Thalidomide in Multiple Myeloma: current status and future prospects
Other side-effects of thalidomide
1. Peripheral neuropathy
This is a major potential problem with thalidomide since neuropathy can be irreversible if the drug is not promptly withdrawn. It is imperative that patients are monitored very closely, especially during the first few months of therapy. Patients must know that they should stop the drug if significant numbness or parasthesiae occur. However, the assessment of neuropathy in patients with myeloma is complex since neuropathy and other neurological symptoms are likely to be multifactorial in any given patient (e.g. vincristine effect, paraprotein-mediated neuropathy, amyloid, radicular or spinal cord compression etc).
Certain guidelines which have been published, primarily with the use of thalidomide in chronic inflammatory disorders in mind (Powell et al, 1994), are probably inappropriate for patients with myeloma. For instance, it has been recommended that nerve conduction studies (NCS) should be repeated for each 10g increment. This would translate to the requirement for NCS every 12-13 days in patients with myeloma, which is clearly both inappropriate and undesirable.
The approach adopted by the UKMF is more pragmatic and the MPT and T-VAD protocols state that the drug should be stopped if there are symptoms of peripheral neuropathy. In addition, it is recommended that nerve conduction studies (NCS) be performed at the earliest opportunity, ideally prior to commencing thalidomide and should be repeated if necessary. However, for the patient who requires therapy, treatment should not be delayed if NCS cannot be performed immediately. Abnormal NCS in the absence of symptoms should not necessarily preclude the use of thalidomide if the potential benefits of therapy are considered significant, since if symptoms occur the drug can be stopped promptly. Prospectively performed NCS may help identify a particular pattern signifying those most at risk of developing neuropathy.
2.Sedation
Since thalidomide was first introduced as a sedative agent, it is to be expected that somnolence is a common effect. The degree of sedation appears to decrease with continued administration at a constant dose and can be minimised by taking the drug in the evening. If the drug is taken approximately 3-4 hours before going to bed, then any 'hang-over' effect is minimised for the following morning. This is frequently a dose limiting side effect.
3. Constipation
This can be a significant problem particularly when doses over 400 mg are taken. Again, the use of extra dietary fibre and laxatives can usually overcome this problem.
4. Birth defects
Dysmelia, particularly phocomelia, remains the most feared and devastating adverse event following thalidomide exposure. Every effort must be made to ensure that patients are fully aware of this risk and that the drug is not given to women of child-bearing potential. If, after due consideration of the potential risks and benefits, the drug is to be given to such women, then extreme caution must be exercised with the use of two methods of contraception and regular pregnancy tests. With respect to myeloma, the overwhelming majority of affected women will be post-menopausal so that these particular risks will not be present. Nevertheless, patients must be clearly instructed to store the drug in a secure place and to return any unused drug to the hospital pharmacy. Men must be counselled to use barrier contraception if their partner is of child-bearing age since it is not known whether thalidomide is present in semen.
5. Neutropenia
This has been reported as a rare side-effect.
6. Hypothyroidism
One study has suggested that patients treated with thalidomide are at increased risk of developing biochemical and clinical hypothyroidism (Badros et al, 2000).
7. Rash
This has been most markedly noted when given in escalating doses with high dose dexamethasone (Rajkumar et al 2000b) but has been noted on occasion when used as a single agent.
8. Bradycardia
This has been reported as a side effect.