A Pilot Study of Melphalan, Lenalidomide and Dexamethasone In AL Amyloidosis: Interim Results

AL amyloidosis is a clonal disorder of light-chain secreting plasma cells. The light chains deposit as beta-pleated sheets, resulting in significant hematologic and organ toxicity. A recent randomized trial failed to demonstrate superiority of myeloablative melphalan followed by autologous stem cell infusion over the less toxic oral melphalan and high-dose dexamethasone regimen (Jaccard, New Engl J Med 2007). Furthermore, chemotherapeutic options now often include lenalidomide; however, this agent has had limited evaluation in combination with melphalan and dexamethasone and has been hampered by high rates of toxicity at doses of 25mg/day. To assess whether combination therapy at reduced doses would be tolerable and effective, we conducted a single center prospective clinical trial of an oral three drug regimen consisting of melphalan, lenalidomide and dexamethasone (MLD) in AL amyloidosis.

The primary endpoint is evaluation of the safety and tolerability of MLD in patients with AL amyloidosis. The secondary endpoint is evaluation of the hematologic response rate, the relevant organ responses and the time to progression. Enrolled patients had a biopsy-proven diagnosis of AL amyloidosis with the presence of measurable disease. Exclusion criteria included absolute neutrophil count < 1000 cells/mm³, platelets < 75,000/mm³, creatinine clearance < 15 ml/min, an ECOG performance status > 3, and potential future candidacy for autologous stem cell transplant. There were no exclusions based on patients’ cardiac function. Treatment consisted of a 28 day cycle of lenalidomide 10 mg days 1–21, melphalan 0.18 mg/kg days 1–4, and dexamethasone 40 mg weekly. Stepwise dose reductions were allowed for toxicity. Evaluation of hematologic response rate was via serum free kappa and lambda light chains and/or serum or urine immunofixation. Relevant organ responses were measured with 24-hour urine protein/serum creatinine for patients with renal amyloidosis, transthoracic echocardiogram, troponin-I and NT-BNP for patients with cardiac amyloidosis, and alkaline phosphatase for patients with hepatic amyloidosis. The trial has been expanded from the originally planned 15 patients to 25 patients given rapid enrollment; this report reflects an interim analysis of the first 12 patients.

Twelve patients have been enrolled. One patient died prior to initiation of therapy, and thus was excluded from further evaluation. The median age of the remaining 11 patients was 65 years (range of 62–84). The median number of organs involved was 2 (range of 1–4). Ten patients had cardiac involvement, 3 patients had renal involvement, and 2 patients had hepatic involvement. Nine of the 11 patients (82%) were newly diagnosed. The mean number of cycles was 3 (range of 1–9 with a total of 36 cycles). A complete hematologic response (CHR) was seen in 3 patients, a partial hematologic response (PHR) was seen in 4 patients, and 3 patients exhibited stable disease, according to consensus criteria (Gertz, Am J of Hem 2005). One patient died during the first cycle and thus response to treatment was not evaluable. Toxicities included: grade 4 neutropenia in 1 patient and grade 3 anemia, thrombocytopenia, and infection in 3 patients. Seven of the 11 patients have died, all of whom had cardiac amyloidosis, of progressive heart failure or arrhythmias. Of these 7 patients, 2 exhibited a CHR and 3 had a PHR. Of the 9 evaluable patients with cardiac amyloidosis, 2 patients exhibited stable cardiac disease, while the other 7 patients had disease progression, primarily via a rising NT-BNP and Troponin-I. Of the 3 patients with renal involvement, 2 had organ disease progression and 1 patient had stable disease, and of the 2 patients with hepatic involvement, 1 had organ disease progression and 1 had stable disease, according to consensus criteria (Gertz, Am J of Hem 2005).

In a patient cohort consisting primarily of newly diagnosed patients with advanced AL amyloidosis, MLD has promising complete and partial hematologic response rates. Hematologic and infectious toxicities remain significant even at reduced doses. Despite promising hematologic response rates, organ responses occur less frequently. Patients with cardiac amyloidosis, particularly those presenting with heart failure, continue to have poor overall prognosis. A larger trial is warranted to further assess drug toxicity and organ response rates.

Witteles:Celgene: Research Funding. Witteles:Celgene: Research Funding. Liedtke:Celgene: Lecture fee, Research Funding. Schrier:Celgene: Research Funding. Off Label Use: Melphalan and Lenalidomide as therapy for AL amyloidosis.