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 #
5R01CA168762-03
Application #
8658060
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Sorbara, Lynn R
Project Start
2012-07-17
Project End
2017-04-30
Budget Start
2014-05-07
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$320,027
Indirect Cost
$118,752
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Rajan, Archana M; Buadi, Francis K; Rajkumar, Vincent (2016) Effective use of panobinostat in combination with other active agents in myeloma in a novel five-drug combination: Case report and interesting observations. Am J Hematol 91:E5-6
Kumar, Shaji K; LaPlant, Betsy R; Reeder, Craig B et al. (2016) Randomized phase 2 trial of ixazomib and dexamethasone in relapsed multiple myeloma not refractory to bortezomib. Blood 128:2415-2422
Rajkumar, S Vincent; Kumar, Shaji (2016) Multiple Myeloma: Diagnosis and Treatment. Mayo Clin Proc 91:101-19
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
Ravi, P; Kumar, S; Larsen, J T et al. (2016) Evolving changes in disease biomarkers and risk of early progression in smoldering multiple myeloma. Blood Cancer J 6:e454
Rajan, A M; Kumar, S (2016) New investigational drugs with single-agent activity in multiple myeloma. Blood Cancer J 6:e451
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
Gonsalves, Wilson I; Timm, Michael M; Rajkumar, S Vincent et al. (2016) The prognostic significance of CD45 expression by clonal bone marrow plasma cells in patients with newly diagnosed multiple myeloma. Leuk Res 44:32-9
Mullikin, Trey C; Rajkumar, S Vincent; Dispenzieri, Angela et al. (2016) Clinical characteristics and outcomes in biclonal gammopathies. Am J Hematol 91:473-5
Rajkumar, S Vincent (2016) Myeloma today: Disease definitions and treatment advances. Am J Hematol 91:90-100

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