SARCLISA 20mg / ml perfusive solution concentrate medication leaflet

SARCLISA 20 mg/mL concentrate for solution for infusion

One ml of concentrate for solution for infusion contains 20 mg of isatuximab.

Each vial contains 100 mg of isatuximab in 5 mL of concentrate (100 mg/5 mL).

Each vial contains 500 mg of isatuximab in 25 mL of concentrate (500 mg/25 mL).

Isatuximab is an immunoglobulin G1 (IgG1) monoclonal antibody (mAb) produced from amammalian cell line (Chinese Hamster Ovary, CHO).

Each vial with 5 ml of concentrate for solution for infusion of isatuximab contains 1 mg of polysorbate80.

Each vial with 25 ml of concentrate for solution for infusion of isatuximab contains 5 mg ofpolysorbate 80.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Colourless to slightly yellow solution, essentially free of visible particulates (pH of 6.0; osmolality of350 to 400 mOsm/kg).

SARCLISA is indicated:

- in combination with pomalidomide and dexamethasone, for the treatment of adult patients withrelapsed and refractory multiple myeloma who have received at least two prior therapies includinglenalidomide and a proteasome inhibitor and have demonstrated disease progression on the lasttherapy.

- in combination with carfilzomib and dexamethasone, for the treatment of adult patients with multiplemyeloma who have received at least one prior therapy (see section 5.1).

- in combination with bortezomib, lenalidomide, and dexamethasone, for the treatment of adultpatients with newly diagnosed multiple myeloma who are ineligible for autologous stem celltransplant.

SARCLISA should be administered by a healthcare professional, in an environment whereresuscitation facilities are available.

Premedication

Prevention of infusion reaction

Premedication should be used prior to SARCLISA infusion with the following medicinal products toreduce the risk and severity of infusion reactions:

* Dexamethasone 40 mg oral or intravenous (or 20 mg oral or intravenous for patients ≥ 75years of age): when administered in combination with isatuximab and pomalidomide,

Dexamethasone 20 mg (intravenous on the days of isatuximab and/or carfilzomib infusions,and oral on the other days): when administered in combination with isatuximab andcarfilzomib.

Dexamethasone 20 mg (intravenous on the days of isatuximab infusion, and oral on the otherdays): when administered in combination with isatuximab, bortezomib, and lenalidomide.

* Acetaminophen 650 mg to 1 000 mg oral (or equivalent).

* H2 antagonists (ranitidine 50 mg IV or equivalent [e.g., cimetidine]), or oral proton pumpinhibitors (e.g., omeprazole, esomeprazole).

* Diphenhydramine 25 mg to 50 mg intravenous or oral (or equivalent [e.g., cetirizine,promethazine, dexchlorpheniramine]). The intravenous use is preferred for at least the first 4infusions.

The above recommended dose of dexamethasone (oral or intravenous) corresponds to the total dose tobe administered only once before the infusion, as part of the premedication and the backbonetreatment, before isatuximab and pomalidomide, before isatuximab and carfilzomib, and beforeisatuximab, bortezomib, and lenalidomide administration.

The recommended premedication agents should be administered 15-60 minutes prior to starting a

SARCLISA infusion. Patients who do not experience an infusion reaction upon their first 4administrations of SARCLISA may have their need for subsequent premedication reconsidered.

Management of neutropenia

The use of colony-stimulating factors (e.g. G-CSF) should be considered to mitigate the risk ofneutropenia. In the event of grade 3 or grade 4 neutropenia or febrile neutropenia and/or neutropenicinfection, SARCLISA administration should be delayed or omitted until recovery (see section 4.4).

Prevention of infection

Antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) according to treatmentguidelines should be considered during treatment (see section 4.4).

The recommended dose of SARCLISA is 10 mg/kg body weight administered as an intravenousinfusion in combination with pomalidomide and dexamethasone (Isa-Pd) or in combination withcarfilzomib and dexamethasone (Isa-Kd), or in combination with bortezomib, lenalidomide, anddexamethasone (Isa-VRd).

SARCLISA dosing schedules are provided in Tables 1 and 2:

Table 1: SARCLISA dosing schedule in combination with pomalidomide and dexamethasone orin combination with carfilzomib and dexamethasone

Cycles Dosing schedule

Cycle 1 (28-day cycle) Days 1, 8, 15 and 22 (weekly)

Cycle 2 and beyond (28-day cycle) Days 1, 15 (every 2 weeks)

Each treatment cycle consists of a 28-day period. Treatment is repeated until disease progression orunacceptable toxicity.

Table 2: SARCLISA dosing schedule in combination with bortezomib, lenalidomide, anddexamethasone

Cycles Dosing schedule

Cycle 1 (42-day cycle) Days 1, 8, 15, 22, and 29

Cycles 2 to 4 (42-day cycles) Days 1, 15, and 29 (every 2 weeks)

Cycles 5 to 17 (28-day cycles) Days 1 and 15 (every 2 weeks)

Cycles 18 and beyond (28-day cycles) Days 1 (every 4 weeks)

Each treatment cycle consists of a 42-day period from cycle 1 to 4, and of a 28-day period from cycle5. Treatment is repeated until disease progression or unacceptable toxicity.

For other medicinal products that are administered with SARCLISA, see section 5.1 and the respectivecurrent summary of product characteristics.

The administration schedule must be carefully followed. If a planned dose of SARCLISA is missed,administer the dose as soon as possible and adjust the treatment schedule accordingly, maintaining thetreatment interval.

No dose reduction of SARCLISA is recommended.

Administration adjustments should be made if patients experience infusion reactions (see “Method ofadministration” below), or in case of Grade 3 or 4 neutropenia, or febrile neutropenia and/orneutropenic infection (see 'Management of neutropenia' above).

For other medicinal products that are administered with SARCLISA, the respective current summaryof product characteristics should be considered.

Based on population pharmacokinetic analysis, no dose adjustment is recommended in elderlypatients.

Based on population pharmacokinetic analysis and on clinical data, no dose adjustment isrecommended in patients with mild (GFR ≥ 60 - < 90 mL/min/1.73m2) to severe(GFR < 30 mL/min/1.73m2) renal impairment including end-stage renal disease(GFR < 15 mL/min/1.73m2) (see section 5.2).

Based on population pharmacokinetic analysis, no dose adjustment is recommended in patients withmild hepatic impairment ([total bilirubin > 1 to 1.5 times upper limit of normal (ULN) or aspartateamino transferase (AST) > ULN). Data in patients with moderate (total bilirubin > 1.5 to 3 times ULNand any AST) and severe (total bilirubin > 3 times ULN and any AST) hepatic impairment are limited(see section 5.2), but there is no evidence to suggest that dose adjustment is required in these patients.

Outside its authorised indications, SARCLISA has been studied in children aged 28 days to less than18 years of age with relapsed or refractory acute lymphoblastic or myeloid leukaemia but efficacy hasnot been established. Currently available data are described in sections 4.8, 5.1, and 5.2.

SARCLISA is for intravenous use. For instructions on dilution of the medicinal product beforeadministration, see section 6.6.

Infusion rates

Following dilution, the SARCLISA infusion should be administered intravenously at the infusion ratepresented in Table 3 below (see section 5.1). Incremental escalation of the infusion rate should beconsidered only in the absence of infusion reactions (see section 4.8).

Table 3: Infusion rates of SARCLISA administration

Dilution Initial rate Absence of Rate increment Maximumvolume infusion ratereaction

First infusion 250 mL 25 mL/hour For 60 minutes 25 mL/hour every 150 mL/hour30 minutes

Second 250 mL 50 mL/hour For 30 minutes 50 mL/hour for 30 200 mL/hourinfusion minutes thenincrease by100 mL/hour

Subsequent 250 mL 200 mL/hour 200 mL/hourinfusions

Administration adjustments should be made if patients experience infusion reactions (see section 4.4)

* In patients necessitating an intervention (Grade 2, moderate infusion reactions), a temporaryinterruption in the infusion should be considered and additional symptomatic medicinalproducts can be administered. After symptom improvement to grade ≤ 1 (mild), SARCLISAinfusion may be resumed at half of the initial infusion rate under close monitoring andsupportive care, as needed. If symptoms do not recur after 30 minutes, the infusion rate maybe increased to the initial rate, and then increased incrementally, as shown in Table 3.

* If symptoms do not resolve rapidly or do not improve to Grade ≤ 1 after interruption of

SARCLISA infusion, persist or worsen despite appropriate medicinal products, or requirehospitalization or are life-threatening, treatment with SARCLISA should be permanentlydiscontinued and additional supportive therapy should be administered, as needed.

* In case of Grade≥ 3 hypersensitivity reactions or infusion reactions, SARCLISA treatmentshould be permanently discontinued.

Hypersensitivity to the active substance or to any of its excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Infusion reactions

Infusion reactions, mostly mild or moderate, have been observed in 38.2 % of patients treated with

SARCLISA in ICARIA-MM, in 45.8 % of patients treated with Isa-Kd in IKEMA, and in 24.0% ofpatients treated with Isa-VRd in IMROZ (see section 4.8). In ICARIA-MM, all infusion reactionsstarted during the first SARCLISA infusion and resolved on the same day in 98 % of the infusions.

The most common symptoms of an infusion reaction included dyspnoea, cough, chills and nausea. Themost common severe signs and symptoms included hypertension, dyspnoea, and bronchospasm. In

IKEMA, the infusion reactions occurred on the infusion day in 99.2 % of episodes. In patients treatedwith Isa-Kd, 94.4 % of those experiencing an IR experienced it during the first cycle of treatment. Allinfusion reactions resolved. The most common symptoms of an infusion reaction included cough,dyspnoea, nasal congestion, vomiting and nausea. The most common severe signs and symptomsincluded hypertension and dyspnoea. In IMROZ, the IRs started on the infusion day in all patients,mostly during the first SARCLISA infusion, and resolved the same day in 97.3% of patients. All IRsresolved. The most common symptoms of an IR included dyspnoea and chills. The most commonsevere sign and symptom was hypertension (see section 4.8).

However, serious infusion reactions including severe anaphylactic reactions have also been observedafter SARCLISA administration (see section 4.8).

To decrease the risk and severity of infusion reactions, patients should be pre-medicated prior to

SARCLISA infusion with acetaminophen, diphenhydramine or equivalent; dexamethasone is to beused as both premedication and anti-myeloma treatment (see section 4.2). Vital signs should befrequently monitored during the entire SARCLISA infusion. When required, interrupt SARCLISAinfusion and provide appropriate medical and supportive measures (see section 4.2). In case symptomsdo not improve to grade ≤ 1 after interruption of SARCLISA infusion, persist or worsen despiteappropriate medicinal products, require hospitalization or are life-threatening, permanentlydiscontinue SARCLISA and institute appropriate management.

In patients treated with Isa-Pd, neutropenia was reported as a laboratory abnormality in 96.1 % ofpatients and as an adverse reaction (1) in 46.7 % of patients, with Grade 3-4 neutropenia reported as alaboratory abnormality in 84.9 % of patients and as an adverse reaction in 45.4 % of patients.

Neutropenic complications have been observed in 30.3 % of patients, including 11.8 % of febrileneutropenia and 25.0 % of neutropenic infections. In patients treated with Isa-Kd, neutropenia wasreported as a laboratory abnormality in 54.8 % of patients and as an adverse reaction (1) in 4.5 % ofpatients, with Grade 3-4 neutropenia reported as a laboratory abnormality in 19.2 % of patients (with17.5 % Grade 3 and 1.7 % Grade 4) and as an adverse reaction in 4.0 % of patients. Neutropeniccomplications have been observed in 2.8 % of patients, including 1.1 % of febrile neutropenia and1.7 % of neutropenic infections. In patients treated with Isa-VRd, neutropenia was reported as alaboratory abnormality in 87.5% of patients and as an adverse reaction in 30% of patients, with Grade3-4 neutropenia reported as a laboratory abnormality in 54.4% of patients (with 35.7% Grade 3 and18.6% Grade 4) and as an adverse reaction in 30% of patients. Neutropenic complications have beenobserved in 12.5% of patients, including 2.3% of febrile neutropenia and 10.6% of neutropenicinfection (see section 4.8).

Complete blood cell counts should be monitored periodically during treatment. Patients withneutropenia should be monitored for signs of infection. No dose reductions of SARCLISA arerecommended. SARCLISA dose delays and the use of colony-stimulating factors (e.g. G-CSF) shouldbe considered to mitigate the risk of neutropenia (see section 4.2).

(1) Haematology laboratory values were recorded as adverse reactions only if they led to treatmentdiscontinuation and/or dose modification and/or fulfilled a serious criterion.

Infection

A higher incidence of infections, including grade ≥ 3 infections, mainly pneumonia, upper respiratorytract infection and bronchitis, occurred with SARCLISA (see section 4.8). Patients receiving

SARCLISA should be closely monitored for signs of infection and appropriate standard therapyinstituted.

Antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) according to treatmentguidelines should be considered during treatment (see sections 4.2 and 4.8).

Second primary malignancies

In ICARIA-MM, second primary malignancies (SPMs) were reported at a median follow-up time of52.44 months in 10 patients (6.6 %) treated with Isa-Pd and in 3 patients (2 %) treated with Pd. SPMwere skin cancer in 6 patients treated with Isa-Pd and in 3 patients treated with Pd, solid tumours otherthan skin cancer in 3 patients treated with Isa-Pd (one patient also had a skin cancer), andhaematological malignancy (myelodysplastic syndrome) in 1 patient treated with Isa-Pd (see section4.8). Patients continued treatment after resection of the new malignancy, except two patients treatedwith Isa-Pd. One patient developed metastatic melanoma and the other developed myelodysplasticsyndrome. In IKEMA study, at a median follow-up time of 56.61 months, SPMs were reported in 18patients (10.2 %) treated with Isa-Kd and in 10 patients (8.2 %) treated with Kd. SPMs were skincancers in 13 patients (7.3 %) treated with Isa-Kd and in 4 patients (3.3 %) treated with Kd, were solidtumours other than skin cancer in 7 patients (4.0 %) treated with Isa-Kd and in 6 patients (4.9 %)treated with Kd, and haematological malignancy (acute myeloid leukaemia) in 1 patient (0.8 %) in the

Kd group. For 1 patient (0.6 %) in the Isa-Kd group, the aetiology of the SPM was unknown. Twopatients (1.1 %) in the Isa-Kd group and one patient (0.8 %) in the Kd group had both skin cancer andsolid tumours other than skin cancer (see section 4.8). Patients with skin cancer continued treatmentafter resection of the skin cancer. Solid tumours other than skin cancer were diagnosed within 3months after treatment initiation in 3 patients (1.7 %) treated with Isa-Kd and in 2 patients (1.6 %)treated with Kd. In IMROZ study, at a median follow-up time of 59.73 months, SPMs were reportedin 42 patients (16.0%) treated with Isa-VRd (0.041 events per patient-year) and in 16 patients (8.8%)treated with VRd (0.026 events per patient-year). SPMs were skin cancers in 22 patients (8.4%)treated with Isa-VRd and in 7 patients (3.9%) treated with VRd, were solid tumours other than skincancer in 17 patients (6.5%) treated with Isa-VRd and in 7 patients (3.9%) treated with VRd, andhaematological malignancy in 3 patients (1.1%) treated with Isa-VRd and in 2 patients (1.1%) treatedwith VRd. Patients with SPM of skin cancer continued treatment after resection of the skin cancer,except one patient in each treatment group. SPMs with fatal outcome were reported in 6 patients(2.3%) treated with Isa-VRd (neuroendocrine carcinoma of the skin, malignant melanoma, squamouscell carcinoma of skin, squamous cell carcinoma of lung, colorectal cancer, and rectaladenocarcinoma) and in 2 patients (1.1%) treated with VRd (metastases to peritoneum andadenocarcinoma of colon). The overall incidence of SPMs in all the SARCLISA-exposed patients is6.0 %. Physicians should carefully evaluate patients before and during treatment as per IMWGguidelines for occurrence of SPM and initiate treatment as indicated.

Cases of tumour lysis syndrome (TLS) have been reported in patients who received isatuximab.

Patients should be monitored closely and appropriate precautions taken.

Interference with serological testing (indirect antiglobulin test)

Isatuximab binds to CD38 on red blood cells (RBCs) and may result in a false positive indirectantiglobulin test (indirect Coombs test). This interference with the indirect Coombs test may persistfor at least 6 months after the last infusion of SARCLISA. To avoid potential problems with RBCtransfusion, patients being treated with SARCLISA should have blood type and screen tests performedprior to the first infusion. Phenotyping may be considered prior to starting SARCLISA treatment asper local practice. If treatment with SARCLISA has already started, the blood bank should beinformed. Patients should be monitored for theoretical risk of haemolysis. If an emergency transfusionis required, non- cross- matched ABO/Rh-compatible RBCs can be given as per local blood bankpractices (see section 4.5).

Interference with determination of complete response

Isatuximab is an IgG kappa monoclonal antibody that could be detected on both serum proteinelectrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring ofendogenous M-protein (see section 4.5). This interference can impact the accuracy of thedetermination of complete response in some patients with IgG kappa myeloma protein. Twenty-twopatients in the Isa-Pd arm who met Very Good Partial Response (VGPR) criteria with only residualimmunofixation-positivity were tested for interference. Serum samples from these patients were testedby mass spectrometry to separate isatuximab signal from the myeloma M-protein signal. In the Isa-Kdarm, out of the 27 patients identified with potential interference and tested by mass spectrometry at thesensitivity level of the immunofixation test (25 mg/dL), 15 non-Complete Response (non-CR) patientsas per Independent Response Committee (IRC) showed no detectable residual myeloma M-protein.

Among these 15 patients, 11 patients had plasma cell < 5% in bone marrow. This indicates that 11additional patients out of the 179 Isa-Kd patients (6.1 %) could have CR as best response leading to apotential CR rate of 45.8 % (see section 4.5).

Data are limited in the elderly population ≥ 85 years old (see section 4.2).

This medicine contains 0.2 mg of polysorbate 80 in each mL of isatuximab concentrate for solution forinfusion, which is equivalent to 0.1 mg/kg of body weight.

Polysorbates may cause allergic reactions.

Isatuximab has no impact on the pharmacokinetics of pomalidomide, or carfilzomib, or bortezomib, orlenalidomide, or vice versa.

Interference with serological testing

Because CD38 protein is expressed on the surface of red blood cells, isatuximab, an anti-CD38antibody, may interfere with blood bank serologic tests with potential false positive reactions inindirect antiglobulin tests (indirect Coombs tests), antibody detection (screening) tests, antibodyidentification panels, and antihuman globulin (AHG) crossmatches in patients treated with isatuximab(see section 4.4). The interference mitigation methods include treating reagent RBCs withdithiothreitol (DTT) to disrupt isatuximab binding or other locally validated methods. Since the Kell

Blood group system is also sensitive to DTT treatment, Kell-negative units should be supplied afterruling out or identifying alloantibodies using DTT-treated RBCs.

Interference with serum protein electrophoresis and immunofixation tests

Isatuximab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assaysused for monitoring disease monoclonal immunoglobulins (M-protein) and could interfere withaccurate response classification based on International Myeloma Working Group (IMWG) criteria (seesection 4.4). In patients with persistent very good partial response, where isatuximab interference issuspected, consider using a validated isatuximab-specific IFE assay to distinguish isatuximab fromany remaining endogenous M protein in the patient’s serum, to facilitate determination of a completeresponse.

Women of childbearing potential treated with isatuximab should use effective contraception duringtreatment and for 5 months after cessation of treatment.

There are no available data on isatuximab use in pregnant women. Animal reproduction toxicitystudies have not been conducted with isatuximab. Immunoglobulin G1 monoclonal antibodies areknown to cross the placenta after the first trimester of pregnancy. The use of isatuximab in pregnantwomen is not recommended.

It is unknown whether isatuximab is excreted in human milk. Human IgGs are known to be excreted inbreast milk during the first few days after birth, which is decreasing to low concentrations soonafterwards; however, a risk to the breast-fed child cannot be excluded during this short period justafter birth. For this specific period, a decision must be made whether to discontinue breast-feeding orto discontinue/abstain from isatuximab therapy taking into account the benefit of breast-feeding for thechild and the benefit of therapy for the woman. Afterwards, isatuximab could be used during breast-feeding if clinically needed.

No human and animal data are available to determine potential effects of isatuximab on fertility inmales and females (see section 5.3).

