RELAPSED/REFRACTORY PATIENTS:

TREATMENT OPTIONS

Velcade® (bortezomib)

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 Relapsed and/or Refractory Myeloma

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

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• What clinical trials are available?

What is Velcade?

Velcade is the first approved cancer therapy in a new class of medicines known as proteasome inhibitors. In the United States, Velcade is approved by the Food and Drug Administration (FDA) for the treatment of patients with multiple myeloma. It was initially approved for the treatment of relapsed and refractory myeloma in 2003, then for relapsed patients in 2005, and most recently was approved for previously untreated patients (also referred to as "upfront therapy") in June 2008. Velcade is now approved for use in myeloma in over 85 countries worldwide.

Velcade is made by Millennium: The Takeda Oncology Company. It is also called bortezomib. Velcade is approved for use in the United States for the treatment of another type of blood cancer known as mantle cell lymphoma.

How is Velcade used in multiple myeloma?

In the United States, Velcade is used for the treatment of myeloma in all phases of the illness, and is approved by the FDA for the treatment of patients with multiple myeloma throughout their course, from diagnosis to first relapse and beyond.

Data from 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.

Data from trials in newly diagnosed or untreated patients show that Velcade is effective in this setting, is superior to standard therapies, and achieves consistently high rates of response, including some of the highest recorded response rates for upfront (or front-line) treatment of myeloma.

In the European Union and many other countries, Velcade is approved for the treatment of patients who have already been treated with at least one other therapy, including those patients who have already had a stem cell transplant, as well as patients who are not eligible for a stem cell transplant.

Velcade is now being studied in combination with other approved myeloma drugs and in combination with new drugs in development.

How does Velcade work?

Velcade is a type of cancer drug called a proteasome inhibitor. Proteasomes are enzymes found in cells and play an important role in regulating cell function and growth by controlling the breakdown of important proteins. Velcade blocks the activity of proteasomes and by blocking the proteasome, Velcade disrupts processes related to the growth and survival of cancer cells, myeloma cells in particular. Importantly, Velcade targets both the myeloma cell and the tumor microenvironment.

New data also suggest that Velcade may significantly improve bone disease in myeloma patients. Velcade's beneficial effect on bone disease appears to be independent of whether or not a patient's myeloma responds to Velcade. Furthermore, Velcade is as active and safe in patients with myeloma-related kidney damage as in patients with normal kidney function.

How is Velcade given?

Velcade is given by injection into the bloodstream. When used in the treatment of relapsed or refractory myeloma, Velcade is usually 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.

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. 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 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

Dosing adjustments of Velcade are not necessary for patients with reduced kidney function (renal impairment), a common feature of myeloma.

Will I need to take any other medications?

If you are being treated with Velcade, your doctor will also consider giving you medication to prevent shingles, a viral infection that causes a painful rash and is due to a reactivation of the herpes zoster virus (the virus that causes chickenpox). In clinical trials, up to 25% of patients who did not receive preventive (prophylactic) medication developed shingles, but only 3% of patients who received antiviral medication developed the condition.

Other medications that may be given with Velcade include agents to prevent possible nausea or diarrhea. Supplements including B vitamins and folic acid, as well as certain amino acids, are sometimes suggested to help prevent peripheral neuropathy, but should not be taken on the same day that Velcade is given. Talk to your doctor about any supplements you use.

What are the possible side effects with Velcade?

The side effects seen with Velcade therapy in studies of previously untreated myeloma (frontline studies) can be slightly different than those seen in studies of relapsed or refractory myeloma. This is mainly due to the fact that Velcade was given along with melphalan and prednisone (MP) in the frontline studies and was given by itself or with steroids in the relapsed or refractory studies.

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

The side effects seen with Velcade-MP are similar to those seen with the individual drugs. In the Phase III VISTA trial, the study upon which the approval of Velcade for previously untreated myeloma was based, the most common side effects seen with Velcade-MP included:

• Low platelet counts, also referred to as thrombocytopenia
• Low numbers of white blood cells known as neutrophils, a condition known as neutropenia
• Nausea, diarrhea, or constipation
• Peripheral neuropathy Anemia, or low numbers of red blood cells

In the VISTA trial, most of the side effects seen with Velcade-MP were mild (Grade 1) or moderate (Grade 2) in severity. Learn More

Sometimes these symptoms can worsen and 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 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

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 severe side effects. Learn More

Most common side effects seen in relapsed or refractory studies

The most common side effects seen when Velcade was used in the treatment of relapsed and refractory disease include:

• 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 are having any 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 may be beneficial. In addition, certain emollient creams, such as cocoa butter, may be helpful. However, prompt dose reduction and a change in the schedule of Velcade administration are essential in managing peripheral neuropathy should it develop.

What types of patients can benefit from Velcade therapy?

Velcade has been shown to be effective in a wide range of patients, including:

• Patients with previously untreated myeloma
• Patients with relapsed or refractory myeloma
• Older patients (≥65 years old) as well as younger patients
• Patients with "high-risk" disease (which indicates a greater likelihood of poor prognosis)
  • Data from the Phase III APEX clinical trial showed that Velcade was effective in patients who had been treated with more than one prior therapy, patients with beta-2 microglobulin higher than 2.5 mg/L, and/or patients who did not respond to their last treatment.
• Patients with a type of aggressive multiple myeloma where there are changes in the patient's DNA, including a deletion of chromosome 13, as well as other cytogenetic abnormalities associated with poor prognosis
• 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.
• Velcade has been shown to be effective in heavily-pretreated patients with relapsed and refractory myeloma. Results from the Phase II SUMMIT trial of 202 patients with relapsed and refractory myeloma who had already been treated with a median of six prior therapies showed that 28% of patients responded to Velcade with a partial response or better, and 35% with a minimal response or better. A number of patients who did not respond to Velcade alone improved their response with the addition of dexamethasone.
• Velcade was also shown to be effective when given at a lower dose. Results from the Phase II CREST clinical trial of 54 patients with relapsed or refractory myeloma who had been treated with at least one prior therapy showed that 4% of patients treated with a lower dose of Velcade (1.0 mg/m2 ) achieved a complete or near complete response and 19% had a partial response. Patients treated with the lower dose of Velcade had less frequent neuropathy and gastrointestinal side effects. These findings suggest that patients who cannot tolerate the full dose of Velcade may benefit from being given a lower dose.

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, Ortho 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.
  • Overall, 69% of 62 evaluable patients responded to this treatment (a partial response or better) and 26% achieved a complete or near-complete response.
  • Patients tended to respond for a prolonged period of time, with disease control for about 12 months on average.
  • The combination was well tolerated, with manageable side effects.

• Velcade, Melphalan, Prednisone, and Thalomid: The addition of Thalomid® (thalidomide, Celgene) and Velcade to the standard melphalan/prednisone combination significantly increases patients' response rates and the length of time patients' remain disease-free following treatment when used in the relapsed setting. Of the 30 patients in this Phase I/II study who received this combination, 17% had a complete response and 27% had a very good partial response. Please note that melphalan-based combinations are not appropriate for patients considering a stem cell transplant.

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

• Velcade and Zolinza® (vorinostat, Merck), a histone deacetylase inhibitor, which appears to be active, even in patients who received Velcade before.
• Two Phase I studies were conducted in a total of 57 patients with relapsed or refractory myeloma to determine safe and effective doses of these two drugs when used together. In these studies, administration of Zolinza with standard doses of Velcade resulted in a partial response or better in over 40% of evaluable patients.
• Velcade-dex and perifosine (KRX-0401, Keryx), an agent that inhibits myeloma cell growth.
• Results of a Phase II study show that the combination is active in patients who had relapsed on, or were refractory to, Velcade, with approximately 6% of patients achieving a complete response, and about 20% achieving a partial response, with encouraging overall survival seen.
• Velcade-dex plus panobinostat (LBH589, Novartis), an oral agent that inhibits many of the enzymes myeloma cells need to grow and survive, which showed promising activity and favorable tolerability in a Phase I trial.

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

What clinical trials are available?

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