General Information

Velcade (bortezomib) is an antineoplastic agent available for intravenous injection. The proteasome is an enzyme complex that exists in all cells and plays an important role in degrading proteins that control the cell cycle and cellular processes. By blocking the proteasome, Velcade disrupts numerous biologic pathways, including those related to the growth and survival of cancer cells.

Velcade for Injection is indicated for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy.

Mechanism of Action

Based on preclinical studies, bortezomib seems to be cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.

The compound bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. These pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining balance within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis which can affect multiple signaling cascades within the cell. This disruption of normal mechanisms can lead to cancer cell death.

Side Effects

Adverse events associated with the use of Velcade may include (but are not limited to) the following:

• asthenia
• nausea
• diarrhea
• appetite decreased
• constipation
• thrombocytopenia
• peripheral neuropathy
• pyrexia
• vomiting
• anemia
• headache
• insomnia
• edema

Dosing/Administration

The recommended dose of Velcade is 1.3 mg/m2/dose administered as a bolus intravenous injection twice weekly for two weeks followed by a 10-day rest period.

Clinical Trial Results

The effectiveness of Velcade is based on response rates. There were no controlled trials demonstrating a clinical benefit, such as an improvement in survival. FDA approval of Velcade was based on an open-label, single-arm, multicenter study of 202 subjects. An IV bolus injection of Velcade 1.3 mg/m2/dose was administered twice weekly for two weeks, followed by a 10-day rest period (21-day treatment cycle) for a maximum of eight treatment cycles. The study employed dose modifications for toxicity. Subjects who experienced a response to Velcade treatment were allowed to continue treatment in an extension study.

Results showed 52 (27.7 percent) subjects achieved an overall response rate, 5 (2.7 percent) achieved a complete response, 47 (25 percent) achieved a partial response and 33 (17.6 percent) demonstrated a clinical remission. The Kaplan-Meier estimated median duration of response was found to be 365 days.

Complete response required 100 percent disappearance of the original monoclonal protein from blood and urine on at least two determinations at least six weeks apart by immunofixation, and <5 percent plasma cells in the 133 bone marrow on at least two determinations for a minimum of six weeks, stable bone disease and calcium.

Partial response required 50 percent reduction in serum myeloma protein and 90 percent reduction of urine myeloma protein on at least two occasions for a minimum of at least six weeks of stable bone disease and calcium.

Clinical remission (SWOG) required 75 percent reduction in serum myeloma protein and/or 90 percent reduction of urine myeloma protein on at least two occasions for a minimum of at least six weeks of stable bone disease and calcium.