High-dose busulfan-melphalan vs melphalan and reinforced VRD for newly diagnosed multiple myeloma: a phase 3 GEM trial.

In retrospective studies, autologous stem cell transplantation (ASCT) conditioning with intravenous busulfan and melphalan (BUMEL) led to longer progression-free survival (PFS) than melphalan alone (MEL200). We compared BUMEL vs. MEL200 outcomes in newly diagnosed multiple myeloma (NDMM) patients receiving intensified bortezomib, lenalidomide and dexamethasone (VRD) induction and consolidation therapy. The GEM12 phase III trial enrolled 458 patients (from 2013 to 2015) who were randomized to BUMEL (n=230) or MEL200 (n=228) conditioning after induction with six reinforced VRD cycles and followed by two similar VRD consolidation cycles. The primary endpoint was PFS, including subgroup analyses by International Staging System (ISS) stages and high-risk genetic abnormalities. Randomization used an open-label 2×2 factorial design and 1:1:1:1 allocation ratio to ensure the balance between the GEM12 and the subsequent phase III GEM14 maintenance trial. After 2 years of maintenance, the global 10⁻⁶ MRD-negative rate was 63%, (68% BUMEL vs. 58% MEL200; OR 1.51, P= 0.035). The PFS was not significantly better in the BUMEL vs. MEL200, even though it was almost 16 months longer (median PFS 89 vs. 73.1 months; HR 0.89, 95%CI, 0.70-1.14, P= 0.3). BUMEL showed benefits in ISS stages 2/3, t(14;16), and del(1p). In a combined subgroup jointly considering patients with ISS2/3 treated with BUMEL and patients with ISS1 treated with MEL200 the median PFS was 96 months (95%CI, 76-NE). No safety concerns emerged. After a median follow-up of 8.4 years, GEM2012 reported one of the longest PFS durations in NDMM patients, with BUMEL significantly favoring advanced ISS stages. The trial is registered at ClinicalTrials.gov (NCT01916252) and EudraCT (2012-005683-10).