Prevalence and Progression of Monoclonal Gammopathies

描述(申请人提供)：多发性骨髓瘤(MM)是一种威胁生命的浆细胞恶性肿瘤。MM有一种临床上可检测到的较长的癌前阶段，称为未确定意义的单克隆性丙种球病(MGUS)，可通过检测分泌的单抗免疫球蛋白(M蛋白)和存在异常的免疫球蛋白kappa/lambda游离轻链(FLC)来识别。在过去的10年里，我们广泛地描述了MM的不同前驱阶段，并进行了大量研究，建立了FLC的单克隆性升高和FLC比率异常作为诊断、预后、反应评估和一系列浆细胞疾病的风险分层的生物标志物。这一更新的目的之一是确定MGUS发生的原因，以及感染或炎症反应中的多克隆浆细胞增殖是否在MGUS、MM和相关恶性肿瘤的发病机制中发挥作用。我们还在调查多发性骨髓瘤发病率存在显著种族差异的原因；例如，年轻黑人的风险是白人的3倍。我们的研究表明，种族差异的一个主要原因是前MGUS阶段在黑人中的发生率明显过高。同样，我们在MGUS和MM中发现了显著的家族易感性。从细胞遗传学的角度来看，MM由多个独特的实体组成，我们需要确定导致种族差异和家族易感性的确切细胞遗传学亚型。因此，两个基本问题是：1)我们能否确定在癌前MGUS阶段(前驱阶段)之前预测MM风险的生物标记物？2)什么特定的细胞遗传学亚型可以解释黑人和一级亲属MM风险的增加？在目标1中，我们将 在近16,000名患者中，确定血清免疫球蛋白FLC的多克隆升高是否与MGUS、MM和相关B细胞恶性肿瘤的风险增加有关。在目标2中，我们将集合和研究800名患有多发性骨髓瘤的黑人队列，以确定与多发性骨髓瘤风险增加相关的特定细胞遗传学亚型(S)，并确定治疗反应和生存的预测因素。在目标3中，我们将进行研究，以确定与MGUS家族易感性相关的特定细胞遗传学亚型。我们相信我们的研究具有很高的创新性，将对我们理解MGUS的病因以及种族差异和家族易感性的细胞遗传学基础产生深远的影响。我们的研究将产生一种有希望的生物标记物，用于在普通人群中识别多发性骨髓瘤和相关恶性肿瘤的高危患者。AIMS 2和AIMS 3将对MGUS和MM患者的管理产生重大影响，特别是非裔美国人和MGUS的一级亲属或患者。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a life-threatening plasma cell malignancy. MM has a prolonged clinically detectable premalignant phase called monoclonal gammopathy of undetermined significance (MGUS) that can be identified by detection of the secreted monoclonal immunoglobulin (M protein) and through the presence of an abnormal immunoglobulin kappa/lambda free light chain (FLC) ratio. Over the last 10 years we have extensively characterized the various precursor stages of MM, and conducted numerous studies establishing monoclonal elevations of FLC and abnormalities in the FLC ratio as biomarkers for diagnosis, prognosis, response assessment, and risk stratification across a spectrum of plasma cell disorders. One of the goals of this renewal is to determine why MGUS occurs, and whether polyclonal plasma cell proliferation in response to infection or inflammation plays a role in pathogenesis of MGUS, MM and related malignancies. We are also investigating the reasons for dramatic racial disparity in incidence of MM; young blacks for example have a 3-fold higher risk than whites. Our studies show that a major reason for the racial discrepancy is a marked excess in the incidence of the precursor MGUS phase in blacks. Similarly, we have uncovered a significant familial predisposition in MGUS and MM. Since MM consists of multiple unique entities from a cytogenetic standpoint, we need to determine the precise cytogenetic subtypes responsible for racial disparity and familial predisposition. Thus two fundamental questions are: 1) Can we identify biomarkers that predict risk of MM prior to the premalignant MGUS stage (precursor of the precursor stage)? 2) What are the specific cytogenetic subtypes that account for the increased risk of MM in blacks and in first degree-relatives? In Aim 1 we will determine if polyclonal elevations of serum immunoglobulin FLC are associated with an increased risk of MGUS, MM and related B cell malignancies in a large cohort of nearly 16,000 patients. In Aim 2 we will assemble and study a cohort of 800 blacks with MM to identify the specific cytogenetic subtype(s) of MM associated with increased risk of MM, and also identify predictors of response to therapy and survival. In Aim 3 we will conduct studies to identify the specific cytogenetic subtypes associated with familial predisposition in MGUS. We believe our studies are highly innovative, and will have a far-reaching impact on our understanding of the etiology of MGUS, and the cytogenetic basis for racial disparity and familial predisposition. Our studies will result in a promising biomarker to identify patients at high risk for MM and related malignancies in the general population. Aims 2 and 3 will have a major impact on the management of patients with MGUS and MM, especially African Americans and first-degree relatives or persons with MGUS.