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.

Keywords: FISH; circulating plasma cells; clonal evolution; cytogenetics; multiple myeloma; primary plasma cell leukemia; secondary plasma cell leukemia.

Figure 1

Clonal evolution as detected by the acquisition of novel abnormalities during multiple myeloma (MM) progression. Each row represents the cytogenetic pattern of a single patient. The baseline aberrations detected at initial FISH examination during MM diagnosis are shown in red, whereas the new acquired aberrations during plasma cell leukemia transformation (sPCL, upper part) or at relapse (bottom part) are shown in green.

Figure 2

(A): Overall survival of patients since the time of their diagnosis with primary and secondary plasma cell leukemia (pPCL and sPCL, respectively). (B): Overall survival of pPCL patients according to their cytogenetic status.

Figure 3

(A): Association of cytogenetic status with the presence of circulating plasma cells (CPCs) in newly diagnosed Multiple Myeloma (NDMM) patients. High-risk patients [i.e., with t(4;14) and/or t(14;16) and/or del(17p13) and/or t(8q24) and/or ≥3 concomitant aberrations] have higher numbers of CPCs. (B): Receiver operating characteristic (ROC) curve for the estimation of the optimal cut-off value of CPCs (red arrow) discriminating among high-risk and low-risk patients. (C): Progression-free survival (PFS) of patients according to their cytogenetic status and the number of CPCs below or higher than 3 × 10⁻⁴ (% of nucleated cells).