Drug Name: Velcade (bortezomib)
Company: Millennium Pharmaceuticals
Approval Status: Approved May 2003
Treatment for: Multiple Myeloma

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.

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 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 2 weeks, followed by a 10-day rest period (21 day treatment cycle) for a maximum of 8 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%) subjects achieved an overall response rate, 5 (2.7%) achieved a complete response, 47 (25%) achieved a partial response and 33 (17.6%) demonstrated a clinical remission. The Kaplan-Meier estimated median duration of response was found to be 365 Days.

Complete Response required 100% disappearance of the original monoclonal protein from blood and urine on at least 2 determinations at least 6 weeks apart by immunofixation, and <5% 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 requires ≥50% reduction in serum myeloma protein and ≥ 90% reduction of urine myeloma protein on at least 2 occasions for a minimum of at least 6 weeks, stable bone disease and calcium.

Clinical Remission (SWOG) required ≥75% reduction in serum myeloma protein and/or ≥90% reduction of urine myeloma protein on at least 2 occasions for a minimum of at least 6 weeks, stable bone disease and calcium.

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

Asthenia
Nausea
Diarrhea
Appetite decreased
Constipation
Thrombocytopenia
Peripheral neuropathy
Pyrexia
Vomiting
Anemia
Headache
Insomnia
Edema

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.