Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in patients with newly diagnosed multiple myeloma on the ECOG-ACRIN E4A03 randomized clinical trial: long-term follow-up.

N Biran,N S Callander,S Jacobus,M E Williams,S V Rajkumar,P R Greipp,M S Katz,R Fonseca,R Abonour,D H Vesole,D S Siegel

doi:10.1038/bcj.2016.68

Abstract

In Eastern Cooperative Oncology Group-ACRIN E4A03, on completion of four cycles of therapy, newly diagnosed multiple myeloma patients had the option of proceeding to autologous peripheral blood stem cell transplant (ASCT) or continuing on their assigned therapy lenalidomide plus low-dose dexamethasone (Ld) or lenalidomide plus high-dose dexamethasone (LD). This landmark analysis compared the outcome of 431 patients surviving their first four cycles of therapy pursuing early ASCT to those continuing on their assigned therapy. Survival distributions were estimated using the Kaplan–Meier method and compared with log-rank test. Ninety patients (21%) opted for early ASCT. The 1-, 2-, 3-, 4- and 5-year survival probability estimates were higher for early ASCT versus no early ASCT at 99, 93, 91, 85 and 80% versus 94, 84, 75, 65 and 57%, respectively. The median overall survival (OS) in the early versus no early ASCT group was not reached (NR) versus 5.78 years. In patients <65 years of age, median OS in the early versus no early ASCT groups was NR in both, hazard ratio 0.79, 95% confidence interval: (0.50, 0.25). In patients ⩾65 years of age, median OS in the early versus no early ASCT was NR versus 5.11 years. ASCT dropped out of statistical significance (P=0.080). Patients opting for ASCT after induction Ld/LD had a higher survival probability and improvement in OS regardless of dexamethasone dose density.

Highlights

Number and characteristics of patients included in the landmark analysis (LM) analysis of therapy relative to the population not pursuing early autologous peripheral blood stem cell transplant (ASCT) and Of the 431 patients including in the LM analysis, 183 (42.5%)
Of the 341 patients who did not pursue early ASCT, 93 patients went off Patients enrolled on the Eastern Cooperative Oncology Group (ECOG)-ACRIN E4A03 randomized phase 3 clinical trial, the results of which have been previously published,[16] were included in the current analysis
The difference in survival probabilities between early ASCT and no early ASCT increased with each year of followup, with a doubling of the difference in the subset of patients aged 65 years or older between years 3 and 5

Summary

Introduction

High-dose chemotherapy and autologous peripheral blood stem cell transplant (ASCT) were demonstrated in large, randomized clinical trials, to improve progression-free survival (PFS) and overall survival (OS) compared with standard chemotherapy in patients with multiple myeloma (MM)[1,2] Other randomized trials demonstrated an improvement only in PFS with no significant OS benefit.[3,4] Because of the improved PFS resulting in prolonged time off treatment without symptoms with improved quality of life,[3,5] ASCT following induction therapy has become an integral part of treatment in patients with newly diagnosed MM (NDMM)and continues to be the recommended treatment for transplant eligible NDMM by the International Myeloma Working Group.[6]Over the last decade, immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) have led to a significant improvement in PFS, OS and response rates for patients with NDMM.[7,8,9] Because of the response rates, especially the depth of response to IMiDs and PIs, the role of ASCT in the upfront setting has become more controversial. In the subset of patients age o 65 years, the difference in survival probability between those who had early ASCT versus no early ASCT at 1, 2, 3, 4 and 5 years was 5, 6, 12, 16 and 15%, respectively.

Results

Conclusion