For other medicinal products that are administered with isatuximab, refer to the respective currentsummary of product characteristics.

SARCLISA has no or negligible influence on the ability to drive and use machines. Fatigue anddizziness have been reported in patients taking SARCLISA and this should be taken into accountwhen driving or using machines. For other medicinal products that are administered with SARCLISA,refer to the respective current summary of product characteristics.

In ICARIA-MM, the most frequent adverse reactions (> 20%) are neutropenia (46.7 %), infusionreactions (38.2 %), pneumonia (30.9 %), upper respiratory tract infection (28.3 %), diarrhoea (25.7 %)and bronchitis (23.7 %). Serious adverse reactions occurred in 61.8 % of patients receiving Isa-Pd.

The most frequent serious adverse reactions are pneumonia (25.7 %) and febrile neutropenia (6.6 %).

Permanent discontinuation of treatment because of adverse reactions was reported in 7.2 % of patientstreated with Isa-Pd. Adverse reactions with a fatal outcome during treatment were reported in 7.9 % ofpatients treated with Isa-Pd (those occurring in more than 1 % of patients were pneumonia occurringin 1.3 % of patients and other infections occurring in 2.0 % of patients).

In IKEMA, the most frequent adverse reactions (≥ 20%) are infusion reactions (45.8 %), hypertension(36.7 %), diarrhoea (36.2 %), upper respiratory tract infection (36.2 %), pneumonia (28.8 %), fatigue(28.2 %), dyspnoea (27.7 %), insomnia (23.7 %), bronchitis (22.6 %), and back pain (22.0 %). Seriousadverse reactions occurred in 59.3 % of patients receiving Isa-Kd. The most frequent serious adversereaction is pneumonia (21.5 %). Permanent discontinuation of treatment because of adverse reactionswas reported in 8.5 % of patients treated with Isa-Kd. Adverse reactions with a fatal outcome duringtreatment were reported in 3.4 % of patients treated with Isa-Kd (those occurring in more than 1 % ofpatients were pneumonia and cardiac failure both occurring in 1.1 % of patients).

In IMROZ, the most frequent adverse reactions (≥20%) are diarrhoea (54.8%), peripheral sensoryneuropathy (54.4%), pneumonia (39.9%), cataract (38.0%), constipation (35.7%), fatigue (34.6%),upper respiratory tract infections (34.2%), oedema peripheral (32.7%), neutropenia (30.0% as anadverse reaction), infusion reaction (23.6%), insomnia (22.4%), Covid-19 (22.4%), back pain (22.1%),bronchitis (22.1%). and asthenia (21.7%), Serious adverse reactions occurred in 70.7% of patientsreceiving Isa-VRd. The most frequent serious adverse reaction was pneumonia (29.7%, including

Covid-19 pneumonia). Adverse reactions with a fatal outcome during treatment (Grade 5 TEAEs)were reported in 11% of patients with Isa-VRd including Grade 5 infectious TEAEs occurring in 6.5%of patients. Permanent discontinuation of treatment because of adverse reactions was reported in22.8% of patients treated with Isa-VRd.

Adverse reactions are described using the NCI Common Toxicity Criteria, the COSTART and the

MedDRA terms. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10);uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); frequencynot known (cannot be estimated from available data). Within each frequency grouping, adversereactions are presented in the order of decreasing seriousness.

The adverse reactions were reported in clinical studies (see section 5.1) and post-market settings.

Table 4: Adverse reactions reported in patients with multiple myeloma treated with isatuximabin combination with pomalidomide and dexamethasone

System Organ Class Adverse reaction Frequency Incidence

Preferred Term (N = 244)

Any Grade Grade ≥ 3

Infections and Pneumoniaa b Very common34.8 % 27.9 %infestations

Upper respiratory tract Very commoninfection 40.2 % 3.3 %

Bronchitis Very common 20.9 % 3.7 %

Herpes zoster Common 2.5 % 0.4 %

Neoplasms benign, Skin cancer Common 4.9 % 1.6 %malignant and Solid tumour (non-skin Common 2.9 % 1.6 %unspecified (incl cysts cancer)and polyps)c Haematology Uncommonmalignancy 0.4 % 0.4 %

Blood and lymphatic Neutropenia Very common 52.5 % 51.6 %system disorders Thrombocytopenia Very common 12.7 % 11.9 %

Febrile neutropenia Common 7.4 % 7.4 %

Anaemia Common 6.1 % 4.5 %

Lymphopenia Not known

Immune system Anaphylactic reactiond Uncommon 0.3 % 0.3 %disorders

Metabolism and Decreased appetite Very common 11.5 % 1.2 %nutrition disorders

Cardiac disorders Atrial fibrillation Common 5.7 % 2.5 %

Respiratory, thoracic Dyspnoea Very commonand mediastinal 25.8 % 5.7 %disorders

Gastrointestinal Diarrhoea Very common34.0 % 2.5 %disorders

Nausea Very common22.1 % 0 %

Vomiting Very common14.8 % 0.8 %

Investigations Weight decreased Common 4.9 % 0 %

Injury, poisoning Infusion reactionb Very common 39.3 % 2.0 %and proceduralcomplicationsa The term pneumonia is a grouping of the following terms: atypical pneumonia, bronchopulmonaryaspergillosis, pneumonia, pneumonia haemophilus, pneumonia influenza, pneumonia pneumococcal, pneumoniastreptococcal, pneumonia viral, pneumonia bacterial, haemophilus infection, lung infection, pneumonia fungaland pneumocystis jirovecii pneumonia.b See “Description of selected adverse reactions”.c Based on second primary malignancies reported during study treatment period and during post-treatmentperiod.d Based on post-marketing adverse reactions.

Table 5a: Adverse reactions reported in patients with multiple myeloma treated with isatuximabin combination with carfilzomib and dexamethasone

System Organ Class Adverse reaction Frequency Incidence

Preferred Term (N = 177)

Any Grade Grade ≥ 3

Infections and Pneumoniab c Very common28.8 % 20.9 %infestations

Upper respiratory tract Very common 3.4 %infection 36.2 %

Bronchitis Very common 22.6 % 2.3 %

Herpes zoster Common 2.3 % 0.6 %

Neoplasms benign, Skin cancers Common 7.3 % 1.7 %malignant andunspecified (incl cysts Solid tumours (non-skin Common4.0 %and polyps)d cancers) 3.4 %

Blood and lymphatic Anaemia Common 5.1 % 4.5 %system disorders

Neutropenia Common 4.5 % 4.0 %

Thrombocytopenia Common 2.8 % 2.3 %

Lymphopenia Not known

Immune system Anaphylactic reactione Uncommon 0.3 % 0.3 %disorders

Vascular disorders Hypertension Very common 36.7 % 20.3 %

Respiratory, thoracic Dyspnoea Very common27.7 % 5.1 %and mediastinal Cough Very commondisorders 19.8 % 0 %

Gastrointestinal Diarrhoea Very commondisorders 36.2 % 2.8 %

Vomiting Very common15.3 % 1.1 %

General disordersand administration Fatigue Very common 28.2 % 3.4 %site conditions

Injury, poisoning Infusion reactionc Very common 45.8 % 0.6 %and proceduralcomplicationsa Cut-off date of 07-Feb-2020. Median follow-up time = 20.73 months.b The term pneumonia is a grouping of the following terms: atypical pneumonia, pneumocystis jiroveciipneumonia, pneumonia, pneumonia influenza, pneumonia legionella, pneumonia streptococcal, pneumonia viral,and pulmonary sepsis.c See “Description of selected adverse reactions”.d Cut-off date of 07-Feb-2023. Median follow-up time = 56.61 months. Based on second primary malignanciesreported during study treatment period and during post-treatment period.e Based on post-marketing adverse reactions.

Table 6: Adverse reactions reported in patients with multiple myeloma treated with isatuximabin combination with bortezomib, lenalidomide, and dexamethasone

Incidence

System Organ Adverse reaction Frequency (N=336)

Class Any Grade Grade ≥3

Preferred Term

Infections and Pneumoniaa Very common 34.2% 24.1%infestations

Bronchitis Very common 22.6% 3.0%

Covid-19 Very common 19.9% 1.2%

Neoplasms benign, Skin cancer Common 8.0% 2.7%malignant and Solid tumour (non-skincancer) Common 5.7% 3.6%unspecified (inclcysts and polyps) Haematology Uncommonmalignancy 0.9% 0.3%

Blood and lymphatic Neutropenia Very common 28.0% 27.1%system disorders Thrombocytopenia Very common 13.4% 10.7%

Anaemia Common 6.3% 2.7%

Lymphopenia Not known

Immune system Anaphylactic reaction Uncommon 0.3% 0.3%disorders

Eye disorders Cataract Very common 36.0% 13.1%

Gastrointestinal Diarrhoea Very common 56.8% 8.3%disorders

Vomiting Common 9.5% 0.3%

General disorders Fatigue Very common 32.7% 6.5%and administrationsite conditions

Injury, poisoning Infusion reaction Very common 27.4% 0.6%and procedural

Incidence

System Organ Adverse reaction Frequency (N=336)

Class Any Grade Grade ≥3

Preferred Termcomplicationsa The term pneumonia is a grouping of the following terms: Atypical pneumonia, Bronchopulmonaryaspergillosis, Covid-19 pneumonia, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia bacterial,

Pneumonia haemophilus, Pneumonia influenzal, Pneumonia klebsiella, Pneumonia legionella, , Pneumoniapneumococcal, Pneumonia pseudomonal, Pneumonia respiratory syncytial viral, Pneumonia viral, Pulmonarysepsis, Tuberculosis.

MedDRA 26.0

Infusion reactions

In ICARIA-MM, infusion reactions were reported in 58 patients (38.2 %) treated with SARCLISA.

All patients who experienced infusion reactions, experienced them during the 1st infusion of

SARCLISA, with 3 patients (2.0 %) also having infusion reactions at their 2nd infusion, and 2 patients(1.3 %) at their 4th infusion. Grade 1 infusion reactions were reported in 3.9 %, Grade 2 in 31.6 %,

Grade 3 in 1.3 %, and Grade 4 in 1.3 % of the patients. All infusion reactions were reversible andresolved the same day in 98 % of the infusions. Signs and symptoms of Grade 3 or 4 infusion reactionsincluded dyspnoea, hypertension, and bronchospasm.

