IMPROVED OVERALL SURVIVAL WITH AUTOLOGOUS TRANSPLANTATION VS CYCLOPHOSPHAMIDE-LENALIDOMIDE-DEXAMETHASONE IN NEWLY DIAGNOSED MYELOMA: A PHASE 3 TRIAL

Background

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves survival in multiple myeloma (MM) patients. The introduction of novel agents has challenged the role of ASCT at diagnosis.

Aims

We conducted a multicentre international randomized phase 3 trial to compare ASCT with conventional chemotherapy plus lenalidomide in patients ≤ 65 years with newly diagnosed MM. The primary endpoint was progression-free survival (PFS), the secondary endpoints included safety and overall survival (OS).

Methods

Eligible patients ≤ 65 years of age with newly diagnosed MM were enrolled. All patients received lenalidomide-dexamethasone induction (four 28-day cycles of lenalidomide 25 mg day 1–21 and low-dose dexamethasone 40 mg day 1, 8, 15, 22) followed by stem cell mobilization. Patients were randomized to receive consolidation with 2 cycles of MEL200-ASCT (melphalan 200 mg/m² with stem-cell support) or cyclophosphamide-lenalidomide-dexamethasone (CRD) [six 28-day cycles of cyclophosphamide (300 mg/m² day 1,  8, 15), dexamethasone (40 mg  days 1, 8, 15, 22) and lenalidomide (25 mg days 1–21)].

Results
Three-hundred and eighty-nine patients were enrolled in the trial. Patient characteristics were well balanced between MEL200-ASCT and CRD. After a median follow-up of 4 years, the median PFS was 42 months for MEL200-ASCT and 28 months for CRD (HR 0.67, 95% CI 0.48-0.93, P=0.014). The 4-year OS was 87% for MEL200-ASCT and 71% for CRD (HR 0.51, 95% CI 0.28-0.93, P=0.028). The advantage in PFS and OS for MEL200-ASCT vs CRD was noticed in most of the analysed subgroups.  The rate of grade 3-4 hematologic (84% vs 26%, P<0.001) and non-hematologic (39% vs 22%, P=0.008) adverse events (AEs) was higher in the MEL200-ASCT arm compared with the CRD arm. The main non-hematologic AEs were infections (19% with MEL200-ASCT vs 6% with CRD, P=0.004) and gastrointestinal AEs (20% with MEL200-ASCT vs 5% with CRD, P<0.001). Toxicities were however manageable. Despite the increase in grade 3-4 AEs with MEL200-ASCT, the rate of serious hematologic (0% vs 2%, P=0.49) and extra-hematologic AEs (7% vs 10%, P=0.393) was similar between MEL200-ASCT and CRD arms. No toxic deaths were reported in the MEL200-ASCT arm; 1 patient died of septic shock in the CRD arm. Four patients who went off protocol before consolidation developed a second primary malignancy (SPM): 1 renal cancer, 1 breast cancer, 1 squamous cell carcinoma, 1 gastrointestinal cancer. Eight patients randomized to MEL200-ASCT developed a SPM:  6 squamous cell carcinomas, 1 melanoma,  and 1 prostate cancer. Five patients randomized to CRD developed an SPM: 1 squamous cell carcinoma, 1 renal cancer, 1 breast cancer, 1 gastrointestinal cancer and 1 glioblastoma.

Summary

MEL200-ASCT significantly prolonged PFS and OS in comparison with CRD. No increase in serious AEs, toxic deaths, and SPMs were reported with MEL200-ASCT.

Keyword(s): Cyclophosphamide, Imids, Transplant, Young adult

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