Familial aspects of multiple myeloma and Waldenström macroglobulinemia: understanding the predisposition in relatives and the importance of early diagnosis.

Abstract

Multiple myeloma (MM) and Waldenström macroglobulinemia (WM) are B-cell malignancies with emerging evidence of familial predisposition. While most cases are sporadic, recent genomic studies have identified germline mutations and polygenic risk factors that contribute to familial clustering. This review synthesizes current data on inherited susceptibility to MM and WM, focusing on germline variants, polygenic risk scores, and familial patterns. We evaluate the functional relevance of implicated genes and explore biological mechanisms including DNA repair, telomere maintenance, and immune regulation. Germline variants in DNA repair genes (e.g. BRCA1/2, TP53), immune regulators (e.g. TNFRSF13B, TREX1), and telomere-related pathways (e.g. POT1, TERT) have been associated with familial cases. Polygenic inheritance also plays a significant role, with risk loci influencing plasma cell survival and transformation. These findings have direct implications for risk assessment, early diagnosis, and surveillance in at-risk relatives.