Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120)

Abstract

All cases of clinical myeloma (CMM) are preceded by an asymptomatic monoclonal gammopathy (AMG), classified as either monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic multiple myeloma (AMM). We analyzed data from AMG patients (n = 331) enrolled in a prospective, observational clinical trial (S0120). Baseline data from clinical variables, gene expression profiles (GEP) of purified tumor cells, and findings of magnetic resonance imaging (MRI) were correlated with the risk of progression to CMM requiring therapy. GEP of purified tumor cells revealed that all molecular subtypes of CMM are also represented in the AMG phase. An increased risk score (>-0.26) (based on a 70-gene signature, GEP70) was an independent predictor of the risk of progression to CMM. Combination of elevated serum free light chain, M-spike, and GEP70 risk score identified a subset with high risk (67% at 2 years) of progression to CMM requiring therapy. Importantly, absence of these factors in AMM patients predicted low risk similar to MGUS. Detection of multiple (>1) focal lesions by MRI also conferred an increased risk of progression. These data demonstrate that signatures associated with high-risk CMM impact disease risk and support inclusion of genomic analysis in the clinical management of AMGs.

Trial registration: ClinicalTrials.gov NCT00900263.

Figure 1

Analysis of time to progression to CMM requiring therapy. (A) Time-to-progression for the entire cohort. (B) Time to progression by AMG disease type (MGUS/AMM) by International Myeloma Working Group criteria. N, number.

Figure 2

Risk groups in AMGs based on clinical/genomic risk factors. (A) Risk groups based on independent variables in the MV model including GEP-SFLC >25 mg/dL, serum M spike ≥3 g/dL, and GEP70 risk score >−0.26. (B) Risk groups based on independent clinical variables in the MV model: serum M-protein ≥3 g/dL, bone marrow PCs ≥20%, and age ≥65 years. (C) Time-to-progression to CMM requiring therapy in cohorts based on GEP70 score and disease subtype (AMM or MGUS). (D) Time-to-progression to CMM requiring therapy in AMM patients based on risk factors 0, 1, or 2+ (risk factors: SFLC >25 mg/dL, serum M spike ≥ 3g/dL, and GEP70 risk score >−0.26). N, number; RF, risk factors.