Abstracts of Clinical Meeting on 12-July-2002
MRC Myeloma VII and VIII
Dr Tony Child, Consultant Haematologist, The General Infirmary at Leeds, Leeds LS1 3EX
I. MRC Myeloma VII
Background
This study compared patient survival in a prospective randomised phase III trial of two different therapeutic approaches in patients aged less than 65 years of age: ABCM to plateau with α-IFN maintenance versus a three-phase regimen of C-VAMP, high dose melphalan (with autologous stem cell support) and α-IFN maintenance.
Data analysis
The first in-depth analysis of response and survival data has been carried out. The primary endpoints were survival and progression-free survival. Secondary endpoints included response to treatment and quality of life assessments. Survival analysis was carried out with a median follow up of 41 months for survivors. There is improved survival in the intensive treatment group (median survival 54.8 months compared with 42.3 months in the standard treatment group, p=0.0398 log-rank test, p = 0.0302 Wilcoxon test). A presentation of the results of overall survival, progression-free survival analyses and including impact of β2-microglobulin levels on treatment effect and survival time. The results of the trial were presented at the MRC Adult Leukaemia Annual Review Meeting and will also be presented at the UKMF Clinical Meeting on July 12th.
II. MRC Myeloma VIII
Background
For patients presenting with multiple myeloma at the age of 65 years or over, the trial compares treatment with ABCM to plateau vs 3 courses ABCM then C weekly to plateau.
Observations in the Vth MRC myelomatosis trial and subsequent pilot studies indicate that changing to weekly cyclophosphamide after starting treatment with ABCM may be as effective as continuing to give ABCM until plateau is reached (Lancet, 1992 339: 200-205). The modified treatment: 1) Causes less marrow toxicity than either conventional melphalan regimens or ABCM. 2) Uses less adriamycin than continued ABCM and so is less cardiotoxic. 3) Improves treatment options after relapse from plateau. 4) The management of treatment is easier and less expensive than when ABCM is used until plateau. Given these advantages a result showing either equal or improved efficacy of ABCM followed by C weekly would be taken as an indication for using this modified regimen.
Data analysis
The trial opened for entry on 1 November 1993 and 594 patients have been registered into the study, the last in March 2002. The trial will be analysed when a minimum of one year of follow up is available on all patients randomised.
MRC Myeloma IX
Dr Tony Child. Consultant Haematologist, The General Infirmary at Leeds, LS1 3EX
Status: Awarded funding by MRC; for activation 2002
Background
The introduction of autologous stem cell-supported high dose therapy (HDT) for younger/fitter patients with myeloma has resulted in improved response rates with attainment of low levels of residual disease in the majority of patients so treated. MRC Myeloma VII provided crucial evidence in this respect and the basis for the now "standard" approach carried over to Myeloma IX. A major challenge now is to prolong such remissions, improving the prospects for the maintenance of a good quality of life (QoL) and long term survival.
There is also a need to optimise conventional dose therapy and prolong asymptomatic plateau phase. The rôles of thalidomide and newer bisphosphonates need to be investigated further and low intensity conditioning (LIC) allogeneic transplants, which offer the possibility of a therapeutic graft versus myeloma (GvM) effect, require systematic evaluation in larger numbers of patients. Finally the identification and better definition of key prognostic factors at presentation and following treatment is a prerequisite of delineating risk groups for more selective and innovative therapy in the future.
This trial will embody two main treatment pathways: intensive for younger/fitter patients, non-intensive for older/less fit patients. The two groups will be combined for two of the primary comparisons. This trial proposal was put forward with the support of both the MRC Adult Leukaemia Working Party and the UK Myeloma Forum after extensive soundings. It is estimated that 400 patients per year will be entered into the trial (180 younger/fitter; 220 older/less fit patients) with a target recruitment of 2000 over 5 years.
The Principal Areas for Clinical Investigation
- The rôle of thalidomide
- Oral versus infusional chemotherapy
- Third generation versus second generation bisphosphonate: zoledronate versus clodronate
- The rôle of low intensity chemotherapy conditioning allogeneic transplants
Linked Scientific Studies
Bolt-on research studies to be carried out in conjunction with the proposed trial will address the following questions:
- Can the sensitive measurement of malignant plasma load, using flow cytometry and PCR, be used to monitor disease activity and predict outcome? (Extension of bolt-on studies linked to MRC Myeloma VII)
- Is it possible to define high and low risk groups, using molecular cytogenetics, for which different treatment strategies could be developed? (Pilot study in progress funded by the Leukaemia Research Fund)
- What is the value of serum free light chain (flc) measurement as a prognostic factor and in monitoring disease?
- Other studies will include central investigation of serological response (linking with the above), assessment of serum antibody responses to specific vaccination antigens and biochemical measures of bone formation and resorption. Data generated from Myeloma IX will in due course contribute to the further development of a prognostic index.
The Proposed Trial
Patients will be randomised at diagnosis to clodronate or zoledronate and to the induction chemotherapy appropriate for age and performance status. Younger/fitter patients for whom HDT is planned will be randomised to either C-VAD or C-Thal-Dex (C-TD) and will then receive high dose melphalan (HDM) with autologous peripheral blood stem cell transplant (PBSCT). Patients with a tissue-compatible donor will be offered a sub-myeloablative LIC allograft (post-HDM + PBSCT). Older/less fit patients, for whom intensification treatment is not thought appropriate, will be randomised to receive either standard MP or C-Thal-Dex attenuated (C-TDa). Following HDT or the achievement of plateau, there will be a further randomisation to thalidomide or no thalidomide as maintenance therapy.
Randomisation will be through the NYCTRU (University of Leeds) which will serve as the coordinating centre.
Intensive pathway
Non-intensive pathway
Notes:
- Randomisation on day 1 for bisphosphonate and chemotherapy regimen
- 4-6 courses
- Minimum 6 months and then continued to plateau
- Post-consolidation therapy randomisation for maintenance thalidomide
Pilot Studies
In order to inform the process of producing the definitive protocol for Myeloma IX, a number of pilot studies are being carried out (in association with the UK Myeloma Forum) and data from other studies in the UK and USA has been made available.
Further details of the UKMF-associated studies which have been through MREC may be obtained from: Richard W. Jones, UKMF Administrator, Department of Haematology, Guy's Hospital, London SE1 9RT. Tel: 020 7955 2031.