Velcade is the first approved cancer therapy in a new class of medicines known as proteasome inhibitors. In the United States, Velcade is approved by the Food and Drug Administration (FDA) for the treatment of patients with multiple myeloma. It was first approved for the treatment of relapsed and refractory myeloma in 2003, then for relapsed patients in 2005, and most recently was approved as a treatment for previously untreated patients (also referred to as "upfront therapy") in June 2008. Velcade is now approved for use in myeloma in over 85 countries worldwide.

Velcade is made by Millennium: The Takeda Oncology Company. It is also called bortezomib. Velcade is approved for use in the United States for the treatment of another type of blood cancer known as mantle cell lymphoma.

In the United States, Velcade is used for the treatment of myeloma in all phases of the illness, and is approved by the FDA for the treatment of patients with multiple myeloma throughout their course, from diagnosis to first relapse and beyond.

Data from numerous clinical trials have demonstrated that many patients with relapsed and refractory myeloma respond to Velcade therapy (that is, the level of M protein drops or is no longer detectable and/or there is other evidence of benefit) and that Velcade delays worsening of disease and improves survival. Velcade has also been show to be effective in patients who have received multiple previous therapies, including patients who have already received Velcade before.

Data from trials in newly diagnosed or untreated patients show that Velcade is effective in this setting, is superior to standard therapies, and achieves consistently high rates of response, including some of the highest recorded response rates for upfront (or front-line) treatment of myeloma.

In the European Union and many other countries, Velcade is approved for the treatment of patients who have already been treated with at least one other therapy, including those patients who have already had a stem cell transplant, as well as patients who are not eligible for a stem cell transplant.

Velcade is now being studied in combination with other approved myeloma drugs and in combination with new drugs in development.

Velcade is a type of cancer drug called a proteasome inhibitor. Proteasomes are enzymes found in cells and play an important role in regulating cell function and growth by controlling the breakdown of important proteins. Velcade blocks the activity of proteasomes and by blocking the proteasome, Velcade disrupts processes related to the growth and survival of cancer cells.

New data also suggest that Velcade may significantly improve bone disease in myeloma patients. Velcade's beneficial effect on bone disease appears to be independent of whether or not a patient's myeloma responds to Velcade. Furthermore, Velcade is as active and safe in patients with myeloma-related kidney damage as in patients with normal kidney function.

Velcade is given by injection into the bloodstream. The dose and schedule of administration of Velcade for individuals with previously untreated myeloma can be different from that for individuals with relapsed or refractory myeloma.

The approval for Velcade for previously untreated myeloma was based on its effectiveness when used in combination with oral melphalan and oral prednisone (MP), a common treatment for myeloma. When used as part of this combination, Velcade is usually given for nine 6-week treatment cycles. Each treatment cycle consists of 11 days of therapy, a 10-day rest period, 11 days of therapy, and a 10-day rest period.

• During the first four treatment cycles, Velcade is given at a dose of 1.3 mg/m² twice a week. Doses are typically given on Monday and Thursday, Tuesday and Friday, or Wednesday and Saturday because doses need to be spaced out at least 72 hours apart.
• During cycles five through nine, Velcade is given at a dose of 1.3 mg/m² once weekly.

This chart shows how Velcade might be given in combination with melphalan and prednisone (Velcade-MP).

If you are taking Velcade as part of a clinical trial or as part of a different combination therapy, you may receive a different dose and/or follow a different schedule. When Velcade is used in the upfront setting, it can also be given in the same way as it is for relapsed or refractory myeloma, as detailed below.

Prior to receiving a cycle of therapy with Velcade-MP, your doctor will do a blood test to see if the numbers of platelets and neutrophils in your blood are adequate. This is because treatment with Velcade-MP may cause levels of these blood cells to drop.

When used in the treatment of relapsed or refractory myeloma, Velcade is usually given at a dose of 1.3 mg/m² twice a week for 11 days, followed by a 10-day rest period. This is called a treatment cycle. Doses are typically given on Monday and Thursday, Tuesday and Friday, or Wednesday and Saturday because doses need to be spaced out at least 72 hours apart.

