OAB-055: Gain and amplification of 1q induce transcriptome deregulation and worsen the outcome of newly diagnosed Multiple Myeloma patients

Background Gain and/or amplification of chromosome 1q are frequently associated with multiple myeloma (MM). The number of 1q copies correlates with a poor prognosis. Our aim was to evaluate the impact on clinical outcome and the transcriptome changes induced by Gain1q (3 copies of 1q) and 1q amplification (Amp1q, ≥4 copies of 1q) in patients (pts) enrolled in the randomized FORTE trial (NCT02203643). Methods Fluorescence in situ hybridization (FISH) on CD138+ purified bone marrow plasma cells was centralized and performed at baseline. The cut-off level of Gain1q was 10% of nuclei with ≥3 copies of 1q, while Amp1q was defined as ≥20% of nuclei with ≥4 copies of 1q. Transcriptome data from pts enrolled in the MMRF CoMMpass study (NCT01454297) were used to find differentially expressed genes (DEGs) in Gain/Amp1q pts. An independent cohort enrolled in the FORTE trial was subjected to RNAseq and used as validation. Results A total of 474 pts were enrolled in the FORTE trial. 1q copy number was missing in 74 pts; thus, 400 pts were evaluable. The median follow-up was 51 months; 219 (55%) pts belonged to the Normal 1q, 129 (32%) to the Gain1q, and 52 (13%) to the Amp1q group. In a multivariate analysis, progression-free survival (PFS) was shorter in the presence of Gain1q (HR 1.65 vs Normal 1q, p=0.005) and Amp1q (HR 3.13 vs Normal 1q, p Conclusion Amp1q universally predicts poor PFS and OS, despite the use of new drug combinations. A gene network centered on Myc may contribute to the high-risk behavior of these pts. The study of DEGs associated with Gain and Amp1q can identify new ‘druggable’ targets to be further tested in this high-risk patient population.