Case report Late and localized extramedullary relapse of a ... - Nature

Bone Marrow Transplantation, (2000) 25, 115–117  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt

Case report Late and localized extramedullary relapse of a light chain kappa myeloma after syngeneic bone marrow transplantation F Trullemans1, R Schots1, G Storme2 and B Van Camp1 Departments of 1Medical Oncology and Hematology and 2Radiotherapy, AZ-VUB, Brussels, Belgium

Summary: We report the case of a 54-year-old female patient with stage IIIA kappa light chain myeloma (MM) who relapsed 7 years after syngeneic bone marrow transplantation (BMT). The relapse occurred as a voluminous soft tissue plasmacytoma in the leg, developing after local trauma. The patient was successfully treated with local radiotherapy and has remained progression-free for more than 2 years. This case represents one of the longest survivors, in complete remission, after syngeneic transplantation for MM. The presentation of recurrent disease as localized plasmacytoma with extramedullary growth is unusual in the post-transplant setting. Bone Marrow Transplantation (2000) 25, 115–117. Keywords: myeloma; extramedullary relapse; syngeneic BMT

At present, MM is an incurable malignancy with a median survival of 35–40 months when conventional therapy is used. Of patients achieving remission, less then 20% remain progression-free at 5 years from initial therapy.1 Results may be improved with autologous BMT but most patients still relapse and the 5-year disease-free survival is less than 30%.2 After allogeneic BMT, 30–50% of patients achieving CR remain disease-free after 3 to 6 years.3 However, treatment-related mortality is high and only a limited number of patients have compatible bone marrow donors. A small number of MM patients treated with syngeneic BMT have been reported in the literature and in some of them prolonged remissions have been observed.4–6 In this report, we describe a MM patient with a localized and extramedullary relapse after a 7-year remission following syngeneic BMT. Case report A 54-year-old lady presented in 1987 with an expanding mass in the skull. Based on bone marrow aspirate as well Correspondence: Dr R Schots, BMT Unit, AZ-VUB, Laarbeeklaan 101, 1090 Brussels, Belgium Received 13 May 1999; accepted 1 August 1999

as biopsy specimen of the mass, the diagnosis of MM was made. She was treated with standard chemotherapy but had progressive disease as evidenced by an expanding plasmacytoma in the skull. She was referred to our hospital for further treatment in March 1989. Blood examination showed: hypogammaglobulinemia with no apparent spike on serum protein electrophoresis, monoclonal light chain kappa on serum immuno-electrophoresis, absence of leukopenia, anemia or thrombopenia, normal renal function and calcemia, normal beta-2 microglobulin. On urine analysis, the immunoelectrophoresis showed trace amounts of monoclonal light chain kappa. Cytomorphological examination of the marrow showed only 4% monoclonal plasma cells with normal morphological features but expressing kappa light chain only in the cytoplasm. Radiographic bone survey showed several osteolytic lesions in the skull, the processus pterygoideus, the left humerus, left clavicula, the sixth left rib and pathologic fractures of several vertebrae. There were no lesions in the bones of the lower legs. A large tumor, compatible with a plasmacytoma infiltrating the right orbit was documented on CT scan. We concluded that it was a progressive kappa light chain MM, stage III (Salmon–Durie). After local radiation therapy (30 Gy), a syngeneic BMT was performed in June 1989. The conditioning therapy consisted of high-dose cyclophosphamide (120 mg/kg) and high-dose melphalan (100 mg/m2). Re-evaluation at 2 months after BMT showed disappearance of monoclonal light chains on serum- and urine immuno-electrophoresis. There were no monoclonal plasma cells detectable in the bone marrow. The several osteolytic lesions, including the skull-localized plasmacytoma remained stable and some degree of recalcification occurred. The patient remained in complete remission for 7 years, with undetectable monoclonal light chains. In July 1996, she hit the posterior part of the left leg while falling down the stairs, followed by local pain for a few hours. A mass gradually developed in the leg during the following 3 months. On X-ray and CT scan a soft tissue swelling was noted with disruption of the adjacent bone cortex (Figure 1). The mass was biopsied and immunohistologically diagnosed as a light chain kappa plasmacytoma. Again, no monoclonal protein could be detected in the serum or urine and the bone marrow showed absence of monoclonal plasma cells. Other blood examinations were unremarkable and no new osteolytic lesions could be found on X-ray. The clonal relationship between the MM cells

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Figure 1 CT scan of the left leg showing a large plasmocytoma (5 × 5 × 11.2 cm), involving soft tissues with disruption of the posterior cortex fibulae.