The incidence of infusion interruptions because of infusion reactions was 28.9 %. The median time toinfusion interruption was 55 minutes.

Discontinuations from treatment due to infusion reaction were reported in 2.6 % of patients in Isa-Pdgroup.

In IKEMA, infusion reactions were reported in 81 patients (45.8 %) treated with Isa-Kd. Grade 1infusion reactions were reported in 13.6 %, Grade 2 in 31.6 %, and Grade 3 in 0.6 % of the patientstreated with Isa-Kd. All infusion reactions were reversible and resolved the same day in 73.8 % ofepisodes in Isa-Kd patients and in more than 2 days in 2.5 % of episodes in Isa-Kd patients. Signs andsymptoms of Grade 3 infusion reactions included dyspnoea and hypertension. The incidence ofpatients with isatuximab infusion interruptions because of infusion reactions was 29.9 %. The mediantime to isatuximab infusion interruption was 63 minutes. Isatuximab was discontinued in 0.6 % ofpatients due to infusion reactions.

In IMROZ, infusion reactions were reported in 63 patients (24.0%) treated with Isa-VRd. Grade 1 IRswere reported in 1.9%, Grade 2 in 21.3%, Grade 3 in 0.4%, and Grade 4 in 0.4% of the patients treatedwith Isa-VRd. The IRs started on the infusion day in all patients, mostly during the first SARCLISAinfusion, and resolved the same day in 97.3% of patients. All IRs resolved. Signs and symptoms of

Grade 3 or 4 IRs included hypertension, bronchospasm, and hypoxia. The incidence of patients withisatuximab infusion interruptions because of infusion reactions was 20.9%. The median time toisatuximab infusion interruption was 66.0 minutes. Isatuximab was discontinued in 0.8% of patientsdue to infusion reactions. (see sections 4.2 and 4.4).

In ICARIA-MM, the incidence of Grade 3 or higher infections was 42.8 %. Pneumonia was the mostcommonly reported severe infection with Grade 3 reported in 21.7 % of patients in the Isa-Pd groupcompared to 16.1 % in the Pd group, and Grade 4 in 3.3 % of patients in the Isa-Pd group compared to2.7 % in the Pd group. Discontinuations from treatment due to infection were reported in 2.6 % ofpatients in the Isa-Pd group compared to 5.4 % in the Pd group. Fatal infections were reported in3.3 % of patients in the Isa-Pd group and 4.0 % in the Pd group. In IKEMA, the incidence of Grade 3or higher infections was 38.4 %. Pneumonia was the most commonly reported severe infection with

Grade 3 reported in 15.8 % of patients in the Isa-Kd group compared to 10.7 % in the Kd group, and

Grade 4 in 3.4 % of patients in the Isa-Kd group compared to 2.5 % in the Kd group. Treatment wasdiscontinued due to infection in 2.8 % of patients in the Isa-Kd group compared to 4.9 % in the Kdgroup. Fatal infections were reported in 2.3 % of patients in the Isa-Kd group and 0.8 % in the Kdgroup. In IMROZ, the incidence of Grade 3 or higher infections was 44.9% in the Isa-VRd group and38.1% in the VRd group. Pneumonia was the most commonly reported severe infection with Grade 3reported in 25.1% of patients in the Isa-VRd group compared to 15.5% in the VRd group, Grade 4 in2.3% of patients in the Isa-VRd group compared to 3.9% in the VRd group. Grade 5 pneumonia, basedon preferred term, occurred in 1.5% of patients in the Isa-VRd group compared to 1.1% in the VRdgroup. Discontinuations from treatment due to infection were reported in 8.4% of patients in the Isa-

VRd group compared to 9.4% in the VRd group. Fatal infections were reported in 6.5% of patients inthe Isa-VRd group and 4.4% in the VRd group. (see section 4.4).

In relapsed and refractory multiple myeloma clinical studies, herpes zoster was reported in 2.0 % ofpatients. In ICARIA-MM, the incidence of herpes zoster was 4.6 % in the Isa-Pd group compared to0.7 % in the Pd group, and in IKEMA, incidence was 2.3 % in the Isa-Kd group compared to 1.6 % inthe Kd group. In newly diagnosed multiple myeloma clinical trials, herpes zoster was reported in 3.3%of patients. In IMROZ, the incidence of herpes zoster was 5.7% in the Isa-VRd group compared to5.5% in the VRd group.

Cardiac failure

In IKEMA, cardiac failure (including cardiac failure, cardiac failure congestive, cardiac failure acute,cardiac failure chronic, left ventricular failure, and pulmonary oedema) was reported in 7.3 % ofpatients with the Isa-Kd group (4.0 % of Grade ≥ 3) and in 6.6 % of patients with the Kd group (4.1 %of Grade ≥ 3). Serious cardiac failure was observed in 4.0 % of patients in the Isa-Kd group and in3.3 % of patients in the Kd group. Cardiac failure with a fatal outcome during treatment was reportedin 1.1 % of patients in the Isa-Kd group and not reported in the Kd group (see the current prescribinginformation for carfilzomib).

Haematology laboratory values

Table 7: Haematology laboratory abnormalities in patients receiving isatuximab combined withpomalidomide and dexamethasone versus pomalidomide and dexamethasone (ICARIA-MM)

Laboratory SARCLISA + Pomalidomide + Pomalidomide + Dexamethasoneparameter Dexamethasone n (%)n (%) (N = 147)(N = 152)

All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

Anaemia 151 (99.3) 48 (31.6) 0 145 (98.6) 41 (27.9) 0

Neutropenia 146 (96.1) 37 (24.3) 92 (60.5) 137 (93.2) 57 (38.8) 46 (31.3)

Lymphopenia 140 (92.1) 64 (42.1) 19 (12.5) 137 (93.2) 52 (35.4) 12 (8.2)

Thrombocytopenia 127 (83.6) 22 (14.5) 25 (16.4) 118 (80.3) 14 (9.5) 22 (15.0)

The denominator used for the percentage calculation is the number of patients with at least 1evaluation of the laboratory test during the considered observation period.

Table 8: Haematology laboratory abnormalities in patients receiving isatuximab combined withcarfilzomib and dexamethasone versus carfilzomib and dexamethasone (IKEMA)

Laboratory SARCLISA + Carfilzomib + Carfilzomib + Dexamethasoneparameter Dexamethasone %% (N = 122)(N = 177)

All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

Anaemia 99.4 22.0 0 99.2 19.7 0

Neutropenia 54.8 17.5 1.7 43.4 6.6 0.8

Lymphopenia 94.4 52.0 16.9 95.1 43.4 13.9

Laboratory SARCLISA + Carfilzomib + Carfilzomib + Dexamethasoneparameter Dexamethasone %% (N = 122)(N = 177)

All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

Thrombocytopenia 94.4 18.6 11.3 87.7 15.6 8.2

The denominator used for the percentage calculation is the number of patients with at least 1evaluation of the laboratory test during the considered observation period.

Table 9: Haematology laboratory abnormalities in patients receiving isatuximab combined withbortezomib, lenalidomide, and dexamethasone versus bortezomib, lenalidomide, anddexamethasone (IMROZ and TCD13983)

Laboratory SARCLISA + Bortezomib + Bortezomib + Lenalidomide +parameter Lenalidomide + Dexamethasone Dexamethasone(N=336) (N=181)

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4

Anaemia 99.1% 15.8% 0% 97.8% 16.0% 0%

Lymphopenia 96.1% 45.5% 18.5% 92.3% 37.6% 15.5%

Thrombocytopenia 94.6% 16.7% 14.6% 84.5% 19.3% 8.3%

Neutropenia 86.9% 35.4% 17.3% 80.1% 28.2% 8.8%

The denominator used for the percentage calculation is the number of patients with at least 1 evaluation of thelaboratory test during the considered observation period.

CTCAE version: 4.03.

Of the total number of patients in clinical studies of SARCLISA, 42.7% (763 patients) were less than65, 43.2% (772 patients) were 65-74, and 14.1% (252 patients) were 75 or older. Differences in safetywere observed between older versus younger age groups. Grade >3 TEAEs were reported in 64.6% ofpatients less than 65, 79.7% of patients 65-74 and 76.2% of patients 75 or older, Grade 5 TEAEs werereported in 5.5% of patients less than 65, 7.5% of patients 65-74, and 12.3% of patients 75 or older.

Serious TEAEs were reported in 46.7% of patients less than 65, 58.8% of patients 65-74, and 60.7% ofpatients 75 or older. TEAEs leading to definitive treatment discontinuation were reported in 6% ofpatients less than 65, 14% of patients 65-74, and 15.5% of patients 75 or older.

In IMROZ study, no Grade 5 TEAEs were reported in patients less than 65, they were reported in10.7% of patients 65-74, and in 13.2% of patients 75 or older.

Across 9 clinical studies in relapsed or refractory multiple myeloma (RRMM) with isatuximab singleagent and combination therapies including ICARIA-MM and IKEMA (N = 1023), the incidence oftreatment emergent anti-drug antibodies (ADAs) was <2%. No effect of ADAs was observed onpharmacokinetics, safety or efficacy of isatuximab. Across 3 clinical studies in newly diagnosedmultiple myeloma (NDMM) with isatuximab in combination therapy with bortezomib, lenalidomide,and dexamethasone, including IMROZ, ADA incidence ranged from 8.7% to 21.6%. In IMROZ, out ofthe 263 patients with NDMM treated with isatuximab in combination with bortezomib, lenalidomide,and dexamethasone, 253 were evaluable for the presence of ADA, 22 patients (8.7%) tested positive fortreatment-emergent ADAs, with 21 patients considered to have a transient ADA response and 1considered to have an indeterminate ADA response. Among these 22 ADA-positive patients, 13 hadneutralizing antibodies (incidence of neutralizing antibodies: 5.1%). In IMROZ, a trend to lowerexposure was observed in ADA-positive patients. In patients with ADA-positive status to isatuximab nomeaningful impact of ADAs on efficacy of isatuximab was observed. No conclusions can be drawn onsafety due to the small subgroup of ADA positive patients.

