Post‐transplant lymphoproliferative disorder presenting as multiple myeloma
Authors: Mary J. Ninan, Yvonne H. Datta
Journal: American Journal of Hematology (2010)

Post-transplant lymphoproliferative disorders (PTLD) comprise a heterogeneous group of lymphoid proliferations, which have been a recognized complication of solid organ and hematopoietic stem cell transplantation for 40 years. The majority of these disorders are thought to be driven by EBV infection and subsequent proliferation of B cells in a weakened host. Risk factors include lack of previous exposure to EBV [1], or aggressive immunosuppression with agents such as cyclosporine or OKT3 [2]. Post transplant multiple myeloma is a rare entity, with only a few case reports in the literature [3-12]. Here we report a case of aggressive EBV-associated myeloma that occurred in a patient after retransplantation for renal graft failure. A 57-year-old man with history of renal/pancreas transplant for diabetic nephropathy in 1991 was diagnosed with a plasmacytoma of the lumbar spine in 2001. The EBV status of the plasmacytoma is not known. He was treated with radiation, cyclophosphamide, and thalidomide and went into remission. He gradually developed kidney allograft rejection after treatment for the plasmacytoma and needed to resume dialysis in 2004, however the pancreas transplant remained functional. He underwent another cadaveric kidney transplant in 2007 at which time there was no evidence of systemic myeloma, including on biopsies of the failed kidney. The patient's immunosuppression post transplant was prednisone 5 mg daily, tacrolimus 1 mg bid and mycophenolate mofetil 1 g bid. The patient developed acute rejection of his pancreas approximately 2 weeks after the transplant and was treated with a course of OKT3. His pancreas function improved, but then a month later, on repeat biopsy showed ongoing acute rejection; therefore he was given another brief course of OKT3. The patient did well until 4 months later; he was noted to have an increase in his creatinine, hypercalcemia, and left sciatic pain. Serum and urine protein electrophoresis were positive for monoclonal kappa light chains and peripheral blood quantitative PCR of Epstein-Barr virus (EBV) EBNA-1 gene revealed 123,800 copies/ml whole blood (normal <1000, or 5.1 log copies with normal <3.0) [13]. Ten days later, the patient was admitted for fever, anorexia, night sweats, weight loss, productive cough, back and abdominal pain. Exam was significant for the patient appearing uncomfortable, but no respiratory distress. There were a few shotty lymph nodes in the neck, heart exam revealed tachycardia with a 2/6 systolic murmur, and there was diffuse abdominal tenderness with no masses. There were chronic fibrotic changes in the skin on the lower extremities. Laboratory values included Hgb 12.0 mg/dl, WBC 5.6 × 109/L, Plt 170 × 109/L, Cr 1.76 mg/dl, and Ca 12.8 mg/dl. The EBV titer had increased to 2, 693,900 copies/ml whole blood. CT scan of chest/abdomen/pelvis revealed a new 2 cm × 6 cm × 3 cm pleural-based mass between the right 5th and 7th ribs, new hepatosplenomegaly, two new ∼3 × 3 cm masses involving the left posterior iliac wing and left L4 spinous process, and soft tissue masses involving left scapula and right femoral neck. CT guided biopsies of the right chest wall and right femoral masses revealed abnormal plasma cells that on immunohistochemistry were positive for CD138, EMA, and dim 56, and lacked PAX5, CD20, CD43, CD45. The neoplastic cells were positive for EBV by in-situ hybridization. This was interpreted as consistent with a plasmacytoma, EBV positive post-transplant lymphoproliferative disorder (PTLD). The patient's immunosuppression was discontinued, and treatment for the multiple myeloma was initiated with dexamethasone 40 mg IV daily for 4 days. Because of the presence of EBV, the patient was also started on gancyclovir and rituximab 375 mg/m2 weekly to eliminate CD20+ B-cells that may harbor EBV. However, the patient's status gradually declined with respiratory and renal failure. The EBV PCR titer declined, however there was no change in the lung masses based on portable chest X-rays. The patient died because of respiratory failure 10 days after initiating treatment. This case report illustrates a rare case in which PTLD presented as disseminated EBV-positive multiple myeloma after receiving aggressive immunosuppression for organ transplant rejection. EBV infection produces self-limiting illness in young adults and persists as latent infection in B cells. In vitro, EBV can transform B lymphocytes into immortalized lymphoblastoid cell lines [14]. EBV-specific cytotoxic T-lymphocyte responses are impaired in patients who are treated with immunosuppressants, and this in turn can lead to lymphoproliferative disorders [15]. Early PTLD lesions can present as plasmacytic hyperplasia, which has been shown in some cases to evolve into a plasma cell dyscrasia, [4] however, this is less common than other lymphoid malignancies [3]. In case series, the incidence of PTLD myeloma is reported to be <1% [5]. Review of literature showed a number of case reports and series of post transplant multiple myeloma [3-12, 16]. Reported cases for which treatment and outcome data are known are listed in Table I. In one study, the incidence of post transplant myeloma was associated with older age, transplant from deceased donor, and ATG treatment [17]. In a large retrospective study, analyzing 7040 patients who received solid organ transplantation, of the 78 patients who developed PTLD, only 7 had plasmacytoma/multiple myeloma [15]. However, this is higher than the incidence in the general population. About 75% of these plasma cell dyscrasias were found to be EBV positive [16]. The reasons for the lower incidence of myeloma compared with lymphoma in the transplant patients are not clear. One observation is that, as myeloma is a disease of elderly and transplant patients in general are younger, overall incidence might be lower in the transplant group [5]. The receptor for EBV on mature B cells, CD21, is not found on plasma cells, which may also account for the lower risk of myeloma [12]. Our patient received aggressive immunosuppression with OKT3 for acute allograft rejection before the diagnosis of his recurrent myeloma. There are a number of retrospective studies examining the role of aggressive immunosuppression and the development of PTLD. In general, the use of OKT3 has been associated with an increased risk of PTLD [2, 18, 19], although there were a few studies in which there was no association [20, 21]. The risk of PTLD may be related to the total degree of immunosuppression, rather than to a single specific agent. Anti-viral prophylaxis has been used to prevent PTLD, [18, 22, 23] however, its benefit has not been demonstrated in a randomized controlled trial. An important issue is whether it is safe for kidney transplant patients with PTLD who have a failed graft to undergo retransplantation. One small retrospective study has shown that retransplantation can be safely done, after waiting 2 years after complete remission [24]. The minimal waiting time is unknown. Initial management of patients with PTLD includes reduction of immunosuppresion [25]. Plasmacytic hyperplasia and monoclonal gammopathies have been shown to respond to decrease in the immunosuppression alone [25]. However in patients who develop monomorphic plasma cell dyscrasias, usual practice is to treat systemically with chemotherapeutic agents similar to immunocompetent patients [3]. In summary, plasmacytoma and multiple myeloma need to be recognized as part of the spectrum of PTLD. A reduction in immunosuppression plus standard therapy should be given to those patients who can tolerate it. The role of gancyclovir and rituximab in the management of EBV-positive myeloma PTLD is unclear. Close monitoring for recurrence, and avoidance of extremely high-intensity immunosuppression in patients with a history of PTLD is warranted. Mary J. Ninan*, Yvonne H. Datta*, * Department of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis.