Sarclisa (isatuximab-irfc)

What Is Sarclisa?

SARCLISA® is a monoclonal antibody that binds to the CD38 (cluster of differentiation 38) receptor on the surface of myeloma cells. The CD systemis designed to classify more than 200 proteins that can be expressed on (stick out of) the surface of a cell.  

CD38 is widely expressed on the surface of myeloma cells but is only expressed at low levels on the surface of other cells. Sarclisa is a targeted anti-myeloma therapy that binds to and kills myeloma cells directly. It also recruits surrounding immune cells to enhance its myeloma-killing process. 

How Does Sarclisa Work?

Sarclisa works in three distinct ways to reduce the number of myeloma cells in your body: 

• It finds and binds to myeloma cells and exposes them for elimination by your immune system. 
• It helps boost your immune system, making it harder for myeloma cells to survive. 
• It directly kills myeloma cells. 

Who Is a Candidate for Sarclisa?

• The FDA has approved Sarclisa for the treatment of adult patients with relapsed or refractory myeloma as part of the following combination therapies:  
  • In combination with the proteasome inhibitor Velcade® (bortezomib), the immunomodulatory agent Revlimid® (lenalidomide), and the steroid dexamethasone, or Isa-VRd, for adult patients with newly diagnosed multiple myeloma (NDBMM) who are not eligible for an autologous stem cell transplant (ASCT).
  • In combination with Kyprolis® and dexamethasone (Isa-Kd) for patients with relapsed or refractory myeloma who have received 1 to 3 prior lines of therapy. 
  • In combination with the immunomodulatory agent Pomalyst® (pomalidomide) and the steroid dexamethasone (Isa-Pd) for patients who have received at least 2 prior therapies, including the immunomodulatory agent Revlimid® (lenalidomide) and a proteasome inhibitor, such as Velcade® (bortezomib), Ninlaro® (ixazomib), or Kyprolis (carfilzomib). 

Learn more about drugs used in combination with Sarclisa in the folllowing IMF publications:

• Understanding Dexamethasone in the Treatment of Myeloma
• Understanding KYPROLIS® (carfilzomib)
• Understanding POMALYST® (pomalidomide)
• Understanding REVLIMID® (lenalidomide)
• Understanding VELCADE® (bortezomib)

Three different combinations are approved for administering Sarclisa.  

The Isa-VRd regimen

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)

Isa-VRd as first-line treatment

Previously, the triplet combination of Velcade, Revlimid, and dexamethasone (VRd) had been considered the standard-of-care (SOC) for most patients. (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.)

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.

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.

Here are some more details about how these medications function:

• 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

Isa-VRd for patients eligible for autologous stem cell transplant (ASCT)

The GMMG-HD7 clinical trial final analysis presented at the 2024 ASH annual meeting showed that the majority of patients achieved MRD-negativity 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.

Isa-VRd for patients NOT eligible for autologous stem cell transplant (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 improvement 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 once-weekly instead of twice-weekly), lower doses of Revlimid, and faster dose-reduction of dexamethasone.

What is the dose and schedule of Isa-Vrd for patients NOT eligible for ASCT?

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 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.

Monitoring the Isa-VRd regimen

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.

The Isa-KRd regimen

In December 2023, a plenary session at the ASH annual meeting presented the results from the ISKIA phase III clinical trial of 302 patients with NDMM who were ASCT-eligible. Patients were randomized to two study arms with 151 patients in each arm. One arm received Isa-KRd, and the other arm received KRd alone. The study assessed the efficacy and safety of Isa-KRd as pre-ASCT induction therapy and post-ASCT consolidation therapy.

The addition of Sarclisa to KRd induction and consolidation therapies significantly increased the rates of MRD-negativity in every treatment phase, with no new safety concerns, including in patients with high-risk multiple myeloma (HRMM).

The Isa-Pd regimen 

The FDA approval of Sarclisa in 2020 was based on data from the ICARIA-MM phase III clinical trial. This trial compared Isa-Pd to Pd alone. The study included 307 patients from 96 centers across 24 countries. The main efficacy outcome measure was progression-free survival (PFS) using IMWG criteria. In patients treated with Isa-Pd, the improvement in PFS represented a 40% reduction in the risk of disease progression or death.

Median PFS for the patients in the Isa-Pd study arm was 11.53 months vs. 6.47 months for the patients in the Pd arm. The Isa-Pd regimen consistently prolonged PFS across subgroups, including Revlimid-refractory patients.

Adding Sarclisa to Pd improved PFS in both standard-risk patients and those with HRMM, which was defined as myeloma with one or more of these chromosomal abnormalities: del(17p), t(4;14), or t(14;16). Nearly 32% of patients in the Isa-Pd arm had at least a 90% response to therapy (defined as very good partial response [VGPR]), as compared to only 8.5% of the patients in the Pd arm. MRD-negativity occurred in 5.2% of Isa-Pd patients and in 0% of Pd patients

Warnings and Precautions

Infusion-related reaction 

Infusion-related reaction (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.

Infection

Sarclisa can cause severe, life-threatening, or fatal infections. In the above-cited clinical trials, serious infections occurred in 46% of study patients who received Sarclisa at the recommended dose, Grade 3 or 4 infections occurred in 43%, and fatal infections occurred in 4.7%. The most common serious infection reported was pneumonia, which occurred in 32% of study patients. Immediately contact your doctor if you experience: 

• fever 
• flu-like symptoms (body aches, sweating, chills) 
• sore throat 
• cough 
• shortness of breath 
• chest pain when you breathe or cough

Prevention and treatment of infection 

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 

Neutrophils, the most abundant type of white blood cell (WBC), are the body’s “first responders” in fighting infections. Neutropenia is a reduced level of neutrophils, which can lead to infection caused by bacteria or fungi. Neutropenia occurred in 81% of patients who received Sarclisa in the above-cited clinical trials, with Grade 3 or 4 in 52% of study patients. Fever is the most common sign of neutropenia. If you develop a fever, you must get immediate medical attention.

