Understanding Velcade (bortezomib) for Injection

Multiple Myeloma | Cancer of the Bone Marrow

Understanding

VELCADE

®

(bortezomib)

March 2025 Edition

HAVE QUESTIONS? WE CAN HELP The IMF InfoLine team is here to support you and your loved ones with the most up-to-date information about myeloma Call the IMF InfoLine at 1.800.452.CURE (toll-free in the U.S. & Canada) or 1.818.487.7455 (worldwide), or email InfoLine@myeloma.org with your questions, or if you wish to discuss the contents of this booklet.

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Contents

You are not alone

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What you will learn from this booklet

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Indications for the use of Velcade

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How Velcade works

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Administration of Velcade

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Frontline therapy with Velcade

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Velcade in relapsed disease settings

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Dose and schedule of Velcade

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Kidney impairment, chromosomal abnormalities, and VTE

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Possible side effects of Velcade

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Velcade in clinical trials

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In closing

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You are not alone

The International Myeloma Foundation (IMF) is here to help you. The IMF is committed to providing information and support for patients with multiple myeloma (which we refer to simply as “myeloma”) and their care partners, friends, and family members.

We achieve this through a broad range of resources available on our website myeloma.org, and through numerous programs and services such as seminars, webinars, workshops, and the IMF InfoLine, which consistently provides the most up-to-date and accurate information about myeloma in a caring and compassionate manner. Contact the IMF InfoLine at 1.818.487.7455 or InfoLine@myeloma.org.

What you will learn from this booklet

Myeloma is a cancer that is not known to most patients at the time of diagnosis. If you have myeloma, it is important and helpful for you to learn about your disease, its treatment options, and supportive care measures in order to play an active role in your own medical care and to make good decisions about your care in partnership with your doctor.

If you are a patient with myeloma, we suggest that you read the IMF’s publication, Patient Handbook for Multiple Myeloma, which will help you to better understand this disease. In addition, this booklet will direct you to resources that may be relevant in your particular case. All IMF publications are free-of-charge and can be read, downloaded, or requested in printed format at publications.myeloma.org.

The IMF’s Understanding-series publications address specific drugs, drug classes, and combination therapies used to treat myeloma. These booklets also discuss supportive care measures that may help manage the symptoms and side effects of myeloma and its treatments. The IMF’s publication, Understanding Your Test Results, explains how myeloma is diagnosed, monitored, and assessed throughout the disease course.

Words in bold+blue type are explained in the IMF’s companion publication, Understanding Myeloma Vocabulary, a comprehensive glossary that also can be helpful in discussions with your doctor. Myeloma is complicated, but the language that describes it doesn’t have to be hard to understand.

If you are reading this booklet in electronic format, the light blue links will take you to the corresponding resources.

This booklet discusses Velcade® (also known as bortezomib, its generic drug name), the first proteasome inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of myeloma. Velcade plays an important role in many treatment options throughout the myeloma disease course.

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Indications for the use of Velcade Velcade 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 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, and as treatment for patients whose myeloma has relapsed or has become refractory.

How Velcade works

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 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, and 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.

Administration of Velcade 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 myeloma.org

Figure 1. Sites for sequential rotation of SQ injections of Velcade

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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.

Frontline therapy with Velcade If you have newly diagnosed multiple myeloma (NDMM), discuss with your doctor the most appropriate treatment strategy for your disease. Your choice may be affected by personal preference, plans for transplant (or not), the presence or absence of kidney problems or neuropathy, and whether or not you have high-risk multiple myeloma (HRMM), as well as 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 + hyaluronidasefihj), proteasome inhibitor Velcade, immunomodulatory agent Revlimid® (lenalidomide), and a steroid (dexamethasone). Each drug in this combi­ nation 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. Further, 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).

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The Isa-VRd regimen In September 2024, the FDA approved the “quadruplet” regimen of monoclonal antibody Sarclisa® (isatuximab) + Velcade + Revlimid + 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, which 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 + 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 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. myeloma.org

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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.

For a more comprehensive discussion of the drugs that are part of the XVd regimen, read these IMF publications: ¡ Understanding Dexamethasone in the Treatment of Myeloma ¡ 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 reduc­ tion 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.

Table 1. Velcade dose-level treatment algorithm

Dose level 0 Age < 65 years 1.3 mg/m²; days 1, 4, 8, 11 3 weeks

Dose level –1 Age 65–75 years 1.3 mg/m²; days 1, 4, 8, 11 3 weeks or 1.3 mg/m²; days 1, 8, 15, 22 5 weeks

Dose level –2 Age > 75 years 1.0–1.3 mg/m²; days 1, 8, 15, 22 5 weeks

If a Grade 3–4 AE (adverse event, or side effect) occurs: 1. discontinue therapy; 2. wait for a Grade 1 AE; 3. restart at a lower dose

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Table 2. Velcade treatment algorithm for frail patients

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, renal.

