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F Trullemans1, R Schots1, G Storme2 & B Van Camp1
1Department of Medical Oncology and Hematology, AZ-VUB, Brussels, Belgium
2Department of Radiotherapy, AZ-VUB, Brussels, Belgium
Correspondence to: Dr R Schots, BMT Unit, AZ-VUB, Laarbeeklaan 101, 1090 Brussels, Belgium
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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.4,5,6 In this report, we describe a MM patient with a localized and extramedullary relapse after a 7-year remission following syngeneic BMT. Case reportA 54-year-old lady presented in 1987 with an expanding mass in the skull. Based on bone marrow aspirate as well 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 immuno- histologically 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 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. DiscussionWe 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.4,5,6 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 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 IL-6 and TNF-alpha, known to have proliferative effects on MM cells.
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