Circulating IGF-I levels linked to increased Multiple Myeloma risk in observational and genetic studies

The role of insulin-like growth factor I (IGF-I) in cancer development, particularly in Multiple Myeloma (MM), has been a subject of inconsistent findings. IGF-I is a crucial hormone involved in cell growth, proliferation, and survival, often acting through the IGF-1R pathway. While IGF-I is known to influence metabolic health and has been implicated in various cancers, its precise association with MM risk has remained ambiguous. Current standard-of-care for MM focuses on treatment post-diagnosis, highlighting a critical gap in understanding early risk factors and potential preventative strategies. Clarifying IGF-I's contribution could open avenues for risk stratification or early intervention.

Researchers investigated the association between total circulating IGF-I concentrations and Multiple Myeloma (MM) risk using a two-pronged approach. First, they analyzed baseline serological data from 444,187 UK Biobank participants, identifying 732 incident MM cases. This observational cohort study measured IGF-I levels and tracked MM incidence. Second, a two-sample Mendelian randomization (MR) analysis was performed. This MR study utilized identified genetic variants associated with circulating total IGF-I and IGF-binding protein 3 (IGFBP-3) from the InterLymph consortium, involving 2434 MM cases and 2567 controls. The primary endpoint for both analyses was the risk of MM, with additional lymphoid neoplasm subtypes included for comparative analysis.

The study found a significant positive association between circulating IGF-I levels and Multiple Myeloma (MM) risk. In the UK Biobank serological analysis, a one standard deviation (SD) increase in IGF-I was associated with an 11% higher risk of MM (Hazard ratio [HR] = 1.11, 95% confidence interval [CI]: 1.01-1.22; p-value = 0.03), with this association being particularly strong closer to diagnosis. The Mendelian randomization (MR) analysis further corroborated these findings, indicating that genetically inferred IGF-I levels were associated with a 27% increased MM risk (odds ratio [OR] = 1.27, 95% CI: 1.05-1.54). This genetic association was specific to MM and not observed with other lymphoid neoplasms (LNs). Genetically inferred IGFBP-3 levels showed no association with any LN evaluated. In a secondary analysis, IGF-I levels were also linked to the risk of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) in males with higher body mass index, showing a 36% increased risk per one SD increase in obese males (HR = 1.36, 95% CI: 1.14-1.61).