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Journal of Clinical Oncology, Vol 23, No 10 (April 1), 2005: pp. 2426-2428 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.079
Side Effects and Good Effects from New Chemotherapeutic AgentsCASE 3. Bortezomib in Primary Refractory PlasmacytomaUniversity Departments of Medicine, Radiology and Pathology, Queen Mary Hospital, University of Hong Kong, Hong Kong A 58-year-old woman presented with rapidly progressive sternal bulging. Computed tomography (CT) scan (Fig 1A) showed a huge mediastinal mass with bony destruction, with intense tracer uptake on whole-body F-18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET; Fig 1B). Biopsy showed a diffuse infiltrate of plasma cells, with occasional atypical ones having enlarged nuclei, prominent nucleoli, and multinucleated forms (Fig 2). Immunohistochemistry showed lambda light chain restriction and an immunoglobulin G immunophenotype. The plasma cells expressed CD79a, but not CD56. Skeletal survey was normal, and bone marrow aspiration showed only 3% plasma cells. Serum immunoelectrophoresis showed monoclonal immunoglobulin G gammopathy with a paraprotein of 9 g/L. She received radiotherapy of 44 Gy to the mediastinum, with partial response. However a left cervical lymph node developed shortly afterward. Biopsy confirmed recurrent plasmacytoma. Despite multiple combination chemotherapy regimens including MP (melphalan and prednisolone), VCMP (vincristine, cyclophosphasmide, melphalan, and prednisolone), and VAD (vincristine, adriamycin, and dexamethasone), new soft tissue masses developed subsequently over the anterior chest wall at the Hickman catheter exit site and Hickman catheter tunnel tract (Fig 3A, long arrows). CT scan showed a focal heterogeneous enhancing mass in the body of pancreas suggestive of plasmacytoma (Fig 1C) in addition to residual mediastinal mass. She developed a fever with gradual deterioration of the general condition. Her serum albumin then dropped from 41 g/L to 25 g/L (normal, 42 to 54 g/L), and serum paraprotein rose from 9 g/L to 25 g/L. A repeat bone marrow aspirate then showed 5% plasma cells only, and absence of lytic bone lesions. She received bortezomib at the dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 3-week cycle. After the first cycle, she became afebrile, and all plasmacytoma tumors resolved completely (Fig 3B) with marked improvement of serum albumin level (from 25 to 38 g/L), with reduction of paraprotein level (25 g/L to 8 g/L). Repeat CT after the third cycle showed complete resolution of the mediastinal and pancreatic masses (Fig 1D). Bortezomib resulted in complete resolution of all tumors with a two-thirds reduction of paraprotein level. She remained plasmacytoma-free for 3 months. She underwent nonmyeloablative allogeneic bone marrow transplantation with marrow from an human leukocyte antigen–identical sibling. She engrafted on day 23 but developed grade 4 gut and liver graft-versus-host disease and died afterwards.
Plasma cell dyscrasia may manifest as plasmacytoma, multiple myeloma (MM), primary amyloidosis, or monoclonal gammopathy of unknown significance.1 It comprises clonal proliferations of plasma cells, which are cytologically and immunophenotypically identical to those of myeloma, and may arise either from the bone or extramedullary sites. Extramedullary plasmacytoma (EMP) constitutes 4% of all plasma cell tumors, and the majority (80%) involve the upper aerodigestive tract.2 Conventional treatment includes surgery, radiotherapy, or combination chemotherapy.2 Our patient presented with an aggressive primary plasmacytoma refractory to multiple chemotherapy regimens, including VAD, which produces a high response rate in patients with MM.3 The aggressive nature was further illustrated by the enhanced tracer uptake on PET,4 in contrast to the lack of increased uptake in indolent plasmacytoma.5 The mediastinum is rarely involved by extramedullary plasmacytoma,2 and the subsequent development of plasmacytoma in the skin, Hickman catheter tunnel and exit site, and the pancreas has been hitherto unreported. The proteasome is a ubiquitous, multicatalytic enzyme complex that degrades protein regulators of the cell cycle or the survival/apoptosis pathways.6 Neoplastic plasma cells exhibit constitutive activation of nuclear factor kappa B (NF  B), and thus are protected from apoptosis. NFB activation, however, requires prior proteasomal degradation of its inhibitor, I kappa B (IB).7 Bortezomib is a proteasome inhibitor, and thus inhibits the degradation of IB. This results in inhibition of NFB, and consequent susceptibility of neoplastic plasma cells to apoptosis. While bortezomib can induce a response rate of 35% in patients with refractory MM,6 the successful treatment of our patient has further demonstrated the efficacy of bortezomib in refractory plasmacytoma with unusual extramedullary manifestations. This case report has also highlighted the clinical utility of PET in imaging plasmacytoma. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES 1. Salmon S, Cassady JR: Plasma cell neoplasms, in DeVita VT, Hellman S, Rosenberg S (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, JB Lippincott, 1997, pp 2344 2. Alexiou C, Kau RJ, Dietzfelbinger H, et al: Extramedullary plasmacytoma: Tumor occurrence and therapeutic concepts. Cancer 85:2305-2314, 1999[CrossRef][Medline] 3. Kumar A, Loughran T, Alsina M, et al: Management of multiple myeloma: A systematic review and critical appraisal of published studies. Lancet Oncol 4:293-304, 2003[CrossRef][Medline]
4. Durie BG, Waxman AD, D'Agnolo A, et al: Whole-body (18)F-FDG PET identifies high-risk myeloma. J Nucl Med 43(11):1457-1463, 2002
5. Chim CS, Ooi GC, Loong F, et al: Solitary bone plasmacytoma: Role of MRI and PET. J Clin Oncol 22:1328-1330, 2004
6. Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003 7. Mitsiades CS, Mitsiades N, Poulaki V, et al: Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: Therapeutic implications. Oncogene 21(37):5673-5683, 2002[CrossRef][Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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