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 #
5R01CA107476-09
Application #
8220848
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Sorbara, Lynn R
Project Start
2004-03-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
9
Fiscal Year
2012
Total Cost
$293,441
Indirect Cost
$99,238
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
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
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
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
Rajan, A M; Kumar, S (2016) New investigational drugs with single-agent activity in multiple myeloma. Blood Cancer J 6:e451
Mullikin, Trey C; Rajkumar, S Vincent; Dispenzieri, Angela et al. (2016) Clinical characteristics and outcomes in biclonal gammopathies. Am J Hematol 91:473-5

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