High-dose therapy with autologous stem-cell rescue is an effective first-line treatment for patients with multiple myeloma who are younger than 65 years of age.

Purpose: Medical Research Council (MRC) Myeloma IX was a phase III trial evaluating bisphosphonate and thalidomide-based therapy for newly diagnosed multiple myeloma. Results were reported previously after a median follow-up of 3.7 years (current controlled trials number: ISRCTN68454111). Survival outcomes were reanalyzed after an extended follow-up (median, 5.9 years).Experimental Design: At first randomization, patients (N ¼ 1,970) were assigned to bisphosphonate (clodronic acid or zoledronic acid) and induction therapies [cyclophosphamide-vincristine-doxorubicindexamethasone (CVAD) or cyclophosphamide-thalidomide-dexamethasone (CTD) followed by highdose therapy plus autologous stem cell transplantation for younger/fitter patients (intensive pathway), and melphalan-prednisone (MP) or attenuated CTD (CTDa) for older/less fit patients (nonintensive pathway)]. At second randomization, patients were assigned to thalidomide maintenance therapy or no maintenance. Interphase FISH (iFISH) was used to analyze cytogenics.Results: Zoledronic acid significantly improved progression-free survival (PFS; HR, 0.89; P ¼ 0.02) and overall survival (OS; HR, 0.86; P ¼ 0.01) compared with clodronic acid. In the intensive pathway, CTD showed noninferior PFS and OS compared with CVAD, with a trend toward improved OS in patients with favorable cytogenics (P ¼ 0.068). In the nonintensive pathway, CTDa significantly improved PFS (HR, 0.81; P ¼ 0.007) compared with MP and there was an emergent survival benefit after 18 to 24 months. Thalidomide maintenance improved PFS (HR, 1.44; P < 0.0001) but not OS (HR, 0.96; P ¼ 0.70), and was associated with shorter OS in patients with adverse cytogenics (P ¼ 0.01).Conclusions: Long-term follow-up is essential to identify clinically meaningful treatment effects in myeloma subgroups based on cytogenetics.