Isatuximab

Isatuximab is an IgG1-derived monoclonal antibody that binds a specific extracellular epitope of CD38, a transmembrane glycoprotein that is highly expressed on multiple myeloma cells and present in smaller amounts on other lymphoid and myeloid cells. It acts through several routes at once: immune effector mechanisms, direct induction of apoptosis and inhibition of the enzymatic activity of CD38. The intravenous and subcutaneous formulations contain the same antibody.

Mechanism of Action

• Immune-mediated killing (shown in vitro): through its Fc region, isatuximab triggers antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC).
• Direct effect: it can also trigger tumour cell death by inducing apoptosis through a mechanism that does not depend on the Fc region.
• Enzyme inhibition: CD38 makes and breaks down cyclic ADP-ribose (cADPR), a calcium-mobilising molecule, from extracellular NAD. Isatuximab blocks this activity and reduces cADPR production in myeloma cells.
• NK cell activation: in vitro it can activate natural killer (NK) cells even when no CD38-positive target cells are present.
• Effect on immune cells: in patients given isatuximab alone, absolute counts of NK cells, B cells, CD4-positive T cells and regulatory T cells fell in peripheral blood, and the T-cell receptor repertoire showed clonal expansion, which points to an adaptive immune response.
• With pomalidomide: in vitro, the combination increased the lysis of CD38-expressing myeloma cells by effector cells and direct tumour cell killing compared with isatuximab alone. In a mouse model of human multiple myeloma it gave greater antitumour activity than either drug alone.

Pharmacokinetics

• Pattern: isatuximab shows non-linear pharmacokinetics with target-mediated drug disposition, because it binds CD38. Data come from 476 patients given 1 to 20 mg/kg. Exposure (AUC) rises more than in proportion to dose from 1 to 20 mg/kg every 2 weeks, but is dose-proportional between 5 and 20 mg/kg given weekly for 4 weeks and then every 2 weeks, because target-mediated clearance, which contributes strongly below 5 mg/kg, becomes negligible at higher doses.
• Steady state: after 10 mg/kg weekly for 4 weeks and then every 2 weeks, the median time to steady state was 18 weeks, with 3.1-fold accumulation. In ICARIA-MM (with pomalidomide and dexamethasone) the predicted steady-state Cmax was 351 µg/mL and the AUC 72,600 µg·h/mL; in IKEMA (with carfilzomib and dexamethasone) they were 637 µg/mL and 152,000 µg·h/mL. Changing from a weight-based volume of infusion to a fixed volume had a limited effect on exposure.
• Distribution: the predicted volume of distribution is 8.13 L.
• Metabolism: like other antibodies, isatuximab is likely to be broken down by catabolism into smaller proteins and peptides.
• Elimination: total clearance falls as the dose rises and with repeated dosing. At steady state it takes about 2 months after the last dose to eliminate at least 99% of isatuximab from plasma.
• Special populations: the SmPC recommends no dose adjustment for age, for renal impairment of any degree including end-stage disease, or for mild hepatic impairment. Data in moderate and severe hepatic impairment are limited, but nothing suggests that adjustment is needed.

Both the intravenous and the subcutaneous formulation are authorised for the same indications, in adults:

• Relapsed and refractory multiple myeloma, with pomalidomide and dexamethasone: patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor, and have shown disease progression on the last therapy.
• Multiple myeloma, with carfilzomib and dexamethasone: patients who have received at least one prior therapy.
• Newly diagnosed multiple myeloma, with bortezomib, lenalidomide and dexamethasone: patients who are ineligible for autologous stem cell transplant.
• Newly diagnosed multiple myeloma, induction treatment: with bortezomib, lenalidomide and dexamethasone, in patients who are eligible for autologous stem cell transplant.

• Hypersensitivity to isatuximab or to any of the excipients.

Across all combinations (2,656 patients, subcutaneous or intravenous), the most frequent reactions were infusion-related or systemic administration reactions (27.5%), diarrhoea (27.2%), neutropenia (25.1%), upper respiratory tract infection (23%), pneumonia (22%) and fatigue (20.7%). The most frequent serious reaction was pneumonia (16.5%). Side effects led to permanent discontinuation in 10.2% of patients and to a fatal outcome during treatment in 5.9% (pneumonia in 1.9%). The groups below follow the SmPC table for isatuximab with pomalidomide and dexamethasone (Isa-Pd), which pools 827 patients given the subcutaneous or intravenous form.

Very common (≥1/10): pneumonia, upper respiratory tract infection, neutropenic infection, bronchitis, COVID-19, neutropenia, insomnia, peripheral sensory neuropathy, dyspnoea, cough, diarrhoea, constipation, nausea, back pain, arthralgia, muscle spasms, fatigue, peripheral oedema, pyrexia, systemic administration (infusion) reaction with the intravenous form.

