Thalidomide in Multiple Myeloma: current status and future prospects
Conclusions and future prospects
Thalidomide has significant activity both as a single agent and in combination with other therapies in patients with de novo and advanced myeloma. However, several major questions remain unanswered. Indeed, the optimal dose is still uncertain, as is its role in maintenance therapy following high dose melphalan. The potential benefit of combining thalidomide with dexamethasone as induction therapy for newly diagnosed patients with myeloma is being investigated by ECOG and results are awaited with considerable interest. Similarly, the combination of thalidomide with chemotherapy is still of uncertain benefit. All of these questions need to be addressed in prospective randomised clinical trials before recommendations about the precise role of thalidomide can be given.
Thalidomide has a significant side-effect profile but is tolerated by the majority of patients. A minority of patients need to terminate treatment due to the development of peripheral neuropathy. So long as both physician and patient are aware of this potential problem, the drug can be stopped before severe, irreversible damage occurs. There seems little requirement for routine repeated nerve conduction studies in this setting. VTE has emerged as the most troublesome adverse event associated with the drug, particularly when thalidomide is used in combination with chemotherapy and/or dexamethasone as primary therapy for newly diagnosed patients. It is hoped that combined clinical and laboratory research will elucidate the mechanisms that result in a prothrombotic state and better delineate effective prophylactic measures.
Despite the difficulties and uncertainties, the use of thalidomide is a major advance in the clinical management of myeloma. Indeed, thalidomide represents a new paradigm for therapy in that it works primarily as a 'biological' agent rather than as a conventional cytotoxic drug. A series of alternative new 'biological' agents also show promise in myeloma and include proteosome inhibitors, bcl-2 antisense, angiogenesis inhibitors and farnesyl transferase inhibitors. In order to best define the utility of thalidomide and other new agents it is essential that they are tested appropriately in the context of prospective clinical trials.
Summary and recommendations
- Thalidomide is an appropriate therapy for patients with relapsed or refractory disease.
- Patients not responding to thalidomide alone may respond to the combination of dexamethasone and thalidomide.
- It is not possible to make recommendations regarding the appropriate dose of thalidomide. However the majority of patients will respond at doses of 300-400mg or less and most patients are unable to tolerate doses greater than 600mg.
- Thalidomide alone or in combination with dexamethasone should only be given to newly diagnosed patients in the context of a clinical trial.
- There is an increased risk of VTE in patients treated with thalidomide in combination with dexamethasone or other drugs which varies in different patient groups and with different protocols.
- The mechanism of VTE is unexplained and at present it is not possible to make firm recommendations regarding anti-thrombotic prophylaxis.
- Routine serial nerve conduction studies are not practical for patients with myeloma, but clinical vigilance is essential to avoid serious neurotoxicity.
BCSH haematology/ oncology task force
The task force membership consisted of Dr DW Milligan (Chairman), Dr SA Johnson (Secretary) Dr S Rule, Dr J Cullis, Dr J Trealeven, Dr MJ Mills and Dr P Carrington.
Acknowledgments
Work in the Department is funded by an International Myeloma Foundation (UK) Research Award. Dr H. Oakervee is the recipient of an Aylwen Bursary granted by the Joint Research Board of The Special Trustees of St Bartholomew's Hospital.