Understanding the VRd Regimen for Newly
Diagnosed Myeloma
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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 the VRd regimen, a highly effective and welltolerated combination therapy approved by the U.S. Food and Drug Administration (FDA) for patients with newly diagnosed multiple myeloma (NDMM). The VRd regimen is also in use for some patients with relapsed or refractory multiple myeloma (RRMM).
The VRd regimen
The “triplet” (3-drug) VRd regimen combines three different drug classes used to treat myeloma: the proteasome inhibitor Velcade® (bortezomib) + the immunomodulatory agent Revlimid® (lenalidomide) + the steroid dexamethasone [ VRd]. Each drug has a different way of attacking myeloma, and each enhances the activity of the other drugs in this combination therapy.
For a more comprehensive discussion of each drug that is part of the VRd regimen, read the following IMF publications, listed here in alphabetical order:
¡ Understanding Dexamethasone in the Treatment of Myeloma
¡ Understanding REVLIMID® (lenalidomide) capsules
¡ Understanding VELCADE® (bortezomib) injection
In 2024, the FDA approved two new “quadruplet” (4-drug) therapies for NDMM that are comprised of VRd plus a fourth drug. Darzalex Faspro® (daratumumab hyaluronidase-fihj) + VRd [DVRd] was approved in July 2024. Sarclisa® (isatuximab-irfc) + VRd [Isa-VRd] was approved in September 2024. For a more comprehensive discussion of these 4-drug combinations, read these IMF publications:
¡ Understanding DARZALEX® (daratumumab) intravenous infusion and DARZALEX FASPRO® (daratumumab + hyaluronidase-fihj) subcutaneous injection
¡ Understanding SARCLISA® (isatuximab-irfc)
Clinical trial experience with VRd
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.
VRd was accepted as the standard-of-care (SOC) regimen based on data from the phase III SWOG (Southwest Oncology Group) 0777 clinical trial, in which 539 newly diagnosed patients from 139 institutions were randomly assigned to receive either VRd or Revlimid + dexamethasone (Rd). VRd demonstrated superior progression-free survival (PFS) and overall survival (OS) compared to Rd in patients with newly diagnosed myeloma without intent for immediate autologous stem cell transplant (ASCT). Treatmentrelated side effects were well balanced between the two treatment groups.
In May 2020, Blood Cancer Journal published a longer term follow-up of SWOG 0777. At a median follow-up of 84 months, VRd for induction therapy resulted in a statistically significant and clinically meaningful improvement in PFS as well as better OS, demonstrating that VRd continues to represent an appropriate standard of care irrespective of a patient’s age. In December 2022, the post hoc analysis of 471 study patients aged < 65 years at enrollment demonstrated a median PFS of 55.4 months with VRd and 36.6 months with Rd.
The notion of adding Darzalex to the VRd regimen was introduced by the GRIFFIN phase II clinical trial in 2019. At the June 2022 annual meeting of the American Society of Clinical Oncology (ASCO), the post hoc analysis of sustained minimal residual disease (MRD) from the GRIFFIN clinical trial demonstrated that the addition of Darzalex to VRd [DVRd] induction and consolidation therapy, followed by Revlimid maintenance therapy, may lead to durable MRD-negativity in ASCT-eligible patients with NDMM, high-risk cytogenetics, ISS stage III myeloma, and those who achieve complete response (CR) or stringent complete response (sCR).
At the December 2023 annual meeting of the American Society of Hematology (ASH), the primary results of the PERSEUS phase III clinical trial of DVRd in ASCT-eligible patients with NDMM demonstrated that DVRd, with subcutaneous (SQ) injection of Darzalex Faspro, significantly improved PFS and increased depth of response (DpR) with consistent and clinically meaningful PFS benefit across clinically relevant subgroups. The safety profile was consistent with the known safety profiles for Darzalex Faspro and VRd. These data support the use of DVRd followed by maintenance therapy with Darzalex + Revlimid [D-R] as a new standard of care for ASCT-eligible patients with NDMM when compared to VRd alone followed by maintenance with Revlimid.
At the December 2024 annual meeting of ASH, the final analysis was presented of progression-free survival (PFS) from the first randomization in Part 1 of the GMMG-HD7 phase III clinical trial of VRd vs. Isa-VRd induction therapy for transplant-eligible patients with NDMM. Isa-VRd led to deeper minimal residual disease (MRD)-negative response post-transplant when compared with VRd alone. At a median follow-up of 48 months, 18 weeks of Isa-VRd induction therapy – without consolidation therapy – resulted in a 30% reduction in risk of progression or death compared with VRd regardless of which maintenance therapy was received by the patient. The FDA approval of the Isa-VRd regimen in September 2024 was based on the results of the IMROZ phase III clinical trial, which demonstrated longer PFS in ASCT-ineligible patients with NDMM who received Isa-VRd, when compared to patients who received VRd alone.
Dose and schedule of the VRd regimen
¡ Velcade is given at a dose of 1.3 mg/m2 (milligram per square meter of body mass) on days 1, 4, 8, and 11 of a 21-day Cycle. In 2003, Velcade was approved by the FDA as an intravenous (IV) infusion. In 2012, Velcade was approved as an SQ injection. Currently, Velcade is usually administered by SQ injection but you may receive it by either method:
IV infusions of Velcade are injected through a peripheral IV line (usually in the arm) or a central IV line (usually in the chest). Velcade is injected over a short period of 3–5 seconds.
SQ injections of Velcade should be given using a sequential rotation of four sites: the left and right sides of the abdomen and the left and right thighs. There is no data from clinical trials to support SQ injections given in the arm.
¡ Revlimid is a capsule taken orally with water at 25 mg per day on days 1–14 of a 21-day Cycle
¡ Dexamethasone is taken in pill form either with food or after a meal at 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day Cycle.
Figure 1. Sites for sequential rotation of SQ injections
Doses of each of these three drugs can be adjusted as determined by your doctor. Dexamethasone may be given once-weekly. Velcade can be given at a lower dose and/or once-weekly instead of twice-weekly. The “VRd-lite” regimen with weekly Velcade and a starting dose of 15 mg of Revlimid is used for patients who are older and/or frail. There is also an alternative schedule of the VRd regimen of 28-day Cycles: treatment is given for 21 days followed by 7 days off treatment.
Important precautions while taking VRd
All patients taking VRd should receive the following preventive medications:
¡ An anticoagulant (blood thinner) to prevent blood clots will be prescribed by your doctor. The choice of medication will depend on your medical history and your doctor’s assessment of your risk for a blood clot. The combination of Revlimid + dexamethasone is known to increase the risk for blood clots.
¡ Antiviral therapy to prevent herpes zoster (“shingles”), which is caused by the reactivation of the varicella-zoster virus (VZV), the same virus that causes varicella (chickenpox). When reactivated, the herpes zoster infection frequently affects nerves. All proteasome inhibitors, including Velcade, are known to increase the risk of shingles.
Possible side effects of VRd
Side effects of VRd that occurred in 10% or more of patients include fatigue, neuropathy, anemia, low levels of certain types of white blood cells called lymphocytes and neutrophils, and low levels of blood cells called platelets. Your blood counts will be monitored frequently, especially during your first two Cycles of therapy. Dose interruptions or reductions may be required.
Fatigue
Fatigue is a debilitating side effect that is commonly associated with cancer and with cancer therapy. Fatigue that is related to cancer and its treatments is different from and more severe than normal fatigue, tends to last longer, and includes the feeling of overall weakness (the medical term for this is asthenia). For more information, read the IMF’s publication Understanding Fatigue in Myeloma.
Prevention and treatment of fatigue
Let your doctor and/or nurse know how you feel. Your doctor may prescribe a medication to minimize your fatigue. The effects of fatigue may also be minimized by maintaining the following:
¡ A moderate level of activity
¡ A healthy diet and proper fluid intake
¡ A consistent sleeping schedule
¡ Regularly scheduled visits with your doctor to monitor your red blood cell count and to discuss issues that may contribute to your fatigue
¡ A careful review of the side effects of any other medications you are taking to ensure that they are not contributing to your fatigue.
