Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation’s Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study (NCT01454297) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

多发性骨髓瘤是一种可治疗但目前无法治愈的浆细胞血液恶性肿瘤，其特点是肿瘤遗传学多样且复杂，缺乏精准的医学治疗方法。多发性骨髓瘤研究基金会的“将多发性骨髓瘤的临床结果与个人遗传图谱评估相关”研究 (NCT01454297) 是一项针对新诊断的多发性骨髓瘤患者 ( n = 1,143) 的纵向观察性临床研究，其中使用全基因组测序对肿瘤样本进行表征、诊断和进展时的全外显子组测序和 RNA 测序，以及每 3 个月收集一次临床数据。对基线队列的分析确定了作为反复功能获得和功能丧失事件目标的基因。共识聚类分别鉴定了骨髓瘤的 8 种和 12 种独特拷贝数和表达亚型，鉴定了高风险遗传亚型并阐明了这些独特生物群体的许多分子基础。对系列样本的分析表明，25.5% 的患者在进展时转变为高风险表达亚型。我们观察到该亚型中免疫治疗靶标的强烈表达，这表明了一种潜在的治疗选择。