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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Sorbara, Lynn R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Kumar, Shaji K (2018) Timing of treatment of smoldering myeloma: delay until progression. Blood Adv 2:3050-3053
Clay-Gilmour, Alyssa I; Kumar, Shaji; Rajkumar, S Vincent et al. (2018) Risk of MGUS in relatives of multiple myeloma cases by clinical and tumor characteristics. Leukemia :
Go, Ronald S; Rajkumar, S Vincent (2018) How I manage monoclonal gammopathy of undetermined significance. Blood 131:163-173
Kyle, Robert A; Larson, Dirk R; McPhail, Ellen D et al. (2018) Fifty-Year Incidence of Waldenström Macroglobulinemia in Olmsted County, Minnesota, From 1961 Through 2010: A Population-Based Study With Complete Case Capture and Hematopathologic Review. Mayo Clin Proc 93:739-746
Sidana, Surbhi; Tandon, Nidhi; Dispenzieri, Angela et al. (2018) Prognostic significance of circulating plasma cells by multi-parametric flow cytometry in light chain amyloidosis. Leukemia 32:1421-1426
(2018) Multiple myeloma: 2018 update on diagnosis, risk?stratification, and management Am J Hematol 93:981-1114
Ravi, Praful; Kumar, Shaji K; Cerhan, James R et al. (2018) Defining cure in multiple myeloma: a comparative study of outcomes of young individuals with myeloma and curable hematologic malignancies. Blood Cancer J 8:26
Kyle, Robert A; Larson, Dirk R; Therneau, Terry M et al. (2018) Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance. N Engl J Med 378:241-249
Ravi, Praful; Kumar, Shaji K; Roeker, Lindsey et al. (2018) Revised diagnostic criteria for plasma cell leukemia: results of a Mayo Clinic study with comparison of outcomes to multiple myeloma. Blood Cancer J 8:116
Yanamandra, Uday; Kumar, Shaji K (2018) Minimal residual disease analysis in myeloma - when, why and where. Leuk Lymphoma 59:1772-1784

Showing the most recent 10 out of 155 publications