Systemic Diseases

Therapy of AL amyloidosis (or Ig light-chain amyloidosis), with renal involvement in most patients, remains a major challenge. An editorial recently written by an expert in that field, Dr. M.A. Gertz, has a provocative title: “I don't know how to treat amyloidosis” (1). There are good reasons for pessimism; there are also good reasons for hope. Heher et al. stress the latter point of view in their review article (2). In their conclusions, they state that: “Wider use of kidney biopsy to identify monoclonal protein deposition in patients with mild degrees of kidney dysfunction may be indicated as therapeutic options improve.” The regimen of melphalan and dexamethasone is now widely considered the standard for patients who do not receive stem-cell transplants. The study performed in Pavia, Italy, demonstrated a progression-free survival of 3.8 years and median overall survival of 5.1 years (3). The results of trials in AL amyloidosis are very heterogeneous because the mix of patients is very important in determining overall outcome (1). Indeed prognosis depends of age, proportion of patients with cardiac involvement, and the number of organs involved. The major predictor of survival in AL amyloidosis is the extent of cardiac involvement, and this can be estimated by measurement of cardiac troponin-T and NT-proBNP (N-terminal-probrain natriuretic peptide). In selected patients (younger age without significant organ dysfunction) high-dose melphalan with stem-cell transplantation may be associated with higher complete response and extended survival (4). There is a need for effective treatment of patients with symptomatic heart involvement and of patients with refractory disease. This is the goal of the retrospective study performed by Kastritis et al. from three centers where 94 patients with AL amyloidosis were managed. Bortezomib (B), which is a reversible proteasome inhibitor, has been used. This drug has shown significant activity in patients with myeloma in relapsed or refractory settings and also as a first-line treatment. Plasma cells produce amyloidogenic light chains that lead to increases in endoplasmic stress and are largely dependent on proteasome function. Amyloidogenic light chains also have a direct toxic effect on cardiomyocytes. In AL amyloidosis patients, B was prescribed at various doses in this multicenter retrospective study. However B was the first-line therapy in 19% of the patients at 1.3 mg/m2 on days 1, 4, 8, and 11, with dexamethasone at 40 mg on days 1 through 4 every 21 days. Eleven percent of patients received B without dexamethasone. Among the 94 patients analyzed, 76 (81%) had at least one prior therapy and 51% had refractory disease. The heart was involved in 73% and the kidneys were involved in 75% (11 [12%] were dialysis-dependent). A hematologic response was achieved in an average of 72% of patients. A complete response was more frequent in previously untreated patients and in those who received B twice weekly. A heart response was found in 29% of 69 patients, and a kidney response was found in 19% of 70 patients, strongly associated with hematologic response. All cardiac responders were alive after a median of 18 months. A drop in NT-proBNP accompanied cardiac response. The rates of renal responses were somewhat low, probably because of long-standing disease responsible for irreversible renal damage. The renal response may need longer follow-up because up to 25% of patients respond after >12 months. Of importance, renal impairment (even ESRD) was not associated with increased toxicity of B. After a median follow-up of 12 months (range 0.6 to 48 months), 49% of patients had either hematologic or organ progression or died. Twenty-five patients (26%) died; 1-year survival was 76% and cardiac involvement was independently associated with survival. In patients with renal impairment but not undergoing dialysis, only baseline NT-proBNP was significantly associated with survival. In the whole population of patients (excluding dialysis patients), only NT-proBNP and hematologic responses were independently associated with survival. The most common nonhematologic toxicities were peripheral sensory neuropathy (40%) with or without neuropathic pain, exacerbation of orthostatic hypotension (36%), peripheral edema, and intestinal manifestations. This paper shows that B is an effective and rapidly acting treatment: median of 28 days versus 2 to 4 months in dexamethasone-based regimens. As first-line therapy, B achieves a 47% complete remission rate. It also shows activity even in heavily pretreated or refractory patients. However, it should not be used in patients with severe symptomatic heart failure because of the high rate of adverse events (5). New therapeutic possibilities emerged recently in AL amyloidosis after recent advances in myeloma treatment. The tolerance of lenalidomide in a small trial in patients with severe AL amyloidosis has been poor (6). Incorporation of B in the first-line treatment, particularly in high-risk patients, should be investigated in phase III trials.