Common (≥1/100 to <1/10): herpes zoster, skin cancer, solid tumours other than skin cancer, thrombocytopenia, anaemia, febrile neutropenia, decreased appetite, dizziness, atrial fibrillation, vomiting, weight decreased, systemic administration reaction with the subcutaneous form, injection site reactions with the subcutaneous form.

Uncommon (≥1/1,000 to <1/100): haematological malignancy, anaphylactic reaction (from post-marketing experience with the intravenous form).

Not known: lymphopenia.

In the studies of the other combinations the SmPC also lists among the most frequent reactions hypertension (36.7%) and infusion reactions (45.8%) with carfilzomib and dexamethasone (IKEMA), and peripheral sensory neuropathy (54.4%), cataract (38.0%), constipation, peripheral oedema and asthenia with bortezomib, lenalidomide and dexamethasone (IMROZ), alongside diarrhoea, respiratory tract infections, pneumonia and fatigue. In IMROZ, serious reactions occurred in 70.7% of patients, fatal reactions in 11% (infections in 6.5%) and permanent discontinuation in 22.8%.

Important serious reactions: pneumonia and other serious or fatal infections; serious infusion reactions, including severe anaphylactic reactions with fatal outcome; and neutropenia. With Isa-Pd, neutropenia was a laboratory abnormality in 96.1% of patients (grade 3 or 4 in 84.9%), and neutropenic complications occurred in 30.3%, including febrile neutropenia in 11.8% and neutropenic infections in 25.0%. Second primary malignancies were reported (skin cancer 4.2%, other solid tumours 1.7%, haematological malignancy 0.5%). The subcutaneous form caused systemic administration reactions less often (3.1%) than the intravenous form (33.5%); injection site reactions occurred in 11.9% of patients and were all grade 2 or lower.

• Other myeloma medicines: isatuximab does not change the pharmacokinetics of pomalidomide, carfilzomib, bortezomib or lenalidomide, and they do not change its.
• Blood bank tests: CD38 is present on red blood cells, so isatuximab can cause false-positive results in indirect antiglobulin (Coombs) tests, antibody detection (screening) tests, antibody identification panels and antihuman globulin crossmatches. The interference may last at least 6 months after the last dose. It can be reduced by treating the reagent red cells with dithiothreitol (DTT) to disrupt isatuximab binding, or by other locally validated methods. Because the Kell blood group system is also sensitive to DTT, Kell-negative units should be supplied after alloantibodies have been ruled out or identified using DTT-treated red cells.
• Serum protein electrophoresis and immunofixation: isatuximab may be detected in the assays used to monitor myeloma M-protein and can interfere with response classification under the International Myeloma Working Group criteria, again for at least 6 months after the last dose. If interference is suspected in a patient with a persistent very good partial response, a validated isatuximab-specific immunofixation assay (Sebia Hydrashift) can help distinguish isatuximab from remaining M-protein and so support the assessment of a complete response.
• Food: no food interactions are described.

Treatment is prescribed by a specialist in the treatment of malignancies and given by a healthcare professional. Two formulations exist: Sarclisa 20 mg/mL concentrate for intravenous infusion (10 mg/kg) and Sarclisa 1,400 mg solution for subcutaneous injection (fixed dose). The vial labels must be checked so that the right formulation and dose are given, and the subcutaneous solution must never be given intravenously. Treatment can start with either form, and a patient on the intravenous form may switch to the subcutaneous form at any time once cycle 1 is complete.

Premedication

Premedication reduces the risk and severity of infusion or systemic administration reactions. It is given 15 to 60 minutes before isatuximab, and the need for it may be reconsidered after the first 4 administrations if no reaction has occurred.

• Dexamethasone: 40 mg (20 mg from age 75 years) with pomalidomide; 20 mg with carfilzomib, or with bortezomib and lenalidomide. This is the total dose given once before the infusion, serving both as premedication and as part of the combination treatment. In the intravenous regimens with carfilzomib or with bortezomib and lenalidomide, it is given intravenously on isatuximab infusion days and orally on other days.
• Montelukast 10 mg orally (or equivalent): at least at cycle 1 for the intravenous form, at cycle 1 only for the subcutaneous form.
• Paracetamol 650 to 1,000 mg orally (or equivalent).
• Diphenhydramine 25 to 50 mg intravenously or orally (or an equivalent such as cetirizine, promethazine or dexchlorpheniramine); intravenous use is preferred for at least the first 4 administrations.
• Intravenous form only: an H2 antagonist (ranitidine 50 mg intravenously or equivalent, for example cimetidine) or an oral proton pump inhibitor (for example omeprazole or esomeprazole).

