Clinically, multiple myeloma (MM) ranks as the second most common hematological malignancy, arising from the abnormal lineage of plasma cells (1). It originates from monoclonal gammopathy of undetermined significance and can progress to plasma cell leukemia and extramedullary myeloma (2). MM has a median age of onset of 69 years, with the patient population predominantly comprising older adults. These elderly patients frequently have comorbid metabolic syndrome (MetS)-related underlying diseases (3), MetS is primarily characterized by central obesity, insulin resistance, diabetes, dyslipidemia, and hypertension. A study by Gavriatopoulou M et al. (4) demonstrated that the prevalence of MetS and its individual components is significantly higher in MM patients than in the general population. MetS is a pathological state characterized by the clustering of multiple metabolic abnormalities, primarily including abdominal obesity, hyperglycemia, hypertension, and dyslipidemia (such as hypertriglyceridemia, low high-density lipoprotein cholesterol). These factors are interrelated and interact synergistically, significantly increasing the risk of chronic diseases such as cardiovascular disease and type 2 diabetes (5). MetS is a common metabolic disorder syndrome (5). MetS exerts a profound influence on MM. Current literature lacks analyses of the global burden of MM attributable to MetS. Therefore, this study aims to investigate the disease burden of multiple myeloma in the general population across global, regional, and national levels, integrating metabolic factors, to characterize the global distribution of MM linked to metabolic factors, identify high-risk populations and regions (6), assess their associations with metabolic factors, inform public health policy development, and provide a foundation for optimizing prevention and control strategies.

Multiple myeloma (MM) represents 10–15% of hematological malignancies. The biological crosstalk between metabolic syndrome and multiple myeloma (MM) involves multi-dimensional molecular interactions: obesity-induced bone marrow adipocytes (BMAs) secrete adipokines such as adiponectin. Studies by Zhaoyun Liu et al. (7) demonstrated that adiponectin may inhibit the differentiation and maturation of osteoclasts in MM patients by upregulating the expression of AdipoR1 while downregulating the phosphorylation levels of mTOR and 4EBP1. Furthermore, serine, a key amino acid involved in signal regulation, is closely linked to the progression of metabolic syndrome (8). Research by Chunmei Kuang et al. (9) indicated that excessive serine in the bone marrow microenvironment impairs megakaryopoiesis and thrombopoiesis in MM. Additionally, obesity has been shown to increase the risk of MM development and the progression from pre-myeloma to overt MM (10). Dyslipidemia promotes lipid uptake through the aberrant expression of LDL receptors (LDLR) and syndecan-1 on MM cells, while obesity-induced BMA remodeling inhibits apoptosis and exacerbates osteolytic lesions via the secretion of leptin and resistin (11). Collectively, these mechanisms reveal that metabolic syndrome systemically drives the initiation and progression of MM.

Leveraging GBD data (1990–2021), we observed significant increases in both the disability-adjusted of life years (DALYs) rate and mortality rate of MM relevant to metabolic risk factors. Therefore, characterizing the global burden of MM relevant to metabolic risk factors can inform the development of targeted prevention and treatment strategies across regions, holding significant implications for epidemiology and preventive medicine.

The global disease burden of MM relevant to metabolic factors showed a marked escalation from 1990 to 2021. The number of deaths tripled, and DALYs increased 2.8-fold, with significant rises in mortality rate, DALYs rate, Age-Standard Mortality Rate (ASMR), and Age-Standard Death Rate (ASDR). While the upward trajectory of mortality rate temporarily plateaued during 2000–2010, it reaccelerated thereafter. This shift is primarily attributed to global population growth and accelerated aging during 2000–2010, which expanded the pool of susceptible individuals (12, 13); Concurrently, economic development has been associated with unhealthy lifestyles—including high-calorie/high-fat diets and decreased physical activity—that relate to metabolic dysfunction, thereby exacerbating MM incidence (14, 15). Males exhibited significantly higher ASDR and ASMR for metabolic-factor-relevant MM than females, strongly linked to gender-specific lifestyle disparities. Males typically exhibit higher prevalence of metabolism-related risk behaviors (e.g., unhealthy diets, inadequate physical activity), which further elevate disease risk and burden (16–18). In addition, studies by Brigitte Sola et al. (19) have shown that estrogen has the effect of restricting the proliferation of MM cells, which may also be one of the reasons why the disease burden in males is higher than that in females.

Across SDI quintiles, the global disease burden of metabolic-factor-relevant MM exhibits striking regional and gender disparities. The marked rise in ASDR rates in Middle SDI countries is likely linked to accelerated population aging, suboptimal economic development, and limited healthcare accessibility (20, 21). The modest ASDR increase in High SDI countries is attributed to therapeutic advancements, including the adoption of proteasome inhibitors and immunomodulatory drugs (such as G Protein-Coupled Receptor Class C Group 5 Member D) (2, 21–24). Immunomodulatory drugs combat MM by suppressing immune escape (25, 26) while proteasome inhibitors exert therapeutic effects through mechanisms such as inducing tumor cell apoptosis and inhibiting the NF-κB signaling pathway (27–29). Since 2006, new drugs have significantly prolonged the survival period of MM patients in the West. However, from 1990 to 2021, the improvement in the global burden of MM and the progress in treatment did not match. This lag was caused by factors such as population structure, medical equity, treatment toxicity, and data methods. Geographically, the ASDR increase in most regions correlates with the proliferation of high-calorie, low-fiber diets and inadequate physical activity; High-income Asia Conversely, ASDR declines in High-income Asia Pacific and High-income North American regions are strongly associated with advanced therapeutic interventions (10, 17, 30). For instance, countries like Australia, New Zealand, and the United States report lower mortality rates among patients receiving initial therapy with novel agents (thalidomide, lenalidomide, or bortezomib) (31–33).

