Gene expression classifier EMC92/SKY92 and revised ISS robustly identify high-risk multiple myeloma in elderly patients of the HOVON-87/NMSG-18 study

Background: Multiple myeloma (MM) affects mostly elderly people with a median age of 69 years at diagnosis, with 35-40% of patients older than 75. Overall survival (OS) is variable: of patients aged 66-79, 9% survive less than 3 months and 23% survive longer than 10 years. Recently the revised ISS (rISS) has been proposed as a prognostic marker that incorporates ISS, FISH and LDH. Another marker, the SKY92 prognostic gene classifier (published as the EMC92 classifier) was developed in younger, transplant eligible multiple myeloma (MM) patients who were included in the HOVON-65/GMMG-HD4 trial. The SKY92 classifier was thoroughly validated in eight independent cohorts, at the time of its initial publication, and since. Aims: Here, we validated the SKY92 gene expression classifier and rISS in elderly, non-transplant eligible patients included in the HOVON-87/NMSG-18 trial (Zweegman et al. Blood 2016;127(9):1109-1116). Methods: In this trial, melphalan, prednisone, thalidomide (MPT) plus thalidomide maintenance was compared with melphalan, prednisone, lenalidomide (MPR) plus lenalidomide maintenance. The MMprofilerTM CE IVD assay was used to obtain SKY92 scores, classifying a patient as high-risk or standardrisk. In addition, the international staging system, LDH, FISH and rISS were analyzed. Results: The 178 patients in the analysis for which enough bone marrow was available to perform GEP, had a median age of 73 years. At the time of data analysis, the median follow up was 34 months. The SKY92 classifier identified 25 of 178 patients as high-risk (14%). The median OS for the 25 patients classified as SKY92 high-risk was shorter than the median OS of standard-risk patients: SKY92 high-risk 21 months versus SKY92 standard-risk 53 months (hazard ratio (HR)=3.0, 95% confidence interval (CI)=1.7-5.3; p