Relapsed/Refractory Patients:

Treatment Options - Velcade


Velcade

Overview

Velcade in Relapsed and/or Refractory Myeloma

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What is Velcade?

Velcade® (bortezomib) 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 initial therapy in patients who are eligible for high-dose chemotherapy and stem cell transplant and those who are not, 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.

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 is a proteasome inhibitor. Proteasomes play an important role in regulating cell function and growth by controlling the breakdown of important proteins. By blocking the activity of proteasomes, 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.

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. 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:

  • Low blood pressure
  • Heart problems
  • Lung problems
  • Liver problems
  • A rare, reversible brain condition called posterior reversible encephalopathy syndrome (PRES)
  • 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 effective in treating relapsed and/or refractory myeloma?

Velcade is used in the treatment of relapsed and/or refractory myeloma.

Data from a large Phase III clinical trial showed that Velcade was more effective than high-dose dexamethasone (a standard of care at that time). Compared with patients treated with high-dose dexamethasone, patients treated with Velcade had:

  • a significantly longer time-to-disease progression (TTP)

  • higher response rates

  • improved survival

What Velcade combination therapies are effective in relapsed and/or refractory myeloma?

Velcade is commonly used as part of combination therapy for the treatment of relapsed and/or refractory myeloma. Recent clinical trials have shown that treatment with some of these Velcade combinations have resulted in high response rates and improved disease-free survival. Examples include:

  • Velcade and dexamethasone: Dexamethasone is often added to Velcade therapy as it has been shown to improve response rates over that seen with Velcade alone.

  • Velcade, Revlimid, and Dexamethasone: Revlimid® (lenalidomide, Celgene) is thought to make myeloma cells more sensitive to Velcade and dexamethasone. Results from a multicenter Phase II trial show that the three drug combination (VRD or RVD) is very effective as a treatment for relapsed or refractory myeloma. As a result, VRD is often used in this setting and is listed as one of several preferred options for treatment of relapsed or refractory myeloma in current treatment guidelines.

    • Overall, 64% of 64 evaluable patients responded to this treatment (a partial response or better) and 25% achieved a complete or near-complete response.

    • After a median follow-up of almost 36 months, overall survival was encouraging and approached 30 months, and 45% of patients were still alive.

    • The combination was well tolerated, with manageable side effects.


  • Velcade, Cyclophosphamide, and Dexamethasone (VCD): The addition of cyclophosphamide to Velcade-dex has been shown to improve response rates.

  • Velcade and Doxil: Doxil® (doxorubicin HCl liposome injection, Janssen 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 retreatment remains a highly effective therapeutic option for previously treated myeloma. According to an analysis of 23 studies that included a total of 1051 patients, retreatment with Velcade-based therapy was effective and well-tolerated in patients with relapsed/refractory myeloma. The overall response rate to Velcade retreatment across all studies was 39%.

What other Velcade combination therapies are being evaluated in relapsed and/or refractory myeloma?

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. Several novel agent combinations are being evaluated in Phase III trials.

  • Velcade-dex plus panobinostat (LBH589, Novartis), an oral agent that inhibits many of the enzymes myeloma cells need to grow and survive.

    • This three-drug combination is being evaluated in a global Phase III trial (PANORAMA 1) in patients with relapsed myeloma, where it is being compared to Velcade-dex. This trial has completed enrollment. Very preliminary data show that the combination is active and no new or unexpected side effects have been noted to date.

    • Results of a Phase II study suggest that Velcade-dex plus panobinostat is effective in relapsed myeloma that no longer responds to Velcade.

      • The study, called PANORAMA 2, included patients who had received a median of 4 prior treatments and whose disease was refractory to Velcade.

      • Of the 55 patients, 2% achieved a near-complete response and 33% achieved a partial response, including 6% very good partial responses.

      • Low platelet counts were the most common severe side effect and were managed with dose reduction or interruption.

      • Common mild side effects included peripheral neuropathy, fatigue, and weakness.

      • Progression-free survival and time to disease progression were both 5.4 months.

  • Velcade and low-dose dexamethasone plus Pomalyst® (pomalidomide, Celgene), an immunomodulatory drug recently approved by the FDA for use in myeloma. This three-drug combination is being compared with Velcade plus low-dose dex.

