Plasma cell leukemia (PCL) is an aggressive hematological malignancy characterized by an uncontrolled clonal proliferation of plasma cells (PCs) in the bone marrow and peripheral blood. PCL has been defined by an absolute number of circulating PCs exceeding 2.0 × 109/L and/or >20% PCs in the total leucocyte count. It is classified as primary PCL, which develops de novo, and secondary PCL, occurring at the late and advanced stages of multiple myeloma (MM). Primary and secondary PCL are clinically and biologically two distinct entities. After the diagnosis, treatment should be immediate and should include a proteasome inhibitor and immunomodulator-based combination regimens as induction, followed by stem cell transplantation (SCT) in transplant-eligible individuals who have cleared the peripheral blood of circulating PCs. Due to the rarity of the condition, there have been very few clinical trials. Furthermore, virtually all of the myeloma trials exclude patients with active PCL. The evaluation of response has been defined by the International Myeloma Working Group and consists of both acute leukemia and MM criteria. With conventional chemotherapy, the prognosis of primary PCL has been ominous, with reported overall survival (OS) ranging from 6.8 to 12.6 months. The use of novel agents and autologous SCT appears to be associated with deeper response and an improved survival, although it still remains low. The PCL prognostic index provides a simple score to risk-stratify PCL. The prognosis of secondary PCL is extremely poor, with OS of only 1 month.

Complejo Asistencial Universitario de Salamanca Instituto de Investigación Biomédica de Salamanca Salamanca Spain

Dana Farber Cancer Institute Harvard Medical School Boston MA USA

Department of Clinical Therapeutics School of Medicine National and Kapodistrian University of Athens Athens Greece

Department of Hematology and Stem Cell Transplantation South Pest Central Hospital Natl Inst Hematol Infectol Budapest Hungary

Department of Hematology Jagiellonian University Medical College Kopernika 17 Krakow 31 501 Poland

Division of Hematology and Transplants University of Siena Siena Italy

Division of Hematology Mayo Clinic Rochester MN USA

Medical College of Wisconsin Milwaukee WI USA

Service des Maladies du Sang Hôpital Claude Huriez Lille France

The John Theurer Cancer Center at Hackensack UMC Hackensack NJ USA

Translational Genomics Research Institute City of Hope Cancer Center Phoenix Arizona USA

University Hospital Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Zobrazit více v PubMed

Noel P, Kyle RA. Plasma cell leukemia: an evaluation of response to therapy. Am J Med. 1987;83:1062–68. doi: 10.1016/0002-9343(87)90942-9. PubMed DOI

Gluzinski A, Reichentein M. Myeloma und leucaemia lymphatica plasmocellularis. Wien Klin Wochenschr. 1906;19:336.

Kyle RA, Maldonado JE, Bayrd ED. Plasma cell leukemia. Report on 17 cases. Arch Intern Med. 1974;133:813–8. PubMed

Fernández de Larrea C, Kyle RA, Durie BGM, Ludwig H, Usmani S, Vesole DH, et al. Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group. Leukemia. 2013;27:780–91. doi: 10.1038/leu.2012.336. PubMed DOI PMC

García-Sanz R, Orfão A, González M, Tabernero MD, Bladé J, Moro MJ, et al. Primary plasma cell leukemia: clinical, immunophenotypic, DNA ploidy, and cytogenetic characteristics. Blood. 1999;93:1032–7. PubMed

Pellat-Deceunynck C, Barillé S, Jego G, Puthier D, Robillard N, Pineau D, et al. The absence of CD56 (NCAM) on malignant plasma cells is a hallmark of plasma cell leukemia and of a special subset of multiple myeloma. Leukemia. 1998;12:1977–82. doi: 10.1038/sj.leu.2401211. PubMed DOI

Van Valckenborgh E, Mincher D, Di Salvo A, Van Riet I, Young L, Van Camp B, et al. Targeting an MMP-9-activated prodrug to multiple myeloma-diseased bone marrow: a proof of principle in the 5T33MM mouse model. Leukemia. 2005;19:1628–33. doi: 10.1038/sj.leu.2403866. PubMed DOI

Edvardsen K, Chen W, Rucklidge G, Walsh FS, Obrink B, Bock E. Transmembrane neural cell-adhesion molecule (NCAM), but not glycosyl-phosphatidylinositol-anchored NCAM, down-regulates secretion of matrix metalloproteinases. Proc Natl Acad Sci U S A. 1993;90:11463–7. doi: 10.1073/pnas.90.24.11463. PubMed DOI PMC