Go-go Dose level 0

Moderate-go Dose level –1

Slow-go Dose level –2

No risk factors

At least one risk factor

At least one risk factor + any G 3–4 non-hematologic AE

Kidney impairment, chromosomal abnormalities, and 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 in this section of the booklet. 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. myeloma.org

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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 are: 1. 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.

2. 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.

3. S Q 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 side 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.

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Gastrointestinal side effects Gastrointestinal (GI) side effects include 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 platelets per microliter of circulating blood. If the platelet count is less than 50,000, bleeding problems could occur. Major bleeding is usually associated with a reduction to less than 10,000.

Myeloma patients being treated with Velcade often experience thrombo­ cytopenia. 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, myeloma.org

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especially when it occurs after rapidly sitting up or standing from a lyingdown 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 auto­ mobiles. 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 A clinical trial is a medical research study with people who volunteer to test scientific approaches to a new treatment or a new combination therapy.

Each clinical trial is designed to find better ways to prevent, detect, diagnose, or treat cancer and to answer scientific questions.

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.

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In closing This booklet is not meant to replace the advice of your doctors and nurses who are best able to answer questions about your specific healthcare management plan. The IMF intends only to provide you with information that will guide you in discussions with your healthcare team.

To help ensure a good quality of life through effective treatment of your myeloma, you must play an active role in your own medical care.

We encourage you to visit myeloma.org for more information and to join the Myeloma Knowledge Platform at myprofile.myeloma.org.

To receive the most up-to-date information about myeloma in a caring and compassionate manner, call the IMF InfoLine at 1.818.487.7455, email InfoLine@myeloma.org, or schedule a time to talk with an IMF InfoLine Coordinator at mmsm.link/infoline.

To get answers to your questions without having to wait, ask Myelo® anytime 24/7 at myeloma.org. This generative AI assistant is designed to help you find the right resources.

Use the hyperlinks and web addresses included in this publication for quick access to resources from the IMF. Sign up at subscribe.myeloma.org for our quarterly journal Myeloma Today and weekly e-newsletter Myeloma Minute, as well as alerts about IMF news, events, and actions.

myeloma.org

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The International Myeloma Foundation (IMF) is the global leader in myeloma. Our mission is to improve the quality of life of myeloma patients while working toward prevention and a cure. Since 1990, the IMF has been serving the myeloma community through the following four pillars:

RESEARCH At the IMF, finding a cure for myeloma is our top priority.

The IMF Scientific Advisory Board (SAB) of leading myeloma experts identifies key opportunities to drive research forward. The IMF Black Swan Research Initiative® (BSRI®) is pushing the boundaries with early screening for a precursor condition of myeloma as well as cure-focused myeloma clinical trials. The IMF International Myeloma Working Group (IMWG) provides trusted guidelines for diagnosing, treating, and managing myeloma. We also fund innovative research through the IMF Brian D. Novis Research Grants.

EDUCATION Myeloma is a complex and unique journey for each patient.

The IMF offers hundreds of videos and free publications in multiple languages to inform and empower patients and care partners to navigate their myeloma journey. All IMF seminars, webinars, and workshops are free-of-charge and designed to directly connect the patient community with expert myeloma clinicians. The IMF Nurse Leadership Board (NLB) provides recommendations for the management of myeloma. The IMF M-Power Project works to break down barriers and ensure health equity in underserved populations.

SUPPORT Studies show that social support can greatly improve the

quality of life of people with cancer. The IMF offers more than 160 myeloma support groups across North America, including specialized groups for Spanish-speakers, people with smoldering myeloma, care partners of patients with myeloma, and patients who do not have care partners. The IMF InfoLine answers myeloma-related questions. Myelo®, the IMF’s generative AI assistant, is available 24/7 to help you find the right resources.

ADVOCACY In the U.S., the IMF Advocacy team represents your interests

at the federal and state levels. Internationally, the IMF Global Myeloma Action Network (GMAN) works to improve patient access to treatments.

Our Vision:

A world where every myeloma patient can live life to the fullest, unburdened by the disease.

myeloma.org /myeloma

@imfmyeloma

imfmyeloma.bsky.social

@imfmyeloma

IMFMyeloma

international myeloma foundation

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