Bortezomib (Protease Inhibitor)

Bortezomib is a protease inhibitor, which is licensed for the treatment of multiple myeloma. It is used when the disease has progressed, despite the use of at least two therapies. It is given by intravenous injection.

• Patients with multiple myeloma suffer from an impaired immune system. A type of white blood cell called a plasma cell, which produces infection-fighting antibodies, starts reproducing uncontrollably.
• This flood of abnormal plasma (myeloma) cells crowds out healthy blood cells in the bone marrow (the spongy tissue inside large bones) and can lead to fatigue, bone pain, anaemia, kidney failure, and/or recurrent infections.
• Chemotherapy often succeeds in lowering the number of myeloma cells, which puts many patients into remission for two years or longer. Though treatments for the disease are effective at first, the long-term prognosis is generally poor. About 29 percent of patients are alive five years after diagnosis.
• No single therapy has been shown to be most effective in this group of patients, but high doses of steroids such as prednisone or dexamethasone are commonly used, often followed by bone marrow transplant.

Protease inhibitors

These are a new class of targeted therapies that may be more effective in patients with relapsed or refractory (treatment-resistant) blood-cell cancers like multiple myeloma.

• Preclinical studies have shown that protease (or proteosome) inhibitors decrease proliferation, induce apoptosis, enhance the activity of chemotherapy and radiation, and reverse chemo-resistance in a variety of haematological and solid malignancy models, in vitro and in vivo.¹
• The first such therapy to show real promise in phase II studies was bortezomib (Velcade®).
• By targeting a protein that is active in some cancers, bortezomib delays tumour growth and enhances the cell-killing effects of radiation and chemotherapy.

The U.S. Food and Drug Administration (FDA) gave bortezomib fast-track approval for the treatment of patients whose multiple myeloma has progressed after at least two courses of treatment. The phase III trial called the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial² was conducted to provide more definitive evidence. Bortezomib produced significant survival benefits and improved response rates over high-dose dexamethasone at first recurrence and beyond in patients with multiple myeloma.

The treatment is given twice weekly for two weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). This 3-week period is considered a treatment cycle.
The total number of cycles received depends on response:

• Most data are based on 8 cycles of treatment
• It is recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of therapy.
• It is recommended that patients with a confirmed complete response receive 2 additional cycles of treatment, after remission is confirmed.

• Severe hepatic impairment
• Breastfeeding
• Contraception must be used whilst taking the treatment.

• Gastro-intestinal disturbances, pyrexia, postural hypotension, and fatigue are among the most common side-effects.
• Cases of ileus have been reported, therefore patients who experience constipation should be closely monitored.
• The most common haematological toxicity is transient thrombocytopenia.
• The incidence of peripheral neuropathy increases early in the treatment and has been observed to peak during cycle 5.

• Serum M-proteins are the levels of monoclonal antibodies (IgG, IgA) found in myeloma patients. They are used to stage and assess risk of progression of the disease e.g. low/normal M protein levels are <3g/dl; stage III myeloma has high M protein values IgG >7 g/dl, IgA >5 g/dl.
• The levels are measured after 4 cycles of treatment. A reduction in the level indicates that the treatment is working.
• Treatment is only continued where serum M-protein has reduced by 50% or more.