Intravenous Form: Dose and Schedule

The dose is 10 mg/kg body weight as an intravenous infusion, given in an environment where resuscitation facilities are available.

• With pomalidomide and dexamethasone, or with carfilzomib and dexamethasone: cycle 1 (28 days), weekly on days 1, 8, 15 and 22; cycle 2 onward (28-day cycles), every 2 weeks on days 1 and 15. Treatment is repeated until disease progression or unacceptable toxicity.
• With bortezomib, lenalidomide and dexamethasone, transplant-ineligible newly diagnosed myeloma: cycle 1 (42 days), days 1, 8, 15, 22 and 29; cycles 2 to 4 (42-day cycles), every 2 weeks on days 1, 15 and 29; cycles 5 to 17 (28-day cycles), every 2 weeks on days 1 and 15; cycle 18 onward (28-day cycles), every 4 weeks on day 1. Treatment continues until progression or unacceptable toxicity.
• With bortezomib, lenalidomide and dexamethasone, transplant-eligible induction: cycle 1 (42 days), days 1, 8, 15, 22 and 29; cycles 2 to 3 (42-day cycles), every 2 weeks on days 1, 15 and 29. Treatment then stops for intensification (high-dose chemotherapy and autologous stem cell transplant), followed by standard maintenance treatment.

Intravenous Form: Infusion Rates and Reactions

• Rates: the dose is diluted to 250 mL. The first infusion starts at 25 mL/hour for 60 minutes and, without a reaction, rises by 25 mL/hour every 30 minutes to a maximum of 150 mL/hour. The second infusion starts at 50 mL/hour for 30 minutes, then rises by 50 mL/hour for 30 minutes and afterwards by 100 mL/hour, to a maximum of 200 mL/hour. Later infusions run at 200 mL/hour. The rate is escalated only if there are no infusion reactions.
• Grade 2 reaction: consider a temporary interruption and give symptomatic medicines. Once symptoms are grade 1 or lower, the infusion may restart at half the initial rate under close monitoring; if there are no symptoms after 30 minutes, the rate can return to the initial rate and then rise step by step.
• Stopping permanently: if symptoms do not resolve rapidly or improve to grade 1 or lower after interruption, persist or worsen despite treatment, require hospital admission or are life-threatening, treatment is stopped permanently with supportive therapy. Grade 3 or higher hypersensitivity or infusion reactions also mean permanent discontinuation.

Subcutaneous Form: Dose and Administration

• Dose: 1,400 mg as a subcutaneous injection into the abdomen, with the same combinations and the same cycle schedules as the intravenous form (weekly in cycle 1 and every 2 weeks afterwards with pomalidomide or carfilzomib; the 42-day and 28-day schedules with bortezomib and lenalidomide). It is given with the CirCLIQ On-Body Delivery System or, manually, with a syringe and infusion set (10 mL over about 6 minutes).
• Setting: a healthcare professional gives it. For the first dose only, immediate access to medical support must be available for systemic administration reactions. After cycle 1, later injections may be given at the patient’s home by a healthcare professional, as judged appropriate, if there was no systemic administration reaction in the previous cycle.
• Technique: abdomen only, rotating the site each time; no other medicines are injected in that area; skin that is injured, tender, red, hot, scarred or very hairy is avoided, and so is the area within 5 cm of the navel for manual injection.
• Systemic administration reaction, grade 2 or 3: stop the administration without completing it and give diphenhydramine 25 mg intravenously (or equivalent) and/or methylprednisolone 100 mg intravenously (or equivalent) and/or other supportive care. After grade 3, consider resuming at the next planned administration. A third grade 3 reaction, or any grade 4, means permanent discontinuation.
• Injection site reaction: grade 2, interrupt and resume only once it is grade 1 or lower, with pauses (device) or a slower injection (manual); after the injection, continue once recovered to grade 1 or lower. Grade 3 or 4 means permanent discontinuation.

Dose Adjustments, Missed Dose and Infection Prevention

• Dose adjustments: dose reduction is not recommended for the intravenous form and is not permitted for the subcutaneous form; doses are delayed or omitted instead. For grade 3 or 4 neutropenia, or febrile neutropenia and/or neutropenic infection, isatuximab is delayed or omitted until recovery. Colony-stimulating factors such as G-CSF should be considered to reduce the risk of neutropenia.
• Prevention of infection: antibacterial and antiviral prophylaxis, such as herpes zoster prophylaxis, should be considered during treatment.
• Missed dose: give it as soon as possible and adjust the schedule so that the treatment interval is kept.
• Partner medicines: the current SmPC of each medicine given with isatuximab applies to it.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no adjustment in mild to severe impairment, including end-stage renal disease.
• Hepatic impairment: no adjustment in mild impairment; data in moderate and severe impairment are limited, but nothing suggests that adjustment is needed.
• Children and adolescents: safety and efficacy below 18 years have not been established in the authorised indications. The intravenous form has been studied in children aged 28 days to under 18 years with relapsed or refractory acute lymphoblastic or myeloid leukaemia without proven efficacy, and no dose recommendation can be made.

