Accounting & Marketing

6705 Blood Cancer Open Articles

Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) that is characterized by the presence of ≥20% circulating plasma cells. Overall survival remains poor despite advances of anti-MM therapy. The disease biology as well as molecular mechanisms that distinguish pPCL from non-pPCL MM remain poorly understood and, given the rarity of the disease, are challenging to study. In an attempt to identify key biological mechanisms that result in the aggressive pPCL phenotype, we performed whole-exome sequencing and gene expression analysis in 23 and 41 patients with newly diagnosed pPCL, respectively. The results reveal an enrichment of complex structural changes and high-risk mutational patterns in pPCL that explain, at least in part, the aggressive nature of the disease. In particular, pPCL patients with traditional low-risk features such as translocation t(11;14) or hyperdiploidy accumulated adverse risk genetic events that could account for the poor outcome in this group. Furthermore, gene expression profiling showed upregulation of adverse risk modifiers in pPCL compared to non-pPCL MM, while adhesion molecules and extracellular matrix proteins became increasingly downregulated. In conclusion, this is one of the largest studies to dissect pPCL on a genomic and molecular level Articlle

Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) that is characterized by the presence of ≥20% circulating plasma cells. Overall survival remains poor despite advances of anti-MM therapy. The disease biology as well as molecular mechanisms that distinguish pPCL from non-pPCL MM remain poorly understood and, given the rarity of the disease, are challenging to study. In an attempt to identify key biological mechanisms that result in the aggressive pPCL phenotype, we performed whole-exome sequencing and gene expression analysis in 23 and 41 patients with newly diagnosed pPCL, respectively. The results reveal an enrichment of complex structural changes and high-risk mutational patterns in pPCL that explain, at least in part, the aggressive nature of the disease. In particular, pPCL patients with traditional low-risk features such as translocation t(11;14) or hyperdiploidy accumulated adverse risk genetic events that could account for the poor outcome in this group. Furthermore, gene expression profiling showed upregulation of adverse risk modifiers in pPCL compared to non-pPCL MM, while adhesion molecules and extracellular matrix proteins became increasingly downregulated. In conclusion, this is one of the largest studies to dissect pPCL on a genomic and molecular Primary plasma cell leukemia (pPCL) is a rare form of multiple myeloma (MM) defined by the presence of ≥20% circulating plasma cells (PCs) and/or an absolute PC count of 2 × 109/L at diagnosis1,2. It is distinguished from secondary plasma cell leukemia (sPCL) by presenting at MM diagnosis, whereas sPCL is a leukemic transformation of end-stage MM. pPCL is characterized by an aggressive course with poor outcome and short overall survival (OS) of around 24 months3,4,5,6. Despite the advances of anti-MM therapy in recent years, patients with pPCL continue to have dismal survival suggesting that the underlying biology in pPCL differs substantially from patients with non-pPCL MM3,7. Mechanisms that underlie pPCL pathophysiology and distinguish it from MM remain incompletely understood despite being crucial to improve management. Previous reports have shown pPCL to be a highly complex disease enriched in adverse risk genetic aberrations, in particular a higher prevalence of deletions 13q and 17p, amplification of 1q as well as translocation t(14;16) compared to MM7,8,9,10,11,12. While these findings show that pPCL shares biological features of high-risk MM that partially explain the poor risk outcome, some pPCL patients present with traditional low-risk features such as the t(11;14) or hyperdiploidy, and yet will still have a poor outcome. Furthermore, the ability of pPCL cells to become independent of the surroundingbone marrow (BM) niche, which is shown to be crucial for non-pPCL MM to promote tumor growth and disease progression, suggests a distinct disease biology. Identifying mechanisms that underlie pPCL pathophysiology and distinguish it from MM remain incompletely understood and will be crucial to explore therapeutic options. Given the rarity of pPCL with only 1–2% of MM patients being affected, comprehensive studies remain challenging and have included small patient numbers. To address this lack of knowledge, we performed whole-exome sequencing (WES) and gene expression profiling (GEP) on 23 and 41 newly diagnosed pPCL patients, respectively, that presented to the Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, USA from 2003 to 2018. This is one of the largest studies to date to effectively characterize the molecular spectrum of pPCL and to identify new avenues for therapeutic options in this poor risk disease.