In a phase 2 single-arm study conducted in 67 paediatric patients with relapsed or refractory acutelymphoblastic leukaemia or acute myeloid leukaemia, all evaluable for safety, Grade ≥ 3 TEAEs wasreported in 79.1 % of patients. The most common Grade ≥ 3 TEAEs occurring in > 10% of patientsincluded febrile neutropenia (41.8 %), septic shock (11.9 %), and stomatitis (10.4 %). The addition of

SARCLISA to standard chemotherapies did not modify the expected safety profile observed withstandard chemotherapies in this paediatric population and was consistent with isatuximab safety profilefor adults with multiple myeloma in ICARIA and IKEMA studies (see section 4.2).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Signs and symptoms

There has been no experience of overdose of isatuximab in clinical studies. Doses of intravenousisatuximab up to 20 mg/kg have been administered in clinical studies.

There is no known specific antidote for SARCLISA overdose. In the event of overdose, monitor thepatients for signs or symptoms of adverse reactions and take all appropriate measures immediately.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FC02.

Isatuximab is an IgG1-derived monoclonal antibody that binds to a specific extracellular epitope of

CD38 receptor. CD38 is a transmembrane glycoprotein that is highly expressed on multiple myelomacells.

In vitro, isatuximab acts through IgG Fc-dependent mechanisms including: antibody dependent cellmediated cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), and complementdependent cytotoxicity (CDC). Furthermore, isatuximab can also trigger tumour cell death byinduction of apoptosis via an Fc-independent mechanism.

In vitro, isatuximab blocks the enzymatic activity of CD38 which catalyses the synthesis andhydrolysis of cyclic ADP-ribose (cADPR), a calcium mobilizing agent. Isatuximab inhibits thecADPR production from extracellular nicotinamide adenine dinucleotide (NAD) in multiple myelomacells.

In vitro, isatuximab can activate NK cells in the absence of CD38 positive target tumour cells.

In vivo, a decrease in absolute counts of total CD16+ and CD56+ NK cells, CD19+ B-cells, CD4+

T- cells and TREG (CD3+, CD4+, CD25+, CD127-) was observed in peripheral blood of patientstreated with isatuximab monotherapy.

In multiple myeloma patients, SARCLISA monotherapy induced clonal expansion of the T-cellreceptor repertoire indicating an adaptive immune response.

The combination of isatuximab and pomalidomide in vitro enhances cell lysis of CD38 expressingmultiple myeloma cells by effector cells (ADCC), and by direct tumour cell killing compared to thatof isatuximab alone. In vivo animal experiments using a human multiple myeloma xenograft model inmice demonstrated that the combination of isatuximab and pomalidomide results in enhancedantitumour activity compared to the activity of isatuximab or pomalidomide alone.

Relapsed and/or refractory multiple myeloma

ICARIA-MM (EFC14335)

The efficacy and safety of SARCLISA in combination with pomalidomide and dexamethasone wereevaluated in ICARIA-MM (EFC14335), a multicentre, multinational, randomised, open-label, 2-arm,phase III study in patients with relapsed and/or refractory multiple myeloma. Patients had received atleast two prior therapies including lenalidomide and a proteasome inhibitor with disease progressionon or within 60 days after the end of the previous therapy. Patients with primary refractory diseasewere excluded.

A total of 307 patients were randomised in a 1:1 ratio to receive either SARCLISA in combinationwith pomalidomide and dexamethasone (Isa-Pd, 154 patients) or pomalidomide and dexamethasone(Pd, 153 patients). Treatment was administered in both groups in 28-day cycles until diseaseprogression or unacceptable toxicity. SARCLISA 10 mg/kg was administered as an I.V. infusionweekly in the first cycle and every two weeks thereafter. Pomalidomide 4 mg was taken orally oncedaily from day 1 to day 21 of each 28-day cycle. Dexamethasone (oral/intravenous) 40 mg (20 mg forpatients ≥ 75 years of age) was given on days 1, 8, 15 and 22 for each 28-day cycle.

Overall, demographic and disease characteristics at baseline were similar between the two treatmentgroups, with some minor imbalances. The median patient age was 67 years (range 36-86), 19.9 % ofpatients were ≥ 75 years. ECOG PS was 0 in 35.7 % of patients in the isatuximab arm and 45.1 % inthe comparator arm, 1 in 53.9 % in the isatuximab arm and 44.4 % in the comparator arm, and 2 in10.4 % in the isatuximab arm and 10.5 % in the comparator arm, 10.4 % of patients in the isatuximabarm versus 10.5 % in the comparator arm entered the study with a history of COPD or asthma, and38.6 % versus 33.3 % of patients with renal impairment (creatinine clearance < 60 mL/min/1.73 m²)were included in the isatuximab arm versus the comparator arm , respectively. The International

Staging System (ISS) stage at study entry was I in 37.5 % (41.6 % in the isatuximab arm and 33.3 %in the comparator arm), II in 35.5 % (34.4 % in the isatuximab arm and 36.6 % in the comparator arm)and III in 25.1 % (22.1 % in the isatuximab arm and 28.1 % in the comparator arm) of patients.

Overall, 19.5 % of patients (15.6 % in the isatuximab arm and 23.5 % in the comparator arm) hadhigh-risk chromosomal abnormalities at study entry; del(17p), t(4;14) and t(14;16) were present in12.1 % (9.1 % in the isatuximab arm and 15.0 % in the comparator arm), 8.5 % (7.8 % in theisatuximab arm and 9.2 % in the comparator arm) and 1.6 % (0.6 % in the isatuximab arm and 2.6 %in the comparator arm) of patients, respectively.

The median number of prior lines of therapy was 3 (range 2-11). All patients received a priorproteasome inhibitor, all patients received prior lenalidomide, and 56.4 % of patients received priorstem cell transplantation. The majority of patients (92.5 %) were refractory to lenalidomide, 75.9 %to a proteasome inhibitor, and 72.6 % to both an immunomodulatory and a proteasome inhibitor, and59 % of patients were refractory to lenalidomide at last line of therapy.

The median duration of treatment was 41.0 weeks for the Isa-Pd group compared to 24.0 weeks for the

Pd group.

Progression-free survival (PFS) was the primary efficacy endpoint of ICARIA-MM. The improvementin PFS represented a 40.4 % reduction in the risk of disease progression or death in patients treatedwith Isa-Pd.

Efficacy results are presented in Table 10 and Kaplan-Meier curves for PFS and OS are provided in

Figures 1 and 2:

Table 10: Efficacy of SARCLISA in combination with pomalidomide and dexamethasone versuspomalidomide and dexamethasone in the treatment of multiple myeloma (intent-to-treatanalysis)

Endpoint SARCLISA + Pomalidomide +pomalidomide + dexamethasonedexamethasone N = 153

N = 154

Progression-Free Survivala b

Median (months) 11.53 6.47[95 % CI] [8.936-13.897] [4.468-8.279]

Hazard ratioc [95 % CI] 0.596 [0.436-0.814]p-value (stratified log-rank test)c 0.0010

Overall Response Rated

Responders(sCR+CR+VGPR+PR) n(%) 93 (60.4) 54 (35.3)[95 % CI]e [0.5220-0.6817] [0.2775-0.4342]

Odds ratio vs comparator [95 % 2.795 [1.715-4.562]exact CI]p-value (stratified Cochran- < 0.0001

Mantel-Haenszel)c

Stringent Complete Response 7 (4.5) 3 (2.0)(sCR) + Complete Response(CR) n(%)

Very Good Partial Response 42 (27.3) 10 (6.5)(VGPR) n(%)

Partial Response (PR) n(%) 44 (28.6) 41 (26.8)

VGPR or better n(%) 49 (31.8) 13 (8.5)[95 % CI]e [0.2455-0.3980] [0.0460-0.1409]

Odds ratio vs comparator [95 % 5.026 [2.514-10.586]exact CI]p-value (stratified Cochran-Mantel < 0.0001

Haenszel)c

Duration of Responsef *

Median in months [95 % CI]g13.27 [10.612-NR] 11.07 [8.542-NR]a PFS results were assessed by an Independent Response Committee based on central laboratory data for M-protein and central radiologic imaging review using the International Myeloma Working Group (IMWG)criteria.b Patients without progressive disease or death before the analysis cut-off or the date of initiation of further anti-myeloma treatment were censored at the date of the last valid disease assessment not showing diseaseprogression performed prior to initiation of a further anti-myeloma treatment (if any) or the analysis cut-off date,whichever came first.c Stratified on age (< 75 years versus > 75 years) and number of previous lines of therapy (2 or 3 versus > 3)according to IRT.d sCR, CR, VGPR and PR were evaluated by the IRC using the IMWG response criteria.e Estimated using Clopper-Pearson method.f The duration of response was determined for patients who achieved a response of ≥ PR (93 patients in theisatuximab arm and 54 patients in the comparator arm). Kaplan-Meier estimates of duration of response.g CI for Kaplan-Meier estimates are calculated with log-log transformation of survival function and methods of

Brookmeyer and Crowley.

*Cut-off date of 11-Oct-2018. Median follow-up time = 11.60 months. HR < 1 favours Isa-Pd arm.

NR: not reached

In patients with high-risk cytogenetics (central laboratory assessment), median PFS was 7.49 (95 %

CI: 2.628 to NC) in the Isa-Pd group and 3.745 (95 % CI: 2.793 to 7.885) in the Pd group(HR = 0.655; 95 % CI: 0.334 to 1.283). PFS improvements in the Isa-Pd group were also observed inpatients > 75 years (HR = 0.479; 95 % CI: 0.242 to 0.946), with ISS stage III at study entry(HR = 0.635; 95 % CI: 0.363 to 1.110), with baseline creatinine clearance < 60 ml/min/1.73 m²(HR = 0.502; 95 % CI: 0.297 to 0.847), with > 3 prior lines of therapy (HR = 0.590; 95 % CI: 0.356 to0.977), in patients refractory to prior therapy with lenalidomide (HR = 0.593; 95 % CI: 0.431 to 0.816)or proteasome inhibitor (HR = 0.578; 95 % CI: 0.405 to 0.824) and in those refractory to lenalidomideat the last line before to the study entry (HR = 0.601; 95 %CI: 0.436 to 0.828).

Insufficient data is available to conclude on the efficacy of Isa-Pd in patients previously treated withdaratumumab (1 patient in the isatuximab arm and no patient in the comparator arm).

The median time to first response in responders was 35 days in the Isa-Pd group versus 58 days in the

Pd group. At a median follow-up time of 52.44 months, final median overall survival was24.57 months in the Isa-Pd group and 17.71 months in the Pd group (HR = 0.776; 95 % CI: 0.594 to1.015).

