Velcade (bortezomib)

VELCADE® became the first in a class of drugs called proteasome inhibitors to be approved by the FDA for use in myeloma. 

Who Is a Candidate for Velcade?

Velcade (bortezomib) is approved by the FDA for use throughout the myeloma disease course, in combination with nearly all other FDA-approved anti-myeloma therapies. Velcade has demonstrated the ability to produce a beneficial effect even in patients who were already treated with Velcade in a prior line of therapy. 

Velcade is used in the following ways with multiple myeloma:

• as induction therapy for newly diagnosed multiple myeloma (NDMM)
• as part of a conditioning regimen for autologous stem cell transplant (ASCT)
• as consolidation therapy
• as maintenance therapy
• as treatment for patients whose myeloma has relapsed or has become refractory 

How Does Velcade Work?

Velcade is in a drug class of proteasome inhibitors, drugs that interfere with the normal function of the proteasome, a joined group (“complex”) of enzymes (“proteases”) that break down the damaged or unwanted proteins in both normal cells and cancer cells into smaller components. 

Proteasomes also carry out the regulated breakdown of undamaged proteins in the cell, a process that is necessary for the control of many critical cellular functions. These smaller protein components are then used to create new proteins required by the cell. This process is important for maintaining balance within the cell and for regulating cell growth. 

When Velcade inhibits proteasome function, myeloma cells stop dividing and stop producing chemicals that stimulate other myeloma cells. Also, the autocrine feedback loop is interrupted. Myeloma cells are more sensitive to these effects than normal cells, so myeloma cells die while normal cells can recover.  

How Is Velcade Given?

In 2003, Velcade received FDA approval for the treatment of patients with progressive disease after previous treatment, to be administered as an intravenous (IV) infusion at a doctor’s office or a clinic. 

In 2012, the FDA granted approval for Velcade to be administered as a subcutaneous (SQ) injection under the skin. The SQ shot of Velcade is given at a doctor’s office or a clinic at the same dose and on the same schedule as the IV method of administration. SQ injections should be given on a sequential rotation of 4 injection sites: the left and right sides of the abdomen and the left and right thighs. It is important to note that there is no data to support administration of SQ Velcade in the arm. 

Data on side effects from clinical trials with Velcade have demonstrated that SQ administration causes significantly less peripheral neuropathy (PN) than IV administration, and may also reduce the occurrence of gastrointestinal (GI) side effects. If you have pre-existing PN or GI problems, you should discuss using SQ Velcade with your doctor. 

What Is the Dose and Schedule for Velcade?

If you have newly diagnosed multiple myeloma (NDMM), discuss with your doctor the most appropriate treatment strategy for your disease. As a newly diagnosed myeloma patient, your decision to undergo Velcade therapy may be affected by the following factors: 

• your personal preference 
• your plans for transplant (or not) 
• the presence or absence of kidney problems or neuropathy 
• whether or not you have high-risk multiple myeloma (HRMM) 
• your insurance coverage and other personal or medical factors. 

The DVRd Regimen 

In July 2024, the FDA approved the “quadruplet” (4-drug) DVRd regimen for induction therapy and consolidation therapy in patients with newly diagnosed multiple myeloma (NDMM) who are eligible for autologous stem cell transplant (ASCT).

The DVRd regimen combines four FDA-approved drugs, each from a different drug class and with a different way of attacking myeloma:

• monoclonal antibody Darzalex Faspro® (daratumumab + hyaluronidase-fihj),
• proteasome inhibitor Velcade
• immunomodulatory agent Revlimid® (lenalidomide), and
• a steroid (dexamethasone). 

Each drug in this combination therapy enhances the activity of the other drugs.

The FDA approval of DVRd is based on data from the PERSEUS phase III clinical trial of DVRd in ASCT-eligible patients with NDMM. A total of 709 myeloma patients were randomized to receive DVRd (355 patients) or VRd (354 patients). Patients were 70 years or younger and had a performance status of 0 to 2 based on the scale by the Eastern Cooperative Oncology Group (ECOG), now part of the ECOG-ACRIN Cancer Research Group.

