What is Velcade®?

How is Velcade used in multiple myeloma?

Velcade is used in all stages of multiple myeloma.

Velcade is used as initial therapy in patients, regardless of whether they are candidates for high dose chemotherapy and stem-cell transplant.

Velcade is used alone or in combination with a variety of anti-myeloma drugs for the treatment of relapsed and/or refractory myeloma. It may be used in patients who had previously responded to treatment with Velcade and who have relapsed at least 6 months after completing prior Velcade treatment.

In early studies, Velcade used as maintenance therapy was 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.

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
• Patients with high-risk disease (which indicates a greater likelihood of poor prognosis)
• Patients with a type of aggressive multiple myeloma in which there are changes in the patient’s DNA, including a deletion of chromosome 13 or chromosome 17, as well as other genetic abnormalities associated with poor prognosis, such as the translocations t(4;14) or t(14;16)
• 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

How is Velcade Administered?

Velcade is given as an injection, either into the bloodstream (intravenously, IV) or under the skin (subcutaneously, SC or SQ), usually in the thigh or abdomen. SC administration is more frequently used because it is better tolerated than IV administration, and there is reduced risk of peripheral neuropathy, a nerve disorder affecting the hands and feet.

Velcade is given for nine 6-week treatment cycles. In cycles 1–4, Velcade is administered twice a week (days 1, 4, 8, 11, 22, 25, 29, and 32) and in cycles 5–9, Velcade is administered once weekly (days 1, 8, 22, and 29). Different schedules may be used for patients who are receiving treatment for the first time, those receiving treatment for relapsed disease, and those receiving Velcade in combination with other drugs. A typical starting dose is 1.3 mg/m2, but lower IV doses or higher SC doses may also be used. When used as maintenance therapy, Velcade may be administered weekly or less frequently, such as once every 2 weeks, with similar or longer treatment periods.

Dosing adjustments are not necessary for patients with reduced kidney function (renal impairment). However, patients with moderately or severely reduced liver function (hepatic impairment) typically start with a reduced dose of Velcade (0.7 mg/m2). Depending on how this dose is tolerated, subsequent doses may be increased or decreased.

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. You and your doctor can discuss the length of treatment that may be right for you.

If you are being treated with Velcade, your doctor may 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).

What are Velcade side effects?

Velcade side effects vary from patient to patient and may be influenced by the current stage of a patient’s myeloma.

The most common possible side effects of Velcade include:

• Nausea, diarrhea, constipation, or vomiting
• Low platelet counts (thrombocytopenia)
• Low numbers of white blood cells ( neutrophils), a condition known as neutropenia
• Nerve pain or numbness/tingling (peripheral neuropathy, neuralgia)
• Fatigue
• Low numbers of red blood cells (anemia)
• Low numbers of all types of white blood cells, including lymphocytes
• Rash
• Fever

Serious side effects that have been reported with Velcade include:

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

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

Also, let your doctor know if you are taking medication for diabetes, as Velcade can affect your blood glucose levels. Your doctor may ask you to closely monitor your blood glucose levels and may adjust the dose of your diabetes medicine while you are being treated with Velcade.

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.

Patients that develop peripheral neuropathy may be given certain medications that decrease neuropathic pain (such as Neurontin [gabapentin, Pfizer], amitriptyline, Cymbalta [duloxetine, Lilly], or Lyrica [pregabalin, Pfizer]). In addition, certain soothing creams, such as cocoa butter, may be helpful. A number of centers have developed approaches for managing neuropathy.

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 studies have suggested that there may be a blunting of Velcade effects, though clinically this has not been shown.

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

Can anything be done to lessen the risk of developing peripheral neuropathy?

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

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

What have Velcade clinical studies shown?

Clinical studies have shown that Velcade is effective as initial therapy in myeloma, as maintenance therapy, and as therapy for previously treated myeloma.

Is Velcade-dexamethasone effective in previously untreated myeloma?

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

• Velcade-dexamethasone is more effective than the once commonly used VAD (vincristine, doxorubicin, and dexamethasone) therapy as up-front treatment for multiple myeloma in patients eligible for transplant, according to data from a large phase 3 clinical trial.
• Velcade-dexamethasone resulted in good response rates in the phase 3 UPFRONT trial, which compared the safety and efficacy of three Velcade-based regimens in patients who were not eligible for stem cell transplant.

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

Revlimid is thought to make myeloma cells more sensitive to Velcade and dexamethasone. The combination of Velcade, Revlimid, and dexamethasone (VRD or RVD) has been shown to be very effective as frontline therapy, with unprecedented activity seen, even in patients with high-risk features. In some cases, a lower dose of dexamethasone is used and the combination is referred to as VRd or RVd