Figure 1: Kaplan-Meier Curves of PFS - ITT population - ICARIA-MM (assessment by the

IRC)

Figure 2: Kaplan-Meier Curves of OS - ITT population - ICARIA-MM

Cut-off date = 07 February 2023

In the ICARIA-MM (EFC14335) study, a weight-based volume was used for isatuximab infusion. Thefixed volume infusion method as described in section 4.2 was evaluated in study TCD14079 Part Band pharmacokinetics simulations confirmed minimal differences between the pharmacokineticsfollowing injection applying a volume based on patient weight and a fixed volume of 250 mL (seesection 5.2). In study TCD14079 part B, there were no new safety signals or differences in efficacyand safety as compared to ICARIA-MM.

IKEMA (EFC15246)

The efficacy and safety of SARCLISA in combination with carfilzomib and dexamethasone wereevaluated in IKEMA (EFC15246), a multicentre, multinational, randomized, open-label, 2-arm, phase

III study in patients with relapsed and/or refractory multiple myeloma. Patients had received one tothree prior therapies. Patients with primary refractory disease, who had previously been treated withcarfilzomib, or who were refractory to previous anti-CD38 monoclonal antibody treatment wereexcluded.

A total of 302 patients were randomized in a 3:2 ratio to receive either SARCLISA in combinationwith carfilzomib and dexamethasone (Isa-Kd, 179 patients) or carfilzomib and dexamethasone (Kd,123 patients). Treatment was administered in both groups in 28-day cycles until disease progression orunacceptable toxicity. SARCLISA 10 mg/kg was administered as an I.V. infusion weekly in the firstcycle and every two weeks thereafter. Carfilzomib was administered as an I.V. infusion at the dose of20 mg/m² on days 1 and 2; 56 mg/m² on days 8, 9, 15 and 16 of cycle 1; and at the dose of 56 mg/m²on days 1, 2, 8, 9, 15 and 16 for subsequent cycles of each 28-day cycle. Dexamethasone (IV on thedays of isatuximab and/ or carfilzomib infusions, and PO on the other days) 20 mg was given on days1, 2, 8, 9, 15, 16, 22 and 23 for each 28-day cycle.

Overall, demographic and disease characteristics at baseline were similar between the two treatmentgroups. The median patient age was 64 years (range 33-90), 8.9 % of patients were ≥ 75 years. ECOG

PS was 0 in 53.1 % of patients in the Isa-Kd group and 59.3 % in the Kd group, 1 in 40.8 % in the Isa-

Kd group and 36.6 % in the Kd group, and 2 in 5.6 % in the Isa-Kd group and 4.1 % in the Kd group,and 3 in 0.6 % in the Isa-Kd group and 0 % in the Kd group. The proportion of patients with renalimpairment (eGFR< 60 mL/min/1.73 m2) was 24.0 % in the Isa-Kd group versus 14.6 % in the Kdgroup. The International Staging System (ISS) stage at study entry was I in 53.0 %, II in 31.1 %, and

III in 15.2 % of patients. The Revised-ISS (R-ISS) stage at study entry was I in 25.8 %, II in 59.6 %,and III in 7.9 % of patients. Overall, 24.2 % of patients had high-risk chromosomal abnormalities atstudy entry; del(17p), t(4;14), t(14;16) were present in 11.3 %, 13.9 % and 2.0 % of patients,respectively. In addition, gain(1q21) was present in 42.1 % of patients.

The median number of prior lines of therapy was 2 (range 1-4) with 44.4 % of patients who received 1prior line of therapy. Overall, 89.7 % of patients received prior proteasome inhibitors, 78.1 % receivedprior immunomodulators (including 43.4 % who received prior lenalidomide), and 61.3 % receivedprior stem cell transplantation. Overall, 33.1 % of patients were refractory to prior proteasomeinhibitors, 45.0 % were refractory to prior immunomodulators (including 32.8 % refractory tolenalidomide), and 20.5 % were refractory to both a proteasome inhibitor and an immunomodulator.

The median duration of treatment was 80.0 weeks for the Isa-Kd group compared to 61.4 weeks forthe Kd group.

Progression-free survival (PFS) was the primary efficacy endpoint of IKEMA. With a median follow-up time of 20.73 months, the primary analysis of PFS showed a statistically significant improvementin PFS represented by a 46.9 % reduction in the risk of disease progression or death in patients treatedwith Isa-Kd compared to patients treated with Kd.

Efficacy results are presented in Table 11 and Kaplan-Meier curves for PFS and OS are provided inthe Figures 3 and 4:

Table 11: Efficacy of SARCLISA in combination with carfilzomib and dexamethasone versuscarfilzomib and dexamethasone in the treatment of multiple myeloma (intent-to-treat analysis)

Endpoint SARCLISA + carfilzomib Carfilzomib ++ dexamethasone dexamethasone

N = 179 N = 123

Progression-Free Survivala

Median (months) NR 19.15[NR -NR] [15.77-NR][95 % CI]

Hazard ratiob [99 % CI] 0.531 [0.318-0.889]p-value (Stratified Log-Rank test)b 0.0013

Overall Response Ratec

Responders (sCR+CR+VGPR+PR) 86.6 % 82.9 %d [0.8071-0.9122] [0.7509-0.8911][95 % CI]p-value (stratified Cochran-Mantel- 0.3859

Haenszel)b

Complete Response (CR) 39.7 % 27.6 %

Very Good Partial Response 33.0 % 28.5 %(VGPR)

Partial Response (PR) 14.0 % 26.8 %

VGPR or better (sCR+CR+VGPR) 72.6 % 56.1 %[95 % CI]d [0.6547-0.7901] [0.4687 -0.6503]p-value (stratified Cochran- 0.0021

Mantel-Haenszel)b e

CRf 39.7 % 27.6 %[95 % CI]d [0.3244-0.4723] [0.1996 to 0.3643]

Endpoint SARCLISA + carfilzomib Carfilzomib ++ dexamethasone dexamethasone

N = 179 N = 123

Minimal Residual Disease negativerateg 29.6 % 13.0 %[95 % CI]d [0.2303-0.3688] [0.0762-0.2026]p-value (stratified Cochran- 0.0008

Mantel-Haenszel)b e

Duration of Responseh *(PR orbetter)

Median in months [95 % CI]i NR [NR-NR] NR [14.752-NR]

Hazard ratiob [95 % CI] 0.425 [0.269-0.672]a PFS results were assessed by an Independent Response Committee based on central laboratory data for M-protein and central radiologic imaging review using the International Myeloma Working Group (IMWG)criteria.b Stratified on number of previous lines of therapy (1 versus > 1) and R-ISS (I or II versus III versus notclassified) according to IRT.c sCR, CR, VGPR, and PR were evaluated by the IRC using the IMWG response criteria.d Estimated using Clopper-Pearson method.e Nominal p-value.f CR to be tested with final analysis.g Based on a sensitivity level of 10-5 by NGS in ITT population.h Based on Responders in the ITT population. Kaplan-Meier estimates of duration of response.i CI for Kaplan-Meier estimates are calculated with log-log transformation of survival function and methods of

Brookmeyer and Crowley.

* Cut-off date of 7 February 2020. Median follow-up time = 20.73 months. HR< 1 favours Isa-Kd arm.

NR: not reached.

PFS improvements in the Isa-Kd group were observed in patients with high -risk cytogenetics (centrallaboratory assessment, HR = 0.724; 95 % CI: 0.361 to 1.451), with gain (1q21) chromosomalabnormality (HR = 0.569; 95 % CI: 0.330 to 0.981), ≥ 65 years (HR = 0.429; 95 % CI: 0.248 to0.742), with baseline eGFR (MDRD) < 60 mL/min/1.73 m² (HR = 0.273; 95 % CI: 0.113 to 0.660),with > 1 prior line of therapy (HR = 0.479; 95 % CI: 0.294 to 0.778), with ISS stage III at study entry(HR = 0.650; 95 % CI: 0.295 to 1.434), and in patients refractory to prior therapy with lenalidomide(HR = 0.598; 95 % CI: 0.339 to 1.055).

In the sensitivity analysis without censoring for further anti-myeloma therapy, the median PFS was notreached (NR) in the Isa-Kd group versus 19.0 months (95 % CI: 15.38 to NR) in the Kd group(HR = 0.572; 99 % CI: 0.354 to 0.925, p = 0.0025).

Insufficient data is available to conclude on the efficacy of Isa-Kd in patients previously treated withdaratumumab (1 patient in the isatuximab arm and no patient in the comparator arm).

The median time to first response was 1.08 months in the Isa-Kd group and 1.12 months in the Kdgroup. The median time to next anti-myeloma treatment was 43.99 months in the Isa-Kd group and25.00 months in the Kd group (HR = 0.583; 95 % CI: 0.429 to 0.792).

Figure 3 - Kaplan-Meier Curves of PFS - ITT population - IKEMA (assessment by the IRC)

Cut-off date = 07 February 2020.

Figure 4: Kaplan-Meier Curves of OS - ITT population - IKEMA

Cut-off date = 07 February 2023

Among patients with eGFR (MDRD) < 50 mL/min/1.73 m2 at baseline, complete renal response(≥ 60 mL/min/1.73 m2 at ≥ 1 postbaseline assessment) was observed for 52.0 % (13/25) of patients inthe Isa-Kd group and 30.8 % (4/13) in the Kd group. Sustained complete renal response (≥ 60 days)occurred in 32.0 % (8/25) of patients in the Isa-Kd group and in 7.7 % (1/13) in the Kd group. In the 4patients in the Isa-Kd group and the 3 patients in the Kd group with severe renal impairment atbaseline (eGFR (MDRD) > 15 to < 30 mL/min/1.73 m2), minimal renal response (≥ 30 to< 60 mL/min/1.73 m2 at ≥ 1 postbaseline assessment) was observed for 100 % of patients in the Isa-Kdgroup and 33.3 % of patients in the Kd group.

At a median follow-up time of 43.96 months, final PFS analysis showed a median PFS of35.65 months for Isa-Kd group compared to 19.15 months for Kd group, with a hazard ratio of 0.576(95.4 % CI: 0.418 to 0.792). Final complete response, determined using a validated isatuximab-specific IFE assay (Sebia Hydrashift) (see section 4.5), was 44.1 % in Isa-Kd group compared to28.5 % in Kd group, with odds ratio 2.094 (95 % CI: 1.259 to 3.482, descriptive p = 0.0021). In26.3 % of patients in Isa-Kd group, both MRD negativity and CR were met compared to 12.2 % in Kdgroup, with odds ratio 2.571 (95 % CI: 1.354 to 4.882, descriptive p = 0.0015).

