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.
vials containing 3.5 mg powder for reconstitution
Approved indication: multiple myeloma
Australian Medicines Handbook section 14.3.11
Multiple myeloma is a malignancy of plasma cells. Although modern treatments, such as bone marrow transplant, have improved the prognosis there is no cure and the median survival is 3-5 years. The options for patients whose cancers relapse after chemotherapy or transplantation are limited. Progression of the cancer may be related to dysfunction of an enzyme system (26S proteasome) that normally breaks down cellular proteins. Inhibiting this enzyme disrupts cell homeostasis and can cause apoptosis, particularly in proliferating cells.
Bortezomib is an inhibitor of the proteasome. It is a modified dipeptide related to the amino acids leucine and phenylalanine. Experimentally, bortezomib delays tumour growth in a variety of cancers including multiple myeloma.
A phase II trial recruited 202 people whose myeloma had relapsed and was refractory to therapy. They were given injections of bortezomib twice a week in two-week cycles with one treatment-free week between each cycle. Up to eight cycles were allowed and oral dexamethasone could be added to the regimen if there was a poor response. After a median treatment duration of 3.8 months myeloma protein could not be detected by electrophoresis in 19 patients. Overall 53 patients (27%) had at least a partial response to bortezomib.1
As high doses of dexamethasone can be used to treat relapsed myeloma it has been compared with bortezomib. The trial randomised 333 patients to eight cycles of intravenous bortezomib and 336 to oral dexamethasone. There was at least a partial response in 38% of the bortezomib group and 18% of the dexamethasone group. The myeloma protein disappeared in 6% of the bortezomib group but less than 1% of the dexamethasone group. This contributed to a higher rate of survival (80% vs 66%) when the patients were followed up after a year.2
Many patients will not complete eight cycles of therapy. In the phase III trial 37% of the patients given bortezomib stopped treatment because of adverse effects.2 Common adverse reactions include gastrointestinal upsets, peripheral neuropathy, fever and hypotension. The patient's blood count should be checked before each dose as bortezomib can cause anaemia, neutropenia and thrombocytopenia.
Bortezomib is metabolised by several of the cytochrome P450 enzymes, but there are no drug interaction studies. It should probably not be used in patients with hepatic impairment, and the development of abnormal liver function may require treatment to be stopped.
As our understanding of the molecular biology of multiple myeloma improves new approaches to treatment are likely to emerge. For example, thalidomide can be used in refractory myeloma. Some of the patients in the trials had already been treated with thalidomide, so it seems that bortezomib can improve outcomes after a relapse. The size of the improvement is uncertain as there have been questions about the design of the comparison with dexamethasone,3 for example 99% of the dexamethasone group had already been treated with corticosteroids.2 Assuming the results are valid, bortezomib only delays progression by about three months. The median time to progression with bortezomib was 189 days compared with 106 days with dexamethasone.2 As the price of bortezomib will be much greater, the delay in progression will have a high cost and whether this improves the quality of the patient's remaining life is currently unclear.
The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
Notes on references
At the time the comment was prepared, information about this drug was available on the website of the Food and Drug Administration in the USA (www.fda.gov).
At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Agency for the Evaluation of Medicinal Products (www.emea.eu.int).
- Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003;348: 2609-17.
- Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487-98.
- Dispenzieri A. Bortezomib for myeloma - much ado about something. N Engl J Med 2005;352:2546-8.