Melphalan, Lenalidomide, and Dexamethasone Combination Therapy in Patients with AL Amyloidosis.

Organ function in AL amyloidosis is disrupted by the deposition of amyloid fibrils formed from monoclonal immunoglobulin light chains. Standard options for treatment include high dose melphalan with autologous stem cell transplant (HDM/SCT) or oral melphalan and dexamethasone. Newer agents such as thalidomide, lenalidomide and bortezomib are also effective, but their use is hampered by unique toxicities not seen in multiple myeloma patients. In particular, lenalidomide with dexamethasone has been shown to have hematologic response rates of approximately 45%. It is hoped that the addition of an alkylating agent to lenalidomide and dexamethasone could improve the quantity and quality of hematologic responses. To see if combination therapy at reduced doses would be tolerable and effective, a phase II study was undertaken of an oral three drug regimen consisting of melphalan, lenalidomide and dexamethasone (MLD) in AL amyloidosis.

Treatment consists of a 28 day cycle of lenalidomide 10 mg days 1–21, melphalan 5 mg/m² days 1–4, and dexamethasone 40 mg once weekly. Stepwise dose reductions in each medication were allowed for toxicity.

Seven patients have been enrolled, of which six are evaluable for response at this time. The median age of the patients was 65 years (range 57–74) and the median number of organ systems involved was 3 (range 1–4). Four patients had cardiac involvement and 6 had renal involvement. Four patients had received no previous therapy, one had been treated with pulse dexamethasone, and two had relapsed after HDM/SCT and progressed on lenalidomide + dexamethasone. The mean number of cycles received was 3 (range,1–6); a total of 24 cycles have been administered. Four out of 6 evaluable patients had a partial hematologic response according to consensus criteria. Two previously treated patients had stable disease. One patient died of progressive disease before cycle 1 was completed. Several toxicities were noted: grade 3 neutropenia occurred in two patients; grade 3 thrombocytopenia in one patient; and grade 1 or 2 anemia in all. Three patients had a grade 2 or 3 increase in serum creatinine level, two patients had grade 2 or 3 hyperuricemia, and 4 of 6 patients had other metabolic toxicities including hyperglycemia, hypomagnesemia, and hypo- or hyperkalemia. Four out of six patients required dose reductions in lenalidomide, 2 out of 6 required reductions of dexamethasone, and 1 required reduction in melphalan dose.

MLD is an active combination of drugs for the treatment of AL amyloidosis, particularly in patients who have not been pretreated with lenalidomide or melphalan. Hematologic and metabolic toxicities were significant. This regimen appears to warrant further study in the context of clinical trials, possibly in randomized comparison to two drug regimens in the future.

Off Label Use: lenalidomide. melphalan and dexamethasone for treatment of AL amyloidosis.