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Multiple Myeloma

Understanding the Isa-VRd Regimen

for Newly Diagnosed Myeloma

September 2026 Edition

HAVE QUESTIONS? WE CAN HELP The IMF team is here to support you and your loved ones with the most up-to-date information about myeloma Call the IMF at 1.818.487.7455 (and press 1) or visit the web page at mmsm.link/infoline to schedule a time to talk with us about your myeloma experience or if you wish to discuss the contents of this booklet.

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Contents You are not alone

Have questions? We can help

IMF publications

Understanding myeloma vocabulary

What you will learn from this booklet

Who can be treated with Isa-VRd

Frontline therapy

Standard-of-care (SOC)

Quadruplet therapies

Clinical trial experience with Isa-VRd

Dose and schedule for ASCT-ineligible patients

Monitoring

Special precautions

Other possible side effects

Access and support

In closing

You are not alone

The International Myeloma Foundation (IMF) has a mission: Accelerating the prevention and cure of myeloma and improving the quality of life for patients and families. The IMF gives information and support for people with multiple myeloma (also known as “myeloma”) and their care partners, friends, and family members. We do this on our website, myeloma.org, and through many programs and services like booklets, tip cards, classes, webinars, workshops, support groups, and much more.

Have questions? We can help

Myeloma is a cancer that many people have not heard of at the time of their diagnosis. The IMF can help you learn more about myeloma, understand what resources are available, and help you live well with this disease. The IMF can give you current information so you can work with your doctor to make the best decisions for your health. ¡ For information and support, call the IMF at 1.818.487.7455 (and press 1) or visit mmsm.link/infoline to schedule a time to talk with us. ¡ Want answers and don’t want to wait? Ask Myelo®, your AI assistant at myeloma.org. Myelo will help you find the right information and resources 24/7.

IMF publications

The IMF’s Patient Handbook explains what myeloma is, how doctors test for it, and how it affects the body. The Patient Handbook also introduces you to the many ways to treat myeloma and to manage its symptoms. The Patient Handbook also directs you to many helpful resources. The IMF’s Understanding-series booklets offer more information about different myeloma-specific topics, such as symptoms, treatments, and possible side effects. All IMF publications are free and can be read online, downloaded, or mailed to you. If you would like to read IMF publications digitally, just click on the light blue links in this booklet or go to publications.myeloma.org.

Understanding myeloma vocabulary

Myeloma is a complicated disease, but the language that describes it doesn’t have to be hard to understand. Getting comfortable with the language of myeloma will help you learn more about this disease and have better communication with your healthcare team. Words in bold+blue in this booklet are explained in the IMF’s companion publication, Understanding Myeloma Vocabulary, which is located at glossary.myeloma.org. 4

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What you will learn from this booklet

This booklet discusses the treatment regimen called Isa-VRd for short. Isa-VRd is a 4-drug (quadruplet) combination of: ¡ Sarclisa® or Sarclisa Escena™ (generic drug name isatuximab, “isa” for short), a CD38 monoclonal antibody. ¡ Velcade® (bortezomib), a proteasome inhibitor. ¡ Revlimid® (lenalidomide), an immunomodulatory agent. ¡ Dexamethasone (a generic steroid that is also available under several brand names). You will learn who can be treated with Isa-VRd, how it works, how patients receive it, and the findings from clinical trials with Isa-VRd.

Who can be treated with Isa-VRd

In 2024, the U.S. Food and Drug Administration (FDA) approved the use of Isa-VRd for the treatment of adult patients with newly diagnosed multiple myeloma (NDMM) who are not eligible for autologous stem cell transplant (ASCT). At present, the highly effective Isa-VRd combination is one of two standard-of-care (SOC) frontline therapies in myeloma approved by the FDA. The FDA approval of Isa-VRd validates the complex biology of myeloma, which can be better controlled with multiple drugs. The Isa-VRd regimen combines four FDA-approved drugs, each from a different drug class and with a different way of attacking myeloma. Each drug in the Isa-VRd regimen enhances the activity of the other drugs. For a more comprehensive discussion of each drug that is part of the Isa-VRd regimen, read these IMF publications, listed below in alphabetical order: ¡ Understanding Dexamethasone in the Treatment of Myeloma ¡ Understanding REVLIMID® (lenalidomide) ¡ Understanding SARCLISA® and SARCLISA ESCENA™ (isatuximab-irfc) ¡ Understanding VELCADE® (bortezomib)

Frontline therapy

Frontline therapy is the first treatment received by a patient with myeloma after they are diagnosed. The choice of frontline therapy is very important. It has a long-term impact on patients with myeloma because their first remission is usually their longest. Remission (also called response) is the complete or partial disappearance of the signs and symptoms of myeloma. An approval by the FDA of a frontline therapy for NDMM typically requires clinical trial data that demonstrates the treatment’s efficacy and safety. myeloma.org

Standard-of-care (SOC)

SOC is a benchmark treatment that is widely accepted by medical experts as the most appropriate to be used by healthcare professionals in a particular setting. SOC therapies for patients with myeloma continue to evolve as newer and more effective treatments become available, setting new benchmarks. SOC may also be called “best practice” or “best available therapy.”

Quadruplet therapies

Previously, the triplet combination of Velcade + Revlimid + dexamethasone [VRd] had been considered the standard-of-care for most patients. VRd serves as the backbone of Isa-VRd, which builds upon the 3-drug regimen by adding Sarclisa or Sarclisa Escena to create a four-drug regimen. ¡ Sarclisa and Sarclisa Escena are the same in the way they treat myeloma, by targeting a protein called CD38, which is found at high levels on the surface of myeloma cells.  This medication attaches directly to the CD38 protein on the surface of myeloma cells. This can cause the myeloma cell to destroy itself.  This medication marks the cancer cells so the human immune system can easily find and destroy them.  This medication activates other immune cells to make it harder for the myeloma cells to survive and grow. ¡ Velcade disrupts the protein recycling inside myeloma cells, causing the cancer cells to die. ¡ Revlimid helps the immune system to attack myeloma cells. ¡ Dexamethasone reduces inflammation and also kills myeloma cells directly The use of 4-drug regimens in frontline therapy is benefiting the vast majority of patients with NDMM. Myeloma research continues to emerge in support of 4-drug combinations over 3-drug combinations. Adding Sarclisa to the VRd regimen has resulted in improved responses, significantly increasing rates of minimal residual disease (MRD) negativity. The Isa-VRd regimen reduces the risk of disease progression or death when compared to VRd alone. And, despite adding a fourth drug to the VRd regimen, patient-reported quality of life remains comparable to treatment with VRd alone over extended follow-up. 6

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Clinical trial experience with Isa-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 specific conditions, and to answer scientific questions. The goals (endpoints) in clinical trials of quadruplet regimens were progression-free survival (PFS) and overall survival (OS). The advances in the field of myeloma have resulted in a greater duration of OS, making it a difficult endpoint to use as a measure of treatment efficacy. This led to the effort to validate efficacy using minimal residual disease (MRD) as a new endpoint. ¡ PFS: This is the length of time during and after the treatment that a patient lives with myeloma, but it does not get worse. ¡ OS: This is the amount of time measured from diagnosis or start of treatment until death from any cause. In past clinical trials, OS was used to assess if a treatment extended a patient’s life. Current clinical trials use faster endpoints to validate their outcomes. ¡ MRD: The presence of residual tumor cells after treatment has been completed. Highly sensitive testing methods are able to detect 1 myeloma cell among 1,000,000 sampled cells in blood or bone marrow. ¡ MRD-negativity: This is associated with much longer PFS and OS. The following clinical trials of Isa-VRd reported impressive outcomes.

Isa-VRd for patients eligible for ASCT The GMMG-HD7 clinical trial final analysis presented at the 2024 ASH annual meeting showed that the majority of patients achieved MRDnegativity with Isa-VRd plus autologous stem cell transplant (ASCT). Less than half of patients achieved MRD-negativity with the VRd regimen without Sarclisa. 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 when compared with VRd, regardless of which maintenance therapy was received by the patient. This combination is approved in Europe and is being reviewed for approval in the United States. myeloma.org