Prevention and treatment of neutropenia

Your neutrophil count will be monitored while you receive treatment with Sarclisa. If your doctor determines that the level of your neutrophils is low, your doses of Sarclisa may be decreased or interrupted. You may also receive a colony-stimulating factor (CSF) to increase your white blood cell (WBC) production.

Second primary malignancy (SPM)

In the above-cited clinical trials, the incidence of SPMs was increased in patients treated with Sarclisa, occurring in 12% of study patients. The most common SPMs that occurred in 1% or more of study patients included skin cancers and solid tumors (other than skin cancers).

Laboratory test interference

The use of Sarclisa may interfere with the following laboratory tests:

• Sarclisa may interfere with serological testing and may result in a false-positive indirect antiglobulin test. Patients are tested for blood type before their first infusion of Sarclisa. Interference with blood compatibility testing can be resolved using dithiothreitol-treated RBCs.
  • If an emergency transfusion is required, non-cross-matched ABO/RhD compatible RBCs can be given as per local blood bank practices.
• Sarclisa may interfere with serum protein electrophoresis (SPEP) and immunofixation (IFE) tests used to monitor M-protein. This can impact the accuracy of the determination of complete response (CR) in some patients with IgG kappa myeloma protein.

Embryo-fetal toxicity

The mechanism of action (MOA) of Sarclisa can cause fetal harm. Female patients of reproductive potential must use an effective method of contraception during treatment with Sarclisa and for 5 months after the last dose of Sarclisa.

Due to the potential for harm in the breastfed child, lactating women should not breastfeed during treatment with Sarclisa.

What Are Possible Side Effects of Sarclisa?

Anemia (low red blood cell count)

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.

Prevention and treatment of anemia

Your healthcare providers will determine which treatment regimen for anemia is best suited to your needs and safest for you. The following are options for treatment of anemia:

• Adjusting medications.
• Blood transfusions.
• Erythropoietic (red blood cell-making) agents.

Diarrhea 

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 IV fluids or hospitalization. 

Prevention and treatment of diarrhea 

Diarrhea might occur while taking Sarclisa, causing dehydration. Precautions should be taken to prevent dehydration caused by either excessive or persistent diarrhea. Be sure to drink a sufficient amount of water. Contact your doctor if you experience any of the following: 

• dizziness 
• light-headedness 
• fainting
• Your doctor may administer medication or IV hydration

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 that is related to cancer and its treatments is different from – and more severe than – normal fatigue. It tends to last longer, and includes the feeling of overall weakness.

Prevention and treatment of fatigue 

The effects of fatigue may 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 (low red blood cells, or anemia, can cause fatigue) and to discuss issues that may contribute to your fatigue 
• a careful review of the side effects of any other medications you take to ensure that they do not contribute to your fatigue

Learn more on managing fatigue in the IMF Publication Understanding Fatigue. 

Hypertension 

Hypertension (HTN) is a medical condition in which the blood pressure (BP) in the arteries is elevated. It is also known as high blood pressure (HBP).

Prevention and treatment of hypertension 

If you have HTN before starting treatment with Kyprolis, your doctor should optimize the treatment of your HTN in advance. Monitor BP carefully when receiving your myeloma therapy, especially during the first month. If very high BP or complications develop, report this to your doctor immediately. Your doctor will determine if your medication should be reduced, interrupted, or discontinued. 

Thrombocytopenia (low number of platelets)

Thrombocytopenia is a low number of thrombocytes (platelets) in the blood. Please note that the “normal” level of platelets may vary from one laboratory to another. 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 may occur. Major bleeding is usually associated with a reduction in count to less than 10,000 platelets.

Prevention and treatment of thrombocytopenia

Due to the possibility of thrombocytopenia during treatment with Sarclisa, your doctor will monitor your blood cell counts. Promptly inform your doctor if you experience excessive bruising or bleeding.

Treatment for low platelet count depends on the severity of the condition. Mild thrombocytopenia might not require treatment. At the discretion of your doctor, management of thrombocytopenia may include medication or platelet transfusion.

Upper respiratory tract infection

Upper respiratory tract infections can be a bacterial or viral infection of the nose, throat, sinuses, or larynx.

Prevention and treatment of upper respiratory tract infection

Report your symptoms to your doctor immediately. If your infection is serious and your white blood cell count is low, the doctor may hold your Sarclisa infusion until you recover or support you with medications to stimulate the production of new white blood cells.

Other possible side effects

Possible common side effects of treatment with Sarclisa may also include the following:

• trouble sleeping
• back pain
• peripheral neuropathy
• muscle or bone pain
• cataract
• constipation
• rash
• COVID-19
• swelling of the hands, legs, ankles and feet
• Heart failure has occurred during treatment with Sarclisa as part of the Isa-Kd combination therapy.

Access to Sarclisa and Other Resources

CareASSIST by Sanofi Genzyme helps eligible patients with access and support for Sarclisa. To explore the services and resources that may be available for you, please call 1.833.930.2273 or visit https://www.sanoficareassist.com/sarclisa/.