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). 

How Is Sarclisa Administered?

Sarclisa is administered by intravenous (IV, or through the vein) infusion. 

Subcunateous Administration of Sarclisa (not yet FDA-approved)

In June 2022, results of an interim phase Ib clinical trial of subcutaneous (SQ) injection of Sarclisa by a hands-free on-body delivery system (OBDS) were presented at the annual meeting of the American Society of Clinical Oncology (ASCO). This study of the Isa-Pd regimen in patients with RRMM demonstrated that SQ administration of Sarclisa by OBDS haa safety profile consistent with intravenous (IV) infusion of Sarclisa. Efficacy in the SQ cohort was comparable to the results of the ICARIA-MM phase III clinical trial. At this time, SQ administration of Sarclisa is not approved by the FDA.

What Are the Dose and Schedule of Sarclisa Regimens?

Three different combinations are approved for administering Sarclisa.  

The Isa-VRd regimen

In December 2024, at the annual meeting of the American Society of Hematology (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.

In September 2024, the FDA approval of the Isa-VRd “quadruplet” (4-drug) combination therapy was based on the results of the IMROZ phase III clinical trial. This trial demonstrated that when Sarclisa is added to VRd in patients with NDMM who are ASCT-ineligible, these patients experienced longer PFS compared to those who received VRd alone.

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 was not reached in the Isa-VRd arm; 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. For patients with myeloma, frontline therapy has a long-term effect as the first remission is usually the longest. 

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 and the other arm received KRd alone. The study assessed 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 and 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 

Serious IRRs, including life-threatening anaphylactic reactions, have occurred with Sarclisa treatment in less than 1% of patients who participated in the ICARIA-MM, IKEMA, and IMROZ clinical trials. Signs and symptoms may include the following:

• cardiac arrest
• hypertension
• hypotension
• bronchospasm
• dyspnea
• angio edema
• swelling

In clinical trials with Sarclisa, IRRs were related to treatment discontinuation in 1% of patients

IRR can occur with many IV-administered cancer therapies. IRR is caused by cytokines, small proteins released from cells targeted by the monoclonal antibody in order to affect the behavior of other cells, and from immune cells that are recruited to the area.

Reactions are often flu-like, and include:

• nasal congestion
• fever
• chills
• cough 
• throat irritation
• shortness of breath
• low blood pressure
• nausea
• rash

Prevention and treatment of IRR

To decrease the risk and severity of IRRs, patients are given medication before and/or during Sarclisa infusions. Medications may include

• acetaminophen,
• H2 antagonists,
• diphenhydramine or equivalent,
• and/or dexamethasone.

If an IRR occurs, the infusion may be stopped.

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. Diarrhea occurred in 36% of the patients in the Isa-Kd arm versus 29% in the Kd arm of the IKEMA clinical trial.  

Grade 3 diarrhea was noted in 2.8% vs. 2.5% of patients, respectively. No Grade 4 cases were reported. 

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). HTN occurred in 37% of the patients in the Isa-Kd arm versus 32% in the Kd arm of the IKEMA clinical trial. 

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
• and 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/.