At a median follow-up time of 56.61 months, median overall survival was not reached in the Isa-Kdgroup (95 % CI: 52.172 to NR) and was 50.60 months in Kd group (95 % CI: 38.932 to NR)(HR = 0.855; 95 % CI: 0.608 to 1.202).

Newly diagnosed multiple myeloma

IMROZ (EFC12522)

The efficacy and safety of SARCLISA in combination with bortezomib, lenalidomide, anddexamethasone were evaluated in IMROZ (EFC12522), a multicentre, international, randomized,open-label, 2-arm, phase III study in patients with newly diagnosed multiple myeloma (NDMM) whoare not eligible for stem cell transplantation. Patients over the age of 80 years were excluded, as wellas patients with comorbidities that do not allow transplant procedures in patients with NDMM, basedon investigator’s medical assessment (e.g., lung or coronary heart disease).

A total of 446 patients were randomized in a 3:2 ratio to receive either SARCLISA in combinationwith bortezomib, lenalidomide, and dexamethasone (Isa-VRd, 265 patients) or bortezomib,lenalidomide, and dexamethasone (VRd, 181 patients) administered in both groups during 4 cycles of42-day for the induction period. After completion of cycle 4, patients entered the continuous treatmentperiod starting from cycle 5, 28-day cycles administered up to disease progression or unacceptabletoxicity. During the continuous treatment period, patients of the Isa-VRd group received SARCLISAin combination with lenalidomide, and dexamethasone (Isa-Rd), and patients in the VRd groupreceived lenalidomide, and dexamethasone (Rd).

During the induction period (cycle 1 to 4, 42-day cycles), SARCLISA 10 mg/kg was administered asan I.V. infusion on day 1, 8, 15, 22, and 29, in the first cycle and on day 1, 15, and 29, from cycle 2 to4. Bortezomib was administered subcutaneously at the dose of 1.3 mg/m² on days 1, 4, 8, 11, 22, 25,29, and 32 of each cycle. Lenalidomide was administered per os at the dose of 25 mg/day from day 1to 14 and from day 22 to 35 of each cycle. Dexamethasone (I.V. on the days of isatuximab infusions,and PO on the other days) 20 mg/day was given on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29,30, 32, and 33 of each cycle, and administered on days 1, 4, 8, 11, 15, 22, 25, 29, and 32 of each cyclefor patients ≥75 years old.

During the continuous treatment period (from cycle 5, 28-day cycles), SARCLISA 10 mg/kg wasadministered as an I.V. infusion on day 1 and 15 from cycle 5 to 17, and on day 1 from cycle 18.

Lenalidomide was administered per os at the dose of 25 mg/day from day 1 to 21 of each cycle.

Dexamethasone (I.V. on the days of isatuximab infusions, and PO on the other days) 20 mg/day wasgiven on days 1, 8, 15, and 22 of each cycle.

Overall, demographic and disease characteristics at baseline were similar between the two treatmentgroups. The median patient age was 72 years (range 60-80), 26% of patients were ≥75 years. ECOG

PS was 0 in 46.4% of patients in the Isa-VRd group and 43.6% in the VRd group, 1 in 42.3% in the

Isa-VRd group and 45.9% in the VRd group, and 2 in 10.9% in the Isa-VRd group and 10.5% in the

VRd group,and 3 in 0.4% in the Isa-VRd group and 0% in the VRd group. The proportion of patientswith renal impairment (eGFR<60 mL/min/1.73m2) was 24.9% in the Isa-VRd group versus 34.3% inthe VRd group. The Revised International Staging System (R-ISS) stage at study entry was I in 24.9%,

II in 61.5%, and III in 10.2% of patients. Overall, 15.1% of patients had high-risk chromosomalabnormalities at study entry; del(17p), t(4;14), and t(14;16) were present in 5.7%, 7.9% and 1.9% ofpatients, respectively. In addition, 1q21+ was present in 35.8% of patients.

The median duration of treatment was 53.2 months for the Isa-VRd group compared to 31.3 monthsfor the VRd group.

Progression-free survival (PFS) was the primary efficacy endpoint of IMROZ. With a median follow-up time of 59.73 months, the pre-planned second interim analysis of PFS showed a statisticallysignificant improvement in PFS representing a 40.4% reduction in the risk of disease progression ordeath in patients treated with Isa-VRd compared to patients treated with VRd.

Efficacy results are presented in Table 12 and Kaplan-Meier curves for PFS are provided in Figure 5:

Table 12*: Efficacy of SARCLISA in combination with bortezomib, lenalidomide, anddexamethasone versus bortezomib, lenalidomide, and dexamethasone in the treatment ofmultiple myeloma (intent-to-treat analysis)

Endpoint SARCLISA + bortezomib + Bortezomib +lenalidomide + lenalidomide +dexamethasone dexamethasone

N =265 N = 181

Progression-Free Survival a

Median (months) NR 54.34[95% CI] [NR-NR] [45.21-NR]

Hazard ratio b [98.5% CI]0.596 [0.406-0.876]p-value (Stratified Log-Rank test)b 0.0009

CR or better (sCR and CR) 74.7% 64.1%[95% CI]c [0.6904-0.7984] [0.5664-0.7107]p-value (Stratified Log-Rank test)b 0.0160

Minimal Residual Disease negativitydand CR 55.5% 40.9%[95% CI]c [0.4927-0.6155] [0.3365-0.4842]p-value (stratified Cochran-Mantel- 0.0026

Haenszel)b

Overall Response Ratee 91.3% 92.3%

Responders (sCR+CR+VGPR+PR) [0.8726-0.9442] [0.8736-0.9571][95% CI]c

Stringent Complete Response (sCR) 10.9% 5.5%

Complete Response (CR) 63.8% 58.6%

Very Good Partial Response 14.3% 18.8%(VGPR)

Partial Response (PR) 2.3% 9.4%a PFS results were assessed by an Independent Response Committee based on central laboratory datafor M-protein and central radiologic imaging review using the International Myeloma Working Group(IMWG) criteria.b Stratified by age (<70 years vs ≥70 years) and Revised International Staging System (R-ISS) stage (Ior II vs. III or not classified) according to IRTc Estimated using Clopper-Pearson method.

d Based on a sensitivity level of 10-5 by NGS in ITT population.e sCR, CR, VGPR, and PR were evaluated by the IRC using the IMWG response criteria. Resultsshould be interpreted descriptively.

* Cut-off date of 26 September 2023. Median follow-up time=59.73 months.

NR: not reached

PFS improvement in the Isa-VRd group was confirmed by the sensitivity analyses sand was observedacross most subgroups of patients, including patients with 1q21+ chromosomal abnormality(HR=0.407; 95% CI: 0.253 to 0.653), ≥70 years (HR=0.671; 95% CI: 0.463 to 0.972), with baselineeGFR (MDRD) < 60 mL/min/1.73 m² (HR=0.63; 95% CI: 0.371 to 1.068), and with ECOG PS>1(HR=0.606; 95% CI: (0.246 to 1.493).

NGS MRD negativity (10-5 sensitivity threshold) was reached in 58.1% of patients in the Isa-VRdgroup with a median time to first NGS MRD negativity of 196.5 days (range: 87-1834). In the VRdgroup, NGS MRD negativity (10-5 sensitivity threshold) was reached in 43.6% of patients with amedian time to first NGS MRD negativity of 197.0 days (range: 107-1512).

Sustained NGS MRD negativity rate for at least 12 months occurred in 46.8% of patients in the Isa-

VRd group and in 24.3% in the VRd group.

The median time to progression was not reached in the Isa-VRd group and was 59.70 months (95%

CI: 48.164 to NR) in the VRd group (HR=0.414; 95% CI: 0.286 to 0.598). The median duration ofresponse was not reached in the Isa-VRd group and was 58.25 months (95% CI: 44.583 to NR) in the

VRd group. The median time to first response was 1.51 months in the Isa-VRd group and 1.48 monthsin the VRd group. In the Isa-VRd group, 52.1% of patients discontinued the study treatment, 14.3%due to disease progression. In the VRd group, 75.7% of patients discontinued the study treatment.37% due to disease progression. The median time to next anti-myeloma treatment was not reached inthe Isa-VRd group and was 63.57 months in the VRd group (HR=0.376; 95% CI: 0.265 to 0.534).

Median overall survival was not reached for either treatment group. Based on the descriptive analysisof overall survival data, 26% of patients in the Isa-VRd group and 32.6% of patients in the VRd grouphad died (HR=0.776; 99.97% CI: 0.407 to 1.48).

Figure 5 - Kaplan-Meier Curves of PFS - ITT population - IMROZ (assessment by the IRC)

Cutoff date = 26-September-2023.

The European Medicines Agency has deferred the obligation to submit the results of studies with

SARCLISA in one or more subsets of the paediatric population in the treatment of malignantneoplasms of the haematopoietic and lymphoid tissue. See section 4.2 for information on paediatricuse.

A phase 2, single-arm, study in 67 paediatric patients was conducted in 3 separate disease cohorts.

Fifty-nine patients with relapsed or refractory T-acute lymphoblastic leukaemia (T-ALL, 11 patients),

B-acute lymphoblastic leukemia (B-ALL, 25 patients), and acute myeloid leukaemia (AML, 23patients) were evaluable for efficacy. For patients with T-ALL and B-ALL, the treatment consisted ofone induction cycle and one consolidation cycle. For patients with AML, the treatment consisted of upto two induction cycles. The median age was 8 years (range 17 months to 17 years). Patients weretreated with SARCLISA in combination with standard chemotherapies (e.g., antimetabolites,anthracyclines, and alkylating agents). At interim analysis, complete response rate (the primaryefficacy endpoint, defined as complete response, CR, or complete response with incomplete peripheralrecovery, CRi), did not meet the pre-specified statistical threshold in the 3 cohorts with 52.0 % of B-

ALL patients, 45.5 % of T-ALL patients, and 60.9 % of AML patients reaching complete response(CR+CRi). The study was stopped after the prespecified interim analysis.

