Clinical, genomic, and imaging predictors of malignancy: Analysis of the first U.S. cooperative group prospective clinical trial in asymptomatic monoclonal gammopathies (SWOG S0120).

Abstract

8515 Background: Asymptomatic monoclonal gammopathies (AMG) are the most common plasma cell dyscrasia classified as either monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic multiple myeloma (AMM). Clinical outcome in AMGs can be highly variable and there is an unmet need to identify newer clinical, genomic and imaging parameters from prospective studies to guide patient management. Methods: We analyzed clinical, genomic and imaging data from AMG patients (n=334) enrolled in a prospective observational clinical trial (S0120) conducted under the auspices of SWOG. Baseline data from clinical variables, as well as gene expression profiles of purified tumor cells and the findings on magnetic resonance imaging (MRI) were correlated with the risk of progression to symptomatic myeloma (MM) requiring therapy. Results: In addition to serum M spike, percent bone marrow plasma cells and the ratio of involved/uninvolved serum free light chains, the level of serum beta-2-microglobulin was associated with an increased risk of progression to clinical myeloma requiring therapy. Gene expression profiles (GEP) of purified tumor cells revealed that all of the known molecular GEP subtypes of human MM are also represented in the precursor phase. An increased risk score (> - 0.26) based on a 70-gene signature (GEP70) was an independent predictor of the risk of progression to clinical MM requiring therapy. The presence of focal lesions on MRI also conferred an increased risk of disease progression but was not independent of other clinical and genomic features. Conclusions: These data represent the first comprehensive evaluation of clinical, genomic and imaging features of AMGs in the context of a prospective US-cooperative group trial, and demonstrate that while all genetic subtypes of MM have a precursor phase, genetic signatures previously associated with high risk myeloma also predict the risk of progression to clinical malignancy requiring therapy. These findings suggest the need to integrate both clinical assessment of tumor bulk and genomic properties of tumor cells in the clinical management of these patients. Clinical trial information: NCT00900263.