Genomic analysis of primary plasma cell leukemia reveals complex structural alterations and high-risk mutational patterns

Abstract

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.

Gain/Amplification of Chromosome Arm 1q21 in Multiple Myeloma

“…SMM patients with 1q21+ progress to MM more frequently than those without 1q21+ [ 22 , 50 ]. It is also found in about 70% of patients with primary plasma cell leukemia [ 51 ], and in about 90% of patients with a rare morphologic variant of MM, anaplastic myeloma [ 52 ]. 1q21+ is likely to be associated with the disease progression and drug resistance of MM, and the aggressive phenotype of plasma cell disorders.…”

Transcriptomic Analysis in Multiple Myeloma and Primary Plasma Cell Leukemia with t(11;14) Reveals Different Expression Patterns with Biological Implications in Venetoclax Sensitivity

“…Several studies investigating the gene mutation patterns [ 6 ] and differential gene and miRNAs expression profiles [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ], compared to pPCL and MM at molecular and biological levels. Overall, pPCLs have elevated genomic instability, especially for karyotypic complexity, and a higher prevalence of 17p13 deletions and 1q gains compared to MMs.…”

“…However, in the context of pPCLs, those harboring the t(11;14) do not show a better clinical outcome, as generally observed in the MM setting. Recently, it has been reported that enrichment of complex structural changes and high-risk mutational patterns is associated with pPCL patients, particularly with those carrying the t(11;14) [ 10 ]. Therefore, mechanisms underlying pPCL pathophysiology compared to intramedullary MM need to be further elucidated, being potentially relevant for improving therapeutic approaches.…”

Clinical characteristics of testicular extramedullary involvement in multiple myeloma

“…While detailed genomic characterization of EMD is lacking, the wholeexome sequencing and gene expression profiling analysis in primary PCL, the most aggressive form of MM showed enrichment for highrisk mutation like TP53 and RAS, in addition to downregulation of adhesion molecules supporting plausible "bone marrow escape phenomenon" akin to those expected in EMD. 12,13 There is lack of a feasible and accurate prediction model that can predict occurrence of EMD, although we have shown that GEP70 7 high risk molecular subtype MF, PR, centromere index of ≥3 and abnormal cytogenetics at diagnosis were associated with increased risk of EMD (odd ratio of 6.39, 3.79 and 2.77 respectively). 4 Thus far, this series of 14 patients is the largest single institution series of testicular EMD to be reported.…”