study included patients with MGUS, including immunoglobin G, immunoglobin A, or light chain MGUS, from the nationwide US Veterans Health Administration database from October 1, 1999, to December 31, 2021. A published natural language processing–assisted model was used to confirm diagnoses of MGUS and progression to MM. Data were analyzed from February 12 to November 4, 2024. Exposures Cumulative EBMI was calculated by area under the curve of measured BMI subtracting the reference BMI at 25 during the first 3 years after MGUS diagnosis. Main Outcomes and Measures The main outcome was progression from MGUS to MM. Multivariable Fine-Gray time-to-competing-event analyses, with death as the competing event, were used to determine associations. Results The cohort included 22 429 patients with MGUS (median [IQR] age, 70.5 [63.5-77.9] years; 21 613 [96.4%] male), with 8329 Black patients (37.1%) and 14 100 White patients (62.9%). There were 4862 patients (21.7%) with reference range BMI (18.5 to <25), 7619 patients (34.0%) with BMI 25 to less than 30, and 8513 patients (38.0%) with BMI 30 or greater at the time of MGUS diagnosis. Compared with reference range BMI at MGUS diagnosis, patients with BMI 25 to less than 30 (adjusted hazard ratio [aHR], 1.17; 95% CI, 1.03-1.34) or 30 or greater (aHR, 1.27; 95% CI, 1.09-1.47) at MGUS diagnosis had higher risk of progression to MM. In patients with reference range BMI at MGUS diagnosis, each 1-unit increase of EBMI per year was associated with a 21% increase in progression risk (aHR, 1.21; 95% CI, 1.04-1.40). However, for patients with BMI 25 or greater at MGUS diagnosis, the incremental risk associated with cumulative EBMI exposure was not statistically significant. Conclusions and Relevance This cohort study found that, for patients with BMI 18.5 to less than 25 at the time of MGUS diagnosis, cumulative exposure to BMI 25 or greater was associated with an increased risk of progression. These findings suggest that for these patients, maintaining a healthy and stable weight following MGUS diagnosis may prevent progression to MM.

Background: The global obesity epidemic has been well characterized over decades of research, linking increased body mass index (BMI) ≥ 25 to multiple medical conditions including increased cancer risk, morbidity, and mortality. The International Agency for Research on Cancer (IARC) group found a positive correlation between obesity to 13 cancers and multiple studies suggest leukemia should be added to this list. The causation behind this risk in leukemia however is not well understood and the prognostic factors have not been well characterized. Acute Myeloid Leukemia (AML) specifically defines risk based on cytogenetics between favorable, intermediate and unfavorable which significantly affects treatment decisions. The link between obesity and cytogenic risk factors in AML have not previously been thoroughly evaluated. To address this knowledge gap, we conducted a comprehensive meta-analysis aiming to evaluate the cytogenetic risk with obesity and prognostic significance in patients with AML. Methods: A systematic search was conducted across major databases until June 2023, using tailored search structures, subject headings, and keywords developed in collaboration with a medical research librarian. Two investigators independently screened the studies for inclusion. The inclusion criteria encompassed retrospective and prospective clinical studies that reported on the association between established cytogenetic classifications and standardized measures of excessive weight (BMI 25-30) and obesity (BMI ≥ 30). Meta-analysis was conducted using restricted maximum likelihood random-effects model. Results: From an initial pool of 1673 identified studies, eleven studies met the inclusion criteria, encompassing a total of 5887 patients. Among these patients, 1363 met the criteria for obesity (BMI ≥ 30) and 2176 met the criteria for excessive weight (BMI 25-30). The median patient's age was 54 (ranging from 15 to 89). The included studies originated from diverse geographic regions, including the USA, Japan, and France. Baseline patient characteristics are summarized in Table 1. Compared to overweight patients, our meta-analysis revealed a significant association between obesity and higher odds of unfavorable/intermediate cytogenetic risk (odds ratio [OR] 1.27, 95% CI [1.04; 1.54]), as seen in Figure 1. However, no meaningful statistical inference could be made regarding the association between obesity and specific gene mutations (such as FLT3, NPM1, CEBPa, TET2, IDH1, IDH2, RUNX1, and KRAS) due to the limited number of studies and small number of patients involved. Conclusion: Our meta-analysis demonstrates a significant association between obesity and unfavorable/ intermediate cytogenetic risk in patients with AML. Although the precise biological mechanisms remain elusive, several potential explanations have been proposed. These include the impact of obesity leading to chronic low-grade inflammation, altered adipokine secretion and insulin resistance, and metabolic changes on leukemic cell growth and survival. Despite the limitations of unknown cytogenetic risk in 590 patients and limited mutation data in some studies, our findings suggest that obesity may impact the prognosis of AML. Future research should address these limitations and provide a more comprehensive understanding of the intricate interplay between obesity, cytogenetics, and AML prognosis.