Elsevier

The Lancet Oncology

Volume 16, Issue 16, December 2015, Pages 1617-1629
The Lancet Oncology

Articles
Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial

https://doi.org/10.1016/S1470-2045(15)00389-7Get rights and content

Summary

Background

High-dose melphalan plus autologous stem-cell transplantation (ASCT) is the standard approach in transplant-eligible patients with newly diagnosed myeloma. Our aims were to compare consolidation with high-dose melphalan plus ASCT versus chemotherapy (cyclophosphamide and dexamethasone) plus lenalidomide, and maintenance with lenalidomide plus prednisone versus lenalidomide alone.

Methods

We did an open-label, randomised, multicentre, phase 3 study at 59 centres in Australia, Czech Republic, and Italy. We enrolled transplant-eligible patients with newly diagnosed myeloma aged 65 years or younger. Patients received a common induction with four 28-day cycles of lenalidomide (25 mg, days 1–21) and dexamethasone (40 mg, days 1, 8, 15, and 22) and subsequent chemotherapy with cyclophosphamide (3 g/m2) followed by granulocyte colony-stimulating factor for stem-cell mobilisation and collection. Using a 2 × 2 partial factorial design, we randomised patients to consolidation with either chemotherapy plus lenalidomide (six cycles of cyclophosphamide [300 mg/m2, days 1, 8, and 15], dexamethasone [40 mg, days 1, 8, 15, and 22], and lenalidomide [25 mg, days 1–21]) or two courses of high-dose melphalan (200 mg/m2) and ASCT. We also randomised patients to maintenance with lenalidomide (10 mg, days 1–21) plus prednisone (50 mg, every other day) or lenalidomide alone. A simple randomisation sequence was used to assign patients at enrolment into one of the four groups (1:1:1:1 ratio), but the treatment allocation was disclosed only when the patient reached the end of the induction and confirmed their eligibility for consolidation. Both the patient and the treating clinician did not know the consolidation and maintenance arm until that time. The primary endpoint was progression-free survival assessed by intention-to-treat. The trial is ongoing and some patients are still receiving maintenance. This study is registered at ClinicalTrials.gov, number NCT01091831.

Findings

389 patients were enrolled between July 6, 2009, and May 6, 2011, with 256 eligible for consolidation (127 high-dose melphalan and ASCT and 129 chemotherapy plus lenalidomide) and 223 eligible for maintenance (117 lenalidomide plus prednisone and 106 lenalidomide alone). Median follow-up was 52·0 months (IQR 30·4–57·6). Progression-free survival during consolidation was significantly shorter with chemotherapy plus lenalidomide compared with high-dose melphalan and ASCT (median 28·6 months [95% CI 20·6–36·7] vs 43·3 months [33·2–52·2]; hazard ratio [HR] for the first 24 months 2·51, 95% CI 1·60–3·94; p<0·0001). Progression-free survival did not differ between maintenance treatments (median 37·5 months [95% CI 27·8–not evaluable] with lenalidomide plus prednisone vs 28·5 months [22·5–46·5] with lenalidomide alone; HR 0·84, 95% CI 0·59–1·20; p=0·34). Fewer grade 3 or 4 adverse events were recorded with chemotherapy plus lenalidomide than with high-dose melphalan and ASCT; the most frequent were haematological (34 [26%] of 129 patients vs 107 [84%] of 127 patients), gastrointestinal (six [5%] vs 25 [20%]), and infection (seven [5%] vs 24 [19%]). Haematological serious adverse events were reported in two (2%) patients assigned chemotherapy plus lenalidomide and no patients allocated high-dose melphalan and ASCT. Non-haematological serious adverse events were reported in 13 (10%) patients assigned chemotherapy plus lenalidomide and nine (7%) allocated high-dose melphalan and ASCT. During maintenance, adverse events did not differ between groups. The most frequent grade 3 or 4 adverse events were neutropenia (nine [8%] of 117 patients assigned lenalidomide plus prednisone vs 14 [13%] of 106 allocated lenalidomide alone), infection (eight [8%] vs five [5%]), and systemic toxicities (seven [6%] vs two [2%]). Non-haematological serious adverse events were reported in 13 (11%) patients assigned lenalidomide plus prednisone versus ten (9%) allocated lenalidomide alone. Four patients died because of adverse events, three from infections (two during induction and one during consolidation) and one because of cardiac toxic effects.