Typically, a total of eight cycles of Velcade therapy are given. After eight cycles, Velcade may be continued on the same schedule or on a maintenance schedule. For maintenance, Velcade is usually given once a week for 4 weeks, and is followed by a 13-day rest period.

If you are taking Velcade as part of a clinical trial, particularly as part of combination therapy, you may receive a different dose and/or follow a different schedule.

The length of treatment with Velcade may be different from patient to patient and is based on how well the drug is working and if the side effects are manageable. If a complete response (CR) is achieved, usually two additional cycles are given and the treatment is considered complete. If less than a CR is achieved, therapy will usually continue.

In clinical trials, patients were able to receive Velcade for up to eight cycles. However, patients who were still benefiting usually continued for additional cycles, including maintenance treatment. You and your doctor can discuss the length of treatment that may be right for you.

If you develop significant side effects, your doctor will most likely reduce your dose or temporarily stop treatment with Velcade. Once the side effects are resolved and/or successfully treated, Velcade can then be started again, but usually at a 25% reduced dose (e.g., if a patient had been receiving Velcade at 1.3 mg/m², it is typically restarted at 1.0 mg/ m²; if receiving 1.0 mg/m², it is restarted at 0.7 mg/m²).

If you develop peripheral neuropathy, a disorder of the nerves in your hands and feet, your doctor may adjust your Velcade dose. Learn More

Dosing adjustments of Velcade are not necessary for patients with reduced kidney function (renal impairment), a common feature of myeloma.

If you are being treated with Velcade, your doctor will also consider giving you medication to prevent shingles, a viral infection that causes a painful rash and is due to a reactivation of the herpes zoster virus (the virus that causes chickenpox). In clinical trials, up to 25% of patients who did not receive preventive (prophylactic) medication developed shingles, but only 3% of patients who received antiviral medication developed the condition.

Other medications that may be given with Velcade include agents to prevent possible nausea or diarrhea. Supplements including B vitamins and folic acid, as well as certain amino acids, are sometimes suggested to help prevent peripheral neuropathy.

The side effects seen with Velcade therapy in studies of previously untreated myeloma (frontline studies) are slightly different than those seen in studies of relapsed or refractory myeloma. This is mainly due to the fact that Velcade was given along with melphalan and prednisone (MP) in the frontline studies and was given by itself in the relapsed or refractory studies.

The side effects seen with Velcade-MP are similar to those seen with the individual drugs. In the Phase III VISTA trial, the study upon which the approval of Velcade for previously untreated myeloma was based, the most common side effects seen with Velcade-MP included:

• Low platelet counts, also referred to as thrombocytopenia
• Low numbers of white blood cells known as neutrophils, a condition known as neutropenia
• Nausea, diarrhea, or constipation
• Peripheral neuropathy Anemia, or low numbers of red blood cells

In the VISTA trial, most of the side effects seen with Velcade-MP were mild (Grade 1) or moderate (Grade 2) in severity. Learn More

Sometimes these symptoms worsen and become serious, so it is important to talk with your doctor if you are having any side effects.

In the VISTA trial, a number of patients receiving Velcade-MP as frontline therapy experienced serious (Grade 3) or less commonly, very serious (Grade 4) side effects during the course of their treatment. Serious side effects included:

• Low blood cell counts (platelets, white blood cells, and red blood cells)
• Neuropathy or nerve pain
• Fatigue or loss of strength
• Pneumonia
• Diarrhea
• Low potassium levels

Side effects of Velcade can often be managed with other medications, increasing the amount of fluids, reducing the dose of Velcade, or stopping Velcade treatment temporarily until symptoms resolve.

Your doctor may modify or delay your dose if you experience low blood counts or severe side effects. Learn More

The most common side effects seen when Velcade was used in the treatment of relapsed and refractory disease include:

• Tiredness or weakness
• Nausea, vomiting, diarrhea, or constipation
• Loss of appetite
• Fever
• Burning, tingling, or numbness in the hands or feet, also known as peripheral neuropathy

In the Phase III APEX study, the study upon which the approval of Velcade for relapsed/refractory myeloma was based, most of the side effects were mild (Grade 1) or moderate (Grade 2) severity. Learn More

Sometimes these symptoms worsen and become serious, so it is important to talk with your doctor if you are having any side effects.

