Occurrence of multiple myeloma three years after successful renal transplantation

A living-related renal transplant recipient developed premature progressive allograft dysfunction 3 years after transplantation. Histopathologic examination of a transplant biopsy specimen demonstrated kappa light chain nephropathy, whereupon the diagnosis of multiple myeloma was subsequently confirmed. A variety of tumors have been reported to develop in the successful renal allograft recipient, although multiple myeloma is decidedly uncommon. This may be due to the relatively young age of transplant recipients. Histopathologic examination of renal tissue in the evaluation of premature or unexpected renal failure in the transplant recipient is underscored.     

Multiple myeloma derived from a kidney transplant donor who also developed myeloma after kidney donation

Patients who undergo kidney transplantation are at increased risk of cancer due to the long‐term use of immunosuppressive treatment. Postrenal transplant cancers usually originate from recipient cells, but donor‐related cancers have been rarely reported. We report the case of 49‐year‐old woman who developed multiple myeloma of donor origin 7 years after kidney transplantation. The donor was the mother of the recipient and also developed multiple myeloma 1 year after kidney donation. The diagnosis of multiple myeloma was based on IgG lambda monoclonal protein and the infiltration of plasma cells in bone marrow. The renal biopsy did not reveal plasmacytoma in the transplanted kidney. Epstein‐Barr virus DNA load was negative in peripheral blood. The patient responded to lenalidomide and dexamethasone, and subsequently received autologous stem cell transplantation. Donor chimerism was detected in the recipient marrow by short tandem repeat analysis; however, studies of Ig gene rearrangement were inconclusive due to insufficient DNA quality. The chromosomal abnormalities in the two myelomas were different. This case suggests that donor cells with myeloma‐initiating potential can be transferred to a recipient via a renal graft and can lead to the development of donor‐derived multiple myeloma in the recipient under immunosuppression.     

Kidney Transplantation After Hematopoietic Cell Transplantation in Plasma Cell Dyscrasias: Case Reports

The plasma cell dyscrasias (PCDs) include a number of entities such as multiple myeloma, primary amyloidosis, and monoclonal immunoglobulin deposition disease. Hematopoietic cell transplant (HCT) is the only cure for a variety of hematologic and oncologic diseases. Clinically significant renal impairment is a common feature in plasma cell myeloma, affecting 20% to 55% of patients at initial diagnosis; 2% to 3% of patients present with failure sufficiently severe to require hemodialysis.This circumstance is associated with a high early mortality. The necessity for immunosuppression after HCT could complicate its management and may precipitate the development of complications. In some patients an effective alternative could be kidney transplant (KT); however, the presence of 2 transplants will require optimal adjustment of immunosuppression and management of complications.At present, there are few published cases of KT after HCT, and the experience of managing 2 transplants is limited. We would like to describe our experience with 4 patients who had a PCD and initially received HCT and received subsequent KT.In our experience the progress and outcome of KT after HCT were optimal. We would like to address that a higher incidence of cytopenia associated with the combination of immunosuppression (lenalidomide, tacrolimus, mycophenolate, etc.) and other drugs (ie, valganciclovir) should be considered together with an increased risk of opportunistic infections and PCD relapse.     

Recombinant human erythropoietin in a patient with multiple myeloma and end-stage renal disease.

Recombinant human erythropoietin (rHuEpo) is an established, effective treatment for the anemia of chronic renal failure. Recent reports also suggest it may be efficacious in the anemias of drug toxicity, rheumatoid arthritis, and multiple myeloma without renal failure. We describe the positive response to rHuEpo in an end-stage renal disease patient with active multiple myeloma and ongoing chemotherapy. Before rHuEpo therapy, the patient was transfusion dependent, but after rHuEpo was initiated, transfusions were not required. Multiple myeloma with renal failure does not preclude a response to rHuEpo. Further trials of rHuEpo in the treatment of multiple myeloma with and without renal failure are warranted.     

The immunological effects of extracorporeal photopheresis unraveled: induction of tolerogenic dendritic cells in vitro and regulatory T cells in vivo

Extracorporeal photopheresis (ECP) may represent an alternative to immunosuppression, as a means of reducing rejection after thoracic organ transplantation. The mechanism by which ECP exerts its protective effects has, until now, remained elusive. We analyzed peripheral blood mononuclear cells of four children with chronic heart and lung transplant rejection, who received ECP in addition to conventional immunosuppressive treatment. The effects of ECP were evaluated at each cycle, comparing blood samples from the same patient collected before and after treatment. In vitro, peripheral blood mononuclear cells treated with ECP undergo apoptosis and are phagocytosed by immature dendritic cells, which, in turn, acquire a tolerogenic phenotype. The frequency of T cells, with a regulatory phenotype and strong suppressive activity, was significantly increased in the blood of ECP-treated patients. The immunomodulatory effects of ECP may be explained by its ability to increase the frequency of regulatory T cells with inhibitory action on transplant immune rejection.     

