Long-term follow-up of MRC Myeloma IX Trial: survival outcomes with bisphosphonate and thalidomide treatment

Morgan, Gareth J., Davies, Faith E., Gregory, Walter M., Bell, Susan E., Szubert, Alexander J., Cook, Gordon, Drayson, Mark T., Owen, Roger G., Ross, Fiona M., Jackson, Graham H. and Child, J. Anthony (2013) Long-term follow-up of MRC Myeloma IX Trial: survival outcomes with bisphosphonate and thalidomide treatment. Clinical Cancer Research, 19 (21), 6030-6038. (doi:10.1158/1078-0432.CCR-12-3211). (PMID:23995858)

Abstract

Purpose: 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 re-analyzed after an extended follow-up (median: 5.9 years).

Experimental design: At first randomization, patients (N = 1,970) were assigned to bisphosphonate (clodronic acid or zoledronic acid) and induction therapies (cyclophosphamide-vincristine-doxorubicin-dexamethasone [CVAD] or cyclophosphamide-thalidomide-dexamethasone [CTD] followed by high-dose 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 [non-intensive 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; hazard ratio [HR], 0.89; P = 0.02) and overall survival (OS; HR, 0.86; P = 0.01) compared with clodronic acid. In the intensive pathway, CTD demonstrated non-inferior PFS and OS compared with CVAD, with a trend toward improved OS in patients with favorable cytogenics (P = 0.068). In the non-intensive pathway, CTDa significantly improved PFS (HR, 0.81; P = 0.007) compared with MP and there was an emergent survival benefit after 18-24 months. Thalidomide maintenance improved PFS (HR, 1.44; P < 0.0001) but not OS (HR, 0.96; P = 0.70), and was associated with shorter OS in patients with adverse cytogenics (P = 0.01).

Conclusions: Long-term follow-up is essential to identify clinically meaningful treatment effects in myeloma subgroups based on cytogenetics.

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