Kidney dysfunction during lenalidomide treatment for AL amyloidosis.

BACKGROUND: Lenalidomide is an immunomodulatory agent used to treat plasma cell dyscrasias. We previously observed worsening of kidney function in a high proportion of patients with AL amyloidosis during lenalidomide treatment. The objective of this study is to characterize alterations in kidney function among patients with AL amyloidosis undergoing treatment with lenalidomide. METHODS: This is a secondary analysis of an ongoing clinical trial at a single referral centre. Forty-one patients with AL amyloidosis received lenalidomide with or without dexamethasone in monthly cycles. Kidney dysfunction was defined as ≥ 50% increase in serum creatinine. Severe kidney dysfunction was defined as ≥ 100% increase in serum creatinine. Recovery of renal function was defined as a return of serum creatinine to within 25% of the pre-treatment value or discontinuation of dialysis. RESULTS: Twenty-seven of 41 patients (66%) developed kidney dysfunction during lenalidomide treatment. The kidney dysfunction was severe in 13 of these patients (32%); four of whom required initiation of dialysis (10%). The median time to kidney dysfunction after starting lenalidomide was 44 days (interquartile range 15-108 days). Four of eight patients without underlying renal amyloidosis developed kidney dysfunction. Patients with severe kidney dysfunction were older and had a higher frequency of underlying renal amyloidosis, greater urinary protein excretion, and lower serum albumin. Recovery of renal function occurred in 12 patients (44%). CONCLUSIONS: Among patients with AL amyloidosis, worsening of kidney function occurs frequently during lenalidomide treatment. While a causal role of the drug has not been established, our findings suggest that kidney function should be monitored closely during treatment with this drug.

Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial.

In immunoglobulin light chain (AL) amyloidosis, amyloid fibril deposits derived from immunoglobulin light chains produced by a clonal plasma cell dyscrasia accumulate in tissues and damage vital organs. Treatment regimens used in multiple myeloma can be effective in AL amyloidosis; however, patients with this disease often tolerate these regimens poorly because of multisystem organ dysfunction. Thalidomide and lenalidomide have both been shown to be effective in myeloma. In this report, we describe results of a phase 2 trial of the use of lenalidomide, as a single agent and in combination with dexamethasone, for the treatment of AL amyloidosis. Thirty-four patients with AL amyloidosis, most with prior therapies, were enrolled in the trial. The initial dose of lenalidomide used (25 mg/d) was poorly tolerated; however, a reduced dose of 15 mg/d was generally well tolerated. Of 24 evaluable patients, 7 (29%) achieved a hematologic complete response and 9 (38%) achieved a partial hematologic response, for an overall hematologic response rate of 67%. Hematologic responses were also associated with clinical responses. Fatigue and myelosuppression were the most common treatment-related adverse events (35%), while thromboembolic complications (9%) were the most serious. Findings from this trial indicate that lenalidomide can be effective in treating AL amyloidosis.

Tolerability and efficacy of thalidomide for the treatment of patients with light chain-associated (AL) amyloidosis.

Thalidomide is an effective therapy for multiple myeloma, although its mechanisms of action remain unclear. Light chain-associated (AL) amyloidosis is a plasma cell disorder related to multiple myeloma, but in AL amyloidosis, fibrillar tissue deposits of clonal immunoglobulin light chains produce organ dysfunction. To test the toxicity and efficacy of thalidomide in AL amyloidosis we initiated a phase I/II trial for patients with AL amyloidosis, most of whom had failed prior therapy with high-dose melphalan and autologous stem cell transplantation. This trial was designed as an individualized 6-month dose-escalation study with reevaluation of bone marrow plasmacytosis and serum and urine monoclonal proteins after 3 and 6 months. Sixteen patients were enrolled in the study with a median age of 62 years (range, 37-70 years). Fourteen patients had renal involvement, 4 had cardiac involvement, 4 had liver involvement, and 2 had predominant soft tissue or lymph node involvement. The median maximum tolerated dose was 300 mg, with fatigue and other central nervous system side effects being the major dose-limiting toxicities. Side effects not frequently reported for other patient populations included exacerbation of peripheral and pulmonary edema and worsening azotemia. In all, 50% of patients experienced grade 3/4 toxicity, and 25% had to discontinue the study drug. No complete hematologic responses were seen, but 25% of patients had a significant reduction in Bence-Jones proteinuria. Thus, while thalidomide has activity in AL amyloidosis, it also has significant toxicity in this patient population.