In the APEX study, up to 75% of patients with relapsed/refractory myeloma had serious (Grade 3) or less commonly, very serious (Grade 4) side effects during the course of their treatment with Velcade. These serious side effects included:

• Low blood cell counts (platelets, white blood cells, and red blood cells)
• Fatigue or weakness
• Neuropathy
• Diarrhea

Side effects can often be managed with other medications, increasing the amount of fluid you drink, or reducing the dose of Velcade. If side effects are severe, your doctor may stop Velcade treatment temporarily until your symptoms resolve. Velcade can then be started again at a lower dose.

Patients who experience neuropathic pain and/or peripheral neuropathy on Velcade therapy should have their dose and/or schedule adjusted. Learn More

In most patients who experience these side effects, they appear to be reversible.

Velcade has been shown to be effective in a wide range of patients, including:

• Patients with previously untreated myeloma
• Patients with relapsed or refractory myeloma
• Older patients (≥65 years old) as well as younger patients
• Patients with "high-risk" disease (poor prognosis)
  • Data from the Phase III APEX clinical trial showed that Velcade was effective in patients who had been treated with more than one prior therapy, patients with beta-2 microglobulin higher than 2.5 mg/L, and/or patients who did not respond to their last treatment.
• Patients with a type of aggressive multiple myeloma where there are changes in the patient's DNA, specifically a deletion of chromosome 13
• Patients who previously received Velcade
• Patients who have received several prior therapies (heavily-pretreated)
• Patients who previously received high dose chemotherapy and stem-cell transplant
• Patients with reduced kidney function (renal impairment)
• Patients with bone disease

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Velcade is FDA approved for use as a therapy for newly diagnosed or previously untreated patients, often referred to as "frontline" or "upfront" therapy. The approval was based on the results of the large Phase III VISTA clinical trial, which evaluated Velcade in combination with melphalan and prednisone (MP), a frontline therapy commonly used in patients who are ineligible for a stem cell transplant.

• Data from the VISTA trial show that adding Velcade to MP significantly extends the length of time before disease progresses, the length of time a patient remains disease-free following treatment, and improves complete response rates and overall survival compared with patients treated with MP alone.
  • A complete response rate of 30% was seen with patients receiving Velcade-MP compared with 4% seen with those receiving MP alone.
  • There was a 36% reduction in risk of death at 3 years when Velcade was added.
  • Velcade-MP was consistently effective in patients with poor prognostic features (ie, age ≥75 years, impaired kidney function, or high-risk cytogenetics).

• Results of a Phase III trial show that adding Thalomid^® (thalidomide, Celgene) to Velcade-MP (VMPT) further improves the response rate in elderly patients.
• The rate of complete response in the group receiving VMPT was nearly double that seen with Velcade-MP (39% versus 21%).
• Longer follow-up will be needed to see if the improved response leads to longer survival.

Based on its effectiveness in treating patients with relapsed and refractory myeloma, Velcade-dex was then evaluated as a frontline therapy.

Note that although many Velcade-dex studies were conducted in patients who are eligible for high-dose chemotherapy and stem cell transplant, Velcade-dex may also be an option for patients who are not eligible for transplant.

• Velcade and dexamethasone is more effective than the once commonly used VAD (vincristine, Adriamycin, and dexamethasone) therapy as upfront treatment for multiple myeloma, according to data from a large Phase III clinical trial. Nineteen percent of patients treated with Velcade and dexamethasone had a complete response or near-complete response, compared with 8% of patients treated with VAD prior to transplant. In addition, this high complete response rate contributed to 81 patients not requiring a second transplant. Patients receiving Velcade and dexamethasone experienced significantly longer progression-free survival at 2 years than those receiving VAD (69% versus 60%).
• Long-term results from a clinical trial of 50 patients treated with Velcade with or without dexamethasone showed the combination is highly active as a frontline therapy. Patients initially received Velcade, and dexamethasone was added if a patient had a less than an optimal response. Ninety percent of patients had a partial response or better and 19% percent of patients achieved a complete or near-complete response.