Data reveal striking heterogeneity in the disease burden of metabolic-factor-relevant MM across countries from 1990 to 2021. The United States, China, and Germany recorded the highest death tolls, likely linked to their large population sizes and aging demographics. Countries like the Commonwealth of the Bahamas and Principality of Monaco exhibited high age-standardized mortality and DALYs rates, whereas Mali and Niger showed lower rates—correlating with economic status and population metabolic health. Underdiagnosis in less developed nations may stem from limited healthcare resources (13, 34, 35).

From 1990 to 2021, ASDR increased in 190 out of 204 countries and regions, with notable growth in Ghana, Georgia, and other countries. In Ghana, monoclonal gammopathy is not included in routine physical examinations, possibly due to insufficient awareness among primary healthcare institutions and a lack of national testing facilities, which are also one of the reasons for the increased disease burden in the region (36). In Georgia, contributing factors likely include suboptimal fruit/vegetable consumption and high overweight/obesity prevalence among a substantial portion of the population (37); Additionally, the region’s reliance on complementary and alternative medicine (CAM)—which remains outside the formal healthcare system—may further exacerbate disease burden (38, 39). Declines in select countries like Japan are attributed to advanced therapeutic interventions, such as triplet regimens incorporating Carfilzomib, Ixazomib, Elotuzumab, and Daratumumab (17, 40). Collectively, the disease burden of metabolic-factor-relevant MM is shaped by population demographics, economic status, lifestyle patterns, and healthcare interventions, necessitating tailored prevention and control strategies across nations (16, 41).

Across SDI regions, the disease burden of metabolic-factor-relevant multiple myeloma (MM) demonstrated an overall upward trajectory in magnitude from 1990 to 2021, with the oldest age group (70–74 years and above) experiencing sustained increases in both absolute burden and proportional share of the total (16). This suggests that the influence of metabolic factors on MM in older adults has grown more pronounced over time, with their burden escalating and their contribution to the overall disease burden becoming increasingly significant (42–44).

Data from 2021 indicate a positive correlation between metabolic-factor-relevant multiple myeloma (MM) burden and age. Burden remained minimal in younger age groups (20–40 years), accelerated after 50–54 years, and was most pronounced in those aged 70–74 years and older, underscoring higher disease risk and severity from metabolic factors in older adults (16). Gender-wise, males exhibited higher total DALYs and DALYs rates than females, with significantly greater burden observed in males aged 70–74 years and older (45, 46). This highlights a heavier MM burden from metabolic factors in older males. Overall, older male populations should be prioritized in the prevention and control of metabolic factor-related multiple myeloma.

When patients have high blood sugar levels, society can provide systematic public health interventions (such as free blood sugar monitoring, subsidies for essential medications, etc.). The feasibility of these measures depends on the priority of resource allocation (47). Furthermore, studies conducted by YuCheng Chang (48) et al. and Nicholas Grandhi (49) et al. have revealed that glucagon-like peptide-1 (GLP-1) has a highly significant positive effect on patients with diabetes and multiple myeloma. This strategy not only optimizes blood sugar control but also, by inhibiting the tumor microenvironment and protecting heart and kidney functions, has the potential to become a comprehensive treatment plan for such patients. More clinical studies are needed to verify its efficacy and long-term safety in the future.

This study’s reliance on the GBD database entails limitations: GBD employed a multi-level methodology framework, integrating causal inference models with dynamic data calibration techniques, to systematically eliminate the confounding effects between risk factors and disease burden. Therefore, in this study, there is no need to conduct further analysis on the confounding variables. Findings should be interpreted cautiously and contextualized with complementary data and regional specifics. Moreover, health authorities and policymakers should prioritize implementing preventive measures and enhancing quality of life for patients, as underscored by the study’s findings. In high-risk regions, promoting healthy eating habits, regular physical activity, and weight management is critical for at-risk populations. Regular medical screenings, health education, and training programs are essential for early detection and prevention. Furthermore, in regions with a medium SDI, a high body mass index (BMI) has been identified as a key modifiable risk factor that significantly contributes to the burden of MM. Therefore, implementing public health measures focused on weight management, promoting lifestyle changes such as low-salt and low-fat diets, and enhancing physical exercise are of utmost importance for preventing MM before it occurs, improving prognosis, enhancing the quality of life of patients, and reducing the disease burden (50–52).

This study offers critical insights into the global distribution of MM burden. The research highlights striking heterogeneities in metabolic-factor-relevant MM burden across age groups, genders, and regions, alongside an overall upward trajectory. The analysis underscores the urgency of implementing preventive strategies like weight management and lifestyle interventions, and emphasizes the need for targeted prevention and control measures in high-risk populations and regions with elevated burden. The findings offer a scientific foundation for reducing risk factors, stratifying risk, and informing early intervention in MM management, particularly in regions with high disease burden and limited healthcare resources. Clinicians need to incorporate metabolic factors into the entire cycle of management for multiple myeloma (MM) diagnosis and treatment. By integrating biomarkers, targeted therapies, regional strategies and global collaboration, a paradigm shift from disease control to prevention can be achieved.