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Treatment Options - Velcade


Overview

Velcade in Previously Untreated Myeloma

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What is Velcade?

Velcade is the first approved cancer therapy in a 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.

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?

Velcade is used in all stages of myeloma.

When used for as first-line treatment, Velcade is typically used in combination with dexamethasone, another anti-myeloma drug, or as part of a 3-drug combination. Examples of commonly used 3-drug combinations include Velcade-Revlimid-dexamethasone (VRD) or Velcade-cyclophosphamide-dex (VCD or CyBorD/Cybord).

Velcade is used alone or in combination with a variety of anti-myeloma drugs for the treatment of relapsed and/or refractory myeloma.

When used as maintenance therapy, Velcade has also been shown to improve response rates following initial therapy, with or without high-dose chemotherapy and stem cell transplant, in early studies.

Velcade continues to be studied in combination with other approved myeloma drugs and in combination with new drugs in development.

How does Velcade work?

Velcade inhibits the growth and survival of myeloma cells, leading to cell death. 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.

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 as an injection into the bloodstream (intravenously, or IV) or under the skin (subcutaneously, SC, or SQ) usually in the thigh or abdomen. Subcutaneous administration is more commonly used, but different centers and doctors may have different preferences for which route of administration is used for initial therapy and often tailor the choice based on the characteristics of the patient’s myeloma and his or her preferences. The typical starting dose of Velcade is 1.3 mg/m2.

Velcade was initially approved as a twice-weekly injection. However, weekly administration is now commonly used, particularly in older patients or when a patient is at high risk for, or already has, peripheral neuropathy, a disorder of the nerves affecting the hands and feet. Studies have shown that weekly dosing it is just as effective as twice-weekly dosing but may have fewer side effects, including a significantly reduced risk of peripheral neuropathy.

When used as maintenance therapy, Velcade may be administered weekly, or even less frequently, such as once every two weeks.

Subcutaneous administration of Velcade

Subcutaneous administration of Velcade may be particularly beneficial for patients who have poor vein access, existing peripheral neuropathy, or a high risk of developing peripheral neuropathy.

The approval for subcutaneous administration of Velcade was based on the results of a large international phase III trial conducted in 222 patients with relapsed myeloma that compared intravenous Velcade administration and subcutaneous Velcade administration.

  • Subcutaneous administration of Velcade was shown to be just as effective as intravenous administration.

  • Importantly, subcutaneous Velcade was better tolerated than intravenous Velcade, with significantly less peripheral neuropathy.

    • Patients receiving subcutaneous Velcade experienced fewer side effects overall (57% compared with 70% of patients receiving intravenous Velcade).

    • Thirty-eight percent of patients receiving subcutaneous Velcade experienced peripheral neuropathy compared with 53% of patients receiving intravenous Velcade.

    • Only 6% of patients receiving subcutaneous Velcade experienced severe peripheral neuropathy, compared with 15% of patients receiving intravenous Velcade.
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.

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. 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.

Will I need to take any other medications?

If you are being treated with Velcade, your doctor will also give 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?

It is important to remember that side effects of treatment vary from individual to individual.

The most common possible side effects of Velcade include:

  • Nausea, diarrhea, constipation, or vomiting
  • Low platelet counts, also referred to as thrombocytopenia
  • Low numbers of white blood cells known as neutrophils, a condition known as neutropenia
  • Peripheral neuropathy or nerve pain
  • Fatigue
  • Anemia, or low numbers of red blood cells
  • Low numbers of all types of white blood cells, including lymphocytes
  • Rash
  • Fever
  • Loss of appetite

Serious side effects that have been reported with Velcade include:

  • Peripheral neuropathy
  • Low blood pressure
  • Heart problems
  • Lung problems
  • Liver problems
  • A rare, reversible brain condition called posterior reversible encephalopathy syndrome (PRES)
  • Nausea, diarrhea, constipation, or vomiting
  • Low numbers of neutrophils or platelets
  • Tumor lysis syndrome

Note that if you are taking Velcade in combination with other anti-myeloma agents you may experience different side effects.

How are side effects of Velcade 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.

If you develop peripheral neuropathy, your doctor may adjust your Velcade dose.

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If a patient develops peripheral neuropathy, certain medications that decrease neuropathic pain (such as Neurontin® [gabapentin], Elavil® [amitriptyline], Cymbalta® [duloxetine], or Lyrica® [pregabalin]) may be beneficial. In addition, certain soothing creams, such as cocoa butter, may be helpful. A number of centers have developed approaches for managing neuropathy that include these measures, as well as incorporating:

  • Vitamins, such as high-dose multi-B complex vitamins, vitamin E, and essential fatty acids (fish oil, flaxseed oil, and/or evening primrose oil)

  • Amino acids, such as acetyl L-carnitine and alpha-lipoic acid

  • Minerals (magnesium or potassium) or tonic water for muscle cramping

However, always consult with your doctor before taking any supplements or medications. Also, the use of supplements on the day of Velcade administration is not recommended as lab studies have suggested there may be a blunting of Velcade effects, although clinically this has not been shown.

Prompt dose reduction and a change in the schedule of Velcade administration are essential in managing peripheral neuropathy should it develop.

Can anything be done to lessen the development of peripheral neuropathy?

Preventing the development of side effects, when possible, is an important goal of therapy. For example, once-weekly Velcade dosing is now being used more frequently because it has been associated with fewer side effects.

Subcutaneous administration of Velcade may also lessen the development of peripheral neuropathy.