Traceability

The name and batch number of the product given must be clearly recorded, because isatuximab is a biological medicinal product.

Infusion and Systemic Administration Reactions

• Intravenous form: infusion reactions, mostly mild or moderate, occurred in 38.2% of patients with Isa-Pd (ICARIA-MM), 45.8% with carfilzomib and dexamethasone (IKEMA), 24.0% with bortezomib, lenalidomide and dexamethasone (IMROZ) and 12.7% during induction in GMMG-HD7. They usually start with the first infusion and resolved on the same day in 98% of infusions in ICARIA-MM. The most common symptoms are dyspnoea, cough, chills and nausea; the most common severe signs are hypertension, dyspnoea and bronchospasm. Serious reactions, including severe anaphylaxis, have been seen, and anaphylactic reactions with a fatal outcome have been reported.
• Prevention and management: premedication is given, and vital signs are monitored frequently throughout the infusion. If needed, the infusion is interrupted and appropriate medical and supportive care is given. Isatuximab is stopped permanently after an anaphylactic reaction or a life-threatening (grade 4) infusion reaction, or if symptoms do not improve to grade 1 or lower, persist or worsen despite treatment, or require hospital admission.
• Subcutaneous form: systemic administration reactions are much less frequent, and injection site reactions are all grade 2 or lower.

Neutropenia and Infections

Neutropenia is common (see Side Effects). Blood counts should be watched, and the dose is delayed or omitted for grade 3 or 4 neutropenia, febrile neutropenia or neutropenic infection until recovery. Pneumonia and upper respiratory tract infections are the most frequent infections, and some are fatal, so antibacterial and antiviral prophylaxis should be considered.

Interference with Laboratory Tests

Isatuximab interferes with blood bank serology and with M-protein assays for at least 6 months after the last dose; see Drug Interactions.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential use effective contraception during treatment and for 7 months after it stops.
• Pregnancy: there are no data in pregnant women, and animal reproduction studies have not been done. IgG1 antibodies are known to cross the placenta after the first trimester. Use in pregnancy is not recommended.
• Breastfeeding: it is unknown whether isatuximab passes into breast milk. Human IgG appears in milk during the first days after birth and falls to low levels soon afterwards, so a risk to the baby cannot be excluded during that short period, and a decision must be made whether to stop breastfeeding or to stop or avoid isatuximab. Afterwards isatuximab could be used during breastfeeding if clinically needed.
• Fertility: no human or animal data are available.

Excipients

The intravenous vials contain polysorbate 80 (1 mg in the 5 mL vial, 5 mg in the 25 mL vial).

Effect on Driving

Isatuximab has a minor to moderate influence on the ability to drive and use machines. Fatigue and dizziness have been reported and should be taken into account.

Both formulations are stored in a refrigerator at 2–8 °C, in the original package to protect from light. Do not freeze. This is a cold-chain product and is kept refrigerated during transport and storage.

• Subcutaneous vials: unpunctured vials may be kept at room temperature (up to 30 °C) for a single period of up to 24 hours. Once a vial has been taken out of the refrigerator, it must not be returned to it.
• Diluted intravenous solution: no protection from light is needed in the infusion bag. For the time limits, see Shelf Life.
• Subcutaneous device: the CirCLIQ On-Body Delivery System is used at 18 to 28 °C in ambient light; its storage follows its own instructions for use.

• Unopened vials: 3 years, for both formulations.
• Intravenous, after dilution: chemical and physical in-use stability has been shown for 48 hours at 2–8 °C, followed by 8 hours (including the infusion time) at room temperature (15–25 °C). From a microbiological point of view the solution should be used immediately; otherwise in-use times and conditions are the responsibility of the user and would normally not exceed 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.
• Subcutaneous, after the vial is opened: 4 hours (including the injection time) at 15–25 °C in ambient light, for use with the CirCLIQ device or with a syringe. Once the vial is punctured for the device, the injection should be done as soon as possible; if it is not completed within 4 hours, the vial and the device are discarded.

Prescription only (Rx), under restricted medical prescription (Annex II B), on the prescription of a specialist in the treatment of malignancies. Isatuximab is given by a healthcare professional: intravenous infusions in an environment where resuscitation facilities are available, and subcutaneous injections in clinic, with later injections allowed at the patient’s home by a healthcare professional after a first cycle without a systemic administration reaction. It is not self-administered. It is supplied to the hospital or clinic that administers it, in the cold chain at 2–8 °C.