Molecular Prediction of Myeloma Initiation Molecular Prediction of Myeloma Initiation

总结 多发性骨髓瘤（MM）是第二常见的血液系统恶性肿瘤，几乎总是先有 意义不明的单克隆丙种球蛋白病（MGUS）和郁积性骨髓瘤（SMM）。最近 随机试验表明，在SMM阶段的早期治疗干预可以改善进展- 自由和总体生存。这表明在有症状的MM之前进行早期检测和治疗干预 可能导致生存率提高和其他并发症如骨折的发病率降低， 肾衰竭和与骨髓瘤终末器官损伤相关的住院治疗。早期检测需要 对有患MM风险的人群进行全面筛查。患MM的已知风险因素 包括年龄、种族（黑人）和恶性血液病家族史。我们的初步筛选数据 使用灵敏的定量MALDI-TOF质谱，约7，500名具有MM发生风险的不同种族个体 光谱分析显示，在年龄> 50岁且具有以下特征的个体中，单克隆蛋白的患病率为45 我们称之为不确定潜能的单克隆丙种球蛋白病（MGIP）的早期免疫失调。 MGUS在黑人参与者和家族性血液病参与者中明显更普遍。 恶性肿瘤（HM）的历史比白色参与者没有HM家族史。开始描绘 这些早期MGIP克隆进展为MGUS并进一步导致MM的机制，我们计划探索 宿主内在（年龄、种族、生殖系风险因素）和获得性（炎症、抗原活化）风险因素 影响其行为的因素。我们相信MM的下一个前沿 研究的目的是了解骨髓瘤是如何发展的，并在终末器官损伤之前及早治疗。 识别和预防多发性骨髓瘤的早期发展将导致变革性的方法 作为癌症预防的典范。我们假设将风险定义为祖先 分数和基因组特征，而不是通过自我确定的种族来定义风险，可以提高风险 类似地，我们将测试MM的风险因素，而不是使用实足年龄作为MM的风险因素。 假设骨髓小生境的有效年龄赋予发展MM的生物风险。 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， 这一方法将使外地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.