Lenalidomide in Combination with Melphalan and Dexamethasone in Patients with Newly-Diagnosed Light-Chain (AL)-Amyloidosis: a Multicenter Phase I/II Dose Escalation Study.

The combination of melphalan and dexamethasone (M-dex) is widely used in patients with newly diagnosed AL-amyloidosis, with hematologic and organ response rates of 50 and 40%, respectively (Jaccard, New Engl J Med 2007). Lenalidomide has also been evaluated, mainly in the relapse setting, and the initial dose of 25 mg/day was poorly tolerated. However, a 15 mg/day dose regimen was well tolerated and effective, with both hematologic and organ responses (Dispenzieri, Blood 2007 & Sanchorawala, Blood 2007). Combining M-dex with lenalidomide could increase the response rate but the toxicity of this regimen is still unknown. Thus we have initiated a multicenter single-arm open-label phase I/II dose escalation study of lenalidomide administered in combination with M-dex.

The primary endpoint was the incidence of dose limiting toxicities (DLT) during the first cycle of lenalidomide at a given dose level in order to determine the maximum tolerated dose (MTD). In addition to melphalan 0.18mg/kg/day from day 1-4 of each 28 day cycle and dexamethasone 40mg/day from day 1- 4 of each 28 day cycle, patients were successively exposed to escalating doses of lenalidomide (5, 10, 15 and 20 mg once daily on days 1–21 of a 28 day cycle). Nine cycles were planned at each dose level, according to safety and efficacy. DLT was defined using National Cancer Institute common toxicity criteria during the first 4 weeks of treatment (one cycle) as the following: at least grade 2 cardiac arrhythmia, at least grade 3 non hematologic toxicity, grade 4 neutropenia lasting >7 days or any other Grade 4 hematologic toxicity, or treatment delay due to toxicity that occurred during the first cycle. Organ involvement and the response to therapy were evaluated according to the international consensus guidelines (Gertz Am J Hem 2005).

From 03/2008 to 01/2009, 27 patients were enrolled. 1 patient withdrew consent after the first month of therapy and was thereafter lost to follow-up. No DLT was observed among the patients treated at 5 (3 patients), 10 (4 patients) and 15 mg lenalidomide/day (13 patients). 2 / 6 patients treated in cohort 4 at the dose of 20 mg lenalidomide/day experienced DLT, grade 4 hematologic toxicity and treatment delay due to toxicity; thus 15 mg lenalidomide/day, in combination with M-dex, was considered as the MTD. With a median follow-up of 12 months (7-17), 20/26 patients (77%) are alive. Six deaths were observed, due to progressive disease in 5 cases (median time from diagnosis 1 month, 1 to 3), or cholangiocarcinoma in 1 case (7 months after the diagnosis of AL-amyloidosis). Hematologic and organ responses were observed in 68 and 50% of the cases, respectively. At the reference date of Aug15th, 2009 none of the responding patients experienced progression, and all were able to receive 9 cycles according to the protocol.Conclusion: The recommended dose of lenalidomide in combination with M-dex in subjects with AL-amyloidosis previously untreated is 15 mg/day (days 1-21 of a 28 day cycle). Response and survival rates compare favourably with those achieved with M-dex alone. A prospective phase III trial comparing M-dex with M-dex lenalidomide should be valuable.

Moreau:celgene: Speakers Bureau. Off Label Use: lenalidomide in combination with melphalan and dexamethasone in patients with AL-amyloidosis. Jaccard:celgene: Speakers Bureau. Salles:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Alakl:Celgene: Employment. Harousseau:celgene: Speakers Bureau. Fermand:celgene: Speakers Bureau.