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Fall 1999 Volume 3, Issue 6:
Myeloma Today Profile
J. Anthony Child, M.D.
Myeloma Today: What made you want to specialise in haematology and when did you develop an interest in myeloma?

Dr. Child: My interest in haematology was kindled as a medical student at Guy’s Hospital in London about 40 years ago. I was particularly impressed by the close links between the laboratory and clinical practice. In those days, students did blood counts and made slides to look at blood under a microscope and I remember confidently diagnosing Addisonian pernicious anaemia (vitamin B12 deficiency) in one patient and multiple myeloma in another! After being awarded the haematology prize and a travelling scholarship to Hong Kong, my career pathway in haematology was determined. I maintained a strong interest in myeloma which was further stimulated by working with Prof. Jim Malpas at St. Bartholomew’s Hospital and going down to the Royal Marsden Hospital outside London to join Prof. Tim McElwain’s brain storming sessions on myeloma, known to colleagues as a “circus” because of Tim’s free flowing search for solutions for a cure for myeloma. Just before I moved to the General Infirmary at Leeds in 1974, I had become interested in the bone changes that occur in myeloma and in particular the problem of hypercalcaemia. In collaboration with Prof. Nordin in the Medical Research Council (MRC) Mineral Metabolism Unit in Leeds, we carried out studies of the blood calcium lowering drug mithromycin (this was before bisphosphonates became available) and the effects of vigorous rehydration schedules. Another happy chance was the fact that Teddy Cooper was already well established as Professor of Cancer Research in the University of Leeds. He had a research program on tumour markers and the biochemical indicators of disease activity. One potential marker of interest to us was beta 2 microglobulin (ß2m). This molecule forms part of the HLA antigens. It is not a specific marker for myeloma but we found that serum ß2m was a stronger indicator of prognosis in myeloma than any of the previously adopted criteria. Our initial studies in relatively small number of patients (mirrored by very similar investigations in France) required confirmation in larger numbers of patients, as could be obtained by linkage to the national UK trials under the auspices of MRC Trials. The collaboration which stemmed from this and which involved other myeloma researchers, notably Ian MacLennan, continues up to the present time.

MT: Please tell us about your interest in clinical trials, particularly the MRC studies?

Dr. Child: In order to ensure that our treatment approaches in myeloma are appropriate and effective, it is necessary to subject them to critical analysis and review. The experience of the individual clinician in treating the disease is certainly of importance, but the therapeutic options in a given situation need to be guided by the collective data. Similarly the pilot work undertaken by centres pioneering new forms of treatment has to be analysed critically and then, when appropriate, subjected to multicentre trials of adequate size to determine whether or not the new approach confers a statistically proven advantage to patients in terms of objective response and ultimately survival. The MRC has had a seminal influence in designing and carrying out large scale trials. A more recent initiative has been to carry out international overviews based on analysis of the data from the major trials worldwide in order to confirm trends and guide clinical practice. Overviews on trials of standard melphalan and prednisolone versus combination chemo-therapy and of a-interferon have been carried out by the Clinical Trial Service Unit in Oxford on behalf of The Myeloma Trialists' Collaborative Group, which has wide international representation. As a clinician concerned with treating patients with myeloma I became involved with the MRC trials as a participant from the mid 1970's. In the early trials the importance of a high fluid intake in preventing or reversing kidney dysfunction was established – the basis for guidelines which were generally adopted in the UK. In a succession of randomised trials, the most 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. A key aspect of the current MRC Myeloma VII Trial is to try to assess whether the more intensive approach to treatment, involving giving high doses of the well established drug melphalan with supporting autologous transplant confers a survival benefit in comparison with the “standard” less intensive treatment. An important aspect is to systematically assess the gain in terms of the quality of life and also to determine whether or not the more complete eradication of tumour is of particular relevance.

MT: What developments are taking place in your centre?

Dr. Child: One of our “claims to fame” in Leeds is HMDS (Haematological Malignan-cy Diagnostic Service). We receive pathological samples from a wide geographical area for central review. This underpins our clinical role in assessing patients in the centre, advising on treatment strategies and providing some specific forms of treatment such as transplants. This is in tune with the national “Calman initiatives” for the organisation of cancer services in the UK. Key areas of our research program have grown as a consequence of this role in diagnosis and monitoring. We are fortunate in having drawn together a strong team over the last few years. With Dr Andrew Jack developing HMDS and Professor Gareth Morgan and myself directing a clinically-orientated research program and with some excellent young researchers in the team, we have the basis for making significant contributions. In addition to monitoring the blood and marrow changes in patients treated in the MRC Myeloma VII Trial, we plan to continue to expand our work in myeloma. We are keen to explore those factors which modulate the behaviour of the myeloma cell after treatment to find out why relapse occurs and how to inhibit disease progression.

MT: What are your current research interests, either linked to trials or outwith that setting?

