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
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
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

Showing the most recent 10 out of 137 publications