Abstract
Background and Objectives
Systemic immunoglobulin light chain (AL) amyloidosis is characterized by the deposition of misfolding proteins produced by monoclonal plasma cells. The process of amyloid deposition produces tissue damage and eventually organ failure leading to death. Although various organs including heart, kidneys, gastrointestinal tract, and liver are involved, cardiac damage mainly affects prognosis. Median survival time of patients with cardiac amyloidosis has reported to be four to six months. The ideal goal of treatment is the elimination of amyloid protein from involved organs, which is not available so far. We instead try to inhibit the growth of the monoclonal plasma cells to reduce the supply of amyloidogenic light chains. For this purpose, a treatment with high dose melphalan supported by autologous stem cell transplantation (ASCT) was introduced and achieved some positive results. However, treatment-related mortality of ASCT is as high as 10% even if using risk-adapted approach to adjust the dose of melphalan. Moreover, indication of ASCT is limited to "fit" patient. For "unfit" patients, melphalan plus dexamethasone (MD) treatment is the standard of care, which shows similar response rate and better survival to ASCT in a randomized study. One of the concerns in MD treatment is a long time to response. According to a report, median time to response in MD treatment is 4.5 months, which is almost same as median survival in patients with cardiac amyloidosis. In this study, we evaluated the feasibility and activity of MD in combination with bortezomib for patients with AL amyloidosis.
Methods
Patients with histologically proven, newly diagnosed systemic AL amyloidosis received MDB regimen including oral melphalan (10 mg/m2 of body surface area (BSA) on days 1 to 4), oral dexamethasone (40 mg/day on days 1 to 4), and bortezomib (1.3 mg/m2 of BSA on days 8, 15, 22) for up to 12 courses if no severe adverse events occurred. Hematologic response was assessed at the beginning of each cycle according to new consensus criteria of the International Society of Amyloidosis.
Results
Eight patients were retrospectively analyzed in this study, six were men. The median age at diagnosis was 60 years (range, 52 - 69 years). Involvement of one organ was present in two patient, two organs were involved in four, and three or more organs in the remaining two. Seven patients had a lambda monoclonal protein, and the median percentage of plasma cells in the bone marrow was 4.1% (range, 1.0% - 29.8%). No patient has received treatment before MDB regimen. The median number of treatment cycles was four (range, 1 to 12). In seven evaluable patients, the hematologic CR achieved in three patients, VGPR in three, and PR in one. In six cases evaluable by using FLC, the median time to PR (dFLC decrease >50%) was 55 days and median time to VGPR (dFLC <40 mg/L) was 51 days. Involved FLC at baseline and after each cycle of MDB in these cases was shown in figure. Adverse events which required discontinuation include sudden cardiac arrest in one case, deterioration of cardiac function in one case, and fatigue in two cases.
Conclusions
Addition of bortezomib once a week for three weeks to standard melphalan and dexamethasone treatment provides rapid hematologic response (median time to PR: 55 days). With caution of deterioration of cardiac function, the MDB regimen may be a useful option for cardiac amyloidosis patients needing the prompt reduction of pathogenic light chain.
No relevant conflicts of interest to declare.
