Jonathan Hofmann

Ph.D., M.P.H.

NCI

Investigator

PLCO (Learn more about this study)

2018-1019

Sep 20, 2019

A longitudinal investigation of immunologic and obesity-related biomarkers in multiple myeloma development and progression

Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic pre-malignant condition characterized by the presence of monoclonal protein in blood and/or urine. Previous molecular epidemiologic studies of MGUS and MM have identified promising markers that may underlie observed associations with immune dysregulation and obesity, and could potentially be used to improve existing risk stratification models for progression from MGUS to MM. We previously demonstrated that low circulating levels of adiponectin, a metabolic hormone typically underexpressed in obese individuals, was associated with an increased future risk of MM in PLCO (Hofmann et al, 2012). In a more recent investigation involving both MGUS and MM cases in PLCO, we identified six circulating chemokines and angiogenesis markers that were associated with future MM risk; of these, three angiogenesis markers were associated with progression from MGUS to MM (Hofmann et al, in preparation). A composite angiogenesis marker score demonstrated significant improvement in predicting the likelihood of progression from MGUS to MM. We propose to follow up on these findings by assessing whether longitudinal changes in these markers are associated with increased future risk of MM and/or progression from MGUS to MM. Circulating chemokines and angiogenic cytokines will be measured using Luminex-based multiplex bead-based assay panels, and adiponectin levels will be measured using standard ELISA methods; these assays have demonstrated high reproducibility in previous analyses of samples from PLCO. Our investigation will take advantage of the longitudinal information on characteristics of MGUS that is available for MGUS-positive subjects who did and did not progress to MM during follow-up. We propose to measure serum levels of these markers in serial samples (T0-T5 where available) from approximately 241 MM cases, 500 subjects with MGUS who did not progress to MM, and 241 MGUS-free controls who will be matched to the MM cases on age, sex, race, and study and calendar years. As part of this effort, we will assess whether incorporating selected markers into current risk stratification models can improve our ability to identify MGUS-positive subjects at high risk of progression to MM. Findings from the proposed study could have important implications for the clinical management of MGUS patients; improvements in risk stratification modeling could lead to opportunities for secondary prevention of MM, with early therapeutic intervention for MGUS patients at high risk of progression to frank MM.

The specific aims of this study are:

1. To assess whether longitudinal changes in circulating levels of selected chemokines, angiogenesis markers, and adiponectin are associated with future MM risk and progression from MGUS to MM; and

2. To evaluate whether incorporating selected markers into existing risk stratification models can improve our ability to identify MGUS-positive subjects at high risk of progression to MM.