Purpose: Multiple myeloma (MM) is the most common hematologic malignancy affecting Blacks in the USA, with standardized incidence rates that are twofold to threefold higher than Whites. The rationale for the disparity is unclear. Methods: Using participants enrolled in the Molecular And Genetic Epidemiology study of myeloma (259 MM cases; 461 controls), we examined the risk of MM associated with family history of cancer, differences by race and among cases, defining clinical features. Risk estimates were calculated using odds ratios and corresponding 95% confidence intervals from logistic regression adjusted for confounders. Results: Overall, MM risk in cases with relatives affected with any hematologic malignancy was significantly elevated compared to controls (OR 1.89, 95% CI 1.25–2.86). Myeloma risk associated with a family history of MM was higher than the risk associated with any hematologic malignancy (OR 3.75, 95% CI 1.75–8.05), and the effect was greater for Blacks (OR 20.9, 95% CI 2.59–168) than Whites (OR 2.04, 95% 0.83–5.04), among cases with early onset (≤60 years; OR 4.58, 95% CI 1.21–17.3) and with increasing numbers of affected relatives (p trend = 0.001). Overall, frequencies of end organ damage differed in cases with relatives affected with any hematologic malignancy and significantly more cases exhibited κ light chain restriction (OR 3.23, 95% CI 1.13–9.26). Conclusions: The excess risk of MM observed in Blacks and the variation in clinical features observed in MM patients according to family history of hematologic malignancy may be attributed to a shared germline and environmental susceptibility.