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 (SVs), mutations that activate the RAS or NFkB pathways, mutations of DIS3 or FAM46C that drive precursor stages of disease toward MM [3–6]. 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 singlenucleotide 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 multiple myeloma (NDMM) patients enrolled in the CoMMpass study, as well as targeted sequencing of 23 patients with MGUS and 90 patients with SMM. We identified MYC SV in 42% of NDMM, including the majority of Hyperdiploid (HRD)(57%), and a quarter of MM with primary IgH translocations. The majority of these rearrangements resulted in juxtaposition of a super-enhancer (SE) and/or stretch enhancer adjacent to MYC, with one-third involving an Ig super-enhancer, one-third involving another recurrent super/stretch enhancer, and the remaining third split between nonrecurrent super/stretch enhancers, no identified super/stretch enhancer, or rearrangements wholly confined to the region telomeric to MYC, frequently duplications with no exogenous sequences present (Tables S1a, b and S2–4). The IgH MYC rearrangements often were complex—sometimes involving duplications and three or more chromosomes—and the IgH breakpoints were often within or near the 3ʹ SE regions, suggesting a different timing or mechanism than the primary