Velcade has also been evaluated in combination with other commonly used treatments. Data in these settings show superior efficacy over standard therapies and consistently high response rates, including some of the highest recorded response rates for upfront treatment of myeloma. Data from some of these promising combinations are listed here.

Note that although some Velcade-based regimens were specifically evaluated in patients who are eligible for high-dose chemotherapy and stem cell transplant, many may be options for patients who are not eligible for transplant. Certain drugs, such as melphalan, affect stem cells, so regimens containing melphalan are usually only used in patients who are not eligible for transplant.

Revlimid, Velcade, and Dexamethasone (Rev-Vel-Dex):
Revlimid is thought to make myeloma cells more sensitive to Velcade and dexamethasone. The combination of Revlimid, Velcade, and dexamethasone has been shown to be effective in treating relapsed/refractory myeloma, and now also as frontline therapy.

• Data from a Phase I/II clinical trial in 65 previously untreated patients show that 44% of patients treated with the combination of Velcade, Revlimid, and dexamethasone had a complete response or near-complete response and all patients in the study had a partial response or better.

Velcade plus Thalomid and Dexamethasone (VTD):
The combination of Thalomid and dexamethasone (Thal-dex) is a commonly used frontline regimen. Results from several studies have shown that adding Velcade to this regimen improves its effectiveness. For example:

• Data from 460 patients in a Phase III clinical trial show that 32% of patients treated with Velcade plus Thal-dex had a complete response or near complete after three cycles of therapy compared with 12% of patients treated with Thal-dex. Furthermore, the enhancement of complete response or near complete response rates for patients treated with Velcade-Thal-dex was sustained even after transplant.
• 94% of patients receiving Velcade-Thal-dex induction achieved a partial response or better. Progression-free survival at 2 years was also significantly improved with Velcade-Thal-dex.

Velcade plus Doxil and dexamethasone:
The combination of Velcade and Doxil is approved for the treatment of relapsed and refractory multiple myeloma and is now being studied as frontline therapy.

• Data from a Phase II clinical trial of 40 previously untreated patients show that 43% of patients who were treated with Velcade, Doxil, and dexamethasone had a complete response or near-complete response and 93% had a partial response or better. Data from this study also show that more patients treated with this combination had a complete response or better following transplantation compared to patients who had single or tandem transplants but were not treated with this combination.
• Data from 86 previously untreated patients show that giving Velcade, Doxil, and dexamethasone prior to stem cell transplant led to a complete response rate of 21% which increased to 59% following the transplant.

Various Velcade combinations continue to be evaluated as upfront therapy. For more information about additional clinical trials evaluating Velcade in the frontline setting, click here.

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Velcade was initially approved by the FDA for the treatment of patients who had received at least two prior therapies. The approval was later expanded to include patients who had received at least one prior therapy. Velcade, alone (sometimes called "monotherapy" or "single-agent") and in combination with other commonly used treatments, has been studied in patients who have previously received therapy.

Data from a number of clinical trials have demonstrated Velcade's efficacy in delaying disease progression, achieving high response rates, and improving survival in patients with relapsed and refractory myeloma. Velcade has also been shown to be highly effective in heavily-pretreated patients and in retreating patients who had previously received Velcade. Some patients may also benefit when Velcade is given at a lower dose.

• Results from the Phase III APEX clinical trial comparing Velcade with high-dose dexamethasone in 669 people with relapsed/refractory myeloma showed that Velcade was more effective than dexamethasone (a known standard of care). In this study, patients treated with Velcade had a significantly longer time-to-disease progression (TTP), higher response rates, and improved survival compared with patients treated with high-dose dexamethasone. This trial was ended early due to a significant improvement in time-to-disease progression in patients treated with Velcade and patients treated with dexamethasone were allowed to immediately begin treatment with Velcade.
  • Improved time-to-disease progression: There was a 78% improvement in the median time-to-disease progression (approximately 3 months) in patients treated with Velcade compared with patients treated with dexamethasone.
    
