Genomic instability (GIN), an increased tendency to acquire genomic alterations, is a cancer hallmark. However, its frequency, underlying causes, and disease relevance vary across different cancers. Multiple myeloma (MM), a plasma cell malignancy, evolves through premalignant phases characterized by genomic abnormalities. Next-generation sequencing (NGS) methods are deconstructing the genomic landscape of MM across the continuum of its development, inextricably linking malignant transformation and disease progression with increasing acquisition of genomic alterations, and illuminating the mechanisms that generate these alterations. Although GIN drives disease evolution, it also creates vulnerabilities such as dependencies on 'superfluous' repair mechanisms and the induction of tumor-specific antigens that can be targeted. We review the mechanisms of GIN in MM, the associated vulnerabilities, and therapeutic targeting strategies.

基因组不稳定性 (GIN)，即获得基因组改变的趋势增加，是癌症的标志。然而，其频率、根本原因和疾病相关性因不同的癌症而异。多发性骨髓瘤 (MM) 是一种浆细胞恶性肿瘤，通过以基因组异常为特征的癌前阶段发展。下一代测序 (NGS) 方法正在解构 MM 整个发展过程中的基因组景观，将恶性转化和疾病进展与越来越多的基因组改变联系起来，并阐明产生这些改变的机制。尽管 GIN 推动了疾病的演变，但它也产生了一些脆弱性，例如依赖于“多余的”修复机制和可以靶向的肿瘤特异性抗原的诱导。