The PERSEUS study demonstrated a 60% reduction in risk of disease progression or death. Furthermore, there was a significant advantage in overall MRD-negativity rate between the DVRd study arm (57.5%) and VRd study arm (32.5%). Additionally, the MRD negativity among those who also achieved a complete response (CR) or better was 76.6% (DVRd arm) and 58.5% (VRd arm).
 

The Isa-VRd regimen 

In September 2024, the FDA approved the “quadruplet” regimen of monoclonal antibody Sarclisa® (isatuximab), Velcade, Revlimid, and  dexamethasone [Isa-VRd] for transplant-ineligible patients with NDMM. 

The FDA approval of Isa-VRd is based on data from the IMROZ phase III clinical trial. The IMROZ trial compared the efficacy and safety of Isa-VRd vs. VRd for transplant-ineligible patients with NDMM. The study included 446 patients, and the primary endpoint was progression-free survival (PFS). The results showed that Isa-VRd reduced the risk of progression or death by 40.4% compared to VRd. Isa-VRd also led to deep and sustained responses, with higher rates of complete response (CR), MRD-negativity, and sustained MRD-negativity for at least 12 months. The safety profile of Isa-VRd was consistent with the addition of Sarclisa to VRd. 
. 

The VRd regimen 

Please note that the “triplet” (3-drug) combination therapy of Velcade, Revlimid, and dexamethasone [VRd] continues to be used in some regions. 

Recommended reading 

For a more comprehensive discussion of the drugs that are part of the VRd, DVRd, and Isa-VRd regimens, read these IMF publications: 

• Understanding DARZALEX® (daratumumab) intravenous infusion and DARZALEX FASPRO® (daratumumab + hyaluronidase-fihj) subcutaneous injection 
• Understanding Dexamethasone in the Treatment of Myeloma 
• Understanding the Isa-VRd regimen in Newly Diagnosed Myeloma
• Understanding the VRd regimen in Newly Diagnosed Myeloma
• Understanding REVLIMID® (lenalidomide) 
• Understanding SARCLISA® (isatuximab-irfc) 
• The VRd Regimen Tip Card 
   

Velcade in Relapsed Disease Settings 

Therapy with Velcade has been demonstrated to be effective in various combinations and sequences, as well as in the settings of a conditioning regimen, consolidation therapy, maintenance therapy, and relapsed or refractory multiple myeloma (RRMM). 

The XVd regimen 

In 2020, the FDA approved the combination of Xpovio® (selinexor), Velcade, dexamethasone (XVd) for myeloma patients who have received at least 1 prior therapy. The XVd regimen is given once-weekly. The FDA approval of the XVd regimen was based on data from the BOSTON phase III randomized clinical trial. 

The BOSTON clinical trial evaluated the clinical efficacy of XVd compared with Vd in 402 participants (195 in the XVd group and 207 to the Vd group). In the XVd group, the doses of Velcade and dexamethasone were reduced by 40% and 25%, respectively. At the median follow-up of 16.5 months in the Vd group, the PFS was 9.46 months. At the median follow-up of 13.2 months in the XVd group, the statistically significant increase in PFS was 13.93 months. 

The XVd group outperformed the Vd group not only in PFS but also in the overall response rate (ORR): patients over 65 years old, frail patients, patients with high-risk cytogenetics such as del(17p), patients with moderate renal (kidney) insufficiency, and patients who had previously received Velcade or Revlimid. In addition, peripheral neuropathy was less prevalent in the XVd group than in the Vd group. 

Learn more with the IMF publication Understanding XPOVIO® (selinexor).

Dose and Schedule of Velcade 

Velcade may be administered once-weekly or twice-weekly in combination with other drugs. However, clinical trial data have shown that a once-weekly schedule of Velcade is associated with reduction of side effects without reduction in treatment efficacy when compared to the twice-weekly schedule. 

If you experience side effects, have pre-existing medical conditions, or are elderly or frail, your doctor may choose to lower your dose of Velcade, to change your treatment schedule, or to skip your scheduled dose(s) to reduce the severity of a side effect before continuing treatment. 