• For example, data from a large phase 3 study (SWOG S0777) in patients with previously untreated myeloma showed that the addition of Velcade to Revlimid-low-dose dexamethasone (Rd) improved survival.
  • The study included 525 patients, including those who were transplant-eligible and those who were not transplant candidates. All patients received Rd maintenance until their disease progressed or they experienced unacceptable toxicity
  • Patients receiving VRd experienced a significantly longer time before disease progression (progression-free survival, PFS) compared to Rd (43 vs. 30 months)
  • Overall survival was significantly longer in patients receiving VRd compared to Rd (75 vs. 64 months).
• Performing a stem cell transplant early after VRd induction therapy was shown to improve PFS over VRd induction alone in a large phase 3 study (IFM/DFCI 2009).
  • The study included 700 newly diagnosed patients who were eligible for stem cell transplantation. All received VRd induction and half also received an autologous stem cell transplant. All patients then received Revlimid maintenance for 1 year.
  • On average, patients who received a transplant experienced longer PFS (43 vs 34 months), and the percentage of patients surviving without disease progression at 4 years was significantly higher (47% vs. 35%).
  • Among responding patients in either treatment arm, PFS was significantly longer in those who had no evidence of remaining myeloma cells present in the bone marrow (minimal residual disease, MRD) before and after maintenance therapy as detected by very sensitive tests.
  • Patients on this study continue to be followed to determine the effect of transplant on overall survival.

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

Is Velcade-cyclophosphamide-dexamethasone effective in previously untreated myeloma?

The addition of cyclophosphamide to Velcade-dexamethasone has been shown to improve response rates. Velcade-cyclophosphamide-dexamethasone (CyBorD or VCD) is one of several preferred options for frontline therapy in transplant candidates listed in current treatment guidelines. This recommendation is based on the high response rates and rapid responses seen in three phase 2 trials:

• Results of a German trial show CyBorD to be an effective frontline regimen in patients aged 60 years or younger, and also in patients with high-risk myeloma. An overall response rate (partial response or better) of 84% was seen, and 10% of patients achieved a complete response.
• A North American trial of CyBorD induction showed a similar overall response rate (88%) and a complete/near-complete response rate of 39%, which was improved to 70% following transplant.
• The use of frontline Velcade, dexamethasone, and weekly cyclophosphamide in a US study achieved high response rates and rapid responses, with 53% of patients achieving a very good response or better. An overall response rate of 100% was seen, and at 1 year, no patients had progressed.

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

Is Velcade effective as maintenance therapy?

Velcade is sometimes used as maintenance therapy following stem cell transplantation or other therapy as a way to reduce the risk of relapse and extend survival. Results of several phase 3 trials show that maintenance therapy with weekly Velcade can improve outcome. For example:

• Velcade maintenance increased response rates in older transplant-ineligible patients who received a variety of Velcade-based frontline regimens.
• Velcade-based maintenance regimens improved the quality of response in older patients with myeloma.

Velcade maintenance given every other week for up to 2 years following stem cell transplantation has also been shown to be well tolerated and associated with improvement in response rates and survival, including in patients with poor-risk genetic features, according to results of a phase 3 trial conducted in Europe.

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

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 3 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 are often combined, as this combination has been shown to improve response rates more than Velcade alone.
• Velcade, Revlimid, and dexamethasone: According to treatment guidelines, VRd is one of the preferred options for initial therapy of myeloma patients, regardless of whether they are transplant candidates. VRd is highly effective against relapsed or refractory myeloma and is listed in current treatment guidelines as a preferred treatment option for treatment of patients with relapsed or refractory myeloma.
• Velcade, cyclophosphamide, and dexamethasone (VCD): The addition of cyclophosphamide to Velcade-dexamethasone has been shown to improve response rates.
• Velcade and Doxil: Doxil (doxorubicin HCl liposome injection, Janssen) 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 3 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, Farydak, and dexamethasone: Farydak (panobinostat, Novartis) is approved for use in combination with Velcade and dexamethasone to treat patients with myeloma who have received at least two other treatments, including Velcade and an immunomodulatory agent (Revlimid, Thalomid [thalidomide, Celgene], or Pomalyst [pomalidomide, Celgene]). Results from a phase 3 clinical trial show that patients treated with Velcade, Farydak, and dexamethasone were disease-free significantly longer than the patients treated with Velcade-dexamethasone (a median time of 12 months vs 8.1 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 1,051 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 myeloma?

There are many other Velcade combination therapies being evaluated in ongoing clinical trials in myeloma. Some combinations include conventional chemotherapy agents, whereas others include new novel therapies. The following combinations are being tested in phase 3 trials in untreated myeloma:

• Velcade, Darzalex (daratumumab, Janssen), Revlimid, and dexamethasone (D-VRd) vs Velcade, Revlimid, and dexamethasone (VRd) (NCT03652064)
• Velcade, Revlimid, isatuximab, and dexamethasone (IMROZ trial; NCT03319667)
• Velcade or Kyprolis (carfilzomib, Amgen) with Revlimid and dexamethasone (NCT01863550)

The following combinations are being tested in phase 3 trials in relapsed and/or refractory myeloma:

• Velcade–low-dose dexamethasone plus selinexor (BOSTON trial; NCT03110562)
• Velcade–low-dose dexamethasone and Pomalyst (pomalidomide, Celgene) (OPTIMISMM trial; NCT03110562)

Interested in learning more about Velcade clinical trials? Talk to an MMRF Nurse Patient Navigator to learn more or use our clinical trials finder:

FIND CLINICAL TRIALS

Updated February 2019

Please visit the sponsor’s official patient site for up-to-date information on Velcade