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.

Public Health Relevance

Monoclonal gammopathy of undetermined significance occurs in >3% of the population over the age of 50 and carries a lifelong risk of progression to multiple myeloma;and given the incurable nature of MM it is vital to study the timing and causes of origin of MGUS and its progression to malignancy. An important first step is to define the nature and reasons behind the significant racial/ethnic disparities in the incidence of MGUS and MM and the 2-3 fold increased risk of MGUS in first-degree relatives of MM patients. We also need to identify patients who are at high risk of progression to MM in order to consider future preventive strategies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Biomarkers Study Section (CBSS)
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Sorbara, Lynn R
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Mayo Clinic, Rochester
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Gonsalves, Wilson I; Morice, William G; Rajkumar, Vincent et al. (2014) Quantification of clonal circulating plasma cells in relapsed multiple myeloma. Br J Haematol 167:500-5
Greenberg, A J; Rajkumar, S V; Therneau, T M et al. (2014) Relationship between initial clinical presentation and the molecular cytogenetic classification of myeloma. Leukemia 28:398-403
Landgren, O; Graubard, B I; Katzmann, J A et al. (2014) Racial disparities in the prevalence of monoclonal gammopathies: a population-based study of 12,482 persons from the National Health and Nutritional Examination Survey. Leukemia 28:1537-42
Kyle, Robert A; Larson, Dirk R; Therneau, Terry M et al. (2014) Clinical course of light-chain smouldering multiple myeloma (idiopathic Bence Jones proteinuria): a retrospective cohort study. Lancet Haematol 1:e28-e36
Kumar, S K; Dispenzieri, A; Lacy, M Q et al. (2014) Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia 28:1122-8
Ramakrishnan, V; Painuly, U; Kimlinger, T et al. (2014) Inhibitor of apoptosis proteins as therapeutic targets in multiple myeloma. Leukemia 28:1519-28
Gonsalves, Wilson I; Rajkumar, S Vincent; Go, Ronald S et al. (2014) Trends in survival of patients with primary plasma cell leukemia: a population-based analysis. Blood 124:907-12
Gonsalves, W I; Rajkumar, S V; Gupta, V et al. (2014) Quantification of clonal circulating plasma cells in newly diagnosed multiple myeloma: implications for redefining high-risk myeloma. Leukemia 28:2060-5
Larsen, J T; Kumar, S K; Dispenzieri, A et al. (2013) Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia 27:941-6
Bianchi, G; Kyle, R A; Larson, D R et al. (2013) High levels of peripheral blood circulating plasma cells as a specific risk factor for progression of smoldering multiple myeloma. Leukemia 27:680-5

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