The pharmacokinetics of isatuximab were assessed in 476 patients with multiple myeloma treated withisatuximab intravenous infusion as a single agent or in combination with pomalidomide anddexamethasone, at doses ranging from 1 to 20 mg/kg, administered either once weekly; every 2 weeks;or every 2 weeks for 8 weeks followed by every 4 weeks; or every week for 4 weeks followed byevery 2 weeks.

Isatuximab displays nonlinear pharmacokinetics with target-mediated drug disposition due to itsbinding to CD38 receptor.

Isatuximab exposure (area under the plasma concentration-time curve over the dosing interval AUC)increases in a greater than dose proportional manner from 1 to 20 mg/kg following every 2 weeksschedule, while no deviation to the dose proportionality is observed between 5 and 20 mg/kgfollowing every week for 4 weeks followed by every 2 weeks schedule. This is due to the highcontribution of nonlinear target-mediated clearance to the total clearance at doses below 5 mg/kg,which becomes negligible at higher doses. After isatuximab 10 mg/kg administration every week for4 weeks followed by every 2 weeks, the median time to reach steady state was 18 weeks with a 3.1-fold accumulation. In ICARIA-MM, clinical study performed in relapsed and/or refractory multiplemyeloma patients treated with isatuximab in combination with pomalidomide and dexamethasone, themean (CV%) predicted maximum plasma concentration Cmax and AUC at steady state were 351 µg/mL(36.0 %) and 72 600 µg.h/mL (51.7 %), respectively. Although the change from a weight-basedvolume administration method for isatuximab infusion to the fixed volume infusion method resulted inchanges in the tmax, the change had a limited impact on pharmacokinetics exposure with comparablesimulated Cmax at steady state (283 µg/mL vs 284 µg/mL) and Ctrough at 4 weeks (119 µg/mL vs119 µg/mL) for a patient with median weight (76 kg). Also for other patient weight groups, Cmax and

Ctrough were comparable. In IKEMA, clinical study performed in relapsed and/or refractory multiplemyeloma patients treated with isatuximab in combination with carfilzomib and dexamethasone, themean (CV%) predicted maximum plasma concentration Cmax and AUC at steady state were 637 µg/mL(30.9 %) and 152 000 µg.h/mL (37.8 %), respectively. In IMROZ, clinical trial performed in newlydiagnosed multiple myeloma patients treated with isatuximab in combination with bortezomib,lenalidomide, and dexamethasone, the mean (CV%) predicted maximum plasma concentration Cmaxand AUC2weeks at steady state were 494 µg/mL (25.5%) and 119,000 µg.h/mL (31.8%), respectively.

Exposure parameters were consistent in IMROZ and TCD13983 studies.

A trend toward lower exposure was observed in ADA-positive patients in NDMM patients from

IMROZ, with a geometric mean ratio (ADA-positives versus ADA-negatives) of 0.82 and 0.70 forcumulative AUC over the first 4 weeks of treatment (AUC4W) and Ctrough at 4 weeks (CT4W),respectively. However, as ADA kinetics was transient with an onset time primarily at the beginning ofisatuximab treatment (ie during the first month of isatuximab treatment), the mean linear CL at steadystate between ADA-positive and ADA-negative patients remained comparable.

The pharmacokinetics of isatuximab and pomalidomide, or of isatuximab and carfilzomib, or ofisatuximab and bortezomib and lenalidomide were not influenced by their co-administration.

The estimated total volume of distribution of isatuximab is 8.75 L.

As a large protein, isatuximab is expected to be metabolized by non-saturable proteolytic catabolismprocesses.

Isatuximab is eliminated by two parallel pathways, a nonlinear target-mediated pathwaypredominating at low concentrations, and a nonspecific linear pathway predominating at higherconcentrations. In the therapeutic plasma concentrations range, the linear pathway is predominant anddecreases over time by 50 % to a steady state value of 9.55 mL/h (0.229 L/day). This is associatedwith a terminal half-life of 28 days.

The population pharmacokinetic analyses of 476 patients aged 36 to 85 years showed comparableexposure to isatuximab in patients < 75 years old (n = 406) versus ≥ 75 years old (n = 70).

The population pharmacokinetic analysis with 207 female (43.5 %) and 269 male (56.5 %) patientsshowed no clinically meaningful effect of gender on isatuximab pharmacokinetics.

The population pharmacokinetic analysis with 377 Caucasian (79 %), 25 Asian (5 %), 18 Black (4 %),and 33 other race (7 %) patients showed no clinically meaningful effect of race on isatuximabpharmacokinetics.

Weight

Based on a population pharmacokinetics analysis using data from 476 patients, the clearance ofisatuximab increased with increasing body weight, supporting the body-weight based dosing.

No formal studies of isatuximab in patients with hepatic impairment have been conducted. Out of the476 patients of the population pharmacokinetic analyses, 65 patients presented with mild hepaticimpairment [total bilirubin > 1 to 1.5 times upper limit of normal (ULN) or aspartate amino transferase(AST) > ULN] and 1 patient had moderate hepatic impairment (total bilirubin > 1.5 to 3 times ULNand any AST). Mild hepatic impairment had no clinically meaningful effect on the pharmacokineticsof isatuximab. The effect of moderate (total bilirubin > 1.5 times to 3 times ULN and any AST) andsevere hepatic impairment (total bilirubin > 3 times ULN and any AST) on isatuximabpharmacokinetics is unknown. However, since isatuximab is a monoclonal antibody, it is not expectedto be cleared via hepatic-enzyme mediated metabolism and as such, variation in hepatic function is notexpected to affect the elimination of isatuximab (see section 4.2).

No formal studies of isatuximab in patients with renal impairment have been conducted. Thepopulation pharmacokinetic analyses on 476 patients included 192 patients with mild renal impairment(60 mL/min/1.73 m2 ≤ estimated glomerular filtration rate (e-GFR) < 90 mL/min/1.73 m2), 163patients with moderate renal impairment (30 mL/min/1.73 m2≤ e-GFR< 60 mL/min/1.73 m2) and 12patients with severe renal impairment (e-GFR< 30 mL/min/1.73 m2). Analyses suggested no clinicallymeaningful effect of mild to severe renal impairment on isatuximab pharmacokinetics compared tonormal renal function.

A Pharmacokinetics analysis on 22 patients with End-Stage Renal Disease (ESRD) including patientson dialysis (eGFR< 15 mL/min/1.73 m²) showed no clinically meaningful effects of ESRD onisatuximab pharmacokinetics compared to those of normal, mild, or moderate renal function.

In the paediatric patient population (from 17 months to 17 years old), after the first isatuximabadministration, among the 3 cohorts, the mean Cmax ranged from 322 to 433 µg/mL, mean

AUC1week from 28 592 to 31 703 µg.h/mL, and after repeated isatuximab administrations over3 weeks, cumulative mean AUC ranged from 130 862 to 148 397 µg.h/mL. Pharmacokinetics datareported in paediatric population with AML and ALL were consistent with those from adults with

ALL and MM at the same isatuximab dose.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dosetoxicity, albeit the species selected is not pharmacologically responsive and therefore the relevance forhumans is not known. Genotoxicity, carcinogenic potential and toxicity to reproduction anddevelopment studies have not been performed.

Sucrose

Histidine hydrochloride monohydrate

Histidine

Polysorbate 80 (E433)

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened Vial3 years

Chemical and physical in-use stability of SARCLISA infusion solution has been demonstrated for48 hours at 2°C - 8°C, followed by 8 hours (including the infusion time) at room temperature(15°C - 25°C).

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior use are the responsibility of the user and wouldnormally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled andvalidated aseptic conditions.

No protection from light is required for storage in the infusion bag.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

5 ml concentrate containing 100 mg of isatuximab in a 6 mL type I colourless clear glass vial closedwith ETFE (copolymer of ethylene and tetrafluoroethylene)-coated bromobutyl stopper. The vials arecrimped with an aluminium seal with a grey flip-off button. The fill volume has been established toensure removal of 5 mL (i.e. 5.4 mL). Pack size of one or three vials.

25 ml concentrate containing 500 mg of isatuximab in a 30 mL type I colourless clear glass vial closedwith ETFE (copolymer of ethylene and tetrafluoroethylene)-coated bromobutyl stopper. The vials arecrimped with an aluminium seal with a blue flip-off button. The fill volume has been established toensure removal of 25 mL (i.e. 26 mL). Pack size of one vial.

Not all pack sizes may be marketed.

Preparation for the intravenous administration

The preparation of the infusion solution must be done under aseptic conditions.

* The dose (mg) of SARCLISA concentrate should be calculated based on patient weight(measured prior to each cycle to have the administered dose adjusted accordingly, see section4.2). More than one vial may be necessary to obtain the required dose for the patient.

* Vials of SARCLISA concentrate should be visually inspected before dilution to ensure they donot contain any particles and are not discoloured.

* Do not shake vials.

* The volume of diluent equal to the required volume of SARCLISA concentrate should beremoved from a 250 mL sodium chloride 9 mg/mL (0.9 %) solution for injection or glucose5 % solution diluent bag.

* The appropriate volume of SARCLISA concentrate should be withdrawn from the

SARCLISA vial and diluted in the 250 mL infusion bag with sodium chloride 9 mg/mL(0.9 %) solution for injection or glucose 5 % solution.

* The infusion bag must be made of polyolefins (PO), polyethylene (PE), polypropylene (PP),polyvinyl chloride (PVC) with di (2-ethylhexyl) phthalate (DEHP) or ethyl vinyl acetate(EVA).

* Gently homogenize the diluted solution by inverting the bag. Do not shake.

* The infusion solution must be administered by intravenous infusion using an intravenoustubing infusion set (in PE, PVC with or without DEHP, polybutadiene (PBD) or polyurethane(PU)) with a 0.22 micron in-line filter (polyethersulfone (PES), polysulfone or nylon).

* The infusion solution should be administered for a period of time that will depend on theinfusion rate (see section 4.2).

* No protection from light is required for the prepared infusion bag in a standard artificial lightenvironment.

* Do not infuse SARCLISA solution concomitantly in the same intravenous line with otheragents.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Sanofi Winthrop Industrie82 avenue Raspail94250 Gentilly

France

EU/1/20/1435/001

EU/1/20/1435/002

EU/1/20/1435/003

Date of first authorisation: 30 May 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.