  • Velcade plus masitinib (AB1010, AB Science), an oral anticancer agent (tyrosine kinase inhibitor). This trial is being conducted in the United States and France.

Velcade has also been evaluated in combination with Zolinza® (vorinostat, Merck), an oral histone deacetylase inhibitor, in a large Phase III trial.

  • Progression-free survival was longer in patients receiving the combination compared with Velcade and placebo (7.6 vs. 6.8 months). However, overall survival was not significantly improved with the combination.

  • Merck has decided not to pursue further development of Zolinza in myeloma. However, patients may have access to Zolinza through clinical trials or off-label.

Other new cancer drugs that are being studied in combination with Velcade in early clinical trials in relapsed and/or refractory myeloma are listed below.

New Combinations with Velcade: Early Studies (Phase I and II)
Treatment: Velcade plus… Possible anti-myeloma effect
ACY-1215 (Acetylon) Oral histone deacetylase inhibitor
Alisertib (MLN8237, Millennium: The Takeda Oncology Company)* Novel agent (Aurora A kinase inhibitor); results of the Phase I portion of the study showed an overall response rate of 26%; the Phase II is ongoing  
ARRY-520 (Array BioPharma)* Novel agent (kinesin spindle protein [KSP] inhibitor); durable responses and an acceptable safety profile seen in a Phase I study
AT7519 (AT7519M, Astex)*† CDK inhibitor; trial has completed enrollment
BMS-936564 (Bristol-Myers Squibb) Monoclonal antibody directed against a cell marker (CXCR4) normally found on immune cells and in increased levels in various cancer cells; being evaluated alone and in combination with Velcade-dex or Revlimid-dex
Dinaciclib (SCH 727965, Merck) CDK inhibitor that has shown anti-myeloma activity as a single agent in a phase I/II trial; a study evaluating dinaciclib in combination with Velcade-dex is in progress
Elotuzumab (HuLuc63, Abbott/Bristol-Myers Squibb) Antibody that targets myeloma cells; results of a phase I trial are encouraging, with 48% of patients responding to the combination; a phase II trial is in progress
Ganetespib (STA-9090, Synta Pharmaceuticals)* Heat shock protein (HSP90) inhibitor
GSK2110183 (GlaxoSmithKline)*† Oral AKT inhibitor; enrolling patients with myeloma that is refractory to other proteasome inhibitors
Linsitinib (ASP7487, formerly OSI-906; Astellas Pharma)*‡ Novel agent (insulin-like growth factor-1 [IGF-1] receptor inhibitor); Phase I/II trial being conducted in the US and Canada
PD0332991 (Pfizer) and dex Oral agent (CDK inhibitor) that enhances the activity of Velcade-dex; preliminary results of a Phase II study are encouraging
Pomalyst™ (pomalidomide, Celgene) and dex* Oral immunomodulatory agent (IMiD); preliminary results of an ongoing Phase I study that includes low-dose dex show the combination to be active, with an overall response of 75%, including 25% very good partial responses
Siltuximab (CNTO-328, Janssen Biotech, Inc.) Anti-IL-6 monoclonal antibody; results of a randomized phase II study showed higher response rates with the combination, but these did not result in improved survival over Velcade alone
Tabalumab (LY2127399, Lilly) Antibody directed against a protein that activates B cells; results of a phase I trial are encouraging, with 46% of patients responding to the combination, including 4% complete responses. Responses were seen in patients who previously had received Velcade. A Phase II study is currently enrolling.
TH-302 (Threshold Pharmaceuticals) Anticancer drug that is converted to its active form in areas where there is low oxygen (hypoxia), such as within tumors or in the bone marrow where myeloma cells are found
Treanda® (bendamustine, Cephalon, a subsidiary of Teva Pharmaceuticals) a+/- Doxil Alkylating agent; preliminary data on Velcade and Treanda are promising; also being evaluated in combination with other agents

*MMRC-facilitated trial.
† Funded by the MMRF Biotech Investment Award (BIA) program
‡ Funded by the donor-supported MMRF Clinical Fund
aCurrently approved by the FDA for chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma; approved in Germany for myeloma.

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