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)

  • Patients with a type of aggressive multiple myeloma where there are changes in the patient's DNA, including a deletion of chromosome 13 or chromosome 17 (referred to as deletion 17p), as well as other abnormalities associated with poor prognosis, such as the t(4;14) or t(14;16) translocation

  • 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

Is Velcade-dex effective in previously untreated myeloma?

Velcade-dex is an effective initial therapy for patients with myeloma, including patients who are eligible for high-dose chemotherapy and stem cell transplant and those who are not.

  • Velcade and dexamethasone is more effective than the once commonly used VAD (vincristine, Adriamycin, and dexamethasone) therapy as upfront treatment for multiple myeloma in patients eligible for transplant, according to data from a large Phase III clinical trial.

  • Velcade-dex resulted in good response rates in the Phase III UPFRONT trial, which compared the safety and efficacy of three Velcade-based regimens in patients who were not eligible for stem cell transplant.

Is Velcade-Revlimid-dex effective in previously untreated myeloma?

Revlimid is thought to make myeloma cells more sensitive to Velcade and dexamethasone. The combination of Velcade, Revlimid, and dexamethasone (VRD or RVD) has been shown to be very effective as frontline therapy, with unprecedented activity seen, even in patients with high-risk features.

  • For example, data from a Phase I/II study in 66 previously untreated patients show that all patients treated with VRD had a partial response or better.
    • Fifty-two percent of patients had a complete response or near-complete response.

    • Seventy-four percent 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.

    • Similar results were seen in two additional Phase II trials in the frontline setting.

As a result, VRD is now included in myeloma treatment guidelines as one of several preferred options for initial therapy for transplant candidates, and is one of the most commonly used regimens in transplant candidates in the United States. VRD is also used for treating myeloma in patients who are not transplant candidates.

In some cases, a lower dose of dexamethasone is used and the combination is referred to as VRd or RVd.

VRD continues to being evaluated as frontline therapy in several phase III trials.

  • Trials being conducted in the United States are comparing VRD and RD, as well as VRD with and without stem cell transplant.

  • A joint US-French study(DFCI/IFM 2009) is evaluating VRD +/- stem cell transplant, with additional VRD (consolidation) and Revlimid maintenance therapy.

A large phase III trial is comparing two proteasome inhibitors—Velcade or Kyprolis (carfilzomib)—in combination with Revlimid-low-dose dexamethasone (VRd vs. CRd) as frontline therapy.

Is Velcade-Cyclophosphamide-dex effective in previously untreated myeloma?

The addition of the chemotherapy agent cyclophosphamide to Velcade-dex has been shown to improve response rates. Velcade-cyclophosphamide-dex (CyBorD or VCD) is one of several preferred options for frontline therapy in transplant candidates listed in current treatment guidelines. This recommendation is based on the high response rates and rapid responses seen in three phase II trials:

  • Results of a German trial show CyBorD to be an effective frontline 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.

  • A North American trial of CyBorD induction showed a similar overall response rate (88%) and a complete/near-complete response rate of 39%, which was improved to 70% following transplant.

  • The use of frontline Velcade, dexamethasone, and weekly cyclophosphamide in a US study achieved high response rates and rapid responses, with 53% of patients achieving a very good response or better. An overall response rate of 100% was seen, and at 1 year, no patients had progressed.

CyBorD is also used as initial treatment in patients who are not eligible for transplant.

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

Velcade in combination with melphalan and prednisone (MP) is FDA approved for initial treatment of myeloma. However, this regimen, like other melphalan-based therapies, is now infrequently used in the United States due to its long-term side effects and the availability of more effective agents.

  • Results of the large Phase III VISTA clinical trial showed that adding Velcade to MP significantly extended the length of time before disease progressed, the length of time a patient remained disease-free following treatment, and improved complete response rates and overall survival compared with patients treated with MP alone.

Various Velcade combinations that include new novel agents are being evaluated as upfront therapy. Examples include:

  • RVD plus siltuximab in transplant eligible patients

  • RVD plus Zolinza® (vorinostat, Merck)

  • Treanda® (bendamustine, Cephalon, a subsidiary of Teva Pharmaceutical Industries, Ltd.), Velcade, and dexamethasone (BBD) in transplant-ineligible patients

  • RVD plus panobinostat (Novartis)

  • RVD with and without elotuzumab (Bristol-Myers Squibb/Abbott)

  • Velcade plus cyclophosphamide induction followed by alternating cycles of Velcade and Revlimid as maintenance

  • A modified RVD regimen (“RVD lite”) being evaluated in patients who are not eligible for transplant, which is set to begin

  • A study to evaluate Velcade plus pomalidomide (Celgene) is planned.

For more information about additional clinical trials evaluating Velcade in the frontline setting, click here.

Is Velcade effective as maintenance therapy?

Velcade is sometimes used 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 maintenance therapy with weekly Velcade can improve outcome. For example:

  • Velcade maintenance increased response rates in elderly transplantation-ineligible patients who received a variety of Velcade-based frontline regimens.

  • Velcade-based maintenance regimens improved the quality of response in older patients with myeloma.

Velcade maintenance given every other week for up to 2 years following stem cell transplantation has also been shown to be well tolerated and associated with improvement in response rates and survival, including in patients with poor-risk genetic features, according to results of a Phase III trial conducted in Europe.

The potential benefits of Velcade maintenance therapy must be balanced with the potential toxicity associated with long-term use of Velcade.

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.

Reviewed by:
Joseph Mikhael, MD
Associate Professor of Medicine, Consultant Hematologist
Mayo Clinic
Scottsdale, AZ

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