Isolated Crystalloid Podocytopathy With Focal Segmental Glomerulosclerosis in Renal Allograft: An Unusual Presentation of Post-Transplant Monoclonal Gammopathy of Renal Significance—A Case Report

Background

Monoclonal gammopathy of renal significance denotes a spectrum of hematologic disorders that cause direct or indirect renal damage.

Sargramostim (GM-CSF) and lenalidomide in castration-resistant prostate cancer (CRPC): Results from a phase I-II clinical trial

BackgroundGranulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that stimulates dendritic cells (DCs) and promotes uptake of tumor antigens by DCs leading to T-cell cross-priming. Lenalidomide (Revlimid) is an immunomodulatory analog of thalidomide with significant T-cell stimulatory and antiangiogenic properties. GM-CSF in combination with thalidomide induces prostate-specific antigen (PSA) responses in 20% to 25% of patients with castration-resistant prostate cancer (CRPC). In an effort to further evaluate the clinical and immune activity of GM-CSF and lenalidomide, we conducted a phase I-II trial in patients with CRPC.MethodsAsymptomatic patients with CRPC were enrolled. Prior immunotherapy or chemotherapy was not allowed. All the patients received 250 μg of GM-CSF administered subcutaneously 3 times weekly along with 25 mg/d of lenalidomide administered orally on days 1 to 21 of a 28-day cycle. The primary end points were objective, PSA response, and safety. Exploratory end points included activation of circulating DCs, regulatory T cells, and Th1 cytokine production.ResultsThirty-two patients were enrolled in the study. No dose-limiting toxicities occurred in the phase I portion of the study. Although 81% of the patients achieved a decline in the levels of PSA while on therapy, only 4 achieved a PSA level decline of≥50%. The overall response rate among 11 patients with response evaluation criteria in solid tumors-defined measurable disease was 18%. Overall toxicity was G1 and G2 in nature and included fatigue observed in 69% of the patients, nausea/vomiting in 34%, and diarrhea in 28% of the patients. Grade 3 or 4 toxicities occurred in 22% of the patients and were primarily thrombocytopenia (9%) or neutropenia (19%) or both.ConclusionsAdministration of GM-CSF and lenalidomide in patients with CRPC is safe with modest evidence of antitumor activity and no immune changes observed.     

Experiences with leflunomide in solid organ transplantation

BACKGROUND: Leflunomide (Arava), a drug widely used for treatment of rheumatoid arthritis, has a very promising background in experimental transplantation. Its activity in experimental models of chronic rejection, its synergy with calcineurin phosphatase inhibitors, and its inhibitory effects on herpes virus replication are compelling reasons to pursue its clinical evaluation in transplantation. We report the use of this drug over the past 3 years in various clinical situations. METHODS: A retrospective review was performed in 53 liver and kidney transplant recipients receiving Arava. A single-dose pharmacokinetic (PK) study was first performed in stable, renal transplant recipients, and an initially targeted serum level of 100 microg/mL (300 microM) was calculated to require a loading dose of 1200-1400 mg over a 7-day period. We correlate the appearance of toxicity with serum levels of active drug and review the outcomes in patients whose clinical condition required dose reductions of conventional immune suppressive drugs. RESULTS: Fifty-three patients received leflunomide from 5 days to more than 430 days, and 37 patients received the drug for more than 60 days. The primary toxicity was anemia in the renal transplant patients and elevation of liver enzymes in the liver transplant patients. At comparable oral doses, serum levels were substantially lower and anemia more common in patients with serum creatinine >3 mg/dL. In liver and renal recipients with serum creatinine <3 mg/dL, the drug was well tolerated and dose-limiting side effects occurred in less than 15% when drug serum levels were less than 80 microg/ml. Patients with serum creatinine >3 mg/dL often required serum levels of active drug reduced to <60 microg/mL. In 12 of 18 renal patients treated for 200 days or more, the dose of cyclosporine or Prograf was reduced by a mean of 38.5% and stopped in one patient. The prednisone dose was reduced by a mean of 25% in these same 13 patients. Cyclosporine or FK506 was stopped completely in four liver recipients and reduced by 65% in another patient. No evidence of acute rejection developed in any of these liver or kidney transplant patients. CONCLUSION: Leflunomide seems to possess substantial immune suppressive potency in renal and liver transplant recipients and may be safely dosed for more than 300 days. The data suggest that calcineurin phosphatase inhibitors and prednisone can be safely reduced in patients with serum levels of active drug above 50 microg/mL. Because of a wide inter-patient range of active metabolite terminal half-life (>300%), monitoring of serum levels would seem to be an important part of its evaluation.     