Vande Broek I, Vanderkerken K, Van Camp B, Van Riet I. Extravasation and homing mechanisms in multiple myeloma. Clin Exp Metastasis. 2008;25:325–34. doi: 10.1007/s10585-007-9108-4. PubMed DOI

Pérez-Andrés M, Almeida J, Martín-Ayuso M, Moro MJ, Martín-Nuñez G, Galende J, et al. Clonal plasma cells from monoclonal gammopathy of undetermined significance, multiple myeloma and plasma cell leukemia show different expression profiles of molecules involved in the interaction with the immunological bone marrow microenvironment. Leukemia. 2005;19:449–55. doi: 10.1038/sj.leu.2403647. PubMed DOI

Sant M, Allemani C, Tereanu C, De Angelis R, Capocaccia R, Visser O, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood. 2010;116:3724–34. doi: 10.1182/blood-2010-05-282632. PubMed DOI

Bladé J, Kyle RA. Nonsecretory myeloma, immunoglobulin D myeloma, and plasma cell leukemia. Hematol Oncol Clin North Am. 1999;13:1259–72. doi: 10.1016/s0889-8588(05)70125-8. PubMed DOI

Tiedemann RE, Gonzalez-Paz N, Kyle RA, Santana-Davila R, Price-Troska T, Van Wier SA, et al. Genetic aberrations and survival in plasma cell leukemia. Leukemia. 2008;22:1044–52. doi: 10.1038/leu.2008.4. PubMed DOI PMC

Costello R, Sainty D, Bouabdallah R, Fermand JP, Delmer A, Diviné M, et al. Primary plasma cell leukaemia: a report of 18 cases. Leuk Res. 2001;25:103–7. doi: 10.1016/s0145-2126(00)00102-8. PubMed DOI

Pagano L, Valentini CG, De Stefano V, Venditti A, Visani G, Petrucci MT, et al. Primary plasma cell leukemia: a retrospective multicenter study of 73 patients. Ann Oncol. 2011;22:1628–35. doi: 10.1093/annonc/mdq646. PubMed DOI

Jurczyszyn A, Castillo JJ, Avivi I, Czepiel J, Davila J, Vij R, et al. Secondary plasma cell leukemia: a multicenter retrospective study of 101 patients. Leuk Lymphoma. 2019;60:118–23. doi: 10.1080/10428194.2018.1473574. PubMed DOI

Jurczyszyn A, Radocha J, Davila J, Fiala MA, Gozzetti A, Grząśko N, et al. Prognostic indicators in primary plasma cell leukaemia: a multicentre retrospective study of 117 patients. Br J Haematol. 2018;180:831–9. doi: 10.1111/bjh.15092. PubMed DOI

Gundesen MT, Lund T, Moeller HEH, Abildgaard N, et al. Plasma cell leukemia: definition, presentation, and treatment. Curr Oncol Rep. 2019;21:8. doi: 10.1007/s11912-019-0754-x. PubMed DOI PMC

Ravi P, Kumar SK, Roeker L, Gonsalves W, Buadi F, Lacy MQ, et al. Revised diagnostic criteria for plasma cell leukemia: results of a Mayo Clinic study with comparison of outcomes to multiple myeloma. Blood Cancer J. 2018;8:116. doi: 10.1038/s41408-018-0140-1. PubMed DOI PMC

Toma VA, Retief FP, Potgieter GM, Anderson JD. Plasma cell leukaemia. Diagnostic problems in our experience with 11 cases. Acta Haematol. 1980;63:136–45. doi: 10.1159/000207385. PubMed DOI

Woodruff RK, Malpas JS, Paxton AM, Lister TA. Plasma cell leukemia (PCL): a report on 15 patients. Blood. 1978;52:839–45. PubMed

Shah RA, Mohite S, Baladandayuthapani V, Thomas SK, Weber DM, Wang M, et al. Circulating plasma cells by routine complete blood count identify patients with similar outcome as plasma cell leukemia. Blood. 2013;122:5356. doi: 10.1182/blood.V122.21.5356.5356. DOI

