Plasma cell myeloma (PCM) is a hematological malignancy involving clonal proliferation of plasma cells in bone marrow. It is the third most common hematolymphoid malignancy in the USA and primarily affects elderly people with a median onset age of 69 years and a survival duration ranging from a few months to more than 10 years. This variation is due largely to the fact that PCM is a genetically complex and heterogeneous disease. The tumor cells demonstrate a wide range of morphological features, from mature and recognizable plasma cells to pleomorphic forms. In a subset of cases, however, the tumor cells demonstrate plasmablastic morphology which predicts a poor prognosis. We present a patient with an initial diagnosis of plasma cell myeloma with typical morphology and a hyperdiploid karyotype predictive of a favorable outcome. The patient’s disease was unresponsive to chemotherapy and evolved over the course of 43 months into a myeloma with plasmablastic features characterized by a highly complex abnormal karyotype demonstrating previously unidentified poor cytogenetic markers including CKS1B gene duplication and p53 gene deletion by fluorescence in situ hybridization (FISH). Post-mortem evaluation by single nucleotide polymorphism (SNP array) chromosome microarray analysis revealed additional structural abnormalities in the diagnostic specimen as well as significant genomic evolution in the plasmablastic myeloma.