Description

Velcade is a proteasome inhibitor—the first to be tested with humans and the only one to be approved by the U.S. Food & Drug Administration (FDA). Patients in all stages, even those with refractory or rapidly advancing disease, have shown complete clinical responses.

Mechanism of Action

Velcade contains a boron atom that binds to a specific proteasome (26S proteasome). Proteasomes are enzymes that break down important proteins in both healthy and cancerous cells.

In healthy cells, the 26S proteasome regulates the production and function of proteins including those that control apoptosis, a process that tells a cell to die. The 26S proteasome also removes abnormal or misfolded proteins in the cell. Velcade inhibits this process in myeloma cells, leading to a build-up of proteins. It is believed that this excess in protein is what leads to cell death, suppressing tumor growth (related Beacon news).

Myeloma cells are much more sensitive to proteasome inhibition than normal peripheral blood cells and most other cancer cell lines. The reason for this sensitivity is not completely understood.

History

Velcade was developed in 1995 by Myogenics, a company that later changed its name to ProScript. The drug was tested in a small Phase I clinical trial on multiple myeloma patients after promising preclinical results. ProScript was bought by the company Leukosite in May 1999, which in turn was bought by Millennium Pharmaceuticals in October 1999. This turnover resulted in the project dropping in priority relative to others at the new company.

One of the first patients to receive the drug in a clinical trial achieved a complete response and remained alive four years later. This led to subsequent clinical trials that indicated the possibility of a complete response in 15 percent of patients in similar conditions.

In May 2003, the FDA approved Velcade for the treatment of relapsed/refractory myeloma. It was approved in 2005 for patients with relapsed myeloma and in June 2008 for previously untreated myeloma patients. Today, Velcade is approved for use in myeloma in over 85 countries.

In 2004, Velcade was named the Oncology Compound of the Year at the Pharmaceutical Achievement Awards.

Usage in Multiple Myeloma

In the U.S., Velcade is used to treat all phases of myeloma. Data from clinical trials in newly diagnosed or untreated patients shows that Velcade is effective and superior to standard therapies and consistently reduces numbers of myeloma cells.

In several countries, Velcade is approved for myeloma patients who have been treated with at least one other therapy.

New data suggest that Velcade may significantly improve the condition of bone disease in myeloma patients. This benefit appears to be independent from a patient’s response to Velcade. Velcade has also been shown to be active and safe in patients with myeloma-related kidney damage, since the body does not use the kidneys to remove Velcade.

Recent research and clinical trials have been investigating whether combining Velcade with other agents can make the drug more powerful. For instance, the addition of thalidomide (Thalomid), Revlimid (lenalidomide), inhibitors of vascular endothelial growth factor (VEGF), or arsenic trioxide may be beneficial. In laboratory studies, Velcade has been shown to kill myeloma cells more efficiently when combined with histone deacetylase inhibitors, thapsigargin, or Celebrex (celecoxib). The effectiveness of these combinations for myeloma patients has not been confirmed.

Dosage & Administration

Velcade is given by an injection into the bloodstream for three to five seconds at a doctor’s office or clinic. Dosage varies based on the type of myeloma, and the total length of therapy differs for each patient.

In previously untreated myeloma, Velcade is typically given in nine six-week cycles. Each treatment cycle consists of 11 days of therapy, a 10-day rest period, another 11 days of therapy, and a second 10-day rest cycle. During the first four cycles, 1.3 mg/m² of Velcade is given twice per week and doses are spread at least 72 hours apart. During the last five cycles, 1.3 mg/m² of Velcade is given once weekly. Velcade is commonly given in combination with melphalan and prednisone (Velcade-MP).

In relapsed or refractory myeloma, Velcade is usually given in eight three-week cycles. Each treatment cycle consists of 11 days of therapy followed by a 10-day rest period. During each cycle, 1.3 mg/m² of Velcade is given twice per week. After the eight cycles, Velcade treatment may continue on the same schedule or follow a maintenance schedule.

Side Effects

Many of the most common side effects of Velcade-MP affect blood cell counts in the body, such as thrombocytopenia (low numbers of platelets), neutrophilia (low numbers of neutrophils, a type of white blood cell), and anemia (low numbers of red blood cells).

