During the past decade, tremendous improvements have been observed in the outcome of patients with multiple myeloma. This significant improvement is mainly related to the availability of novel drugs, such as thalidomide, bortezomib and lenalidomide. Using a combination of these novel drugs, combined with high-dose melphalan, the median overall survival of patients under 65 years of age is currently around 8–10 years. However, despite these marked improvements, some patients do still present a very poor outcome, with fatal evolution within a few months. Several prognostic parameters have been proposed to identify these ultra high-risk patients. One of the most important factors is described by the ISS stage, especially patients with stage 3, that is, with a β2-microglobulin level >5.5 mg/l.1 The second very important factor is related to chromosomal abnormalities, especially t(4;14) and del(17p).2 Apart from these poor prognosis factors, another strong parameter is a leukemic presentation at diagnosis. So far, very few large studies on this rare form of myeloma (1–2% of the cases at diagnosis) have been reported.3, 4, 5 Our objective was to describe the prognostic parameters of such patients, and to look at their outcome. Furthermore, a secondary objective was to analyze this outcome in the context of the novel drug (thalidomide, bortezomib and lenalidomide) era.
Plasma cell leukemia (PCL) is arbitrarily defined as the presence of 20% of circulating plasma cells (PCs), or an absolute number of PCs >2 G/l. Two types of PCL have been described: primitive (at diagnosis, or pPCL) and secondary (at relapse, or sPCL). The physiopathology of PCL is largely unknown. It is thought that phenotypic changes in surface antigen expression allow the PCs to quit the bone marrow niche and to disseminate in the blood circulation. Cytogenetic characterization of primary PCL has been previously reported, with a higher incidence of t(11;14) and t(14;16).6 Very few reports have analyzed the outcome of patients with pPCL. Most of them include only a small number of patients, but all converge towards a dismal outcome.
To address the issue of pPCL characteristics, we retrospectively analyzed 70 patients with pPCL treated in the centers of the Intergroupe Francophone du Myélome. These 70 patients were extracted from a database of 8142 patients analyzed at the chromosomal level, and with outcome data. Even though this study was not an epidemiologic survey, it confirms the low incidence of pPCL (∼1%). Most of these 70 patients were analyzed by interphase fluorescence in situ hybridization, both on the peripheral blood and on the bone marrow PCs. As expected, no difference was observed between the two sources of PCs. The interphase fluorescence in situ hybridization analyses were focused on del(13), t(4;14), t(11;14), t(14;16), and del(17p). A del(13) was observed in 65% of the patients (vs 45% in non-PCL patients); a t(4;14) was observed in 21% of the patients (vs 15% in non-PCL patients); a t(11;14) was detected in 25% of the patients (vs 20% in non-PCL patients); and a t(14;16) was observed in 17% of the cases (vs 3% in non-PCL patients). Finally, a del(17p) (present in at least 60% of the PCs) was detected in 20% of the patients (vs 7% in non-PCL patients). Thus, this extensive chromosomal analysis revealed a higher incidence of t(4;14), t(14;16) and del(17p), all abnormalities known to confer a poor outcome.
We then looked at the other clinical and biological characteristics. The median age was 60 (range 34–87), and the sex ratio (M/F) was 0.77. The median β2-microglobulin level was 7.3 mg/l, with 63% of the patients presenting an ISS stage 3. Patients under 65 years of age (46 patients) were treated with an induction (vincristin–adriamycin–dexamethasone or bortezomib–dexamethasone), and a double-intensive melphalan (four patients received an autologous/allogeneic sequence and six patients received an allogeneic transplant at relapse). Older patients were treated with a melphalan/prednisone-based chemotherapy, combined with either thalidomide or bortezomib. The median overall survival for the whole population was less than 16 months (Figure 1). When restricted to the youngest patients, who received an intensive approach, the median overall survival was 31 months (Figure 2). We also looked at the impact of novel drugs, especially bortezomib. No survival difference was observed between patients treated with bortezomib and those treated with old drugs, a result that does not confirm previous case reports.7, 8
This study is the largest series of patients with pPCL reported so far. It confirms the very poor prognosis specifically associated with pPCL. This poor outcome can be explained (at least in part) by a high incidence of ISS stage 3, and a higher incidence of both t(4;14) and del(17p). Even though a better outcome was observed in young patients, the overall survival is still short, as compared with non-leukemic patients. This rare entity should benefit from specifically dedicated prospective trials based on dose-dense prolonged chemotherapy. Such a trial is currently ongoing within the Intergroupe Francophone du Myélome.
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The authors declare no conflict of interest.
About this article
World Journal of Clinical Oncology (2019)
Frontiers in Genetics (2019)
Expert Review of Hematology (2019)
Primary plasma cell leukemia in the era of novel agents for myeloma – a multicenter retrospective analysis of outcome
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Real-world data on prognosis and outcome of primary plasma cell leukemia in the era of novel agents: a multicenter national study by the Greek Myeloma Study Group
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