Dr. Child: The “add-on” studies linked to the MRC Myeloma VII Trial represent an important aspect of the laboratory research which we are currently undertaking in Leeds. Using molecular techniques we are assessing the often very low levels of myeloma still present after treatment and monitoring any changes in that status. Identifying cells belonging to the myeloma clone as opposed to the non-malignant plasma cells is now possible and identifying these cells at various stages of the disease before and after treatment is providing valuable information which will help us to find out more about how the disease evolves and the way in which it recurs following treatment. The study of molecules on the surface of the myeloma cell can provide potentially important information about how the cell will behave and, therefore, have prognostic significance. We are also looking at genetic differences and gene mutations and the consequences of these. Though much of this work centres around studying established myeloma, we have also found genetically determined differences in some molecules (tumour necrosis cytokines) that influence the growth of myeloma cells which may actually predispose some individuals to the development of the disease. Like many others we were excited by the reports of the new herpes virus HHV-8 in myeloma bone marrow and the subsequent interest in the role of the dendritic cells. Obviously, everyone is hoping for new immunotherapy based on this, but at the moment much more basic information is required. I was, therefore, delighted when we were able to arrange for one of our promising young researchers, Faith Davies, to spend a year in Boston with Dr. Ken Anderson’s group working in this particular area. We await developments!

MT: What about the role of transplantation for myeloma? When is the best time to transplant and who are the candidates?

Dr. Child: Our ability to deliver intensive chemotherapy safely, now usually with supporting autologous peripheral blood stem cell transplant, has been something of a watershed. We still need much more information to fully evaluate the therapeutic gain for patients, hence the importance of large randomised trials such as those being carried out by the MRC. It is already clear that we have not yet developed curative treatment. However, the fact that we can achieve very low levels of disease is something that we can now build on. As our experience grows and data accumulate we may be able to become more precise as to whether and when to offer this treatment to the individual patient. Although the safety margin has improved with experience, we must remember that these treatments are still quite an undertaking and that there is associated toxicity. Although we call these stem cell supported treatments "transplants", we should probably reserve this term for allogeneic procedures when bone marrow from a tissue identical donor is given. Allo-geneic transplantation is much more likely to be associated with serious toxicity and is currently not undertaken without very careful consideration and usually only in relatively young myeloma patients. In addition to clearance of myeloma cells with the associated intensive chemo/radiotherapy (as with an autograft), there is the additional probability of a significant “graft vs. myeloma” effect. In common with other groups around the world, we are now developing less intensive, less toxic approaches using donor stem cells (so called “mini-allografts”). These sort of approaches will undoubtedly be accompanied by further developments aimed at modulating the immune system and manipulating the biochemical networks which influence the survival of the myeloma cell.

MT: What is your opinion of the IMF?

Dr. Child: I have known about the IMF since shortly after its inception and was delighted to be invited to join its Scientific Advisory Board. The presence of the IMF in the UK with the establishment of the office in Edinburgh has resulted in increasing awareness of the disease and of developments in treatment. The series of seminars held in the UK have been very successful and I have heard very favourable comments from patients. Being able to access information early and keep in touch with “what’s going on” through the IMF is clearly much appreciated. Coincidentally, those of us researching and treating myeloma in the UK have been working to establish closer collaborative links – particularly in the formulation of trials of new agents and regimens. We have now formalised this with the setting up of the UK Myeloma Forum.

I see the Forum as a means of developing more synchronised research at various levels. Its deliberations will also be of key importance in planning the next major UK randomised trial, which I hope will be run in conjunction with the MRC. We should also be able to orchestrate a variety of pilot/phase II studies (including a bisphosphonate study and a phase II trial of thalidomide). The IMF has been very supportive of this initiative and I look forward to a continuing fruitful relationship.

MT: What type of research would you like to see the IMF support?

Dr. Child: It seems likely that we will be "advancing on many fronts" in the battle against myeloma and it would be a mistake to give priority to more fundamental laboratory science rather than closely clinically linked research or, indeed, vice-versa. What is important is the ability to support promising areas of work flexibly. Communication between groups and the encouragement of cross-fertilisation of ideas is also something which needs active encouragement. The growth in research funding provided by the IMF is very much to be welcomed. I would hope that it will be possible to support many more researchers, in some cases enabling them to spend time at other centres and with other groups. This may well involve time in another country. As the IMF spreads its wings, it would seem entirely appropriate to encourage international research fellowships. Susie Novis has often emphasised the need for a worldwide effort without frontiers in the fight against myeloma. I am sure that we now need to provide some tangible initiatives to promote this.

MT: When do you think patients will have access to curative treatment and what form is this likely to take?

Dr. Child: Despite the genuine improvements in a range of treatment which all adds up to better clinical management of the disease we still seem to be only inching forward. The volume of scientific data on the nature of the disease has hugely increased in just a few years, however, and I sense that we are on the verge of exciting developments. Even if truly curative treatment is some way off, it does seem a distinct possibility that we will soon be able to devise strategies to suppress disease progression after reducing the level of disease to an extremely low level. Many patients today would be happy to achieve something short of cure if they were able to enjoy a normal quality of life in the long term.

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