Plasmacytoma-like post-kidney-transplant lymphoproliferative disorder confined to renal allograft and urinary tract: A case report

Post-transplantation lymphoproliferative disorder (PTLD) is a well-know complication after organ transplantation. We report a case of a patient who developed an extramedullary plasmacytoma-like PTLD around his transplanted kidney treated with standard multiple myeloma chemotherapy. Three years after benefiting of a deceased donor kidney transplant for an end stage kidney disease secondary to nephroangiosclerosis, our patient developed an extra-medullary plasmacytoma confined to the transplant compartment. The transplant function was unaltered, and due to the absence of reduction of the lesion after immunosuppression reduction, a chemotherapy by bortezomib-cyclophosphamide-dexamethasone (VCD) known to be efficient in multiple myeloma was initiated. After 6 cycles, positron emission tomography (PET) scan showed complete metabolic remission confirming the biological exams. This case report suggests that a chemotherapy such as VCD can efficiently treat plasmacytoma-like PTLD allowing graft survival. Therefore, transplant removal may not be mandatory as the best second line treatment after unsuccessfulness reduction of immunosuppression.     

造血干细胞移植治疗多发性骨髓瘤(附视频)

自体造血干细胞移植治疗多发性骨髓瘤(MM)始于20世纪80年代。多个历史对照和随机临床研究显示自体造血干细胞移植较传统化疗可提高治疗的反应率、完全缓解率、无事件存活率和/或总存活率,而治疗反应程度与生存相关。由此自体造血干细胞移植在欧美国家已成为年轻、适合移植(年龄≤65岁、肾功能正常和一般状况良好)MM患者的一线标准治疗方法。双次移植有可能进一步提高治疗反应率、无事件存活率和/或总存活率。免疫调节药物沙利度胺及其衍生物来那度胺和蛋白酶体抑制剂硼替佐米等新型抗骨髓瘤药物的发展提高了治疗的反应率和缓解率。目前新药并不能替代自体造血干细胞移植;这些药物运用于移植前后的整体治疗策略进一步提高了移植疗效。尽管如此,MM仍然是难以治愈的疾病。异基因造血干细胞移植有治愈MM的可能,但因清髓性预处理的高死亡率限制了其应用。近年来,联合移植即自体造血干细胞移植后进行减低剂量预处理的异基因造血干细胞移植的研究结果初步显示了其疗效和可行性。     

Localization of Mesenchymal Stromal Cells Dictates Their Immune or Proinflammatory Effects in Kidney Transplantation

Multipotent mesenchymal stromal cells (MSC) have recently emerged as promising candidates for cell‐based immunotherapy in solid‐organ transplantation. However, optimal conditions and settings for fully harnessing MSC tolerogenic properties need to be defined. We recently reported that autologous MSC given posttransplant in kidney transplant patients was associated with transient renal insufficiency associated with intragraft recruitment of neutrophils and complement C3 deposition. Here, we moved back to a murine kidney transplant model with the aim to define the best timing of MSC infusion capable of promoting immune tolerance without negative effects on early graft function. We also investigated the mechanisms of the immunomodulatory and/or proinflammatory activities of MSC according to whether cells were given before or after transplant. Posttransplant MSC infusion in mice caused premature graft dysfunction and failed to prolong graft survival. In this setting, infused MSC localized mainly into the graft and associated with neutrophils and complement C3 deposition. By contrast, pretransplant MSC infusion induced a significant prolongation of kidney graft survival by a Treg‐dependent mechanism. MSC‐infused pretransplant localized into lymphoid organs where they promoted early expansion of Tregs. Thus, pretransplant MSC infusion may be a useful approach to fully exploit their immunomodulatory properties in kidney transplantation.     

