Abstracts of Annual Education Meeting on 25-Nov-2002
The Future Of Myeloma Treatment
Jamie Cavenagh, Senior Lecturer (Hon. Consultant) in Haematology, St Bartholomew's, London
At present, for younger patients with myeloma, an accepted standard of care is induction with VAD or VAD-like chemotherapy consolidated by high dose melphalan with peripheral blood stem cell support. Although this approach is superior to conventional chemotherapy, the median overall survival following stem cell transplantation is only approximately five years. Thus, although this approach is effective, it is far from ideal. Strategies aimed at further intensifying chemotherapy, such as tandem transplantation, have been investigated but available results do not suggest that outcomes are significantly improved for most patients.
A central concept in myeloma is that disease pathogenesis is largely driven by the mutually stimulating interactions between myeloma plasma cells and bone marrow microenvironment. These interactions result in the release of cytokines such as IL-6 and VEGF that drive the malignant proliferation and prevent apoptosis. These biological processes present potential targets for therapy and a variety of such 'biological therapies' are under early investigation.
The paradigm for such biological approaches is the use of thalidomide in myeloma. This drug was first used in myeloma because of its known anti-angiogenesis effects. New blood vessel formation is critical for the growth of solid tumours and is also related to disease activity in myeloma (and other haematological malignancies). Although it is effective in a proportion of patients with myeloma, thalidomide has considerable side-effects. In order to avoid these, new specific anti-angiogenesis agents are now being studied, such as the novel agent SU6668.
Other biological strategies involve the use of agents that inhibit the cellular proteosome complex (eg PS-341). Such inhibition results in the stabilisation of the NF-kB transcription factor in its inactive form. This, in turn, results in the down regulation of IL-6 production, which is a critical growth factor for malignant plasma cells.
Another approach is to target Bcl-2 with Bcl-2 antisense. High Bcl-2 levels in myeloma cells result in a failure of normal programmed cell death (apoptosis) such that the tumour cells 'cannot die'. Inhibiting Bcl-2 may well result in tumour cell death with clinical response.
Further new approaches include the development of non-myeloablative allogeneic stem cell transplantation, the use of a variety of monoclonal antibodies and new agents to prevent myeloma bone disease. In summary, we are now witnessing the development of a range of new and promising agents in myeloma. Hopefully, these agents will have a significant impact on the disease and improve outcomes for patients with myeloma.