4.1. Therapeutic indications

Isatuximab is indicated:

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

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

- in combination with bortezomib, lenalidomide, and dexamethasone, for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

- in combination with bortezomib, lenalidomide, and dexamethasone, for the induction treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.

4.2. Posology and method of administration

Treatment with isatuximab should be prescribed by a specialist in the treatment of malignancies. Isatuximab intravenous should be administered by a healthcare professional, in an environment where resuscitation facilities are available.

Premedication

Prevention of infusion reaction

Premedication should be used prior to isatuximab infusion with the following medicinal products to reduce the risk and severity of infusion reactions (see section 4.4):

• Dexamethasone 40 mg oral or intravenous (or 20 mg oral or intravenous for patients ≥75 years 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 and carfilzomib.

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

• Montelukast 10 mg oral (or equivalent), at least at cycle 1.

• Acetaminophen 650 mg to 1000 mg oral (or equivalent).

• H2 antagonists (ranitidine 50 mg IV or equivalent [e.g. cimetidine]), or oral proton pump inhibitors (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 4 infusions.

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

The recommended premedication agents should be administered 15 – 60 minutes prior to starting an isatuximab infusion. Patients who do not experience an infusion reaction upon their first 4 administrations of isatuximab 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 of neutropenia. In the event of Grade 3 or Grade 4 neutropenia or febrile neutropenia and/or neutropenic infection, isatuximab 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 treatment guidelines should be considered during treatment (see section 4.4).

Posology

The recommended dose of Sarclisa 20 mg/mL concentrate for solution for infusion is 10 mg/kg body weight administered as an intravenous infusion in combination with pomalidomide and dexamethasone (Isa-Pd) or in combination with carfilzomib and dexamethasone (Isa-Kd), or in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd).

Patients may start treatment using intravenous or subcutaneous isatuximab. Patients currently receiving intravenous isatuximab may switch to subcutaneous isatuximab, at any time during their treatment, once cycle 1 is completed.

Isatuximab intravenous dosing schedules are provided in Tables 1, 2 and 3.

Table 1: Dosing schedule in combination with pomalidomide and dexamethasone or in combination with carfilzomib and dexamethasone

Cycles

Dosing schedule

Cycle 1 (28-day cycle)

10 mg/kg IV weekly; days 1, 8, 15 and 22

Cycle 2 and beyond (28-day cycle)

10 mg/kg IV every 2 weeks; days 1, 15

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

Table 2: Dosing schedule in combination with bortezomib, lenalidomide, and dexamethasone for patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT)

Cycles

Dosing schedule

Cycle 1 (42-day cycle)

10 mg/kg IV; days 1, 8, 15, 22, and 29

Cycles 2 to 4 (42-day cycles)

10 mg/kg IV every 2 weeks; days 1, 15, and 29

Cycles 5 to 17 (28-day cycles)

10 mg/kg IV every 2 weeks; days 1 and 15

Cycles 18 and beyond (28-day cycles)

10 mg/kg IV every 4 weeks; day 1

Each treatment cycle consists of a 42-day period from cycle 1 to 4, and of a 28-day period from cycle 5. Treatment is repeated until disease progression or unacceptable toxicity.

Table 3: Dosing schedule in combination with bortezomib, lenalidomide, and dexamethasone for patients with NDMM who are eligible for ASCT

Cycles

Dosing schedule

Induction treatment

Cycle 1 (42-day cycle)

10 mg/kg IV; days 1, 8, 15, 22 and 29

Cycles 2 to 3 (42-day cycles)

10 mg/kg IV every 2 weeks; days 1, 15 and 29

Stop for intensification treatment (high dose chemotherapy and ASCT) followed by SOC maintenance treatment

Each treatment cycle consists of a 42-day period.

Missed dose

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

Dose adjustments

No dose reduction of isatuximab is recommended.

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

For other medicinal products that are administered with isatuximab, the respective current summary of product characteristics should be considered.

Special populations

Elderly

No dose adjustment is recommended in elderly patients (see sections 4.4, 4.8 and 5.2).