Peripheral neuropathy, felt as a burning, tingling, or numbness in the hands or feet, occurs in approximately 30 percent of patients. Occasionally the peripheral neuropathy can be painful, and this may be worse in patients with pre-existing neuropathy.

Other frequent side effects include nausea, diarrhea, or constipation; fatigue or weakness; loss of appetite; and fever.

The side effects considered most serious for myeloma patients are low blood cell counts, peripheral neuropathy, fatigue or weakness, pneumonia, diarrhea, and low potassium levels.

Velcade-MP is also associated with a higher rate of shingles, which is caused by a reactivation of the herpes zoster virus, the virus that causes chickenpox, and results in a painful rash. Velcade-MP can also cause an allergic reaction, characterized by hives, difficulty breathing, or swelling.

If side effects do develop, physicians can reduce dosage, temporarily stop treatment, or manage the side effects with other medications. Drinking more fluids can also help reduce side effects.

Drug Interactions

The extract Epigallocatechin gallate (EGCG), which is found in green tea, has been shown to reduce the effectiveness of Velcade (related Beacon news).

Precautions

Patients should take particular caution if they have previously experienced tingling or numbness in the arms, hands, legs, or feet. Medications designed to reduce blood pressure may cause complications if taken with Velcade, like medications that affect the removal of Velcade from the body, such as azole antifungals, macrolide antibiotics, rifamycins, St. John’s wort, and seizure medications.

Patients with a history of fainting or dehydration should also use caution when taking Velcade. Those with diabetes, heart disease, or respiratory problems may need to be monitored more closely by a physician.

Ongoing Clinical Trials

Open:

Phase 1:

• University of Utah: Velcade with panobinostat in relapsed/refractory myeloma (NCT00891033)
• Dana-Farber Cancer Institute: Velcade with CCI-779 in multiple myeloma (NCT00483262)

Phase 2:

• University of Wuerzburg: Velcade as maintenance treatment following autologous stem cell transplantation(NCT00311337)

Phase 3:

• Merck: Velcade plus Zolinza in relapsed or refractory myeloma (NCT00773747)

Closed

Phase 2:

• Dana-Farber Cancer Institute: Velcade in untreated myeloma (NCT00153920)
• M.D. Anderson Cancer Center: Velcade treatment following allogeneic stem cell transplantation (NCT00504634)
• Janssen-Cilag International NV: Velcade in patients previously treated with and responsive to Velcade (NCT00431769)

For a more detailed listing of clinical trials involving Velcade, see the government’s clinical trials Web site at www.clinicaltrials.gov.

Clinical Trial Results

Velcade Approved As Initial Treatment For Patients With Multiple Myeloma (2008): When given in addition to melphalan and prednisone, Velcade significantly improved time to progression and overall survival in patients with newly diagnosed myeloma. The results of this international Phase 3 trial, called VISTA, led to the FDA’s approval of the drug for use in untreated myeloma patients. For more information, see the abstract in the New England Journal Of Medicine.

Velcade Delays Progression Of Relapsed Multiple Myeloma (2005): The results of APEX, an international Phase 3 trial, show that Velcade was more effective than high-dose dexamethasone in delaying disease progression in patients with relapsed myeloma. Serious side effects occurred in patients taking Velcade, but more of these patients were alive after one year than those taking dexamethasone. For more information, see the abstract in the New England Journal Of Medicine.

Patient Assistance Programs

Velcade Reimbursement Assistance Program
866-VELCADE (835-2233), option 2
www.velcade.com/reimbursement.aspx

Velcade Reimbursement Assistance Program Enrollment Form
www.rxhope.com/PAP/pdf/millennium_velcade_0209.pdf

Chronic Disease Fund, Inc.
877-968-7233
www.cdfund.org

HealthWell Foundation
800-675-8416
www.healthwellfoundation.com

Partnership for Prescription Assistance (PPARx)
888-4PPA-NOW (477-2669)
www.pparx.org

Patient Advocate Foundation, Co-Pay Relief
866-512-3861
www.copays.org

RxAssist
401-729-3284
www.rxassist.org

Links of Interest

Velcade Package Insert
http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/021602lbl.pdf

Millennium’s Web site for Velcade
http://www.velcade.com

Research Article about Velcade's Mechanism of Action
http://bloodjournal.hematologylibrary.org/cgi/content/abstract/