Abstract Purpose: Plasma cell leukemia (PCL) is a rare form of plasma cell dyscrasia that presents either as a progression of previously diagnosed multiple myeloma, namely secondary PCL, or as initial manifestation of disease, namely primary PCL (pPCL). Although the presenting signs and symptoms include those seen in multiple myeloma, pPCL is characterized by several aspects that define a more aggressive course. Here, we have investigated the transcriptome of pPCLs and correlated differential expression profiles with outcome to provide insights into the biology of the disease. Experimental Design: The expression profiles of 21 newly diagnosed pPCLs included in a multicenter prospective clinical trial were generated using high-density microarray, then evaluated in comparison with a representative series of patients with multiple myeloma and in association with clinical outcome. Results: All but one of the pPCLs had one of the main immunoglobulin heavy-chain locus translocations, whose associated transcriptional signatures resembled those observed in multiple myeloma. A 503-gene signature distinguished pPCL from multiple myeloma, from which emerged 26 genes whose expression trend was associated with progressive stages of plasma cells dyscrasia in a large dataset from multiple institutions, including samples from normal donors throughout PCL. Finally, 3 genes were identified as having expression levels that correlated with response to the first-line treatment with lenalidomide/dexamethasone, whereas a 27-gene signature was associated with overall survival independently of molecular alterations, hematologic parameters, and renal function. Conclusions: Overall, our data contribute to a fine dissection of pPCL and may provide novel insights into the molecular definition of patients with poorer prognosis. Clin Cancer Res; 19(12); 3247–58. ©2013 AACR.