Causal insights into multiple myeloma: The impact of circulating inflammatory proteins and metabolites

Multiple myeloma (MM) is a heterogeneous hematologic malignancy characterized by high recurrence rates and incurability despite therapeutic advances. Emerging evidence implicates circulating inflammatory proteins, plasma metabolites, and leukocyte characteristics in MM pathogenesis, though their specific causal roles remain unclear. To investigate these relationships, we employed a 2-sample Mendelian randomization approach using genome-wide association study data. Genetic variants served as instrumental variables for biomarkers and MM outcomes. Our analysis identified 4 circulating inflammatory proteins with suggestive causal associations to MM and implicated 50 plasma metabolites in MM risk. However, no clear causal links were found between leukocyte characteristics and MM. Mediation analysis further revealed that the effects of inflammatory proteins on MM risk were not mediated by plasma metabolites. Collectively, these findings provide evidence for potential causal roles of specific inflammatory proteins and metabolites in MM, offering new insights into its biological mechanisms.