An G, Qin X, Acharya C, Xu Y, Deng S, Shi L, et al. Multiple myeloma patients with low proportion of circulating plasma cells had similar survival with primary plasma cell leukemia patients. Ann Hematol. 2015;94:257–64. doi: 10.1007/s00277-014-2211-0. PubMed DOI

Granell M, Calvo X, Garcia-Guiñón A, Escoda L, Abella E, Martínez CM, et al. Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition. Haematologica. 2017;102:1099–104. doi: 10.3324/haematol.2016.158303. PubMed DOI PMC

Jelinek T, Kryukov F, Rihova L, Hajek R. Plasma cell leukemia: from biology to treatment. Eur J Haematol. 2015;95:16–26. doi: 10.1111/ejh.12533. PubMed DOI

Kraj M, Kopeć-Szlęzak J, Pogłód R, Kruk B. Flow cytometric immunophenotypic characteristics of 36 cases of plasma cell leukemia. Leuk Res. 2011;35:169–76. doi: 10.1016/j.leukres.2010.04.021. PubMed DOI

Royer B, Minvielle S, Diouf M, Roussel M, Karlin L, Arnulf CH, et al. Bortezomib, doxorubicin, cyclophosphamide, dexamethasone induction followed by stem cell transplantation for primary plasma cell leukemia: a prospective phase II study of the Intergroupe Francophone du Myélome. J Clin Oncol. 2016;34:2125–32. doi: 10.1200/JCO.2015.63.1929. PubMed DOI

Musto P, Simeon V, Martorelli MC, Petrucci MT, Cascavilla N, Di Raimondo F, et al. Lenalidomide and low-dose dexamethasone for newly diagnosed primary plasma cell leukemia. Leukemia. 2014;28:222–5. doi: 10.1038/leu.2013.241. PubMed DOI

Avet-Loiseau H, Daviet A, Brigaudeau C, Callet-Bauchu E, Terré C, Lafage-Pochitaloff M, et al. Cytogenetic, interphase, and multicolor fluorescence in situ hybridization analyses in primary plasma cell leukemia: a study of 40 patients at diagnosis, on behalf of the Intergroupe Francophone du Myélome and the Groupe Français de Cytogénétique Hématologique. Blood. 2001;97:822–5. doi: 10.1182/blood.v97.3.822. PubMed DOI

Mosca L, Musto P, Todoerti K, Barbieri M, Agnelli L, Fabris S, et al. Genome-wide analysis of primary plasma cell leukemia identifies recurrent imbalances associated with changes in transcriptional profiles. Am J Hematol. 2013;88:16–23. doi: 10.1002/ajh.23339. PubMed DOI

Jiménez-Zepeda VH, Domínguez VJ. Plasma cell leukemia: a rare condition. Ann Hematol. 2006;85:263–7. doi: 10.1007/s00277-005-0054-4. PubMed DOI

van de Donk NWCJ, Lokhorst HM, Anderson KC, Richardson PG. How I treat plasma cell leukemia. Blood. 2012;120:2376–89. doi: 10.1182/blood-2012-05-408682. PubMed DOI PMC

Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516–20. doi: 10.1182/blood-2007-10-116129. PubMed DOI PMC

Richardson PG, Mitsiades C, Schlossman R, Munshi N, Anderson K. New drugs for myeloma. Oncologist. 2007;12:664–89. doi: 10.1634/theoncologist.12-6-664. PubMed DOI

Gavriatopoulou M, Musto P, Caers J, Merlini G, Kastritis E, van de Donk N, et al. European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias. Leukemia. 2018;32:1883–98. doi: 10.1038/s41375-018-0209-7. PubMed DOI

Musto P, Statuto T, Valvano L, Grieco V, Nozza F, Vona G, et al. An update on biology, diagnosis and treatment of primary plasma cell leukemia. Expert Rev Hematol. 2019;12:245–53. doi: 10.1080/17474086.2019.1598258. PubMed DOI

Munshi PN, Hari P, Vesole DH, Jurczyszyn A, Zaucha J, Davila O, et al. Breaking the glass ceiling of age in transplant in multiple myeloma. Blood. 2019;134:782. doi: 10.1182/blood-2019-124804. PubMed DOI

Katodritou E, Terpos E, Kelaidi C, Kotsopoulou M, Delimpasi S, Kyrtsonis MC, et al. Treatment with bortezomib-based regimens improves overall response and predicts for survival in patients with primary or secondary plasma cell leukemia: analysis of the Greek myeloma study group. Am J Hematol. 2014;89:145–50. doi: 10.1002/ajh.23600. PubMed DOI

