Relapsed/Refractory Patients:

Treatment Options - Velcade


Velcade

Overview

Velcade in Relapsed and/or Refractory Myeloma

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 NEWS FLASH:
 Subcutaneous Route of Administration for Velcade Now Available

Last year, the US Food and Drug Administration approved the subcutaneous administration of Velcade. Click here for more information.

What is Velcade?

Velcade® (bortezomib) 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. Subcutaneous administration of Velcade was approved in January 2012. Velcade is now approved for use in myeloma in over 90 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?

Throughout the world, 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.

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 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 as an injection into the bloodstream (intravenously, or IV) or under the skin (subcutaneously) in the thigh or abdomen. Starting Velcade subcutaneously may be considered for patients with pre-existing peripheral neuropathy or those who are at high-risk of peripheral neuropathy.

Velcade was initially approved as a twice-weekly injection. However, new dosing schedules are now also being used.

When used in the treatment of relapsed or refractory myeloma, Velcade can be 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. 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 because some studies have shown it is just as effective as twice-weekly dosing but may have fewer side effects.

If you already have significant peripheral neuropathy, a disorder of the nerves affecting the hands and feet, your doctor will determine whether you should receive Velcade. This is because Velcade can make neuropathy worse.

Subcutaneous administration of Velcade

In January 2012, the FDA approved a supplemental new drug application (sNDA) allowing Velcade to be administered as an injection under the skin (subcutaneous or s.q. route). This approval was based on the results of a large international phase III trial conducted in 222 patients with relapsed myeloma that compared conventional intravenous Velcade administration and subcutaneous Velcade administration.

  • Subcutaneous administration of Velcade was shown to be just as effective as intravenous administration with regard to overall response rate, complete response rate, time to disease progression, and progression-free survival.

  • 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.

The option of 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 Phase III trial upon which the approval of subcutaneous Velcade was based was conducted in patients in their first relapse who had never received Velcade before. For patients with more advanced disease, the intravenous route may be preferred, as there are theoretical reasons that intravenous administration may be more active in this setting.

Weekly dosing of Velcade

Once-weekly Velcade dosing is being used more frequently than twice-weekly dosing in many patient populations, particularly when Velcade is used as part of combination therapy, in older patients, or when a patient is at high risk for, or already has, peripheral neuropathy. 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. In some cases, the schedule of rest periods with weekly Velcade dosing may be different or fewer than those used with twice-weekly dosing.

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

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 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 or decreased. LEARN MORE »

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 as part of 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 ».

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?

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 relapsed or refractory studies
  • 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 experience any of these side effects.

Serious side effects seen in relapsed or refractory studies

In the APEX study, up to 75% of patients with relapsed/refractory myeloma had significant (typically described as Grade 3) or less commonly, more 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
How are side effects of Velcade therapy managed in the relapsed or refractory setting?

Side effects can often be managed with other medications, increasing the amount of fluid you drink, replenishing fluids intravenously, administering growth factors to increase blood counts, administering platelet or red blood cell transfusions if needed, or reducing the dose of Velcadeif necessary. If side effects are severe, your doctor may stop Velcade treatment temporarily until your symptoms resolve. Velcade can then usually 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.

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 emollient 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, using the standard 1.3 mg/m2 dose or up to 1.6 mg/m2, 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. Results of a large phase III trial conducted in patients with relapsed myeloma show that subcutaneous administration of Velcade is better tolerated, with fewer severe side effects and significantly less peripheral neuropathy, but was just as effective as conventional intravenous administration.

What types of patients can benefit from Velcade therapy?

  • 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 or the short arm of chromosome 17 (referred to as deletion 17p), as well as other cytogenetic 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 was initially approved by the FDA for the treatment of patients who had received at least two prior therapies and were progressing despite treatment. 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 and less frequently.

  • 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 high-dose dexamethasone (a standard of care at that time). 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 on average) in patients treated with Velcade compared with patients treated with dexamethasone.


    • Higher response rates: Response rates with Velcade were significantly improved over those seen with dexamethasone both at the time of early termination of the study and at an updated analysis with longer follow up.

      • 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 only patients who received Velcade all along were analyzed.

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

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, 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, 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 suggest that the three drug combination (Rev-Vel-dex or RVD) is very effective, and RVD 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 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.

    • Interim 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 evaluable 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.

    • In a Phase Ib trial that was facilitated by the MMRC (n=62), the combination of Velcade and panobinostat led to a partial response or better in 55% of the heavily-pretreated patients.

      • Responses were seen in 42% of the patients who had previously stopped responding to Velcade therapy. As such, Velcade-panobinostat is among the most active combination therapies in Velcade-refractory disease.

      • Severe side effects included low blood cell and platelet counts that could be managed with dose modification and platelet transfusions.

      • This study used a dose of Velcade that was lower than the standard dose, which led to a low incidence of peripheral neuropathy.

  • 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-dex and perifosine (Aeterna Zentaris), an oral agent that inhibits myeloma cell growth. A global Phase III study is comparing this three-drug combination with Velcade-dex. It is currently recruiting patients who have received 1 to 4 prior therapies, one of which was Velcade.

  • 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 (Vantage 088). This trial, which enrolled 637 patients who had received a median of two prior treatments, has been completed and results were presented at ASH in December 2011.

  • 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.

  • Based on these data and the results of a Phase II trial showing improved overall response rate with Velcade and Zolinza compared with Velcade alone, this combination is now listed as a treatment option for relapsed/refractory myeloma in NCCN myeloma treatment guidelines.

  • 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
BMS-936564 (Bristol-Myers Squibb) Monoclonal antibody being evaluated alone and in combination with Velcade-dex or Revlimid-dex
Chloroquine and cyclophosphamide Antimalarial drug and chemotherapy agent; the combination of all three agents may act together to kill myeloma cells more effectively
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 set to begin
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
Folotyn® (pralatrexate, Allos Therapeutics)a Chemotherapy drug
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
KW-2478 (Kyowa Kakko Kirin Co.) HSP90 inhibitor; trial has completed enrollment
Mozobil® (plerixafor, Genzyme) Agent that helps mobilize stem cells, which also reduces myeloma cells’ ability to adhere to bone marrow cells and sensitizes them to Velcade; encouraging responses and minimal toxicity seen in a Phase I study.
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 73%, including 27% 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)c +/- Doxil Alkylating agent; preliminary data on Velcade and Treanda are promising

*MMRC-funded trial.
aCurrently approved by the FDA for peripheral T-cell lymphoma (PTCL).
bCurrently approved by the FDA for kidney cancer.
cCurrently approved by the FDA for chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma; approved in Germany for myeloma.

For more information about additional clinical trials evaluating Velcade in relapsed and refractory myeloma, click here.

What clinical trials are available?

Click here to go to the MMRF Clinical Trial Matching Service to view a list of ongoing Velcade clinical trials.


Reviewed by:
Paul G. Richardson, MD
Clinical Director, Jerome Lipper Center for Multiple Myeloma
Dana-Farber Cancer Institute
Boston, MA