Molecular Prediction of Myeloma Initiation Molecular Prediction of Myeloma Initiation

摘要 多发性骨髓瘤(MM)是第二种最常见的血液系统恶性肿瘤，几乎总是先于 未确定意义的单克隆性伽马病(MGUS)和阴燃骨髓瘤(SMM)。近期 随机试验表明，SMM阶段的早期治疗干预可以改善进展- 自由而全面的生存。这表明，在有症状的多发性骨髓瘤之前，应及早发现并进行治疗干预 发生骨折可能会提高存活率，降低骨折等其他并发症的发病率， 与骨髓瘤的终末器官损害相关的肾功能衰竭和住院治疗。及早发现需要 多发性骨髓瘤高危人群综合筛查已知多发性骨髓瘤危险因素 包括年龄、种族(黑人)和恶性血液病家族史。我们初步的筛查数据 约7,500名有患多发性骨髓瘤风险的种族个体使用灵敏的定量MALDI-TOF质量法 光谱分析显示，在50岁和50岁以下的人中，单克隆蛋白的患病率为45%。 一种早期的免疫失调，我们称之为不确定潜能的单克隆性伽马病(MgiP)。 MGUS在黑人参与者和有家族血液病的参与者中显著更常见 恶性肿瘤(HM)病史高于没有HM家族史的白人参与者。开始描绘 这些早期的MgiP克隆进展到MGUS并进一步导致MM的机制，我们计划探索 宿主固有(年龄、种族、生殖系危险因素)和获得性(炎症、抗原激活)危险因素 关于扩张的克隆及其影响其行为的环境。我们相信MM的下一个前沿 研究是为了了解一个人是如何患上骨髓瘤的，并在终末器官损伤之前及早治疗。 查明和预防多发性骨髓瘤早期阶段的发展将导致变革性的方法 治疗癌症并成为预防癌症的典范。我们假设将风险定义为祖先 分数和基因组签名，而不是通过自我认同的种族来定义风险，可以提高风险 类似地，我们不使用按时间顺序排列的年龄作为MM的风险因素，而是测试 假设骨髓微环境的有效年龄具有发生MM的生物学风险。 总之，我们相信这些研究将有助于确定致癌物质的机制基础。 与MM相关的流程。这种方法将使实地工作从纯粹的人口统计学风险定义过渡到 变成了生物学上的。

SUMMARY Multiple Myeloma (MM) is the second most common hematologic malignancy and is almost always preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Recent randomized trials have shown that early therapeutic intervention at the stage of SMM can improve progression- free and overall survival. This indicates that early detection and therapeutic intervention before symptomatic MM occurs may lead to improved survival and decreased morbidity from other complications such as bone fractures, renal failure and hospitalizations related to end-organ damage from myeloma. Early detection requires a comprehensive screening of the population at risk for developing MM. Known risk factors for developing MM include aging, race (Blacks), and familial history of hematologic malignancies. Our preliminary data of screening ~7,500 ethnically diverse individuals at risk of developing MM using a sensitive quantitative MALDI-TOF mass spectrometry has shown a prevalence rate of monoclonal protein in 45% in individuals of age >50y and having an early immune dysregulation that we termed Monoclonal Gammopathy of Indeterminate Potential (MGIP). MGUS was significantly more prevalent in Black participants and participants with familial hematologic malignancy (HM) history than in White participants with no family history of HM. To begin to delineate mechanisms by which these early MGIP clones progress to MGUS and further lead to MM, we plan to explore the host intrinsic (age, race, germline risk factors) and acquired (inflammation, antigenic activation) risk factors on the expanding clone and its environment that influence its behavior. We believe the next frontier in MM research is to understand how one develops myeloma and treat it early before end-organ damage. Identifying and preventing the development of the earliest stages of MM will lead to transformative approaches to treatment and serve as a paragon of cancer prevention. We hypothesize that defining risk as ancestry scores and genomic signatures, instead of defining risk by self-identified race, can improve risk prediction for MM. Similarly, instead of using chronological age as a risk factor for MM, we will test the hypothesis that the effective age of the bone marrow niche confers biological risk of developing MM. Together, we believe that these studies will help define the mechanistic underpinnings of the carcinogenic process linked to MM. This approach will allow the field to transition from a purely demographic definition of risk to a biological one.