Lawless S, Iacobelli S, van Biezen A, Koster L, Chevallier P, Blaise D, et al. Comparison of haematopoietic stem cell transplantation approaches in primary plasma cell leukaemia. Clin Lymphoma Myeloma Leuk. 2017;17:E23. doi: 10.1016/j.clml.2017.03.039. DOI

Mina R, Joseph NS, Kaufman JL, Gupta VA, Heffner LT, Hofmeister CC, et al. Survival outcomes of patients with primary plasma cell leukemia (pPCL) treated with novel agents. Cancer. 2019;125:416–23. doi: 10.1002/cncr.31718. PubMed DOI

Jung SH, Lee JJ, Kim K, Suh C, Yoon DH, Min CK, et al. The role of frontline autologous stem cell transplantation for primary plasma cell leukemia: a retrospective multicenter study (KMM160) Oncotarget. 2017;8:79517–26. doi: 10.18632/oncotarget.18535. PubMed DOI PMC

Nishihori T, Abu Kar SM, Baz R, Alsina M, Harousseau JL, Kharfan-Dabaja MA. Therapeutic advances in the treatment of primary plasma cell leukemia: a focus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013;19:1144–51. doi: 10.1016/j.bbmt.2013.02.003. PubMed DOI

Neri A, Todoerti K, Lionetti M, Simeon V, Barbieri M, Nozza F, et al. Primary plasma cell leukemia 2.0: advances in biology and clinical management. Expert Rev Hematol. 2016;9:1063–73. doi: 10.1080/17474086.2016.1244002. PubMed DOI

Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood. 2007;109:3489–95. doi: 10.1182/blood-2006-08-040410. PubMed DOI

Fonseca R, Blood EA, Oken MM, Kyle RA, Dewald GW, Bailey RJ, et al. Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients. Blood. 2002;99:3735–41. doi: 10.1182/blood.v99.10.3735. PubMed DOI

Sonneveld P, Avet-Loiseau H, Lonial S, Usmani S, Siegel D, Anderson KC, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127:2955–62. doi: 10.1182/blood-2016-01-631200. PubMed DOI PMC

Gonsalves WI, Buadi FK, Kumar SK. Combination therapy incorporating Bcl-2 inhibition with Venetoclax for the treatment of refractory primary plasma cell leukemia with t (11;14) Eur J Haematol. 2018;100:215–17. doi: 10.1111/ejh.12986. PubMed DOI

Jelinek T, Mihalyova J, Kascak M, Duras J, Popkova T, Benkova K, et al. Single-agent venetoclax induces MRD-negative response in relapsed primary plasma cell leukemia with t(11;14) Am J Hematol. 2019;94:E35–E7. doi: 10.1002/ajh.25331. PubMed DOI

Van De Donk NWCJ, van der Holt B, Schjesvold FH, Wu KL, Spada S, Roeloffzen W, et al. Treatment of primary plasma cell leukemia with carfilzomib and lenalidomide-based therapy: results of the first interim analysis of the phase 2 EMN12/HOVON129 study. Blood. 2019;134:693. doi: 10.1182/blood-2019-125120. DOI

Kumar S, Kimlinger T, Morice W. Immunophenotyping in multiple myeloma and related plasma cell disorders. Best Pract Res Clin Haematol. 2010;23:433–51. doi: 10.1016/j.beha.2010.09.002. PubMed DOI PMC

Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47. doi: 10.1182/blood-2016-08-733196. PubMed DOI PMC

Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:E328–E46. doi: 10.1016/S1470-2045(16)30206-6. PubMed DOI

Gonsalves WI, Rajkumar SV, Go RS, Dispenzieri A, Gupta V, Singh PP, et al. Trends in survival of patients with primary plasma cell leukemia: a population-based analysis. Blood. 2014;124:907–12. doi: 10.1182/blood-2014-03-565051. PubMed DOI PMC

Dimopoulos MA, Palumbo A, Delasalle KB, Alexanian R. Primary plasma cell leukaemia. Br J Haematol. 1994;88:754–9. doi: 10.1111/j.1365-2141.1994.tb05114.x. PubMed DOI

