Myeloma IX


Study aim: To compare 2nd and 3rd generation bisphosphonates, induction chemotherapy regimens and thalidomide maintenance in newly diagnosed multiple myeloma patients of all ages.

Study design: A phase III randomised open factorial trial, comprising an Intensive Pathway for younger/fitter patients where intensive high dose treatment with stem cell support is considered appropriate, and a Non-Intensive Pathway for older/less fit patients where standard dosed chemotherapy is considered appropriate.

Younger/fitter patients will be randomised to receive i) clodronate versus zoledronic acid, ii) CVAD versus CTD (both followed by high-dose melphalan and autograft) and iii) thalidomide maintenance versus no thalidomide. Younger/fitter patients with a tissue-compatible sibling will also be offered a mini-allogeneic transplant.

Older/less fit patients will be randomised to receive i) clodronate versus zoledronic acid, ii) MP versus CTDa and iii) thalidomide maintenance versus no thalidomide.

In optional sub-protocols, patients may be offered BD if they do not respond to induction chemotherapy, or at first relapse.

Objectives:
Primary – Intensive pathway
• To compare two induction regimens, CVAD (infusional) v CTD (oral)
• To assess low-intensity conditioning (LIC) allogeneic stem cell transplantation (‘mini-allograft’) following high-dose melphalan plus autograft in patients with donors available.
• To assess the response to BD in patients not responding to the randomised induction therapy.

Primary – Non-intensive pathway
• To compare two induction/consolidation regimens, MP v CTD attenuated (CTDa)

Secondary (both pathways)
• To compare two bisphosphonates, sodium clodronate (2nd generation) v zoledronic acid (3rd generation)
• To assess the value of giving low-dose thalidomide in maintenance (versus no treatment)
• To investigate quality of life in the short-term (during induction chemotherapy/bisphosphonate treatment) and in the long-term (during maintenance therapy)
• To determine the relevance of genetic/cytogenetic changes and define risk groups
• To determine the relevance of immunophenotypic changes and molecular evidence of residual disease
• To evaluate serum free light chain (flc) measurement as a prognostic factor and in monitoring disease
• To determine the relevance of biochemical markers of bone metabolism in monitoring disease.
• To determine the effect of cytogenetic group and prior treatment regimen on progression-free survival and response rate to BD at first relapse.

Endpoints:
Primary
• Overall survival
• Progression-free survival
• Response

Secondary
• Quality of life
• Skeletal-related events (bone fractures, radiation to bone, surgery to bone, spinal cord compression)
• Height loss
• Toxicity (thromboembolic events, renal toxicity, haematologic toxicity, graft versus host disease (GvHD))
• Proportion receiving BD as ‘early rescue’ on induction chemotherapy
• Proportion receiving BD at relapse

Number of centres: 141 (UK)

Number of patients:

Pathway Target Actual
Intensive Pathway 1080 1114
Non-Intensive Pathway 850 856
Maintenance 762 820

Useful links:
ISRCTN: http://www.controlled-trials.com/ISRCTN68454111/68454111
NIHR CRN Clinical Research Portfolio: http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=1176

Key: C: cyclophosphamide; T: thalidomide; D: dexamethasone; V: vincristine; A: Adriamycin; M: melphalan; P: prednisolone; B: bortezomib

Trial Status: Closed.  The relapse sub-protocol remains open to patients already randomised into the trial.

Chief Investigators:
Professor JA Child (University of Leeds)
Professor GJ Morgan (Royal Marsden Hospital, London)
Professor GH Jackson (Freeman Hospital, Newcastle)

Trial Contact:
Phil Best
Tel: 0113 343 8392
Email: p.best@leeds.ac.uk