A gene expression signature for high-risk multiple myeloma

Abstract

There is a strong need to better predict the survival of patients with newly diagnosed multiple myeloma (MM). As gene expression profiles (GEPs) reflect the biology of MM in individual patients, we built a prognostic signature based on GEPs. GEPs obtained from newly diagnosed MM patients included in the HOVON65/GMMG-HD4 trial (n ¼ 290) were used as training data. Using this set, a prognostic signature of 92 genes (EMC-92-gene signature) was generated by supervised principal component analysis combined with simulated annealing. Performance of the EMC-92-gene signature was confirmed in independent validation sets of newly diagnosed (total therapy (TT)2, n ¼ 351; TT3, n ¼ 142; MRC-IX, n ¼ 247) and relapsed patients (APEX, n ¼ 264). In all the sets, patients defined as high-risk by the EMC-92-gene signature show a clearly reduced overall survival (OS) with a hazard ratio (HR) of 3.40 (95% confidence interval (CI): 2.19-5.29) for the TT2 study, 5.23 (95% CI: 2.46-11.13) for the TT3 study, 2.38 (95% CI: 1.65-3.43) for the MRC-IX study and 3.01 (95% CI: 2.06-4.39) for the APEX study (Po0.0001 in all studies). In multivariate analyses this signature was proven to be independent of the currently used prognostic factors. The EMC-92-gene signature is better or comparable to previously published signatures. This signature contributes to risk assessment in clinical trials and could provide a tool for treatment choices in high-risk MM patients.

Multiple Myeloma, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology

“…Several groups have identified and developed 15-gene, 70-gene, and 92-gene models based on GEP signatures of MM cells. [26][27][28] Studies show that patients in the high-risk group based on the 15-gene, 26 70-gene, 27 or 92-gene 28 models had shorter survival compared with the low-risk group. The NCCN panel unanimously agreed that although GEP is not currently routinely used in clinical practice during diagnostic workup, GEP is a useful tool and may be helpful in selected patients to estimate disease aggressiveness and individualize treatment.…”

Novel Prognostic Modalities in Multiple Myeloma

“…The prognostic validity of the GEP-70 high risk signature has been confirmed in several independent patient cohorts (IFM 99 trial [55], ECOG E4A03 trial [55], HOVON-65 trial [57]). The Intergroupe Francophone du Myélome (IFM) have developed a 15-gene model [55], which described a set of genes that control proliferation and chromosomal instability.…”

Maintenance Therapy for Multiple Myeloma

“…Understanding risk should allow for developing strategies for long term disease control based on diagnostic disease characteristics. In addition to cytogenetic risk stratification, gene expression profiling (GEP) has been developed for defining high risk patients 77,78 . However, the optimal treatment approach for these high risk patients has yet to be defined and these high risk patients should be evaluated for new approaches.…”