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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA168762-02
Application #
8512677
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Sorbara, Lynn R
Project Start
2012-07-17
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$310,130
Indirect Cost
$115,080
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Landgren, O; Graubard, B I; Kumar, S et al. (2017) Prevalence of myeloma precursor state monoclonal gammopathy of undetermined significance in 12372 individuals 10-49 years old: a population-based study from the National Health and Nutrition Examination Survey. Blood Cancer J 7:e618
Ghosh, Toshi; Gonsalves, Wilson I; Jevremovic, Dragan et al. (2017) The prognostic significance of polyclonal bone marrow plasma cells in patients with relapsing multiple myeloma. Am J Hematol 92:E507-E512
Ravi, P; Kumar, S; Gonsalves, W et al. (2017) Changes in uninvolved immunoglobulins during induction therapy for newly diagnosed multiple myeloma. Blood Cancer J 7:e569
Chaudhry, Hafsa M; Mauermann, Michelle L; Rajkumar, S Vincent (2017) Monoclonal Gammopathy-Associated Peripheral Neuropathy: Diagnosis and Management. Mayo Clin Proc 92:838-850
Gonsalves, W I; Rajkumar, S V; Dispenzieri, A et al. (2017) Quantification of circulating clonal plasma cells via multiparametric flow cytometry identifies patients with smoldering multiple myeloma at high risk of progression. Leukemia 31:130-135
Majithia, N; Rajkumar, S V; Lacy, M Q et al. (2016) Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents. Leukemia 30:2208-2213
Rajkumar, S Vincent; Kumar, Shaji (2016) Multiple Myeloma: Diagnosis and Treatment. Mayo Clin Proc 91:101-19
Kyle, Robert A; Ansell, Stephen M; Kapoor, Prashant (2016) Prognostic factors and indications for treatment of Waldenström's Macroglobulinemia. Best Pract Res Clin Haematol 29:179-186
Jack Jr, Clifford R; Therneau, Terry M; Wiste, Heather J et al. (2016) Transition rates between amyloid and neurodegeneration biomarker states and to dementia: a population-based, longitudinal cohort study. Lancet Neurol 15:56-64
Rajkumar, S Vincent; Harousseau, Jean Luc (2016) Next-generation multiple myeloma treatment: a pharmacoeconomic perspective. Blood 128:2757-2764

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