Melphalan, Lenalidomide and Dexamethasone Combination Therapy In Patients with AL Amyloidosis

Abstract 2924

Melphalan and dexamethasone treatment offers hematologic response, organ response and improved survival in subjects with AL Amyloidosis. In view of promising results of lenalidomide and dexamethasone in the treatment of AL amyloidosis, we developed a phase II clinical trial evaluating the combination of lenalidomide, melphalan and dexamethasone in the treatment of AL amyloidosis (ClinicalTrials.govIdentifier: NCT00679367). The primary objectives of this trial were the safety and tolerability of this combination and the hematologic response rate. The secondary objectives were to assess clinical and organ responses. Eligibility criteria for enrollment in the trial required evidence of tissue diagnosis of amyloidosis with an associated underlying plasma cell dyscrasia and adequate measures of hematologic parameters and performance status. The treatment protocol consisted of melphalan 5mg/m² D1-4, lenalidomide 10mg D1-21 and dexamethasone 20–40mg D1, 8, 15, 22 every 28 days for a total of 12 cycles. All subjects were given aspirin to minimize thrombotic risk associated with lenalidomide and a proton pump inhibitor to minimize gastropathy associated with steroid use. Dose modifications were prompted by either CTCAE v3.0 grade 3 or 4 toxicities and performed in a stepwise fashion. Hematologic responses were measured at 3, 6, and 9 months and at the completion of 12 cycles of protocol-directed treatment. Hematologic and organ responses were defined as per consensus criteria. Sixteen subjects with AL amyloidosis were enrolled from 2008–2011 of which 14 are evaluable for assessment of hematologic response. The median age was 70 years (range 57–84) and M: F ratio was 3 :5. The median number of organs involved was 2 (range, 1–5). There were 11 subjects (69%) with cardiac, 9 subjects (44%) with renal and 4 (25%) with hepatic involvement with AL amyloidosis. Of the subjects with cardiac involvement, 9 subjects (81%) had cardiac stage II or III biomarker stages. The median time from diagnosis to enrollment in the clinical trial was 5 months (range, 1–60). Five subjects (31%) had received prior therapies. The median number of cycles received was 5 (range, 1–12). Grade 3 and 4 toxicities were experienced by 65% (n=10) of which 60% had hematologic and 70% had non-hematologic toxicities. Thirty-eight % of the subjects experienced grade 3 and 4 neutropenia and 19% experienced grade 3 fatigue. Dose reductions occurred in 85% (n=12/14) subjects. Dose reductions in dexamethasone occurred at a mean of 2 cycles and lenalidomide at a mean of 3 cycles. Majority of subjects (79%, n=11/14) required dose reduction of lenalidomide and 50% (n=7/14) required dose reductions of both lenalidomide and dexamethasone. Hematologic partial responses were achieved by 50% (n=7/14), however, there were no hematologic complete responses. All hematologic responses occurred within 3 months after initiation of protocol-directed treatment. Two (13%) subjects died while receiving protocol-directed treatment due to disease progression. Eleven subjects (69%, n=11/16) are alive at a median follow-up of 23 months. In conclusion, the combination of melphalan, lenalidomide and dexamethasone is associated with significant toxicities, most notably myelosuppression and fatigue, requiring frequent dose modifications; however it leads to partial hematologic responses in AL amyloidosis.