Interpretation

Consolidation with high-dose melphalan and ASCT remains the preferred option in transplant-eligible patients with multiple myeloma, despite a better toxicity profile with chemotherapy plus lenalidomide.

Funding

Celgene.

Introduction

High-dose therapy with autologous stem-cell transplantation (ASCT) prolongs progression-free survival and overall survival compared with conventional chemotherapy in patients with newly diagnosed multiple myeloma, and this strategy is currently the standard of care for patients eligible for high-dose chemotherapy aged 65 years or younger.1, 2, 3 Immunomodulatory drugs (eg, thalidomide and lenalidomide) and proteasome inhibitors (eg, bortezomib) significantly improved survival in transplant-eligible and transplant-ineligible patients.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 In view of reported survival in transplant-ineligible patients and the substantial toxic effects recorded with high-dose melphalan (200 mg/m2 dose), the role of ASCT has become an area of debate, and comparison with less toxic, oral, novel agents is a research priority. The combination of cyclophosphamide, lenalidomide, and dexamethasone led to 85% of patients achieving a partial response, and had a good safety profile.16 To date, one study has compared high-dose melphalan plus ASCT with melphalan, prednisone, and lenalidomide, showing an improvement in progression-free survival and overall survival with high-dose melphalan and ASCT.17 Two other trials are ongoing to compare high-dose chemotherapy plus ASCT with bortezomib, melphalan, and prednisone and with bortezomib, lenalidomide, and dexamethasone (ClinicalTrials.gov: NCT01208766; and NCT01191060 and NCT01208662).

Immunomodulatory drugs and proteasome inhibitors have been used as part of maintenance strategies to extend progression-free and overall survival.18 In four randomised studies, lenalidomide maintenance significantly reduced the risk of progression (hazard ratio [HR] 0·34–0·50) by comparison with no maintenance, but the survival advantage was inconsistent.13, 14, 15, 17 A randomised trial showed a significant progression-free survival benefit in patients receiving maintenance with pharmacological (50 mg every other day) versus physiological doses of prednisone.19 Maintenance with thalidomide plus prednisone prolonged progression-free survival, with conflicting results for overall survival.20, 21

In this study, we aimed to compare the efficacy and safety of consolidation with chemotherapy (cyclophosphamide and dexamethasone) plus lenalidomide versus high-dose melphalan plus ASCT, followed by maintenance with lenalidomide plus prednisone versus lenalidomide alone, in patients with newly diagnosed multiple myeloma who were eligible for transplantation.

Section snippets

Study design and participants

We did a 2 × 2 partial factorial, randomised, open-label, phase 3 trial. We recruited patients from 59 centres in Australia, Czech Republic, and Italy (appendix pp 20, 21). Patients were eligible for study inclusion if they were aged 65 years or younger and had symptomatic, measurable, newly diagnosed multiple myeloma, defined according to standard criteria.22 Other inclusion criteria were: Karnofsky performance status of 60 or higher; life expectancy longer than 6 months; absolute neutrophil

Results

Between July 6, 2009, and May 6, 2011, 389 patients were enrolled to the study, of whom 387 entered the induction and mobilisation phase (figure 1). After the induction and mobilisation phase, the random assignment was disclosed for 256 patients who were eligible for consolidation; 129 patients were assigned chemotherapy (cyclophosphamide and dexamethasone) plus lenalidomide and 127 were assigned high-dose melphalan and ASCT. The main reason for discontinuation during the induction and

Discussion

In this randomised trial in patients with newly diagnosed multiple myeloma, consolidation with chemotherapy (cyclophosphamide and dexamethasone) plus lenalidomide significantly increased the risk of progression or death and shortened overall survival compared with high-dose melphalan and ASCT. With the present follow-up, maintenance with lenalidomide plus prednisone did not significantly improve progression-free survival or overall survival compared with lenalidomide alone. These results

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