Elsevier

The Lancet Oncology

Volume 11, Issue 1, January 2010, Pages 29-37
The Lancet Oncology

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Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial

https://doi.org/10.1016/S1470-2045(09)70284-0Get rights and content

Summary

Background

High-dose dexamethasone is a mainstay of therapy for multiple myeloma. We studied whether low-dose dexamethasone in combination with lenalidomide is non-inferior to and has lower toxicity than high-dose dexamethasone plus lenalidomide.

Methods

Patients with untreated symptomatic myeloma were randomly assigned in this open-label non-inferiority trial to lenalidomide 25 mg on days 1–21 plus dexamethasone 40 mg on days 1–4, 9–12, and 17–20 of a 28-day cycle (high dose), or lenalidomide given on the same schedule with dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle (low dose). After four cycles, patients could discontinue therapy to pursue stem-cell transplantation or continue treatment until disease progression. The primary endpoint was response rate after four cycles assessed with European Group for Blood and Bone Marrow Transplant criteria. The non-inferiority margin was an absolute difference of 15% in response rate. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00098475.

Findings

445 patients were randomly assigned: 223 to high-dose and 222 to low-dose regimens. 169 (79%) of 214 patients receiving high-dose therapy and 142 (68%) of 205 patients on low-dose therapy had complete or partial response within four cycles (odds ratio 1·75, 80% CI 1·30–2·32; p=0·008). However, at the second interim analysis at 1 year, overall survival was 96% (95% CI 94–99) in the low-dose dexamethasone group compared with 87% (82–92) in the high-dose group (p=0·0002). As a result, the trial was stopped and patients on high-dose therapy were crossed over to low-dose therapy. 117 patients (52%) on the high-dose regimen had grade three or worse toxic effects in the first 4 months, compared with 76 (35%) of the 220 on the low-dose regimen for whom toxicity data were available (p=0·0001), 12 of 222 on high dose and one of 220 on low-dose dexamethasone died in the first 4 months (p=0·003). The three most common grade three or higher toxicities were deep-vein thrombosis, 57 (26%) of 223 versus 27 (12%) of 220 (p=0·0003); infections including pneumonia, 35 (16%) of 223 versus 20 (9%) of 220 (p=0·04), and fatigue 33 (15%) of 223 versus 20 (9%) of 220 (p=0·08), respectively.

Interpretation

Lenalidomide plus low-dose dexamethasone is associated with better short-term overall survival and with lower toxicity than lenalidomide plus high-dose dexamethasone in patients with newly diagnosed myeloma.

Funding

National Cancer Institute, Rockville, MD, USA.

Introduction

For over three decades, the mainstay of therapy for multiple myeloma was melphalan and prednisone.1 Autologous stem-cell transplantation (ASCT) later prolonged survival compared with conventional chemotherapy.2, 3, 4 More recently, thalidomide,5 bortezomib,6 and lenalidomide7 have emerged as effective therapies.

High-dose dexamethasone was first used in combination with infusional vincristine and doxorubicin for the treatment of refractory myeloma.8 Later, it was incorporated alone or in combination into various pre-transplant induction regimens for the treatment of newly diagnosed disease.9, 10, 11 Although effective, regimens containing high-dose dexamethasone are associated with significant toxicity10, 12, 13 and a treatment-related early mortality rate of over 10% in some randomised trials.10, 12

Lenalidomide is an analogue of thalidomide that has significant clinical activity in relapsed or refractory myeloma.14, 15 In a phase 2 trial, lenalidomide plus standard high-dose pulse dexamethasone showed high response rates (91%) with lower toxicity than previously seen with thalidomide plus dexamethasone in patients with newly diagnosed myeloma.16 Preliminary results of a randomised trial showed the superiority of lenalidomide plus high-dose dexamethasone compared with dexamethasone alone in newly diagnosed myeloma.17 The purpose of this trial was to test the hypothesis that the efficacy of lenalidomide plus high-dose dexamethasone could be preserved, but toxicity reduced, with a lower dexamethasone dose.

Section snippets

Patients

For the full protocol for this study see http://www.ecog.org/cite/E4A03DOC.html

Patients were eligible if they had previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥10% plasma cells or sheets of plasma cells) or a biopsy proven plasmacytoma, and measurable disease defined as serum monoclonal protein of more than 10 g/L or urine monoclonal protein of 0·2 g per day or more. Patients had to have haemoglobin of more than 70 g/L, platelet count of 75×109 per litre

Results

445 patients were accrued (table 1); 223 were randomly assigned to receive lenalidomide plus high-dose dexamethasone and 222 to receive lenalidomide plus low-dose dexamethasone. 149 patients (67%) in the high-dose group had bone disease at baseline compared with 127 (57%) of 222 in the low-dose group. 422 patients were eligible for analysis (figure 1). As of December, 2008, 404 (91%) of 445 patients are off study.

Median duration of therapy was 4 months (95% CI 3·7–4·7) in the high-dose group

Discussion

Despite high response rates, the use of high-dose dexamethasone did not result in superior time to progression, progression-free survival, or overall survival compared with low-dose dexamethasone in newly diagnosed myeloma. Overall survival at 1 year was significantly better with low-dose than with high-dose dexamethasone, resulting in early closure of the study and crossover to low-dose dexamethasone. The lack of correlation between response and overall survival has been previously reported in

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