Onset and biomarkers for progression of monoclonal gammopathies

描述（由申请人提供）：多发性骨髓瘤（MM）是一种危及生命的血液恶性肿瘤。尽管取得了重大进展，但中位生存期仍然只有5年。骨髓瘤有一个长期的临床可检测的癌前期，称为未确定意义的单克隆伽玛病（MGUS），可以很容易地用分泌的生物标志物单克隆免疫球蛋白（M蛋白）来识别。还有一个中间临床阶段被称为阴燃多发性骨髓瘤（SMM）。SMM由大约50%的MGUS患者组成，他们患有克隆但非恶性疾病，50%的早期MM患者已经发生了生物学上的恶性转化，但临床尚未明显。骨髓瘤在癌症中是独一无二的，因为它在发病率上存在巨大的种族差异；例如，年轻的黑人患这种疾病的风险是白人的3倍。其次，我们最近发现近亲中发病率增加：一级亲属患MGUS的风险高出2-3倍。第三，尽管有成熟的早期干预的中间SMM阶段，我们在预防骨髓瘤的能力上受到削弱，因为我们无法区分恶性疾病（MM）和克隆性非恶性疾病（MGUS），除非通过存在或不存在临床终末器官损伤。目前迫切需要能够可靠地区分两者的生物标志物。我们已经确定了需要回答的3个基本问题：1)mgu何时以及为什么产生？2)黑人和直系亲属患病风险增加的原因是什么？关于该病的病因学，它能告诉我们什么？3)哪些特异性生物标志物可以准确识别早期恶性肿瘤的SMM患者，从而在2年内注定进展为症状性MM ？我们对MGUS、SMM和MM的理解做出了重大贡献，并准备好解决这三个关键问题。在目的1中，我们将通过研究12540名年龄在10-49岁的患者的血液样本，首次确定MGUS的发病和危险因素，这些患者代表了美国的分层随机抽样，其中少数民族的代表性较高。在Aim 2中，我们将研究MM患者一级亲属中MGUS的发病率和危险因素。在Aim 3中，我们将识别表明SMM中存在恶性转化的生物标志物，从而预测即将进展为症状性MM。我们认为我们的研究具有高度创新性，将对我们了解MGUS的病因，种族差异和家族发病率增加的原因产生深远影响。并为早期发现恶性肿瘤提供生物标志物。我们也相信我们的结果将从根本上改变这种疾病的早期诊断和治疗。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a life-threatening hematologic malignancy. Despite major advances, median survival is still only 5 years. Myeloma has a long clinically detectable premalignant phase called monoclonal gammopathy of undetermined significance (MGUS) that can be identified easily using the secreted biomarker monoclonal immunoglobulin (M protein). There is also an intermediate clinical stage referred to as smoldering multiple myeloma (SMM). SMM consists of approximately 50% of patients with MGUS who have clonal but nonmalignant disease and 50% of patients with early stage MM in whom the malignant transformation has occurred biologically but is not yet clinically apparent. Myeloma is unique among cancers because of the dramatic racial disparity in incidence; young blacks for example have a 3 fold higher risk of the disease than whites. Second, there is an increased incidence in close relatives that we have recently identified: first degree relatives hav a 2-3 fold higher risk of MGUS. Third, despite having an intermediate SMM stage that is ripe for early intervention, we are crippled in our ability to prevent myeloma since we are unable to discriminate malignant disease (MM) from clonal non malignant disease (MGUS) except through the presence or absence of clinical end-organ damage. Biomarkers that can reliably distinguish the two are critically needed. We have identified 3 fundamental questions that need to be answered: 1) When and why does MGUS originate? 2) What is the reason for the increased risk in blacks and in first degree relatives and what can it teach us about the etiology of the disease? 3) What are the specific biomarkers that can accurately identify SMM patients who have early malignancy and therefore destined to progress to symptomatic MM within 2 years? We have made major contributions to the understanding of MGUS, SMM, and MM and are well poised to address these 3 crucial questions. In Aim 1, we will determine for the first tim the onset and risk factors for MGUS by studying blood samples from 12,540 patients age 10-49 representing a stratified random sampling of the United States with overrepresentation of minorities. In Aim 2, we will study the incidence and risk factors for MGUS in first-degree relatives of patients with MM. In Aim 3, we will identify biomarkers that indicate the presence of malignant transformation in SMM, and thereby predict for imminent progression to symptomatic MM. We believe that our studies are highly innovative, and will have a far-reaching impact on our understanding of the etiology of MGUS, the reasons for the racial disparity and increased familial incidence, and provide biomarkers for early detection of malignancy. We also believe our results will fundamentally alter the early diagnosis and treatment of this disease.