The following two tables show how Velcade may be dosed:

Table 1 Velcade Treatment for Frail Patients* 

*Note: Frail patients here are defined as having the following risk factors:
•    Age: over 75 years.
•    Mild, moderate, or severe frailty: help needed for household and personal care.
•    Comorbidities and organ dysfunction: cardiac, pulmonary, hepatic, and/or renal

Table 2 Velcade Treatment for All Other Patients*

Note: If a Grade 3–4 AE (adverse event, or side effect) occurs with the above dosing:

1. discontinue therapy
2. wait for a Grade 1 AE
3. restart at a lower dose

Kidney Impairment, Chromosomal Abnormalities, and Venous Thromboembolism (VTE)

Several clinical trials have confirmed the safety and efficacy of Velcade for patients with renal (kidney) impairment. Clinical trials with Velcade have also demonstrated its ability to help prevent bone loss in myeloma patients.

In addition, clinical trials using various treatment strategies incorporating Velcade have shown that Velcade can help overcome chromosomal abnormalities, t(4;14) in particular, and significantly improve overall survival.

There is low risk of venous thromboembolism (VTE) with Velcade, and Velcade may even provide a protective effect against VTE in combination with immunomodulatory agent-based regimens.
 

Possible Side Effects of Velcade 

Most of the side effects associated with Velcade are manageable and predictable. The most significant and most frequently occurring side effects are described here. Your doctor can provide more information in greater detail. Be sure to promptly report any changes in your health to your doctor. 

Peripheral neuropathy

Peripheral neuropathy (PN) is a serious condition that affects nerves in the hands, feet, lower legs, and/or arms. Symptoms of PN may include a feeling of numbness, tingling, burning, and/or pain. Myeloma patients may experience PN from the effects of the disease itself or from treatments for myeloma.

Prevention and treatment of PN

SQ Velcade causes significantly less PN than IV Velcade. In a French trial that compared SQ to IV Velcade, only 6% of the patients who received SQ Velcade had PN of Grade 3 or 4, while 16% of the IV Velcade patients had Grade 3 or 4 PN.

Contact your doctor immediately if you experience new or worsening symptoms of PN, as early detection and dose modification may prevent progression of this condition. Recommendations for Velcade dose and schedule modifications are based on the following key principles:

• Avoid progressive PN, especially if any significant pain develops (what is called Grade 2). Although PN can be reversible, it may be partly but not fully reversible. Prevention is the best approach. This requires early, proactive dose and/or schedule modifications.
• Discuss options for dose/schedule/method of administration changes with your doctor. The main types of modification ar
  • Dose reduction. This is done in stepwise fashion:
    • Full dose: 1.3 mg/m2 of body surface area.
    • First dose reduction: 1.0 mg/m2.
    • Half dose: 0.7 mg/m2.
  • One day per week option. Several clinical trials have shown that using Velcade 1 day/week instead of the standard 2 day/week schedule can retain full efficacy (with some of the major combinations now used) and significantly reduce the risk of neuropathy of Grade 2 or higher.
  • SQ administration option. SQ Velcade causes significantly less peripheral neuropathy than IV Velcade.

For more information, read the IMF’s publication Understanding Neuropathy in Myeloma.

Fatigue

Fatigue caused by cancer or cancer treatment is a distressing, persistent, subjective sense of tiredness or exhaustion that is not proportional to recent activity and interferes with usual functioning. Fatigue is a common ssssssssssside effect associated with Velcade therapy.

Prevention and treatment of fatigue

Management of fatigue may include supportive care as determined by your doctor. The effects of fatigue may be minimized by maintaining:

• A moderate level of daily activity.
• A healthy diet and proper fluid intake.
• A consistent sleeping schedule with enough rest at night.
• Regularly scheduled visits with your doctor or healthcare professional.

For more information about managing this debilitating side effect, read the IMF’s publication Understanding Fatigue.
 

Gastrointestinal side effects

Gastrointestinal (GI) side effects include the following:

• nausea, 
• vomiting, 
• diarrhea,
• constipation,
• bloating, or
• any other side effects that affect the digestive tract.

Nausea may occur while taking Velcade, and it may lead to vomiting, dehydration, dizziness, lightheadedness, or fainting. Precautions should be taken to prevent dehydration caused by vomiting. Your doctor may prescribe IV hydration and/or medication to prevent vomiting.

Diarrhea is defined as 3 or more loose stools per day. Severe diarrhea is defined as 7 or more loose stools per day requiring treatment with intravenous (IV) fluids or hospitalization. Precautions should be taken to prevent dehydration caused by either excessive or persistent diarrhea. Your doctor may prescribe IV hydration and/or antidiarrheal medication.

