Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
5 mg, 10 mg, 15 mg and 25 mg capsules
Approved indication: multiple myeloma
Australian Medicines Handbook section 14.3
Multiple myeloma is a cancer of plasma cells in bone marrow. This disease is characterised by increased levels of paraprotein, an abnormal type of immunoglobulin produced by tumour cells. Multiple myeloma is incurable with conventional treatments and the median survival time after diagnosis is 3–5 years.1 Modern treatments such as bone marrow transplant, bortezomib (Aust Prescr 2006;29:84–7) and thalidomide (Aust Prescr 2003;26:146–51) have improved the prognosis.
Lenalidomide is an analogue of thalidomide. Its mechanism of action is not clearly understood although it is thought to modulate the immune system. It inhibits proliferation of certain haematopoietic tumour cells, prevents the growth of blood vessels within tumours and induces proliferation of specialised immune cells that attack cancerous cells.
Following oral administration in patients with multiple myeloma, lenalidomide is rapidly absorbed and maximum plasma concentrations are reached within 0.5–4 hours. In healthy volunteers, its elimination half-life increases with dose from about three hours with 5 mg up to nine hours with 400 mg. Most of the drug is excreted unchanged in urine. Lenalidomide should be taken at least one hour before or two hours after food.
In studies of multiple myeloma, patient responses are generally judged by changes in concentrations of paraprotein. In an open-label trial, the efficacy of lenalidomide was investigated in patients with relapsed or relapsed and refractory multiple myeloma. Responses were observed in 1 of 5 patients given 10 mg/day lenalidomide, 2 of 3 patients given 25 mg/day and 12 of 13 patients given 50 mg/day.2
In another trial, patients with relapsed or relapsed and refractory multiple myeloma received either 30 mg lenalidomide once daily (67 patients) or 15 mg lenalidomide twice daily (35 patients) for 21 days of a 28 day cycle. Patients with stable or progressive disease after two cycles of treatment had dexamethasone added. Overall, 25% of patients responded to lenalidomide treatment. Four patients had a complete response in the once-daily group, whereas there were no complete responses in the twice-daily group. During the trial, 68 of the 102 patients had dexamethasone added and 20 of these patients responded to the addition. The median progression-free survival time was 7.7 months with the single dose of lenalidomide and 3.9 months with the twice-daily dose.3
In two phase III trials totalling 704 patients with relapsed or refractory multiple myeloma, lenalidomide (25 mg once daily for 21 days of a 28 day cycle) or placebo was added to dexamethasone treatment (40 mg). Results were similar in each trial with more patients taking lenalidomide plus dexamethasone responding to treatment compared to those taking dexamethasone alone (approximately 61% vs 22%). Median time to progression was around 11 months with combination therapy compared to just under 5 months with dexamethasone alone.4-5
Monitoring of complete blood counts is recommended because neutropenia and thrombocytopenia are very common with lenalidomide (especially when used with dexamethasone) and patients often need their dose to be reduced or interrupted. Growth factors may be needed for patients with neutropenia.
There is also an increased risk of deep vein thrombosis and pulmonary embolism in patients taking lenalidomide with dexamethasone so patients and doctors should be vigilant for symptoms. Erythropoietic drugs or drugs that increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution. Prophylactic measures may be needed in high-risk patients.
Other adverse events associated with lenalidomide (30 mg once daily) include constipation (25% of patients), anaemia (16%), peripheral neuropathy (10%), fatigue (7%) and diarrhoea.3 Lenalidomide is renally excreted, so the risk of adverse events is expected to be greater in patients with impaired renal function.
Lenalidomide increases the plasma exposure of digoxin, so it is advisable to monitor digoxin concentrations if these drugs are taken concomitantly. As fatigue, dizziness, somnolence and blurred vision have been reported with lenalidomide, caution is recommended when driving or operating machinery.
Due to its structural similarity with thalidomide, lenalidomide is a potential teratogen and should be avoided during pregnancy. Male patients should use condoms throughout treatment and for one week after cessation. Lenalidomide is only available under a restricted distribution program. Doctors and pharmacists must be registered in the program before they can prescribe or dispense the drug.
Lenalidomide is indicated for the treatment of multiple myeloma in patients who have received at least one prior therapy, and who have progressive disease. Its effectiveness seems to be higher when used in combination with dexamethasone and investigations are underway for its use in combination with other treatments such as doxorubicin and vincristine. Using lenalidomide with dexamethasone for newly diagnosed multiple myeloma is also being studied.1
The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
- Richardson PG, Mitsiades C, Schlossman R, Munshi N, Anderson K. New drugs for myeloma. Oncologist 2007;12:664-89.
- Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, et al. Immuno modulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002;100:3063-7.
- Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006;108:3458-64.
- Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007;357:2123-32.
- Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007;357:2133-42.