Neuropathy
Neuropathy occurs when nerve tissue is damaged or inflamed, or when degeneration of nerve tissue has occurred, leading to changes in the way nerves function. Patients may experience neuropathy from the effects of the monoclonal protein (myeloma protein, M-protein) and/or from treatments for myeloma. The symptoms of nerve damage depend on the type of nerves affected (sensory, motor, or autonomic). Symptoms of neuropathy can occur symmetrically (on both sides of the body; for example, in both hands and both feet) and may include a feeling of numbness, tingling, burning, and/or pain.
If you have pre-existing neuropathy before you begin taking Velcade, it is especially important that you have a discussion with your doctor before you begin treatment with VRd. Your doctor may decide to administer SQ Velcade, which causes significantly less neuropathy than IV Velcade, and/or may decide to start your Velcade at a reduced dose. There are different strategies for mitigating and managing neuropathy, which may be reversible if detected early.
Pay close attention to the extent of your neuropathy discomfort and promptly report any worsening of your neuropathy to your doctor. For more information about neuropathy, read the IMF’s publication Understanding Neuropathy in Myeloma.
Prevention and treatment of neuropathy
You should be aware that very detailed recommendations for Velcade dose and schedule modifications are available. These are the key principles:
¡ Avoid progressive neuropathy, especially if any significant pain develops. Prevention is the best approach, with early and 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. If you are receiving IV Velcade, ask your doctor about switching to SQ Velcade, which causes significantly less neuropathy.
2. One day per week option. Clinical trial data show that using Velcade once-weekly instead of twice-weekly can retain full efficacy with some of the major treatment combinations now used and can significantly reduce the risk of neuropathy.
3. Dose reduction 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.
Anemia
Red blood cells contain hemoglobin, a protein that carries oxygen to the body’s tissues and organs. Anemia is usually defined as a decrease in hemoglobin < 10 g/dL or as a decrease of ≥ 2 g/dL from the normal level for an individual. More than 13–14 g/dL is considered normal. Low levels of oxygen in the body may cause shortness of breath and feelings of exhaustion. Many newly diagnosed myeloma patients have anemia. Revlimid can cause anemia or make existing anemia worse.
Prevention and treatment of anemia
Your doctor will determine which treatment regimen for anemia is best suited to and safest for you.
The following are options for treatment of anemia:
¡ Dose reduction, or pausing or discontinuing therapy
¡ Blood transfusions
¡ Erythropoietic (red blood cell-making) medication.
Lymphopenia and neutropenia
Lymphopenia (also called “lymphocytopenia”) is a low level of B cells (B lymphocytes), T cells (T lymphocytes), and natural killer (NK) cells. Together, these lymphocyte cells constitute approximately 30% of white blood cells. B cells and T cells help the immune system cells attach to specific antigens on the cell surfaces of infectious organisms, tumors, and other foreign substances.
Neutropenia is a reduced level of neutrophils, a type of white blood cell necessary to combat bacterial infection. Having too few neutrophils or lymphocytes can lead to infection.
Fever (an oral temperature greater than 100.4°F or 38°C) is the most common sign of neutropenia or lymphopenia. If you have a fever, you must get immediate medical attention.
Prevention and treatment of neutropenia and lymphopenia
Your blood counts will be monitored closely during your treatment with VRd. You will also be monitored for signs and symptoms of infection. Call your doctor immediately if you have a fever, and make sure you have an emergency or after-hours number to reach a doctor who is covering the
practice. You may be given a prescription for medication if you are showing signs of infection. Your doctor may also give you a white blood cell growth factor (G-CSF, or granulocyte-colony stimulating factor) to increase production of your white blood cells.
Thrombocytopenia
Thrombocytopenia is a low number 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 or more platelets per microliter of circulating blood. Bleeding problems could occur if the count is less than 50,000 platelets. Major bleeding is usually associated with a reduction to less than 10,000 platelets. Your platelet level can fall with VRd treatment but should return to your baseline level by the beginning of the next Cycle.
Prevention and treatment of thrombocytopenia
You should inform your doctor if you experience excessive bruising or bleeding. Management of a low platelet level may include changes in the dose and/or schedule of your medications, interruption or discontinuation of one or more of the drugs in your regimen, or platelet transfusions, at the discretion of your doctor.
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.
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.
