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Velcade (Bortezomib)

Velcade Overview

Velcade in Previously Untreated Myeloma

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What is Velcade?

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 initially approved for the treatment of relapsed and refractory myeloma in 2003, then for relapsed patients in 2005, and most recently was approved 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.

How is Velcade used in multiple myeloma?

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 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.

How does Velcade work?

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, myeloma cells in particular. Importantly, Velcade targets both the myeloma cell and the tumor microenvironment.

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.

How is Velcade given?

Velcade is given by injection into the bloodstream.

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.

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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. In addition, once-weekly Velcade dosing, using the standard 1.3 mg/m2 dose or up to 1.6 mg/m2, is now being used more frequently for all treatment cycles because some studies have shown it is just as effective as twice-weekly dosing but may have fewer side effects, including a significantly reduced risk of peripheral neuropathy, a disorder of the nerves affecting the hands and feet.

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.

If you already have significant peripheral neuropathy, your doctor will determine whether you should receive Velcade. This is because Velcade can make neuropathy worse.

Do patients with reduced kidney or liver function need lower doses of Velcade?
Dosing adjustments of Velcade are not necessary for patients with reduced kidney function (renal impairment), a common feature of myeloma.

However, patients with moderately or severely reduced liver function (hepatic impairment) should be started on a reduced dose of Velcade. During the first cycle, patients with significant hepatic impairment receive Velcade at 0.7 mg/m2 per injection. Depending on how this dose is tolerated, the subsequent Velcade dose can be increased.

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How long is the treatment with Velcade?

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 any side effects that develop 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.


What if I develop side effects?

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.


Will I need to take any other medications?

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 but should not be taken on the same day that Velcade is given. Talk to your doctor about any supplements you use.


What are the possible side effects with Velcade?

The side effects seen with Velcade therapy in studies of previously untreated myeloma (frontline studies) can be 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 or with steroids in the relapsed or refractory studies.


Most common side effects seen in frontline studies of Velcade-MP

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 can become serious, so it is important to talk with your doctor if you are experiencing any of these side effects.


Serious side effects seen in frontline studies of Velcade-MP

In the VISTA trial, a number of patients receiving Velcade-MP as frontline therapy experienced serious (Grade 3) or much 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, which typically appear as weakness

How are side effects of front-line Velcade-MP managed?

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 any other significant side effects. Learn More

If a patient develops peripheral neuropathy, certain medications that decrease neuropathic pain may be beneficial. In addition, certain emollient creams, such as cocoa butter, may be helpful. However, prompt dose reduction and a change in the schedule of Velcade administration are essential in managing peripheral neuropathy should it develop.

What types of patients can benefit from Velcade therapy?

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 (which indicates a greater likelihood of 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, including 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, as Velcade has been shown to have positive effects on bone

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Is Velcade-MP effective in previously untreated myeloma?

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 in part 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).

Researchers are trying to improve the efficacy of Velcade-MP by adding additional drugs or by adding maintenance therapy following initial therapy.

  • 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 (35% versus 21%).
    • Part way through this study, the Velcade dosing was changed from the standard twice-weekly schedule to a once-weekly schedule. It was found that once-weekly Velcade was as effective as twice-weekly Velcade when given as part of VMPT or Velcade-MP, but was significantly less toxic, particularly with regard to peripheral neuropathy.

  • Subsequent results from this trial show that VMPT followed by maintenance with Velcade-Thalomid (VT) improves response rates, progression-free survival, and time before next therapy in elderly patients over that seen with Velcade-MP alone.

    • In both treatment arms (Velcade-MP and VMPT-VT), the quality of response was associated with better outcome.
    • Adverse cytogenetics did not appear to adversely affect response or progression-free survival in either treatment arm.

Is Velcade-dex effective in previously untreated myeloma?

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. Fifteen percent of patients treated with Velcade and dexamethasone had a complete response or near-complete response, compared with 7% 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 also 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.

What other Velcade combination therapies are effective in previously untreated myeloma?

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. As a result, there has been a rapid movement toward use of three-drug combinations for initial therapy. 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 or RVD):
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 very effective in treating relapsed/refractory myeloma, and now also as frontline therapy, with unprecedented activity seen, even in patients with adverse cytogenetics.

  • Data from a Phase I/II trial in 66 previously untreated patients show that:
    • Approximately 50% of patients treated with the combination of Velcade, Revlimid, and dexamethasone had a complete response or near-complete response.
    • All (100%) patients in the study had a partial response or better.
    • About 70% of patients achieved a very good partial response or better (a ≥90% reduction in M protein)
    • Treatment was generally well tolerated, with low rates of significant complications reported.

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

  • Side effects were generally managable, however, peripheral neuropathy was more common when Velcade was added.

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.

Velcade, cyclophosphamide, and dexamethasone (VCD or CyBorD)
The combination of Velcade, cyclophosphamide, and dex (VCD) is being evaluated for use as frontline therapy at several centers.

  • Results of a German Phase II/III trial show VCD to be an effective induction regimen in patients 60 years or younger, and also in those patients with high-risk myeloma. An overall response rate (partial response or better) of 84% was seen, and 10% of patients achieved a complete response.

Four-drug combinations

A number of four-drug combinations are showing promise in patients who are eligible for transplant.

  • Updated results of a Phase I/II trial of trial of Revlimid, Velcade, Doxil, and dexamethasone (RVDD, n=70) show the combination to be highly active and well tolerated, with 97% of patients achieving a partial response or better.
  • Preliminary results of a Phase II trial show that the combination of Velcade, dex, cyclophosphamide, and Revlimid (VDCR) resulted in improved quality and duration of response, which was similar to three-drug combinations (VDR or VDC). However, adding additional agents also increased the toxicity of the regimen, so a balance between efficacy and tolerability must be determined.

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.

Is Velcade effective as maintenance therapy?

Velcade is being evaluated for use as maintenance therapy following stem cell transplantation or other therapy as a way to reduce the risk of relapse and extend survival. Results of several Phase III trials show that use of Velcade as maintenance therapy can improve outcome.

  • Velcade maintenance was shown to be more effective than Thalomid maintenance in improving overall response following stem cell transplantation. Patients receiving Velcade maintenance had initially received induction therapy with Velcade, adriamycin, and dexamethasone (PAD), while patients receiving Thalomid maintenance had received induction therapy with vincristine, adriamycin, and dexamethasone (VAD).

  • The use of combination Velcade-Thalomid maintenance improved outcome in elderly patients who were not candidates for transplant. The patients who received maintenance therapy had initially received Velcade, melphalan, prednisone, and Thalomid (VMPT) and had improved response rates, progression-free survival, and time before next therapy over that seen in patients initially receiving VMP without maintenance.

  • Velcade-based maintenance regimens improved the quality of response in older patients with myeloma. Patients received initial therapy with VMP or Velcade-Thalomid-prednisone (VTP), followed by maintenance therapy with VP or VT. The use of maintenance therapy increased the rate of complete responses from 23% following initial therapy to 42% after maintenance. In addition, the Velcade-based combinations led to 2-year overall survival rates of up to 88%. VT maintenance appeared to be associated with longer time to progression compared with VP.

    • What clinical trials are available?

    To find a clinical trial call 1-866-603-MMCT (-6628) or click here to go to the MMRF Patient Navigator Program.

    For More Information on Velcade visit www.velcade.com.

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