Familial Multiple Myeloma: Insights From Epidemiology and Underlying Germline Genetic Predisposition to the Clinic

Familial multiple myeloma (MM) is a relatively rare entity. Data on epidemiology, underlying germline genetic predisposition, and clinical features of familial MM continue to expand, especially in recent years. The risk of MM has been reported to be increased by 2 to 4 times among first-degree relatives of MM patients along with monoclonal gammopathy of undetermined significance (MGUS), other hematological malignancies, and several solid tumors by multiple groups. The association between MM risk and having a first-degree relative with a history of MM is stronger among African Americans/Blacks (OR = 5.52, 95% CI: 1.87-16.28) than European Americans/Whites (OR = 1.26, 95% CI: 0.75-2.10). Although data on clinical features and prognosis of familial cases are limited, preliminary data suggest a better prognosis among familial cases. Sequencing studies in familial cases have discovered rare disease-causing variants among which CDKN2A, USP45, MYH14, EPOR, HERC1, KLHL18, and KLHDC3 are shared by independent groups. Some of these candidate genes possess functions related to myelomagenesis such as B-cell development, immunoglobulin gene regulation, immune pathways, DNA damage/repair, ubiquitination, and cell adhesion mechanisms. Our group has recently completed an analysis among our Turkish MM families to confirm the findings of the International Consortium. The odds ratio (OR) for single nucleotide polymorphism rs28199 in nonfamilial MM cases compared to healthy control was 1.18, with an OR of 2.86 in familial MM cases compared to nonfamilial cases. Despite the accumulation of data, most questions remain to be answered. Future studies may elucidate underlying biological mechanisms, and develop polygenic risk scores, leading advancements in prognostic evaluation and clinical management.