Abstracts of Annual Education Meeting on 25-Nov-2002
The MRC Myeloma Trials
Dr Tony Child, Consultant Haematologist, The General Infirmary at Leeds
The Medical Research Council (MRC) myelomatosis therapy trials were initiated 38 years ago. Since that time the care of patients with the disease has improved appreciably and there are now more treatment options, some of which offer the prospect of better and longer remissions, if not cure.
In the early trials no significant difference in overall survival for patients treated with melphalan or cyclophosphamide alone or in various combinations with prednisolone and/or vincristine could be demonstrated. Melphalan remained the principal drug of choice.
The most important message to emerge from the early trials was that, although the mechanisms underlying renal dysfunction were complex, the relatively simple approach of instituting a regimen of high fluid intake could reverse renal failure in many patients, despite persisting proximal tubular dysfunction and light chain excretion. Pre-treatment hydration became a standard requirement and was adopted by many groups and centres world-wide.
Because large numbers of patients were entered into the trials, it was also possible to obtain valuable data about fundamental aspects of multiple myeloma, including biochemical features of disease. It was shown, for example, that the level of beta-2-microglobulin (β2m) in the blood was a more powerful indicator of prognosis than any of the previously measured parameters.
The emerging chemotherapy agents active in other haematological malignancies did not appear to be very effective in multiple myeloma but following the introduction of an anthracycline (Adriamycin) and a nitrosourea (BCNU) in a preliminary trial, a major trial of combination chemotherapy which also incorporated cyclophosphamide and melphalan (ABCM) versus melphalan alone was initiated (Myeloma V). The median survival of 314 patients randomised to receive ABCM was significantly longer than that of the 316 patients given melphalan alone (32 v 24 months).
In the course of a succession of randomised trials, the more effective treatment from the previous trial has been tested against the newer approach - a logical progression, which has seen the evolution towards the newer, more intensive, forms of treatment. In the recent MRC Myeloma VII trial, applicable to patients under 65 years of age, the "standard" drug combination, ABCM, was compared with a more intensive approach which included high dose melphalan with the support of autologous bone marrow or peripheral blood stem cell transplant. In 401 evaluable patients there was a significantly better remission rate in patients given the more intensive treatment and there was a median survival benefit of about one year (54 v 42 months). Refining and improving the simpler standard treatment was the objective of the MRC Myeloma VIII for patients aged 65 years or more. Early analysis suggests that after initial treatment with ABCM, cyclophosphamide alone (C weekly) is as effective as ABCM.
There have been a number of linked therapy studies carried out in parallel with the main therapeutic trials, for example of alpha(α) interferon and of the bisphosphonate sodium clodronate. Bisphosphonates have a role in controlling the bone destruction which is responsible for the pain and fractures which so often occur in the course of the disease and data from the MRC trials supported the long term administration of clodronate.
Improving the rates and depth of remission will, it is to be hoped, lead to improved survival. But of considerable importance is the issue of quality of life. The MRC studies have highlighted the need to take account of the quality of life following treatment in defining recommended strategies for the overall care of patients with myeloma and a newly devised quality of life assessment was carried out in conjunction with MRC Myeloma VII.
Next year, in close collaboration with the UK Myeloma Forum, the most ambitious and challenging MRC Myeloma Trial to date (Myeloma IX) will be initiated. The key effective treatment tested in the previous trial, namely high dose melphalan with autograft, will be the "core" of a framework for therapy for younger, fitter patients. The possibility that a thalidomide-containing oral regimen CTD (which also includes dexamethasone and cyclophosphamide) may be as effective as standard infusional chemotherapy will be investigated. Patients with potential HLA-matched sibling donors will be offered a mini-allogeneic transplant as an additional treatment. Thalidomide at low dosage will also be tested as maintenance therapy. In older, less fit patients the conventional dose melphalan plus prednisolone will be tested against the thalidomide containing combination and low dose thalidomide will again be assessed as a means of maintaining remissions. Several important scientific studies, including those aimed at the better definition of genetic prognostic factors, will be linked to Myeloma IX.
The MRC trials represent a multicentre collaboration with very wide involvement in the UK whereby carefully developed treatment approaches can be evaluated with detailed treatment protocols and data monitoring and analysis of the highest quality. Their contribution to the care of myeloma patients has been considerable and the new studies are being developed with a good deal of optimism about the prospects for further advances.