Lenalidomide and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma; Dosing of Lenalidomide According to Renal Function and Effect On Renal Impairment.

Abstract 3871

Poster Board III-807

Lenalidomide and dexamethasone (RD) is an active regimen for the management of relapsed and/or refractory multiple myeloma (MM). Over the last 2 years consecutive patients with pre-existing peripheral neuropathy grade ≥ 2 were treated with RD, regardless of their performance status and renal function. Patients with disease refractory to thalidomide, bortezomib and dexamethasone (i.e. progressive disease during treatment or within 60 days of treatment completion) were also included. Lenalidomide was administered on days 1 to 21 according to creatinine clearance (CrCl): 25 mg/day for CrCl >50 ml/min, 10mg/day for CrCl 30-50 ml/min, 15 mg every other day for CrCl 15-30 ml/min and for patients on dialysis, 15 mg three times per week on the day after dialysis. Dexamethasone was administered at a dose of 40mg PO on days 1 to 4 and 15 to 18 for the first 4 cycles and only on days 1 to 4 thereafter. RD was repeated every 28 days till disease progression or unacceptable toxicity. All patients received DVT prophylaxis with aspirin 100 mg/day unless there were already on coumadin or LMWH for pre-existing DVT or for other indications, usually atrial fibrillation. So far, 46 patients have been included and their characteristics were: median age was 69 years (range 43-87 years); median lines of prior therapy were 3 (range 1-6); prior treatment with thalidomide-containing regimens: 74% of patients (thalidomide-refractory: 68% of patients); prior treatment with bortezomib-containing regimens: 78% of patients (bortezomib-refractory: 56%); dexamethasone-refractory: 61% of patients; performance status ≥2: 33% of patients; LDH >300 IU/dl (normal value >225 IU/dl): 13% of patients; extramedullary involvement: 9% of patients; renal impairment (RI), defined as CrCl <50 ml/min: 28% of patients (range of CrCl: 13-49 ml/min). Thirty-six patients started with lenalidomide dose of 25mg/day and 10 patients with dose adjusted to renal function (10mg/day: 7 patients, 15mg every other day: 2 patients, 15 threetimes a week after dialysis: 1 patient). Response according to IMWG criteria include: CR: 17%, vgPR:5%, PR: 38%, SD: 22%, PD: 18% (PR or better: 60%). At least PR was observed in 43% of thalidomide-refractory patients, in 76% of bortezomib-refractory patients and in 20% of patients with high LDH. At least PR was documented in 60% of patients with RI and in 58% without RI. Median time to progression was 9 months and median overall survival was 16 months. Main toxicities include: neutropenia (grade 3/4): 26%; thrombocytopenia (grade 3/4): 11%; other toxicities (any grade): fatigue 50%, infections 28%, constipation 17%, diarrhea 15% and skin toxicity 11%. DVT prophylaxis with aspirin was administered to 39 patients (84%) and no patient developed DVT. Dose-reductions of lenalidomide were necessary in 46% of patients. There were no statistical differences in the incidence of adverse events in patients with normal or abnormal renal function. More specifically grade 3/4 thrombocytopenia and neutropenia occurred in 10% versus 11% (p=0.92) and 31% versus 10% (p=0.190) of patients with normal and abnormal renal function, respectively. The effect of treatment on RI reversal was also evaluated: 2 patients achieved complete renal response (i.e. baseline CrCl <50 ml/min improving to ≥60 ml/min) and 2 patients achieved minor renal response (baseline CrCl <15 ml/min improving to 15-29 ml/min or baseline CrCl 15-29 ml/min improving to 30-59 ml/min).Thus, in 4 of 10 patients with RI, treatment with RD resulted in improvement of renal function. We conclude that RD is an active treatment in patients with relapsed/refractory MM, even in patients with more heavily pretreated disease that those in the original report (Dimopoulos et al, N Engl J Med 2007;357:2123). RD is active in thalidomide and bortezomib refractory patients. With dosing of lenalidomide according to renal function, RD can be administered to patients with RI (who may not have other treatment options) without excessive toxicity. Furthermore, RD may improve the renal function in a subset of patients with RI.