The Cytogenetic Profile of Primary and Secondary Plasma Cell Leukemia: Etiopathogenetic Perspectives, Prognostic Impact and Clinical Relevance to Newly Diagnosed Multiple Myeloma with Differential Circulating Clonal Plasma Cells

Abstract

Plasma cell leukemia (PCL) is a rare and aggressive plasma cell dyscrasia that may appear as de-novo leukemia (pPCL) or on the basis of a pre-existing multiple myeloma (MM), called secondary plasma cell leukemia (sPCL). In this prospective study, we have applied a broad panel of FISH probes in 965 newly diagnosed MM (NDMM) and 44 PCL cases of both types to reveal the particular cytogenetic differences among the three plasma cell dyscrasias. In order to evaluate the frequency and patterns of clonal evolution, the same FISH panel was applied both at diagnosis and at the time of first relapse for 81 relapsed MM patients and both at MM diagnosis and during sPCL transformation for the 19 sPCL cases described here. pPCL was characterized by frequent MYC translocations and t(11;14) with a 11q13 breakpoint centered on the MYEOV gene, not commonly seen in MM. sPCL had a higher number of FISH abnormalities and was strongly associated with the presence of del(17p13), either acquired at the initial MM stage or as a newly acquired lesion upon leukemogenesis in the context of the apparent clonal evolution observed in sPCL. In clinical terms, sPCL showed a shorter overall survival than pPCL with either standard or high-risk (t(4;14) and/or t(14;16) and/or del(17p13) and/or ≥3 concomitant aberrations) abnormalities (median 5 months vs. 21 and 11 months respectively, p < 0.001), suggesting a prognostic stratification based on cytogenetic background. These observations proved relevant in the NDMM setting, where higher levels of circulating plasma cells (CPCs) were strongly associated with high-risk cytogenetics (median frequency of CPCs: 0.11% of peripheral blood nucleated cells for high-risk vs. 0.007% for standard-risk NDMM, p < 0.0001). Most importantly, the combined evaluation of CPCs (higher or lower than a cut-off of 0.03%), together with patients’ cytogenetic status, could be used for an improved prognostic stratification of NDMM patients.

A Rare Cause of Extreme Leukocytosis: Primary Plasma Cell Leukemia with High-risk Cytogenetics

“…However, none of them are speci c to PCL. Immunoglobulin heavy chain (IgH) translocations including t(4;14), t(11;14) and t(14;16), 8q24 rearrangements, TP53 inactivation, K-RAS and N-RAS mutations, deletion of chromosome 17, deletion of chromosome 13, 1p loss or lq gains and monosomy 13 have been de ned in PCL [1,11,12]. The t(14;20) is seen less frequently in PCL [13].…”

Role of Conventional Cytogenetics and FISH in the Laboratory Work Up of Plasma Cell Dyscrasias

“…pPCL is frequently associated with t(11;14) and sPCL with t(4;14). 72 Translocation t(11;14) a standard risk marker in MM is associated with an aggressive course in patients of pPCL. [72][73][74] The two genes reported to be involved in t (11;14) are CCND1 and MYEOV.…”

“…72 Translocation t(11;14) a standard risk marker in MM is associated with an aggressive course in patients of pPCL. [72][73][74] The two genes reported to be involved in t (11;14) are CCND1 and MYEOV. MYEOV is not commonly seen involved in MM patients.…”

Genomics of Plasma Cell Leukemia

“…The incidence of IGH translocations is significantly higher in pPCL than in MM. Several studies show that t(11;14) leading to CCND1 dysregulation are significantly more frequent in pPCL than in MM, reaching percentages as high as 45-70% in some series [8,17,18,[21][22][23][24]27,40,41]; also noteworthy is the high proportion of t(14;16) detected in pPCL compared with MM (13-25% vs. 1-5%, respectively), which is supported by five studies [18,21,23,36,41]. Conversely, in most of the studies, t(4;14) has been found to be less frequent in pPCL than in MM [23,36,38].…”

“…MYC rearrangements have also been found in PCL, although the reported incidence varies between 13% and 40% [8,40,48]. Moreover, an association between MYC rearrangement and shorter overall survival of pPCL patients has been shown [8].…”