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

SIMPLE SUMMARY: The growing interest in BCL2 inhibitors for the treatment of multiple myeloma (MM) has led to the need for biomarkers that are able to predict patient’s sensitivity to the drug. The presence of the chromosomal translocation t(11;14) in MM is mainly associated with sensitivity to venetoclax and good prognosis. The incidence of t(11;14) largely increases in primary Plasma Cell Leukemia (pPCL) in association with an unfavorable outcome. Currently, data concerning pPCL sensitivity to venetoclax are virtually absent. In this context, we investigated the transcriptome of MM and pPCL with t(11;14), evidencing that the two clinical entities are likely responsive to venetoclax based on different molecular programs, thus prompting further studies to elucidate better novel potential predictive biomarkers. ABSTRACT: Mechanisms underlying the pathophysiology of primary Plasma Cell Leukemia (pPCL) and intramedullary multiple myeloma (MM) need to be further elucidated, being potentially relevant for improving therapeutic approaches. In such a context, the MM and pPCL subgroups characterized by t(11;14) deserve a focused investigation, as the presence of the translocation is mainly associated with sensitivity to venetoclax. Herein, we investigated a proprietary cohort of MM and pPCL patients, focusing on the transcriptional signature of samples carrying t(11;14), whose incidence increases in pPCL in association with an unfavorable outcome. In addition, we evaluated the expression levels of the BCL2-gene family members and of a panel of B-cell genes recently reported to be associated with sensitivity to venetoclax in MM. Moreover, transcriptional analysis of lncRNAs in the two clinical settings led to the identification of several differentially expressed transcripts, among which the SNGH6 deregulated lncRNA might be relevant in the pathogenesis and prognosis of pPCL with t(11;14). Overall, our data suggest that MMs and pPCLs with t(11;14) might be responsive to venetoclax based on different molecular programs, prompting further studies to elucidate better novel potential predictive biomarkers.