4-drug regimens for patients NOT eligible for ASCT The IMROZ clinical trial was the basis of the FDA approval of the Isa-VRd regimen. Data presented at the 2024 annual meeting of the American Society of Clinical Oncology (ASCO) demonstrated impressive improve ment in PFS. This study evaluated 446 patients who were 80 years of age or younger. An independent review committee assessed PFS efficacy using criteria by the IMF International Myeloma Working Group (IMWG). The median PFS (mPFS) was not reached in the Isa-VRd arm of the study; it was 54.3 months in the VRd arm. In the Isa-VRd arm, 63% of study patients were still in remission at 4 years vs. 45% of patients in the VRd arm. The BENEFIT clinical trial was also presented at 2024 ASCO, comparing Isa-VRd to Isa-Rd. The primary endpoint in this study was not PFS but depth of response as measured by MRD. Isa-VRd patients had an impressive MRD-negativity rate of 18 months. Both IMROZ and BENEFIT studies demonstrate that for patients under the age of 80 who do not intend to proceed to transplant, Isa-VRd is both feasible and effective, with deep and durable responses. The “VRd-lite” approach was used in patients. VRd-lite includes frequent administration of Velcade (i.e., given onceweekly instead of twice-weekly), lower doses of Revlimid, and faster dose-reduction of dexamethasone.

Finding a clinical trial to match your needs

Myeloma clinical research is very exciting, with many studies enrolling patients. To help you with personalized support for identifying clinical trial options across the U.S., the IMF has partnered with SparkCures. Visit myeloma.org/sparkcures or contact the IMF for more information. If you are interested in exploring your potential benefits and risks of clinical trial participation, speak with your myeloma doctor. To learn more about clinical trials in general, read the IMF’s publication Understanding Clinical Trials in Myeloma.

Dose and schedule for ASCT-ineligible patients

Based on factors of your particular case, your myeloma doctor may modify the doses and schedules explained below.

Sarclisa Escena

The FDA approved Sarclisa Escena as a subcutaneous (SQ) injection under the skin in June 2026. Sarclisa Escena is the first anti-cancer treatment delivered via a small on-body injector (OBI). It can also be given as a 8

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manual injection by a healthcare professional. The FDA approval of Sarclisa Escena covers all prior FDA approvals of Sarclisa, which is given as an intravenous (IV) infusion into a vein. Sarclisa Escena SQ offers more convenient and faster administration than Sarclisa IV, with fewer side effects while delivering similar effectiveness. Sarclisa Escena SQ is used at a fixed dose of 1,400 mg for all patients. The dosing of Sarclisa IV is based on the patient’s weight. To reduce the risk of administration reactions, medication is given 15 to 60 minutes prior to each dose of Sarclisa Escena: acetaminophen 650 mg to 1,000 mg taken by mouth, diphenhydramine 25 mg to 50 mg taken by mouth for at least the first 4 doses, and a leukotriene receptor antagonist given during Cycle 1 only on Days 1, 8, 15, and 22. Each treatment Cycle is 28 days (4 weeks). ¡ Cycle 1: Weekly doses are given on Days 1, 8, 15, and 22. ¡ Cycles 2 through 12: A total of 2 doses are given on Days 1 and 15. ¡ Cycles 13 and beyond: A total of 1 dose given on Day 1 of each Cycle.

Velcade

Velcade SQ is given as an injection under the skin at a dose of 1.3 mg/m2 (milligram per square meter of body mass) on Days 1, 8, and 15 of each Cycle. Data show that Velcade can retain full efficacy while significantly reducing the risk of side effects when given at a lower dose. Velcade SQ is given on a sequential rotation of four injection sites: the left and right sides of the abdomen (belly) and the left and right thighs. There is NO support from Velcade SQ studies for giving injections in the arm. Velcade SQ has a lower risk of nerve damage, offers a more convenient and faster administration, and has the same effectiveness against myeloma when compared to Velcade IV.

Revlimid

Revlimid is taken by mouth in the form of a capsule. Your doctor will determine the appropriate dose and schedule for you.

Dexamethasone

Dexamethasone is taken as a tablet with or after a meal. The dose and schedule of dexamethasone as part of the Isa-VRd regimen depends on patient age and treatment phase. Dexamethasone can be effective at doses as low as 4 mg given once-weekly, while reducing or eliminating potential side effects. myeloma.org

Monitoring

Your doctor may order blood tests or imaging studies before or during your course of treatment for reasons that include the following: ¡ To monitor your response to quadruplet therapy, ¡ To manage possible side effects, ¡ To promptly detect possible disease progression, ¡ To determine if it is appropriate to continue with treatment as planned or to adjust the dose/schedule of future Cycles. ¡ To delay treatment while addressing a side effect, or to begin a different treatment regimen.

