The MRC Myeloma IX Trial: beneficial effects of thalidomide and zoledronic acid for newly diagnosed myeloma patients of all ages


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Walter Gregory1, Faith Davies2, Kim Cocks1, Sue Bell1, Alex Szubert1, Nuria NavarroCoy1, Mark Drayson3, Roger Owen4, Gordon Coo4, Fiona Ross5, Graham Jackson6, Sylvia Feyler7, John Ashcroft8, Gareth Morgan2
2The Institute of Cancer Research, Royal Marsden Hospital, London, UK,3University of Birmingham, UK,4St James’s University Hospital, Leeds, UK,5University of Southampton, UK,6University of Newcastle, UK,7Calderdale and Huddersfield NHS Trust, Huddersfield, UK,8Mid Yorkshire Hospitals NHS Trust, Wakefield, UK

Background

The MRC Myeloma IX trial evaluated the effect of thalidomide, during induction and maintenance, in newly diagnosed myeloma patients, and compared the bisphosphonate zoledronic acid (ZOL) with sodium clodronate (CLOD), in terms of survival and inhibiting bone changes

Method

Younger, fitter patients were randomized to CVAD (cyclophosphamide, vincristine, Adriamycin, dexamethasone) or CTD (cyclophosphamide, thalidomide, dexamethasone) at induction, followed by high-dose melphalan and autologous stem-cell transplant (Intensive pathway). Older, less fit patients were randomised to MP (melphalan, prednisolone) or reduced-dose CTD (Non-intensive pathway). Patients were also randomised at induction to ZOL or CLOD, plus a later thalidomide maintenance randomisation.

Results

1960 patients were evaluable, with a median follow-up of 3.7 years overall, 3.2 years from maintenance.  CTD resulted in better overall response rates than CVAD and MP, respectively. Data will be presented on how this translates into PFS and OS.

Maintenance thalidomide significantly improved PFS, with a 13% difference (95% CI 6%-20%) established by two years and maintained to 5½ years, logrank p=.0003, HR 1.36 (95% CI 1.15-1.61).  We show how this would have translated into an OS benefit if relapsed maintenance thalidomide patients subsequently retreated with thalidomide had instead received Velcade at relapse. Beneficial effects were predominantly seen in favourable FISH subgroups.

ZOL significantly reduced the risk of first SREs by 26% v CLOD (HR=0.74; 95%CI: 0.62, 0.87; P=.0004); prolonged median PFS (19.5 v 17.5 months; P<.05) and significantly increased OS (median of 50 v 44.5 months; P=.04) compared with CLOD, independent of the SRE effect (P=.04). Both bisphosphonates were well tolerated; osteonecrosis of the jaw was infrequent (ZOL, 3.6%; CLOD, 0.3%)

Conclusion

This trial demonstrates, for the first time, an OS benefit for zoledronic acid in myeloma, along with important benefits for thalidomide both at induction and maintenance. It highlights the prognostic importance of cytogenetic testing at diagnosis