Abstract 2444Multiple myeloma genomes are characterized by complex structural and numerical abnormalities. Proteasome inhibitors are routinely used to treat multiple myeloma. Despite significant clinical success with these agents, development of resistance often limits therapeutic benefit. However, many questions remain unanswered regarding the molecular mechanisms underlying acquired resistance to proteasome inhibitors.In order to understand the dynamics of structural evolution of the multiple myeloma genome under selective pressure afforded by proteasome inhibition and to identify targets to overcome acquired resistance, we derived global optical maps of two myeloma cancer genomes (DNA extracted from CD138+ tumor cells), obtained sequentially from the same patient before and after development of resistance to bortezomib, the prototypical therapeutic proteasome inhibitor. Optical Mapping offers a high throughput, single molecule, whole genome analysis that offers the highest rate of discovery of structural and numerical variants, free of the confounders associated with hybridization-based approaches. Briefly, the Optical Mapping System assembles entire genomes from large datasets of Rmaps (Rmap = a restriction-mapped individual genomic DNA molecule- see Figure 1) from which novel balanced and complex structural variants (2 kb – entire chromosomes) are discovered and tabulated by our pipeline (Figure 2).We identified multiple structural variants including single nucleotide variations (SNVs), deletions, insertions, inversions, and loss of heterozygosity regions across the entire genome. Some of these variants are common to both bortezomib-sensitive and bortezomib-resistant genomes. We also discovered variants that were unique to the bortezomib resistant genome, implicating a role in acquisition of drug resistance. Many of these structural variants encompass genes, some of which have not been previously associated with multiple myeloma and bortezomib resistance, thus providing a rationale for further interrogation of these novel targets. In addition to novel potential targets, known recurrent events including del(13q) and a deletion spanning the CDKN2C/FAF1 locus on chromosome 1 were detected.Future efforts are directed towards integration and correlation of optical maps with whole genome sequencing and transcriptional profiling as well as establishing the frequency of prioritized genomic perturbations in bortezomib-sensitive and –resistant patient populations. The integration of structural optical maps with base-pair sequence information and transcriptomic tracks will generate an entirely new view of the multiple myeloma cancer genome at a previously unseen resolution. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.