Prevalence and Progression of Monoclonal Gammopathies

描述（由申请人提供）：多发性骨髓瘤（MM）是一种危及生命的浆细胞恶性肿瘤。MM具有延长的临床可检测的癌前期，称为未确定意义的单克隆γ病（MGUS），可通过检测分泌的单克隆免疫球蛋白（M蛋白）和异常的免疫球蛋白kappa/lambda自由轻链（FLC）比率来识别。在过去的10年里，我们广泛地描述了MM的各个前体阶段，并进行了大量的研究，建立了FLC单克隆升高和FLC比率异常作为诊断、预后、反应评估和风险分层的生物标志物。这项更新的目标之一是确定MGUS发生的原因，以及多克隆浆细胞对感染或炎症的反应是否在MGUS、MM和相关恶性肿瘤的发病机制中起作用。我们也在调查MM发病率的巨大种族差异的原因；例如，年轻黑人的患病风险是白人的3倍。我们的研究表明，种族差异的一个主要原因是黑人中前体MGUS阶段的发生率明显过高。同样，我们发现了MGUS和MM的显著家族易感性。从细胞遗传学的角度来看，由于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精确细胞遗传学亚型。因此，两个基本问题是：1)我们能否确定在恶性前MGUS阶段（前体阶段的前体）之前预测MM风险的生物标志物？2)在黑人和一级亲属中导致MM风险增加的特定细胞遗传学亚型是什么？在Aim 1中我们会

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.