Ramsingh G, Mehan P, Luo J, Vij R, Morgensztern D. Primary plasma cell leukemia: a surveillance, epidemiology and end results database analysis between 1973 and 2004. Cancer. 2009;115:5734–9. doi: 10.1002/cncr.24700. PubMed DOI

Mahindra A, Kalaycio ME, Vela-Ojeda J, Vesole DH, Zhang MJ, Li P, et al. Hematopoietic cell transplantation for primary plasma cell leukemia: results from the Center for International Blood and Marrow Transplant Research. Leukemia. 2012;26:1091–7. doi: 10.1038/leu.2011.312. PubMed DOI PMC

Drake MB, Iacobelli S, van Biezen A, Morris C, Apperley JF, Niederwieser D, et al. Primary plasma cell leukemia and autologous stem cell transplantation. Haematologica. 2010;95:804–9. doi: 10.3324/haematol.2009.013334. PubMed DOI PMC

Patel S, Girnius SK, Dhakal B, Gowda L, Fraser R, Davila O, et al. Primary plasma cell leukemia outcomes remain dismal despite novel agents and hematopoietic cell transplantation. Blood. 2019;134:266. doi: 10.1182/blood-2019-127049. DOI

D’Arena G, Valentini CG, Pietrantuono G, Guariglia R, Martorelli MC, Mansueto G, et al. Frontline chemotherapy with bortezomib-containing combinations improves response rate and survival in primary plasma cell leukemia: a retrospective study from GIMEMA Multiple Myeloma Working Party. Ann Oncol. 2012;23:1499–502. doi: 10.1093/annonc/mdr480. PubMed DOI

Iriuchishima H, Ozaki S, Konishi J, Matsumoto M, Murayama K, Nakamura F, et al. Primary plasma cell leukemia in the era of novel agents: a multicenter study of the Japanese Society of Myeloma. Acta Haematol. 2016;135:113–21. doi: 10.1159/000439424. PubMed DOI

Gowda L, Shah M, Badar I, Bashir Q, Shah N, Patel K, et al. Primary plasma cell leukemia: autologous stem cell transplant in an era of novel induction drugs. Bone Marrow Transplant. 2019;54:1089–93. doi: 10.1038/s41409-018-0392-1. PubMed DOI PMC

Katodritou E, Terpos E, Delimpasi S, Kotsopoulou M, Michalis E, Vadikolia C, et al. 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. Blood Cancer J. 2018;8:31. doi: 10.1038/s41408-018-0059-6. PubMed DOI PMC

Ganzel C, Rouvio O, Avivi I, Magen H, Jarchowsky O, Herzog K, et al. Primary plasma cell leukemia in the era of novel agents for myeloma – a multicenter retrospective analysis of outcome. Leuk Res. 2018;68:9–14. doi: 10.1016/j.leukres.2018.02.010. PubMed DOI

Nakaya A, Yagi H, Kaneko H, Kosugi S, Kida T, Adachi Y, et al. Retrospective analysis of primary plasma cell leukemia in Kansai Myeloma Forum registry. Leuk Res Rep. 2018;10:7–10. doi: 10.1016/j.lrr.2018.07.001. PubMed DOI PMC

Cha CH, Park CJ, Huh JR, Chi HS, Suh CW, Kang YK. Significantly better prognosis for patients with primary plasma cell leukemia than for patients with secondary plasma cell leukemia. Acta Haematol. 2007;118:178–82. doi: 10.1159/000109470. PubMed DOI

Gozzetti A, Musto P, Defina M, D’Auria F, Papini G, Steduto T, et al. Efficacy of bortezomib, lenalidomide and dexamethasone (VRD) in secondary plasma cell leukaemia. Br J Haematol. 2012;157:497–8. doi: 10.1111/j.1365-2141.2012.09029.x. PubMed DOI

Jimenez-Zepeda VH, Reece DE, Trudel S, Chen C, Tiedemann R, Kukreti V. Lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone for the treatment of secondary plasma cell leukemia. Leuk Lymphoma. 2015;56:232–5. doi: 10.3109/10428194.2014.893304. PubMed DOI

Dimopoulos MA, Barlogie B, Smith TL, Alexanian R. High serum lactate dehydrogenase level as a marker for drug resistance and short survival in multiple myeloma. Ann Intern Med. 1991;115:931–5. doi: 10.7326/0003-4819-115-12-931. PubMed DOI