Autologous stem cell transplant for light chain deposition disease: Incorporating bortezomib to the induction therapy

Light chain deposition disease (LCDD) is a rare plasma cell dyscrasia characterized by deposition of immunoglobulin fragments [1]. The kidneys are almost always affected, while heart, liver, and other tissues are occasionally involved [2-4]. Most of the patients present with nephrotic range proteinuria and rapidly deteriorating renal function [5]. The outcome of patients with LCDD is variable. Median time to end-stage renal disease (ESRD) is 2.7 years with 5-year ESRD free survival of 37% [3]. There is no standard treatment for patients with LCDD. Chemotherapy with alkylating agents and steroids has shown modest results [6, 7] and high-dose melphalan (HDM) with autologous stem cell transplantation (ASCT) has been used in some patients and has led to improvement of renal function [8-10]. Recently, bortezomib has shown hematologic and organ responses in patients with AL amyloidosis [11, 12] and preliminary data indicates that bortezomib may have a protective role of renal parenchyma due to inhibition of NFκB activity [13]. Based on these data, bortezomib has been introduced in the treatment of patients with LCDD who are eligible for ASCT. In this case series, we report six patients with LCDD who underwent ASCT with three receiving induction bortezomib therapy. Between June 2005 and February 2011, six patients with LCDD underwent ASCT at Princess Margaret Hospital. Patient characteristics are shown in Table I. Of the six patients transplanted, 67% (N = 4) were female. Only one patient had a bone marrow plasma cell count of 15% without evidence of active multiple myeloma. The median number of plasma cells in the bone marrow was 7% (5%–15%). Serum protein electrophoresis showed a monoclonal protein in two patients (IgG kappa). All six patients, however, had elevated serum free light chains and abnormal κ to λ ratio. Eastern cooperative group performance score was 2 or less in all the patients before undergoing ASCT. Treatment before high-dose therapy and ASCT was recorded. Before transplantation, patients received either dexamethasone alone (N = 3) or dexamethasone plus bortezomib (N = 3); dexamethasone was administered at 40 mg/day on days 1–4, 9–12, and 17–20 for variable treatment cycles (ranging from 3 to 6). Bortezomib was administered at 1.3 mg/m2 once weekly for a median of four cycles. Treatment with bortezomib was well tolerated with only Grade 1 peripheral neuropathy in one patient. No dose reduction or discontinuation was reported. Peripheral blood stem cells were collected using intravenous cyclophosphamide (2.5 g/m2) and granulocyte colony stimulating factor. The median number of CD34 cells collected was 5.71 × 106/Kg (range 3.64–8.82) collected within a median of 2 days [1-4]. Five patients were conditioned using melphalan 200 mg/m2, and one received melphalan 140 mg/m2 as per physician discretion. Standard supportive care with prophylactic antibiotics was provided to all patients. Transplanted patients had a median time to higher or equal to ANC 0.5 × 109/L of 13 days (range 11–14). The time to platelets higher or equal to 20 × 109/L was 14 days (range 13–22). Median time to discharge was 17 days (range 13–30). Treatment related mortality with this approach was 0%. The median number of platelet and packed red blood cell transfusions was 3 apheresis units [1-5] and 4 units [4-8], respectively (similar to that seen in MM and AL transplants at our center) [14]. All patients were admitted to the hospital for ASCT. No patients required temporary or permanent dialysis. The nonhematologic adverse events included: febrile neutropenia (n = 4), mucositis (n = 6), nausea requiring antiemetics (n = 6), and fatigue (n = 6). Four patients developed fever and blood cultures were persistently reported as negative. According to response criteria cited by light chain amyloidosis [15], four out of six patients achieved a PR, and 2/6 attained SD after induction therapy. Free light chain assays were abnormal in all six patients at diagnosis, and only two patients exhibited a higher than 10 g/L of monoclonal protein in the serum. At Day-100, post ASCT overall response rate was 100%, four patients achieved complete hematological response, one patient exhibited nCR, and one more attained PR. All evaluable patients have derived clinical benefit, including those who achieved less than CR. At 6 months post-ASCT, all six patients showed organ response manifested mainly by decrease of the proteinuria in > 50% (Table I). Patients receiving velcade and dexamethasone induction showed a median time of kidney response of 3 months versus 6 months for the group receiving only dexamethasone (P = 0.03). No one patient developed Engraftment Syndrome, and no patients have developed long-term complications related to ASCT. Dialysis free survival at 2 years is 100%. LCDD is a rare disorder, and its management is controversial [9]. We report our experience using high-dose chemotherapy and ASCT in patients with LCDD. In this series, only one patient with concurrent MM was reported. All patients who underwent ASCT had excellent hematologic responses. Four of the six patients achieved complete response (CR) and one more achieved n-CR, whereas the sixth achieved partial response (PR). As kidney dysfunction represents the most prominent morbidity in LCDD, it is important to emphasize that the elevated serum creatinine was ameliorated in five out of six patients after ASCT. With a median follow-up of 23 months, all six patients remained disease and dialysis free. Organ response was recorded in all of them after 6 months from ASCT. All patients but one received melphalan 200 mg/m2, a dose that was well tolerated. There was no transplant-related mortality, and no worsening of the kidney function during the peritransplant period. This experience is in keeping with prior reports that have described an important role for ASCT in patients with LCDD [8, 10, 16, 17]. In addition to these findings, we report the use of bortezomib as induction therapy in three of our cases. This is the largest series of patients treated with bortezomib before undergoing ASCT. Despite the small number of our patients, we provide evidence that bortezomib is active in this rare disease in agreement with some small case series reports [18, 19]. With bortezomib-based therapy, hematologic responses are rapid and are normally accompanied by rapid and significant reduction of proteinuria and by improvement of renal function. As is also the case in patients with amyloidosis, the measurement of serum free light chains was useful in the follow-up of our patients with LCDD, and the reduction of involved light chains was associated with significant improvement of proteinuria. The rapid reduction of toxic light chains after treatment with bortezomib resulted in the improvement of renal function, however preclinical data indicate that there may be additional mechanisms for the beneficial effect of bortezomib in LCDD [20]. In LCDD, toxic monoclonal light chains interact with receptors in mesangial cells initiating a cascade of activation of pathways that include the NFκB pathway. NFκB activation results in stimulation of cytokine production causing attraction of inflammatory cells. This results in cell proliferation and activation of genes responsible for collagen and tenascin production, resulting in dramatic changes in mesangial matrix, leading to the pathological picture of glomerulosclerosis [20]. Bortezomib inhibits the NFκB pathway, decreases TGF-B1 levels and may downregulate collagen and TIMP-1 production. Thus, bortezomib may interrupt the cascade that leads to rapid renal deterioration through these pathways by inhibiting progression of glomerulosclerosis and may improve glomerular function thus reducing proteinuria [21]. In summary, HDM with ASCT is a safe and well-tolerated treatment for LCDD showing a 100% overall response rate (ORR) and 2-year dialysis-free survival of 100%. We conclude that bortezomib seems to be active in LCDD, as most of the patients present with renal dysfunction in LCDD, bortezomib should become the preferred initial therapy for patients with LCDD and may help improving the outcomes in patients eligible for ASCT. Victor H. Jimenez-Zepeda, Suzanne Trudel, Andrew Winter, Donna E. Reece, Christine Chen, and Vishal Kukreti designed research, analyzed data, and wrote the article. Each of the authors reviewed and approved the article for submission. Victor H. Jimenez-Zepeda*, Suzanne Trudel*, Andrew Winter*, Donna E. Reece*, Christine Chen*, Vishal Kukreti*, * Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Ontario, Canada.

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