Velcade Overview

• What is Velcade?
• How is Velcade used in multiple myeloma?
• How does Velcade work?
• How is Velcade given?
• What are the possible side effects with Velcade?
• What types of patients can benefit from Velcade therapy?

Velcade in Previously Untreated Myeloma

• Is Velcade-MP effective in previously untreated myeloma?
• Is Velcade-dex effective in previously untreated myeloma?
• What other Velcade combination therapies are effective in previously untreated myeloma?
• Is Velcade effective as maintenance therapy?

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• What clinical trials are available?
  
  

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. 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 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.

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 typically given by injection into the bloodstream, starting with twice a week dosing. However, new dosing schedules and routes of administration are evolving.

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.

Weekly dosing of Velcade

Once-weekly Velcade dosing, using the standard 1.3 mg/m² dose or up to 1.6 mg/m², is being used more frequently than twice-weekly dosing in older patients or when a patient is at high risk for, or already has, peripheral neuropathy. Weekly Velcade dosing is being used more frequently in all upfront treatment cycles when used in combination with MP in elderly patients, as well as when used in combination with other agents. 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.

• For example, a large phase III trial evaluating Velcade in combination with MP with or without Thalomid in elderly patients showed the once-weekly dosing reduced the incidence of peripheral neuropathy and gastrointestinal side effects compared with twice-weekly dosing, but was just as effective. In particular, severe peripheral neuropathy was much less frequent with weekly dosing (8% compared with 28% with twice-weekly dosing).

Weekly Velcade is also commonly used as maintenance therapy.

Subcutaneous administration of Velcade

In April, 2011 Millennium: The Takeda Oncology Company submitted a supplemental new drug application (sNDA) to the FDA to request approval to administer Velcade as an injection under the skin (subcutaneous or s.q. route). This request 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 response rate, time to disease progression, and 1-year survival.
  
  
• Importantly, subcutaneous Velcade was better tolerated than intravenous Velcade, with fewer severe side effects (57% compared with 70%) and significantly less peripheral neuropathy. Only 6% of patients receiving subcutaneous Velcade experienced severe peripheral neuropathy, compared with 16% of patients receiving intravenous Velcade.

Although subcutaneous administration of Velcade is now primarily used in the clinical trial setting, some physicians are using this route of administration in select patients. These patients include those who have poor veins, and intravenous Velcade may be difficult to administer, as well as patients who already have peripheral neuropathy.

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 »

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 (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. The Dana-Farber Cancer Institute has developed an approach for neuropathy with multiple myeloma patients that includes these measures, as well as:

• 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.

In the future, subcutaneous administration of Velcade may be a means of lessening the development of peripheral neuropathy. Results of a large phase III trial being 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?

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 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-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.
    
    
  • At 5 years, patients receiving Velcade-MP had significantly longer overall survival than those treated with MP (56 months versus 43 months). This translates into a 44% improvement in overall survival.
    
    
  • Velcade-MP was consistently effective in patients with poor prognostic features (ie, age ≥ 75 years, impaired kidney function, or high-risk cytogenetics).
    
    
  • The VISTA trial is the largest Phase III study to report long-term overall survival in previously untreated myeloma patients.

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.
  
  
• The risk of disease progression was reduced by 52% with VMPT-VT compared with Velcade-MP.

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%).

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.

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.

The three-drug combinations listed below are now included in myeloma treatment guidelines as recommended options for initial (induction) therapy for transplant candidates.

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.
  
  
• RVD is being evaluated as frontline therapy in three phase III trials. Trials being conducted in the United States are comparing RVD and VD, as well as RVD with and without stem cell transplant. A large combined French and American study is comparing RVD with or without transplant.

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 474 patients in a Phase III clinical trial show that 31% of patients treated with Velcade plus Thal-dex had a complete response or near complete after three cycles of therapy compared with 11% 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 after tandem (double) transplant (54% compared with 42%) and two additional cycles of ‘consolidation’ therapy (60% compared with 44%). The improved responses with added Velcade were seen even in patients with poor prognostic features.
  
  
• Progression-free survival at 3 years was also significantly improved with Velcade-Thal-dex.
  
  
• Side effects were generally manageable, however, peripheral neuropathy was more common when Velcade was added.

Velcade, cyclophosphamide, and dexamethasone (VCD or CyBorD)

The combination of Velcade, cyclophosphamide, and dex (VCD or CyBorD) is a recommended option for frontline therapy in transplant candidates based on high response rates and rapid responses seen in three phase II trials.

• Results of a German Phase 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.
  
  
• 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 the EVOLUTION study achieved high response rates and rapid responses, with 47% of patients achieving a complete or near complete response. An overall response rate of 100% was seen.

Four-drug combinations

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

• Final results of a Phase I/II MMRC trial of trial of Revlimid, Velcade, Doxil^® (doxorubicin HCl liposome injection, Centocor Ortho Biotech), and dexamethasone (RVDD, n=72) show the four-drug combination to be highly active, with rapid and deep responses, and generally well tolerated. Ninety-six percent of patients achieved a partial response or better, and 38% achieved a complete or near-complete response. Responses improved following stem cell transplant, with an increase in the CR/nCR rate to 60%, suggesting that more intensive induction may result in better outcome post-transplant.
  
  
• Updated results of a Phase II trial (EVOLUTION) show that the combination of Velcade, dex, cyclophosphamide, and Revlimid (VDCR) was highly active, but did not appear to offer a substantial increase in response rate over that seen with three-drug combinations (VDR or VDC). 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. Importantly, each of these studies shows that administration of Velcade as maintenance therapy on a weekly schedule, rather that the conventional twice-weekly schedule, was effective and offered an improved safety profile. Also, a recent study showed that Velcade every 2 weeks after transplant for up to 2 years was both well tolerated and effective.

• 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. VT maintenance led to a 52% reduction in risk of progression, and 85% of patients were still alive at 3 years. Greater benefit was seen in patients less than 75 years of age and in patients with low-risk disease.
  
  
• 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.
  
  
• Velcade maintenance increased response rates in elderly transplantation-ineligible patients who received a variety of Velcade-based induction regimens. High response rates seen with Velcade-dex, VTD, and VMP induction in the UPFRONT study were improved with Velcade maintenance.

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.

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

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