Dehydration is excessive loss of water from the body. Symptoms and signs include thirst, dry mouth, weakness, lightheadedness (particularly if worse on standing up), dark urine, and a decrease in urination. You should maintain a proper level of hydration by drinking a sufficient amount of water, and promptly alert your doctor if you experience nausea, vomiting, diarrhea, dizziness, lightheadedness, or fainting.

Thrombocytopenia

Thrombocytopenia is a lowered level of platelets in the blood. Platelets help blood to clot; fewer platelets can lead to easier bruising, bleeding, and slower healing. The “normal” level of platelets varies from laboratory to laboratory. For example, at Mayo Clinic the “normal” level is ≥150,000 ssplatelets per microliter of circulating blood. If the platelet count is less
s than 50,000, bleeding problems could occur. Major bleeding is usually sassociated with a reduction to less than 10,000.

Myeloma patients being treated with Velcade often experience thrombocytopenia. The platelet level falls with treatment but should return to the baseline level by the beginning of the next treatment cycle.

Prevention and treatment of decreased platelet levels

You should inform your doctor if you experience excessive bruising or bleeding. Management may include platelet transfusions at the discretion of your doctor.

Low blood pressure (hypotension)

A drop in blood pressure may occur after receiving Velcade. If you have a history of fainting or low blood pressure or are taking medication that can cause low blood pressure (such as antihypertensive medication, that is, medication to treat high blood pressure), it is important that you tell your doctor about your condition before you begin receiving Velcade. Dizziness, especially when it occurs after rapidly sitting up or standing from a lying-down position, may be a sign of low blood pressure.

Prevention and treatment of low blood pressure

You should seek medical advice if you experience dizziness, lightheadedness, or fainting. Caution is advised when operating machinery, including automobiles. You should take precautions to prevent dehydration (drinking plenty of water, for example), and your doctor may administer medication for the treatment of low blood pressure. It is also important to inform your doctor about any additional medications you are taking, particularly for the treatment of hypertension (high blood pressure).
 

Other side effects of Velcade

All proteasome inhibitors, including Velcade, are known to increase the risk of herpes zoster, also called “shingles” and caused by the reactivation of the varicella-zoster virus (VZV), the same virus that causes varicella (chickenpox). If reactivated, the herpes zoster infection frequently affects nerves, causing an itchy and/or painful rash that is usually located on one side of the body. As a preventive treatment, your doctor will prescribe antiviral medication.

Myeloma patients receiving therapy with Velcade may experience

• headache, 
• insomnia, 
• rash, 
• fever, 
• cough, 
• back pain, and 
• muscle cramps.

Side effects of SQ Velcade are the same as those for IV Velcade, except approximately 6% of patients in clinical trials with SQ Velcade experienced itching, swelling, pain, and/or redness at the injection site.

Velcade in Clinical Trials

The IMF has partnered with SparkCures to help myeloma patients discover and explore clinical trials across the U.S. that best match their needs. To identify a clinical trial personalized to your preferences, visit myeloma.org/sparkcures or contact the IMF InfoLine.

The clinicaltrials.gov online database of the U.S. government also provides information about research studies. However, the government does not review the safety and science of the studies submitted to this website.

If you have an interest in clinical trial participation, be sure to discuss with your myeloma doctor all the potential risks and benefits that may apply in your particular case.

Additional Information

#AskDrDurie: Is it okay to take vitamin B12 on the same day as Velcade?

In this video, Dr. Brian G.M. Durie answers a patient’s question about taking a supplement like vitamin B12 on the same day as Velcade.

Understanding Velcade as a Subcutaneous (SQ) injection videos

VELCADE® Treatment Approaches: A Report of Findings from the 2013 Nurse Leadership Board Roundtable Meeting

The VELCADE® website: Information for patients and clinicians on indications and usage

As someone living with multiple myeloma or relapsed mantle cell lymphoma—or as someone caring for a person with one of these diseases—you may have many questions about the disease and its treatment. Dedicated case managers are available at 1-866-VELCADE(835-2233). Option 2 can provide you and your loved ones with day-to-day and long-term support.