Patients with renal impairment No dose adjustment is recommended in patients with mild (GFR ≥60 – <90 mL/min/1.73 m2) to severe (GFR <30 mL/min/1.73 m2) renal impairment including end-stage renal disease (GFR <15 mL/min/1.73 m2) (see section 5.2).

Patients with hepatic impairment No dose adjustment is recommended in patients with mild hepatic impairment ([total bilirubin >1 to 1.5 times upper limit of normal (ULN) or aspartate amino transferase (AST) >ULN). Data in patients with moderate (total bilirubin >1.5 to 3 times ULN and 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.

Paediatric population

Outside its authorised indications, isatuximab intravenous has been studied in children aged 28 days to less than 18 years of age with relapsed or refractory acute lymphoblastic or myeloid leukaemia but efficacy has not been established. Currently available data are described in sections 4.8, 5.1 and 5.2.

Method of administration

Sarclisa 20 mg/mL concentrate for solution for infusion is for intravenous use. For instructions on dilution of the medicinal product before administration, see section 6.6.

Infusion rates

Following dilution, the isatuximab infusion should be administered intravenously at the infusion rate presented in Table 4 below (see section 5.1). Incremental escalation of the infusion rate should be considered only in the absence of infusion reactions (see section 4.8).

Table 4: Infusion rates of isatuximab administration

Dilution volume

Initial rate

Absence of infusion reaction

Rate increment

Maximum rate

First infusion

250 mL

25 mL/hour

For 60 minutes

25 mL/hour every 30 minutes

150 mL/hour

Second infusion

250 mL

50 mL/hour

For 30 minutes

50 mL/hour for 30 minutes then increase by 100 mL/hour

200 mL/hour

Subsequent infusions

250 mL

200 mL/hour

–

–

200 mL/hour

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 temporary interruption in the infusion should be considered and additional symptomatic medicinal products can be administered. After symptom improvement to grade ≤1 (mild), isatuximab infusion may be resumed at half of the initial infusion rate under close monitoring and supportive care, as needed. If symptoms do not recur after 30 minutes, the infusion rate may be 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 isatuximab infusion, persist or worsen despite appropriate medicinal products, or require hospitalization or are life-threatening, treatment with Sarclisa should be permanently discontinued and additional supportive therapy should be administered, as needed.

• In case of Grade ≥3 hypersensitivity reactions or infusion reactions, isatuximab treatment should be permanently discontinued.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of 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 isatuximab in ICARIA-MM, in 45.8% of patients treated with Isa-Kd in IKEMA, in 24.0% of patients treated with Isa-VRd in IMROZ and in 12.7% of patients treated with Isa-VRd during the induction period in GMMG-HD7 (see section 4.8). In ICARIA-MM, all infusion reactions started during the first isatuximab 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. The most 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 treated with Isa-Kd, 94.4% of those experiencing an IR experienced it during the first cycle of treatment. All infusion reactions resolved. The most common symptoms of an infusion reaction included cough, dyspnoea, nasal congestion, vomiting and nausea. The most common severe signs and symptoms included hypertension and dyspnoea. In IMROZ, the IRs started on the infusion day in all patients, mostly during the first isatuximab infusion, and resolved the same day in 97.3% of patients. All IRs resolved. The most common symptoms of an IR included dyspnoea and chills. The most common severe sign and symptom was hypertension. In GMMG-HD7, during the induction period, in patients treated with Isa-VRd, 88.1% of those experiencing an IR experienced it at the first infusion and 21.4% at the subsequent infusions. All IRs resolved (see section 4.8).

However, serious infusion reactions including severe anaphylactic reactions have also been observed after isatuximab administration. Anaphylactic reactions with a fatal outcome have been reported (see section 4.8).

To decrease the risk and severity of infusion reactions, patients should be pre-medicated prior to isatuximab infusion with montelukast (at least at cycle 1), acetaminophen, diphenhydramine or equivalent; dexamethasone is to be used as both premedication and anti-myeloma treatment (see section 4.2). Vital signs should be frequently monitored during the entire isatuximab infusion. When required, interrupt isatuximab infusion and provide appropriate medical and supportive measures (see section 4.2). In case symptoms do not improve to Grade ≤1 after interruption of isatuximab infusion, persist or worsen despite appropriate medicinal products, require hospitalization or are life-threatening, permanently discontinue Sarclisa and institute appropriate management. In case of anaphylactic reaction or life-threatening (Grade 4) infusion reaction, permanently discontinue Sarclisa and institute appropriate management.