Adeno-associated virus-mediated CTLA4Ig gene transfer protects MHC-mismatched renal allografts from chronic rejection

Short-term results of renal transplantation have improved considerably in the past 20 yr; however, similar improvements in long-term outcome have not been achieved. The primary cause of late graft loss is chronic rejection that might be treated by gene therapeutic approaches. Ideally, one would like to impair locally the contact between transplant antigen and the host immune system without compromising the generalized immune competence of the recipient. This can be achieved by local expression of the therapeutic protein in the site of interest using gene therapy. Here it is shown that chronic allograft rejection can be prevented effectively by local delivery of recombinant adeno-associated virus (AAV) vectors that encode the CTLA4Ig immunosuppressant protein to the donor kidney in a fully MHC-mismatched rat strain combination. AAV CTLA4Ig prevented progressive proteinuria and protected transplant kidneys from renal structural injury. A population of anergic T cells with regulatory activity, which eventually were responsible for the induction of tolerance, were found in recipient lymph nodes and in the graft as long as 120 d after transplantation. These data indicate that AAV-mediated CTLA4Ig gene transfer to donor graft represents a promising tool to prevent the onset of chronic rejection and circumvent the unwanted systemic adverse effects of the administration of immunomodulatory protein.     

Recurrent multiple myeloma following renal transplantation: a case report

Renal transplantation is generally not considered for patients with multiple myeloma (MM) because of their extremely poor prognosis. However, for patients in remission, it offers an alternative to dialysis. There are few reports of MM recurrence among kidney transplant recipients. We report a 57-year-old white man with end-stage renal disease (ESRD) and known multiple myeloma in remission who underwent kidney transplantation. Eighteen months after transplantation upon routine follow-up, he was observed to have an elevated creatinine with no evidence of recurrence of myeloma upon bone marrow aspiration. Light microscopy and immunofluorescence of a renal biopsy showed chronic scarring of the kidney owing to cast nephropathy consistent with MM recurrence. Repeat bone marrow aspiration 1 week later confirmed this diagnosis. A review of the literature of prior studies suggested that it is reasonable to perform renal transplantation in patients with ESRD due to MM in remission, but large prospective studies would help to develop a strategy for prevention of multiple myeloma recurrence.     

Multiple myeloma and AL amyloidosis in a renal transplant recipient

Seven years after a cadaver kidney transplantation a 33-year-old man presented with a monoclonal gammopathy secondarily complicated by AL amyloidosis mainly expressed as a sicca syndrome, gammopathy that ultimately developed into multiple myeloma. The mechanisms responsible for the occurrence of monoclonal gammopathy in renal transplant recipients are discussed.     

Fatal Cardiac and Renal Allograft Rejection With Lenalidomide Therapy for Light‐Chain Amyloidosis

We describe a patient who underwent a successful heart and kidney transplant for light‐chain amyloidosis. She had an excellent hematologic response to bortezomib/dexamethasone therapy. Follow‐up therapy with lenalidomide was started, and the patient quickly had a fatal allograft rejection of the heart and kidney. We present evidence to support the theory that lenalidomide, a known immunomodulator, may have stimulated the immune system and precipitated the fatal rejection episode.     

Long-term survival of patients with multiple myeloma and acute renal failure at presentation

Eight patients presented with simultaneous multiple myeloma and acute renal failure requiring hemodialysis. Patients had no known pre-existing renal disease nor exposure to nephrotoxic agents or x-ray contrast dye. Renal failure was attributed to light chain nephropathy in all cases. In 4 of these patients the diagnosis of myeloma was initially unsuspected. Renal biopsies in 3 of these patients, and post-mortem material in a fourth revealed the changes of "myeloma kidney." No patient regained renal function and all required chronic hemodialysis. Among these eight patients, three survived for periods greater than 21 months.     

Evolving chemotherapy options for the treatment of myeloma kidney: a 40-year perspective

Kidney impairment (KI) at the time of initial diagnosis is common in myeloma. The improvement of kidney function and the reversal of KI are of utmost importance. Recent advances have made it possible to reverse acute kidney damage due to myeloma in most patients, at least if treatment is immediately implemented. Immediate antimyeloma therapy and appropriate hydration are the most commonly used treatment modalities for the management of acute KI related to myeloma. Mechanical approaches can only temporarily reduce the free light-chain load, and without effective chemotherapy they are probably not able to significantly improve kidney function. However, the role of mechanical approaches together with effective chemotherapy is still being explored. Thalidomide, lenalidomide, and bortezomib have improved the survival of myeloma patients, but they have also improved the outcome of patients presenting with KI. Thalidomide is safe to use on patients with KI without dose adjustments. Lenalidomide needs dose modification, but it can improve kidney function in many patients. Bortezomib seems to be the agent of choice for most patients presenting with KI without dose modifications. This review focuses on the management of patients presenting with "myeloma kidney" using modern chemotherapy approaches, especially novel agents.     

