A High-Risk Survival Classifier for Multiple Myeloma

Survival of patients with newly diagnosed multiple myeloma (MM) is highly variable and currently used clinical prognostic markers such as the international staging system (ISS) and cytogenetic markers are insufficiently adequate for defining individual patient prognosis. We established a prognostic signature based on gene expression profiling.

The signature was generated using a training set of 290 newly diagnosed MM patients included in the multicenter, prospective open-label randomized phase 3 HOVON65/GMMG-HD4 trial. Gene expression profiles, obtained from purified plasma cells, were generated using the Affymetrix GeneChip® Human Genome U133 Plus 2.0 platform (GSE19784; Broyl et al.,Blood 2010; 14:2543–2553). The model predictive for survival was built by supervised principal component analysis (Bair et al., J. Amer. Statistical Assoc. 2006;101:119–37) and further optimized by simulated annealing. The generated survival signature was compared to six previously reported MM gene expression signatures (i.e. UAMS-70, UAMS-17 (Shaughnessy et al., Blood. 2007;109:2276–84), gene expression-based proliferation index (GPI, Hose et al., Haematol. 2010; 96: 87–95), MRC-IX-6 gene (Dickens et al., Clin. Cancer Res. 2010;16:1856–1864), Millennium (Mulligan et al., Blood 2007; 109:3177–3188) and IFM (Decaux et al., J. Clin. Oncol. 2008; 26:4798–4805).

A signature of 92 probe sets (EMC-92-gene signature) was highly discriminative for high-risk MM patients, defined as overall survival (OS) < 2 yr (21.7%) vs. standard-risk MM. This performance was confirmed in independent validation datasets of newly diagnosed MM patients (UAMS-TT2, n=351, GSE2658; MRC-IX, n=247, GSE15695) and relapse MM patients (APEX, n=264, GSE9782). In the UAMS-TT2 dataset, a high-risk population of 19.1% was identified which had a hazard-ratio of 3.52 (P = 2.5 × 10⁻⁸). In the MRC-IX study, 20.2% of patients were identified as high risk with a hazard-ratio of 2·38 (P = 3·6 × 10⁻⁶; Figure 1a) The high-risk signature was able to identify patients with significantly shorter survival in both the transplant-eligible and non-transplant-eligible patients included in the MRC-IX study. In non-transplant-eligible patients, 23.8% high risk patients were identified with a hazard-ratio of 2.38 (P = 4.3 × 10⁻⁴), whereas 17.5% of transplant-eligible patients were high-risk with a hazard-ratio of 2.54 (P = 1.5 × 10⁻³). The difference between survival in high-risk and standard risk was not restricted to newly diagnosed patients, as 15.9% of patients included in the APEX relapse study were designated high-risk with a hazard-ratio of 3·14 (P = 5·3 × 10⁻⁹; Figure 1b). In all sets the signature gave consistent and significant results and had good performance in comparison to other published high-risk gene signatures (Figure 2). In a pair-wise comparison to other high-risk gene signatures the EMC-92-gene showed to be among the top performing signatures and independent of all other signatures. In multivariate analyses, the EMC-92-gene signature proved an independent and superior predictor against clinical and cytogenetic variables such as the ISS and unfavourable cytogenetic aberrations including del(17p). Using the independent MRC-IX set, poor prognostic cytogenetic aberrations 1q gain, del(17p), t(4;14), t(14;16), t(14;20) and del(13q), were enriched in high-risk patients, whereas the frequency of standard risk cytogenetic aberrations such as t(11;14) was lower in the high-risk populations. Although enriched in the high-risk population, still more than half of patients in the standard risk group showed one or more poor prognostic cytogenetic markers

We developed a high-risk signature highly discriminative for patients with high-risk versus standard-risk MM, irrespective of treatment regime, age and relapse setting. Use of this signature in the clinical setting may lead to a more informed treatment choice and potentially better outcome for the patient.

van Vliet:Skyline Diagnostics: Employment. van Beers:Skyline Diagnostics: Employment, Patents & Royalties. Mulligan:Millennium Pharmaceuticals, Inc.: Employment. Morgan:Millennium Pharmaceuticals, Inc: Honoraria. Gregory:Celgene: Honoraria. Goldschmidt:Johnson& Johnson: Membership on an entity's Board of Directors or advisory committees. Lokhorst:Genmab: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Skyline Diagnostics: Membership on an entity's Board of Directors or advisory committees.