NeutropeniaIn patients treated with Isa-Pd, neutropenia was reported as a laboratory abnormality in 96.1% of patients and as an adverse reaction (1) in 46.7% of patients, with Grade 3 – 4 neutropenia reported as a laboratory 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 febrile neutropenia and 25.0% of neutropenic infections. In patients treated with Isa-Kd, neutropenia was reported as a laboratory abnormality in 54.8% of patients and as an adverse reaction (1) in 4.5% of patients, with Grade 3 – 4 neutropenia reported as a laboratory abnormality in 19.2% of patients (with 17.5% Grade 3 and 1.7% Grade 4) and as an adverse reaction in 4.0% of patients. Neutropenic complications have been observed in 2.8% of patients, including 1.1% of febrile neutropenia and 1.7% of neutropenic infections. In patients treated with Isa-VRd in IMROZ, neutropenia was reported as a laboratory abnormality in 87.5% of patients and as an adverse reaction in 30% of patients, with Grade 3 – 4 neutropenia reported as a laboratory abnormality in 54.4% of patients (with 35.7% Grade 3 and 18.6% Grade 4) and as an adverse reaction in 30% of patients. Neutropenic complications have been observed in 12.5% of patients, including 2.3% of febrile neutropenia and 10.6% of neutropenic infection. In patients treated with Isa-VRd during the induction period in GMMG-HD7, neutropenia was reported as a laboratory abnormality in 30.9% of patients and as an adverse reaction in 16.1% of patients, with Grade 3 – 4 neutropenia reported as a laboratory abnormality in 5.9% of patients (with 3.1% Grade 3 and 2.8% Grade 4) and as an adverse reaction in 16.1% of patients (see section 4.8).

Complete blood cell counts should be monitored periodically during treatment. Patients with neutropenia should be monitored for signs of infection. No dose reductions of isatuximab are recommended. Isatuximab dose delays and the use of colony-stimulating factors (e.g. G-CSF) should be 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 treatment discontinuation and/or dose modification and/or fulfilled a serious criterion.

Infection

A higher incidence of infections, including Grade ≥3 infections, mainly pneumonia, upper respiratory tract infection and bronchitis, occurred with isatuximab (see section 4.8). Patients receiving isatuximab should be closely monitored for signs of infection and appropriate standard therapy instituted.

Antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) according to treatment guidelines 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 of 52.44 months in 10 patients (6.6%) treated with Isa-Pd and in 3 patients (2%) treated with Pd. SPM were skin cancer in 6 patients treated with Isa-Pd and in 3 patients treated with Pd, solid tumours other than skin cancer in 3 patients treated with Isa-Pd (one patient also had a skin cancer), and haematological malignancy (myelodysplastic syndrome) in 1 patient treated with Isa-Pd (see section 4.8). Patients continued treatment after resection of the new malignancy, except two patients treated with Isa-Pd. One patient developed metastatic melanoma and the other developed myelodysplastic syndrome. In IKEMA study, at a median follow-up time of 56.61 months, SPMs were reported in 18 patients (10.2%) treated with Isa-Kd and in 10 patients (8.2%) treated with Kd. SPMs were skin cancers in 13 patients (7.3%) treated with Isa-Kd and in 4 patients (3.3%) treated with Kd, were solid tumours 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. Two patients (1.1%) in the Isa-Kd group and one patient (0.8%) in the Kd group had both skin cancer and solid tumours other than skin cancer (see section 4.8). Patients with skin cancer continued treatment after resection of the skin cancer. Solid tumours other than skin cancer were diagnosed within 3 months 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 reported in 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 skin cancer in 17 patients (6.5%) treated with Isa-VRd and in 7 patients (3.9%) treated with VRd, and haematological malignancy in 3 patients (1.1%) treated with Isa-VRd and in 2 patients (1.1%) treated with 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, squamous cell carcinoma of skin, squamous cell carcinoma of lung, colorectal cancer, and rectal adenocarcinoma) and in 2 patients (1.1%) treated with VRd (metastases to peritoneum and adenocarcinoma of colon). In GMMG-HD7, during the induction, intensification and follow-up for patients not secondary randomised, SPMs were reported in 2 patients (0.6%) treated with Isa-VRd and in 4 patients (1.2%) treated with VRd. SPMs were skin cancer in 1 patient (0.3%) treated with VRd, were solid tumours other than skin cancer in 1 patient (0.3%) treated with Isa-VRd and in 2 patients (0.6%) treated with VRd, and haematological malignancies in 1 patient (0.3%) treated with Isa-VRd and in 1 patient (0.3%) treated in VRd. The overall incidence of SPMs in all the isatuximab-exposed patients is 6.1%. Physicians should carefully evaluate patients before and during treatment as per IMWG guidelines for occurrence of SPM and initiate treatment as indicated.