Comparison of the temporal profile of calcineurin inhibition by cyclosporine and tacrolimus in renal transplant patients

Calcineurin phosphatase (CaN) activity has been the focus of several recent studies on renal transplant patients as the calcineurin inhibitors tacrolimus (FK) and cyclosporine (CsA) are still the cornerstone in the immunosuppressive treatment. The aim of this study was to compare the temporal inhibition profiles of CaN using CsA or FK in two groups of renal transplant patients. Nineteen tacrolimus-treated and 10 cyclosporine-treated renal transplant patients had blood samples drawn before and at 1, 2, 3, 4, and 6 hours after ingestion of drug. CaN activity was measured as the release of 32P from a previously phosphorylated peptide and radioactivity quantitated by liquid scintillation counting. Results were expressed as units CaN. Blood concentrations of tacrolimus were determined with an IMx method and of CsA with an EMIT assay. FK-treated patients showed maximal inhibition of CaN activity at 1 to 3 hours, returning to the predose level 4 hours after drug intake. CsA-treated patients showed a gradual decrease in CaN activity with a nadir after 3 hours, failing to return to predose levels during the observation period. Both groups showed a significant rise in drug blood concentrations. To conclude, we have demonstrated that two widely used immunosuppressants, CsA and FK, show different CaN inhibitory profiles in renal transplant patients.     

Crystalloid deposits in the kidney

Light chain-producing lymphoproliferative disorders such as multiple myeloma are frequently complicated by renal impairment. Typically, the renal biopsy of a patient with renal failure caused by multiple myeloma shows cast nephropathy, but occasionally crystals may be seen. We describe the case of a patient with acute renal failure caused by multiple myeloma in which, on renal and bone marrow biopsy, there were widespread crystalloid deposits. Crystalloid nephropathy is a very rare condition associated with multiple myeloma and other light chain-secreting disorders. An underlying lymphoproliferative disorder should be considered in the differential diagnosis if crystalloid deposits are seen on a renal or other tissue biopsy.     

The association between renal cell carcinoma and multiple myeloma: insights from population-based data

Study Type – Prevalence (population based cohort) Level of Evidence 3b What’s known on the subject? and What does the study add? Several case‐series have hypothesized a potential association between renal cell carcinoma and multiple myeloma. Nonetheless, this hypothesis has not been systematically explored in a population‐based setting with sufficient sample size to estimate a magnitude of association. Our analyses revealed a bidirectional relation between renal cell carcinoma and multiple myeloma, which typically indicates that common risk factors influence both malignancies. Our findings may be useful for raising awareness among clinicians that a diagnosis of multiple myeloma may be within the spectrum of second malignancies among patients with renal cell carcinoma and that a diagnosis of renal cell carcinoma may be within the spectrum of second malignancies among patients with multiple myeloma.

OBJECTIVE

? To evaluate the hypothesis of an association between renal cell carcinoma and multiple myeloma.

PATIENTS AND METHODS

? Data from nine population‐based registries in the Surveillance, Epidemiology and End Results programme were used to evaluate two separate cohorts of patients diagnosed between 1973 and 2006: patients diagnosed with renal cell carcinoma as a primary malignancy (n= 57 190) and patients diagnosed with multiple myeloma as a primary malignancy (n= 34 156). ? We estimated standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CIs) by dividing the number of observed cases of multiple myeloma within the renal cell carcinoma cohort and the number of renal cell carcinoma cases within the multiple myeloma cohort by the number of expected cases for each malignancy in the US general population.

RESULTS

? The renal cell carcinoma cohort yielded 88 multiple myeloma cases during 293 511 person‐years of follow up. Patients with renal cell carcinoma had a higher relative risk of multiple myeloma than the general population (SIR = 1.51, 95% CI 1.21–1.85). ? The multiple myeloma cohort yielded 69 renal cell carcinoma cases during 100 804 person‐years of follow up. Patients with multiple myeloma had a higher relative risk of renal cell carcinoma than the general population (SIR = 1.89, 95% CI 1.47–2.40).

CONCLUSION

? Our analyses revealed a bidirectional association between renal cell carcinoma and multiple myeloma, which typically indicates shared risk factors.