Association of reproductive factors and exogenous hormone use with the risk of multiple myeloma in men and women

Abstract Background: Multiple Myeloma (MM) is a plasma cell malignancy with known risk factors that include increasing age, male sex, obesity, correlates of Black race and a positive family or personal history of plasma cell disorders. Evidence suggests that reproductive hormones may influence MM risk through immunomodulatory mechanisms; however, their influence on the risk of MM remains unclear. Methods: We evaluated the association of reproductive factors and exogenous hormone use with the risk of MM among 2,254 men and women (849 confirmed MM cases and 1,405 age-, sex-, race- frequency matched controls) enrolled in the Integrative Molecular And Genetic Epidemiology (IMAGE) Study between 2009 and 2020. Risk estimates were calculated using odds ratios and corresponding 95% confidence intervals generated from logistic regression adjusted for confounders and stratified by sex and self-reported race. Results: Reproductive factors including increasing gravidity (P-trend=0.02) in women and number of children fathered in men (P-trend=0.001), by comparison to women and men with no reported pregnancies, were associated with elevated MM risk, and the effect was strongest for women with ≥4 pregnancies (OR=2.18, 95% CI 1.26-3.76) or ≥4 live births (OR=1.98, 95% CI 1.24-3.15). Among women who were ever pregnant, those who had their first live birth after 25 years of age had reduced MM risk compared to younger women (OR=0.59, 95% CI 0.42-0.83). Use of exogenous HRT in post-menopausal women was associated with a significant reduction in MM risk compared to non-users (OR=0.70, 9% CI 0.49-0.99), and the magnitude of this effect was stronger in self-reported Black women (Pinteraction=0.04). No notable associations were observed for oral contraceptive use or other reproductive factors evaluated. Conclusions: Reproductive factors in men and women and exogenous hormone use in women are associated with altered MM risk. Future studies are required to delineate underlying biological mechanisms, which may open the way for new therapies in high-risk populations.