Final Diagnosis -- Recurrent multiple myeloma with plasma cell leukemia



Plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma with poor prognosis characterized by peripheral blood involvement. It is defined by the presence of circulating plasma cells exceeding 20% of peripheral blood leukocytes or 2 x 109/L [1]. PCL is classified as either primary (60%) or secondary (40%). In primary PCL, a malignant plasma cell clone is thought to arise de novo and the peripheral blood proliferation is the presenting condition [2]. Secondary PCL occurs through clonal evolution of an underlying multiple myeloma and is a terminal event. PCL occurs in 2 to 4 percent of myeloma cases and is seen more frequently in light-chain only, IgE, and IgD myeloma, and less frequently in IgG or IgA myeloma [1, 3]. Although similar, PCL exhibits distinct clinical, immunophenotypic, and cytogenetic features that distinguish it from multiple myeloma.

The median age of patients with PCL is 50-60 years with an approximately equal proportion of male and female patients. In both its primary and secondary forms, PCL clinically resembles late-stage multiple myeloma. Patients may present with anemia, cytopenias, recurrent bacterial infections, or renal insufficiency. Osteolytic lesions and pathologic fractures occur but are less frequent in PCL. However, residual marrow function is usually more compromised. Renal failure, lymphadenopathy, and organomegaly are more frequent. PCL displays multiple adverse prognostic indicators at presentation such as elevated lactate dehydrogenase, elevated beta2-microglobulin, hypercalcemia, high percentage of Bence-Jones proteinemia, and extramedullary involvement [1, 2, 4].

Pathologic diagnosis of PCL is based on histologic, immunophenotypic, and cytogenetic findings in addition to circulating plasma cell count. Bone marrow biopsy typically reveals aggregates or sheets of neoplastic plasma cells that displace normal marrow elements. Peripheral blood plasma cells range from mature forms with characteristic "clock-face" chromatin and perinuclear hof, to immature blastic forms with loose reticular chromatin, high nuclear/cytoplasmic ratio, and prominent nucleoli. Immature neoplastic cells may be indistinguishable from myeloblasts. In some instances, plasma cells display lymphoid morphology.

Considerable overlap of immunophenotypic markers exists between multiple myeloma and PCL. However, significant differences in antigen expression have been identified which help to differentiate the two variants. Typical antigen expression profiles are as follows:

Plasma cells in PCL frequently display a more immature phenotype. Expression of pan-B cell antigen CD20 has been shown in 50% of PCL cases compared to 17% of multiple myeloma cases [2]. In addition, neoplastic cells in marrow and peripheral blood in both primary and secondary PCL typically do not express CD56, which is considered to have an important role in anchoring plasma cells to bone marrow stroma. Immunophenotypic differences could be relevant in explaining survival differences between the two entities. Expression of CD56 in a minority of PCL cases has been associated with a favorable prognosis, while CD20 expression has been associated with shorter survival [4].

An increased incidence of cytogenetic abnormalities has been reported in PCL compared to multiple myeloma. Conventional cytogenetic studies have shown abnormal karyotypes in 30 to 40% of myeloma cases compared to 68% of PCL cases [5]. Complex karyotypes with multiple chromosomal gains and losses are the most frequent changes. Specific numeric chromosomal abnormalities described in PCL include monosomy 13, gains or losses in chromosome 1, trisomy 18, and monosomy X in women [4]. Monosomy 13 may be present in up to 85% of PCL cases and, in multiple myeloma, has been associated with short post-treatment survival [6]. The most common structural abnormality involves the immunoglobulin heavy chain (IgH) locus at 14q32, which is usually part of a translocation. Translocation t(11;14)(q13;q32) in particular has been associated with adverse outcome in patients with PCL [5].

There are no curative regimens for primary or secondary PCL. Therefore, as in multiple myeloma, treatment is aimed at prolonging survival and maximizing quality of life. Because of the lack of large prospective series, PCL treatment is based on empiric recommendations or extrapolation of data from multiple myeloma literature. Overall median survival of primary PCL treated with conventional chemotherapy ranges from 2 to 8 months. Secondary PCL is normally not responsive to treatment and has a median survival of 1.3 months [2, 4]. A prospective randomized trial of 200 multiple myeloma patients showed that autologous peripheral blood stem cell transplant is superior to conventional chemotherapy with respect to response rate, 5-year event-free survival, and 5-year overall survival [7]. The median survival of primary PCL patients receiving autologous stem cell transplant has been reported at 28 months, with a maximum reported survival of 106+ months [8]. Thus, autologous stem cell transplant is considered primary treatment for PCL. In addition, thalidomide, with its anti-angiogenic properties and potential anti-tumor activity, is an emerging therapy. Signal transduction inhibitors (farnesyl transferase inhibitors) are also being investigated as monotherapy or as part of multi-drug regimens for PCL [2].

In the case of this 56-year-old patient, secondary PCL was diagnosed 5 years after her initial diagnosis of multiple myeloma. Peripheral blood demonstrated 56% plasma cells, which was well above the minimum diagnostic criteria of 20% established by the World Health Organization. Plasmacytoid cells were also found extensively in the bone marrow. Immunophenotyping showed an antigen expression profile compatible with PCL. Although expression of CD56 is not typical for PCL, it has been reported in a minority of cases and is typical for multiple myeloma. This patient also had a complex karyotype with multiple abnormalities including monosomy 13. She received her stem cell transplant for multiple myeloma approximately 4 years prior to her PCL diagnosis. This scenario is consistent with reportedly improved outcomes for stem-cell-treated myeloma patients over conventional chemotherapy, which has a median survival of less than 1 year.


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  5. Avet-Loiseau H, Daviet A, Brigaudeau C, 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 Myelome and the Groupe Francais de Cytogenetique Hematologique. Blood 2001; 97:822.
  6. Perez-Simon JA, Garcia-Sanz R, Tabernero, et al. Prognostic value of numerical chromosome aberrations in multiple myeloma: a FISH analysis of 15 different chromosomes. Blood 1998; 91:3366.
  7. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996; 335:91-97.
  8. Saccaro S, Fonseca R, Veillon DM, et al. Primary plasma cell leukemia: report of 17 new cases treated with autologous or allogeneic stem-cell transplantation and review of literature. American Journal of Hematology 2005; 78:288-294.

Contributed by Teresa M LaCaria, MD and Sandra Kaplan, MD

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