Special precautions

All medications come with a risk of side effects, which are unwanted or unexpected effects caused by a drug. Many side effects associated are manageable. Some potential side effects are serious enough to require an FDA-mandated Boxed Warning, the strictest warning in the labeling of prescription drugs. You must promptly report to your doctor any changes in your health, including all new or worsening side effects that you experience.

Infusion-Related Reaction (IRR)

IRR is caused by cytokines, small proteins released from cells targeted by monoclonal antibody drugs and also from immune cells that are brought to the area. Reactions are often flu-like, and include: ¡ Nausea, ¡ Rash, ¡ Fever, ¡ Chills, ¡ Cough, ¡ Throat irritation, ¡ Nasal congestion, ¡ Shortness of breath, ¡ Low blood pressure. Medication can decrease the risk and severity of IRRs.

Infections

Infections can be severe, life-threatening, or fatal. Medication will be prescribed to decrease the risk and severity of infections. Immediately 10

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contact your doctor if you experience any signs or symptoms of infection, including fever, shortness of breath, sore throat, flu-like symptoms (body aches, sweating, chills), cough, or chest pain when you breathe or cough. To decrease the risk and severity of infections, you may be given prophylactic medication in accordance with guidelines. You must report any signs or symptoms of infection to your doctor, who will determine how they should be managed.

Neutropenia

Neutropenia is a reduced level of a type of white blood cell (WBC) called neutrophils. Neutropenia can lead to infection. If you develop a fever, you must get immediate medical attention. Your neutrophil count will be monitored by your doctor. You may also receive a colony-stimulating factor (CSF) to increase your WBC production.

Embryo-fetal toxicity

Women of reproductive potential and males with female partners of reproductive potential must use effective birth control (contraception) during treatment and for at least 5 months after the last dose of treatment. Ask your doctor which effective method of birth control you should use. Due to the potential for harm in the breastfed child, lactating women should not breastfeed during treatment and for at least 5 months after the last dose of treatment.

Other possible side effects

The possible common side effects of the four components of the Isa-VRd regimen are discussed in the IMF booklets about each of the drugs. ¡ Understanding Dexamethasone in the Treatment of Myeloma ¡ Understanding REVLIMID® (lenalidomide) ¡ Understanding SARCLISA® and SARCLISA ESCENA™ (isatuximab-irfc) ¡ Understanding VELCADE® (bortezomib)

Access and support

If you and your doctor have decided that the Isa-VRd regimen is appropriate for the treatment of your myeloma, you can choose to enroll in the “CareASSIST” program for personalized assistance with a variety of resources, including potential cost support options. Visit sarclisa.com/paying-for-sarclisa for more information. myeloma.org

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 provides educational information that will guide you in your conversations with your healthcare team. To help ensure a good quality of life through effective treatment, you must have an active role in your own medical care. Please visit myeloma.org and join the IMF Myeloma Knowledge Platform at myprofile.myeloma.org. Click on the links included in this booklet for quick access to a variety of resources. 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.

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myeloma.org

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Founded in 1990, the International Myeloma Foundation (IMF) is the world’s leading organization dedicated to multiple myeloma. The IMF is steadfast in its mission: Accelerating the prevention and cure of myeloma and improving the quality of life for patients and families. The IMF serves people impacted by myeloma at every stage of the disease by combining world-class research, trusted education, global advocacy, and direct support. A cornerstone of this work is the International Myeloma Working Group® (IMWG) – a network of more than 300 internationally renowned researchers and clinicians who establish the guidelines that shape how myeloma is diagnosed, treated, and managed across the globe. Through its global network of support groups, educational programs, its 24/7 generative-AI myeloma assistant Myelo®, and its advocacy for greater healthcare access, the IMF helps people living with myeloma and their care partners navigate diagnosis, treatment, and survivorship. At the same time, the IMF ensures scientific advances translate into better care and outcomes. Learn more at

myeloma.org

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