Saad H Abdalla
MB BS FRCPath
Senior Lecturer in Haematology
Imperial College Faculty of Medicine
Senior Haematology/Oncology Pharmacist
St Mary’s Hospital
Multiple myeloma, a condition that mainly affects older people, constitutes 10% of all haematological malignancies. The disease is characterised by the proliferation of malignant clonal plasma cells, resulting in anaemia, hyper-calcaemia, bone disease, renal impairment and abnormal immunoglobulin production (M-protein).
Multiple myeloma is an incurable disease. The only effective treatment currently available is allogeneic stem cell transplantation, which is largely experimental and is applicable to only a small proportion of patients. Therefore, the aim of the treatment is to prolong life, prevent complications and improve symptoms.
First-line treatments consist of regimens containing alkylating agents in combination with high-dose steroids. Melphalan, in combination with steroids, has been the main first-line treatment since the 1950s. It is suitable for older patients and has a 60% remission rate and a median survival of approximately 2.5 years. In recent years, doxorubicin, used in combination with vincristine and dexamethasone (VAD), has become more popular, with higher success rates; however, VAD requires the use of central intravenous catheters. The main advantage of VAD is that it allows the preservation of autologous stem cells, which can then be mobilised and harvested; autologous stem cell transplant can then be carried out. This latter procedure has increased the median survival of patients to four to five years.
Response to treatment is measured by the reduction in M-protein and marrow plasma cells, in addition to improvement in symptoms. Although complete response with disappearance of the M-protein can occur in about 10–20% of patients treated with VAD/autograft, the condition is rarely cured, and relapse is almost inevitable. Second responses to conventional chemotherapy may occur, although they are usually of shorter duration than in the case of initial treatment.
Thalidomide in the treatment of myeloma
The discovery of the effectiveness of thalidomide as an antimyeloma agent can be viewed as a “new hope” in the management of patients with multiple myeloma. Initial clinical trials using thalidomide as a single agent in heavily pretreated relapsed or refractory myeloma showed a response rate of 32%;(1) these results were confirmed by subsequent studies. Thalidomide is also highly effective when used in combination with dexamethasone or in combination with cytotoxic drugs such as cyclophosphamide and melphalan. Better response rates have been achieved in the treatment of newly diagnosed and previously untreated patients.(2)
Thalidomide did not have an auspicious start as a therapeutic agent. Initially introduced in the early 1960s as a mild sedative and antiemetic, it was quickly found that the drug was highly teratogenic, and its use in early pregnancy resulted in many developmental abnormalities in fetuses, including underdevelopment of the limbs (phocomelia) and organs. Although the drug was withdrawn from general use, it was still produced in small quantities as it was found to be highly effective in an extremely painful condition associated with leprosy, erythema nodosum leprosum. When the immunomodulatory effects of thalidomide were discovered, the drug was also used to ameliorate graft versus host disease and in some autoimmune diseases, such as Behcet’s disease and recurrent aphthous ulcers.
Due to the highly teratogenic nature of the drug, patients now receiving thalidomide are advised on the side-effects and on the need for contraceptive measures. Women of childbearing age should not be pregnant before the start of the treatment, and should use two forms of effective contraception. Many companies supplying thalidomide now insist on proof that counselling has taken place before starting the treatment.
In addition to the teratogenic effects, the use of thalidomide is often associated with side-effects such as somnolence, lethargy, mood changes, constipation and fluid retention. Prolonged use can also be associated with peripheral neuropathy.
Thalidomide use in myeloma: the unanswered questions
Many unanswered questions remain concerning the treatment of myeloma with thalidomide, alone or in combination:
- What is the optimum dose?
- What should be the duration of treatment?
- Should treatment be continued after maximum effect?
- Is there a second response if therapy is reinstated?
Doses generally range between 100 and 800mg, although there is currently a trend to limit the dose to 400mg daily. No systematic studies as to whether maintenance treatment with thalidomide should be used have yet been carried out, but solid remission for prolonged periods after discontinuation of thalidomide has been observed in some patients.(3) In addition, some individuals respond to second treatment after discontinuation of thalidomide.
The mode of action of thalidomide in myeloma patients is still unknown. Although antiangiogenesis was initially thought to be the main mode of action, it is now believed that the drug acts though numerous mechanisms, including apoptosis of tumour cells, immunomodulation and enhancement of antimyeloma T-cells, modulation of the microenvironment and inhibition of tumour growth by interference with intracellular cell signalling.(4)
Emerging drugs in the treatment of myeloma
Because of the problems mentioned above, some analogues of thalidomide have been investigated as potential therapeutic agents against myeloma. Compounds related to thalidomide, or IMiDs (immunomodulatory derivatives of thalidomide), have been developed.
The first such compound to reach clinical trials stage is thalidomide analogue CC-5013 (Revimid), a drug that is 50–2,000 times more potent than thalidomide. The mechanisms of action are thought to be inhibition of growth factors and inflammatory proteins, antiangiogenesis and re-establishment of normal-cell transition cycles. In a small trial involving 27 patients, CC-5013 showed a response rate of 71%. The main adverse event was grade 3–4 myelosuppression, which required dose reduction. Side- effects usually associated with thalidomide, such as somnolence, constipation and neuropathy, were not observed with CC-5013. Whether this compound exhibits the teratogenic properties of thalidomide remains to be demonstrated.(5)
Another class of compounds, the proteasome inhibitors, has also been developed. The most advanced compound in this class is bortezomib, which is now licensed for the treatment of multiple myeloma in patients who have progressed after receiving two or more prior therapies.
Bortezomib is a reversible proteasome inhibitor. The proteasome is a multienzyme complex that degrades the proteins regulating cell-cycle progression. Bortezomib induces apoptosis in myeloma cells and reduces the expression of adhesion molecules. It is administered intravenously twice weekly for two weeks, followed by a 10-day rest (one cycle). The main side-effects of bortezomib are neuropathy and reversible haematological
Although there is currently no data on the extent to which thalidomide and newer drugs prolong life in patients with multiple myeloma, a new hope is being offered to patients who would have otherwise been considered to be at the “end of the road” as far as treatment options are concerned. New drugs such as CC-5013 and bortezomib are also being tested in various combinations, and anecdotal evidence suggests that these combinations may lead to very high response rates.
- Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341:1565-71.
- Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002;20:4319-23.
- Abdalla SH, Mahmoud S. Thalidomide in relapsed or refractory multiple myeloma: how much and for how long? Leuk Lymphoma 2003;44:989-91.
- Richardson P, Hideshima T, Anderson K. Thalidomide in multiple myeloma. Biomed Pharmacother 2002;56:115-28.
- Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002;100:3063-7.
- Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003;348:2609-17.