For the full protocol for this study see http://www.ecog.org/cite/E4A03DOC.html
Fast track — ArticlesLenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial
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
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
References (28)
- et al.
Multiple myeloma
Blood
(2008) - et al.
A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma
Blood
(2006) - et al.
Primary dexamethasone treatment of multiple myeloma
Blood
(1992) - et al.
Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma
Blood
(2005) - et al.
Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy
Blood
(2006) - et al.
Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma
Blood
(2005) - et al.
Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma
Mayo Clin Proc
(2007) - et al.
Impact of risk stratification on outcome among patients with multiple myeloma receiving initial therapy with lenalidomide and dexamethasone
Blood
(2009) - et al.
A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome
N Engl J Med
(1996) - et al.
High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma
N Engl J Med
(2003)