Multiple myeloma (MM) is a plasma cell malignancy preceded by a premalignant stage, named monoclonal gammopathy of undetermined significance (MGUS), and often a smoldering phase (SMM). 1, 2 Primary events, which include recurrent translocations of the IgH locus and hyperdiploidy, occur early in pathogenesis, and are followed by the acquisition of secondary genetic events such as MYC structural variants (SV), mutations that activate the RAS or NFkB pathways, mutations of DIS3 or FAM46C that drive precursor stages of disease toward MM. [3][4][5][6] Whole exome sequencing (WES) studies comparing serial MGUS/SMM and MM samples indicate clonal stability, and no significant increase in mutational load in patients that progress rapidly to MM. 7 In contrast, in 33 unselected MGUS patients single-nucleotide variants (SNVs) were less frequent, and no MYC translocations identified. 8 To study the role of MYC in myeloma we performed an integrated genomic analysis of 612 newly diagnosed myeloma (NDMM) patients enrolled in the CoMMpass study, as well as Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms * shared first co-authors Authorship Contributions PLB, WMK and KM originated concept and design of investigation, KMK EB developed custom capture panel, SVW FISH analysis, GA primary samples, YA GD WMK PLB developed additional bioinformatics methods, NK KM CKS PLB WMK performed analyses, and NK KM CKS WMK PLB composed manuscript. We thank JK and MMRF research network for their work on CoMMpass. All authors read and approved of final manuscript. Conflict of Interest DisclosuresRafael Fonseca works as a consultant for AMGEN, BMS, Celgene, Takeda, Bayer, Jansen, Pharmacyclics, Merck, Sanofi, Kite and Juno. He is on the board of Scientific Advisory Board: Adaptive Biotechnologies. Mayo Clinic and Rafael Fonseca hold a patent for prognosticating myeloma using FISH.

Detecting persistent minimal residual disease (MRD) allows the identification of patients with an increased risk of relapse and death. In this study, we have evaluated MRD 3 months after transplantation in 106 myeloma patients using a commercial next-generation sequencing (NGS) strategy (LymphoTrack®), and compared the results with next-generation flow (NGF, EuroFlow). The use of different marrow pulls and the need of concentrating samples for NGS biased the applicability for MRD evaluation and favored NGF. Despite that, correlation between NGS and NGF was high (R2 = 0.905). The 3-year progression-free survival (PFS) rates by NGS and NGF were longer for undetectable vs. positive patients (NGS: 88.7% vs. 56.6%; NGF: 91.4% vs. 50%; p < 0.001 for both comparisons), which resulted in a 3-year overall survival (OS) advantage (NGS: 96.2% vs. 77.3%; NGF: 96.6% vs. 74.9%, p < 0.01 for both comparisons). In the Cox regression model, NGS and NGF negativity had similar results but favoring the latter in PFS (HR: 0.20, 95% CI: 0.09–0.45, p < 0.001) and OS (HR: 0.21, 95% CI: 0.06–0.75, p = 0.02). All these results reinforce the role of MRD detection by different strategies in patient prognosis and highlight the use of MRD as an endpoint for multiple myeloma treatment.

The t(14;16) translocation, found in 3%-5% of newly diagnosed (ND) multiple myeloma (MM), has been associated with adverse outcomes. However, the studies establishing the characteristics of t(14;16) included solely small cohorts. The goal of the current international, multicenter (n = 25 centers), retrospective study was to describe the char-