obtained from the mass and those at diagnosis could not be examined by molecular techniques because of lack of material. The patient was treated with local radiotherapy (10 × 3 Gy delivered to the whole tibia) and has remained progression-free since with a follow-up of 24+ months. Radiographs of the left leg showed disappearance of soft tissue swelling and healing of the bone cortex (Figure 2). She enjoys more than 9 years survival after syngeneic BMT. Discussion We describe a patient presenting with a late relapse, 7 years after a syngeneic BMT. The relapse was histologically proven but we were not able to document the clonal relationship between the MM cells at relapse and those at diagnosis. However, the occurrence of a second kappa-light chain plasmacytoma in the same patient would be very unlikely, although it cannot be totally excluded. Data on syngeneic BMT in MM are scarce.4–6 The largest series reported includes 11 patients and in five of them complete remission (CR) was achieved after high-dose cyclophosphamide and TBI. In four of the five patients, having IgG kappa MM, the CR was maintained for years. In a fifth patient a stable M-component was observed over 15 years after BMT. Our case adds to this series in demonstrating that prolonged remissions can be achieved by syngeneic BMT. Our patient represents one of the longest survivors, in complete remission, after syngeneic transplantation for MM. It also illustrates that very late relapses may occur and that high-dose cytotoxic therapy alone is very unlikely to cure MM, even if rescue is performed with a graft, without contaminating tumor cells, as is the case in the syngeneic as opposed to the autologous transplantation setting. Another particular feature of this case is the isolated and extramedullary site of relapse. Soft tissue localized plasmacytoma occurs in 80% of cases in the oral cavity or upper respiratory tract and prognosis is excellent after local treatment only.7 In our patient, response to local treatment was complete and maintained for over 2 years at the time of Bone Marrow Transplantation

Figure 2 Standard X-ray of the left tibia, performed 3 years after local radiotherapy, showing healing of the cortex fibulae.

writing. Extramedullary relapse without bone marrow infiltration seems to occur more frequently after autologous BMT as compared to conventional chemotherapy. The reported incidences range from 7%8 to 35%,9 but the number of patients included in these series is low. Selection of biologically different subclones by high-dose chemotherapy or the use of growth factors have been implicated in the pathogenesis.8,10 Alternatively, MM precursor cells which have been identified as B cells originating from the germinal center11 circulate as a dormant MM reservoir until local or systemic conditions favor differentiation into proliferating and expanding plasma cells. The nature of this ‘second hit’ remains highly speculative. A possible explanation in our patient may be that local trauma induced an inflammatory response including the release of cytokines such as IL6 and TNF-alpha, known to have proliferative effects on MM cells.

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References 6 1 Gregory WM, Richards MA, Malpas JS. Combination chemotherapy vs melphalan and prednisone in the treatment of multiple myeloma: an overview of published trials. J Clin Oncol 1992; 10: 334–342. 2 Attal M, Harousseau JL, Stoppa AM et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. New Engl J Med 1996; 335: 91–97. 3 Bensinger WI, Buckner CD, Gahrton G. Allogeneic stem cell transplantation for multiple myeloma. Hematol/ Oncol Clin N Am 1997; 11: 147–157. 4 Topolsky D, Crilley P, Leasure N et al. Syngeneic marrow transplantation in multiple myeloma. Leukemia Res 1992; 16: 415–416. 5 Wolff SN, McCurley TL, Giannone L. High-dose chemoradiotherapy with syngeneic bone marrow transplantation for

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multiple myeloma: a case report and literature review. Am J Hematol 1987; 26: 191–198. Bensinger WI, Demirer T, Buckner CD et al. Syngeneic marrow transplantation in patients with multiple myeloma. Bone Marrow Transplant 1996; 18: 527–531. Soeson M, Paccagnella A, Chiarion-Sileni V et al. Extramedullary plasmacytoma: clinical behaviour and response to treatment. Ann Oncol 1992; 3: 51–57. Moreau P, Bataille R, Mahe´ B et al. High-dose melphalan is not associated with extramedullary relapses in high-risk multiple myeloma. J Clin Oncol 1993; 11: 1832. Lokhorst HM, Meuwissen OJ, Verdonck LF et al. High-risk multiple myeloma treated with high-dose melphalan. J Clin Oncol 1992; 10: 47–51. Celsing F, Hast R, Stenke L et al. Extramedullary progression of multiple myeloma following GM-CSF treatment. Eur J Haematol 1992; 49: 108. Van Riet I, Bakkus M, De Greef C et al. Homing mechanisms in the etiopathogenesis of multiple myeloma. Stem Cells 1995; 13 (Suppl. 2): 22–27.

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