Multiple myeloma (MM) is a plasma cell malignancy that evolves from a premalignant condition called monoclonal gammopathy of undetermined significance (MGUS). Our earlier studies show that MGUS is prevalent in over 3% of the population = age 50. We have identified several risk factors for MGUS progression, and have also found a possible increased risk of the condition in first-degree relatives. Since MM is a devastating, incurable malignancy, the essential aspects of our program are to identify and characterize etiologic factors for MGUS, and risk factors for its progression to MM. We have identified four crucial questions to be addressed: 1) what extent do racial and ethnic factors affect the occurrence of MGUS? 2) what role do genetic and environmental risk-factors play in the causation of MGUS? 3) What are new predictors of progression of MGUS to MM? and 4) what is the prognosis of light chain MGUS (LC-MGUS), a poorly a new entity we defined in the last funding period? Our Specific Aims correspond to these 4 questions.
In Aim 1, we will estimate the differential prevalence of MGUS by race and ethnicity in the US, and study potential risk factors by using blood samples and extensive demographic and laboratory data from the National Health and Nutritional Examination Survey (NHANES) that we have acquired.
In Aim 2, we will confirm the increased prevalence of MGUS in first-degree relatives, and examine the influence of environmental risk factors on familial MGUS.
In Aim 3, we seek to identify improved predictors of progression of MGUS to MM, specifically testing 4 hypothesis-driven risk factors that can be assessed using novel laboratory tests. These include worsening of serum free light chain ratio over time, high-resolution peripheral quantitative computed tomography (HRpQCT) scans to assess micro-architectural changes in bone, heavy water labeling studies to determine plasma cell proliferative rate in MGUS, and measurement of light-chain isotype specific quantitative immunoglobulin levels using the new serum immunoglobulin heavy chain assay (Hevylite).
In Aim 4, we will study newly diagnosed patients with LC-MGUS to determine their progression rate and outcome, in the same manner as we did with typical MGUS in prior studies. The proposed studies are critical to addressing fundamental questions concerning the cause of MGUS, its progression to incurable malignancy at a relentless rate of 1% per year, and form the basis for the institution of preventive measures to halt or delay progression.

Public Health Relevance

Monoclonal gammopathy of undetermined significance (MGUS) is probably the most common pre-cancerous condition in the United States affecting over 3% of the population over the age of 50. The studies in this grant seek to answer a fundamental question as to what causes MGUS by studying carefully various racial and ethnic groups, as well as close family members. We also study why (and how) some but not all people with MGUS progress to the fatal cancer called multiple myeloma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107476-10
Application #
8444694
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Sorbara, Lynn R
Project Start
2004-03-01
Project End
2014-07-31
Budget Start
2013-02-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$275,835
Indirect Cost
$93,284
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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
Bergsagel, P Leif; Mateos, Maria-Victoria; Gutierrez, Norma C et al. (2013) Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma. Blood 121:884-92
Rajkumar, S V; Gupta, V; Fonseca, R et al. (2013) Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma. Leukemia 27:1738-44

Showing the most recent 10 out of 97 publications