  • Higher response rates: Response rates with Velcade were improved over those seen with dexamethasone both at the time of early termination of the study and at an updated analysis.
  • Key:
    CR = complete response
    nCR = near complete response
    PR = partial response
    
  • Improved overall survival: Eighty percent of patients treated with Velcade were alive 1 year after Velcade treatment, compared with 67% of patients treated with dexamethasone. These data include patients treated with dexamethasone who later received Velcade, so the improved survival may have been even greater if one only looked at patients who received Velcade all along.
• Velcade has been shown to be effective in heavily-pretreated patients. Results from the Phase II SUMMIT trial of 202 patients with relapsed and refractory myeloma who had already been treated with a median of six prior therapies showed that 35% of patients responded to Velcade with a partial response or better. A number of patients who did not respond to Velcade alone improved their response with the addition of dexamethasone.
• Velcade was also shown to be effective when given at a lower dose. Results from the Phase II CREST clinical trial of 54 patients with relapsed or refractory myeloma who had been treated with one prior therapy showed that 4% of patients treated with a lower dose of Velcade (1.0 mg/m² ) achieved a complete or near complete response and 19% had a partial response. Patients treated with the lower dose of Velcade had less frequent neuropathy and gastrointestinal side effects. These findings suggest that patients who cannot tolerate the full dose of Velcade may benefit from a lower dose.

Based on the success of Velcade alone in treating patients with relapsed and refractory multiple myeloma, a multitude of combination treatments are now being used or studied in clinical trials. Data from these studies show that treatment with Velcade combinations have resulted in high response rates and improved disease-free survival. Examples of these combinations include:

• Velcade and Doxil: Doxil^® (doxorubicin HCl liposome injection, Ortho Biotech) is approved for use in combination with Velcade to treat relapsed and refractory myeloma patients who have not previously received Velcade and who have received at least one prior therapy. Results from a Phase III clinical trial show that patients treated with Velcade and Doxil were disease-free significantly longer (a median time of 9.3 months) than patients treated with Velcade alone (a median time of 6.5 months).

• Velcade, Revlimid, and Dexamethasone: Revlimid^® (lenalidomide, Celgene) is thought to make myeloma cells more sensitive to Velcade and dexamethasone. Preliminary data from a small Phase II trial suggest that the three drug combination (Rev-Vel-dex) is very effective.
  • Overall, 73% of 33 evaluable patients responded to this treatment and 36% had significant reductions in M protein (a very good partial response, near complete response, or complete response).
  • Patients tended to respond for a prolonged period of time, nearly 10 months.
  • The combination has been well tolerated.

• Velcade and Melphalan: Data from a Phase I/II study of 53 patients with relapsed and refractory myeloma found that 65% of patients treated with Velcade and melphalan responded to therapy (a complete response, a near-complete response, or a partial response). The overall response rate increased to 69% when dexamethasone was added to the regimen for patients who did not optimally respond. Median progression-free survival was 10 months for these patients. Please note that melphalan-based combinations are not appropriate for patients considering a stem cell transplant.

• Velcade, Melphalan, Prednisone, and Thalomid: The addition of Thalomid^® (thalidomide, Celgene) and Velcade to the standard melphalan/prednisone combination significantly increases patients' response rates and the length of time patients' remain disease-free following treatment when used in the relapsed setting. Of the 30 patients in this Phase I/II study who received this combination, 17% had a complete response and 27% had a very good partial response. Please note that melphalan-based combinations are not appropriate for patients considering a stem cell transplant.

There are many other Velcade combination therapies being evaluated in ongoing clinical trials in relapsed or refractory myeloma. Some combinations include conventional chemotherapy agents, while others include new novel therapies. For more information about additional clinical trials evaluating Velcade in relapsed and refractory myeloma, click here.

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There are many other Velcade combination therapies being evaluated in ongoing clinical trials in relapsed or refractory myeloma. Some combinations include conventional chemotherapy agents, while others include new novel therapies. For more information about additional clinical trials evaluating Velcade in relapsed and refractory myeloma, click here.

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