Tumour lysis syndrome

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 indirect antiglobulin test (indirect Coombs test). This interference with the indirect Coombs test may persist for at least 6 months after the last infusion of isatuximab. To avoid potential problems with RBC transfusion, patients being treated with isatuximab should have blood type and screen tests performed prior to the first infusion. Phenotyping may be considered prior to starting isatuximab treatment as per local practice. If treatment with isatuximab has already started, the blood bank should be informed. Patients should be monitored for theoretical risk of haemolysis. If an emergency transfusion is required, non-cross-matched ABO/Rh-compatible RBCs can be given as per local blood bank practices (see section 4.5).

Interference with determination of complete response

Isatuximab is an IgG kappa monoclonal antibody that could be detected on both serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein (see section 4.5). This interference can impact the accuracy of the determination of complete response in some patients with IgG kappa myeloma protein. This interference may persist for at least 6 months after the last administration of isatuximab. Twenty-two patients in the Isa-Pd arm who met Very Good Partial Response (VGPR) criteria with only residual immunofixation-positivity were tested for interference. Serum samples from these patients were tested by mass spectrometry to separate isatuximab signal from the myeloma M‑protein signal. In the Isa-Kd arm, out of the 27 patients identified with potential interference and tested by mass spectrometry at the sensitivity level of the immunofixation test (25 mg/dL), 15 non-Complete Response (non-CR) patients as 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 11 additional patients out of the 179 Isa-Kd patients (6.1%) could have CR as best response leading to a potential CR rate of 45.8% (see section 4.5).

Educational materials

All prescribers who intend to prescribe isatuximab as well as healthcare professionals at blood banks/transfusion centres must ensure they have received and are familiar with the healthcare professional educational material prepared for the management of the risk of interference with serological testing. Prescribers must explain to the patients that isatuximab may affect the results of their serological testing for at least 6 months after their last dose of isatuximab. This is also explained in the patient card that prescribers must give to patients at time of the first dose of isatuximab. The patients must be instructed to carry the card during treatment and for at least 6 months after the treatment has ended and to share it with their healthcare team.

Elderly

Data are limited in the elderly population ≥85 years old (see section 4.8).

Excipient with known effect

This medicine contains 0.2 mg of polysorbate 80 in each mL of isatuximab concentrate for solution for infusion, which is equivalent to 0.1 mg/kg of body weight. Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

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

Interference with serological testing Because CD38 protein is expressed on the surface of red blood cells, isatuximab, an anti-CD38 antibody, may interfere with blood bank serologic tests with potential false positive reactions in indirect antiglobulin tests (indirect Coombs tests), antibody detection (screening) tests, antibody identification panels, and antihuman globulin (AHG) crossmatches in patients treated with isatuximab (see section 4.4). This interference may persist for at least 6 months after the last administration of isatuximab. The interference mitigation methods include treating reagent RBCs with dithiothreitol (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 after ruling out or identifying alloantibodies using DTT-treated RBCs.

Interference with serum protein electrophoresis and immunofixation testsIsatuximab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M-protein) and could interfere with accurate response classification based on International Myeloma Working Group (IMWG) criteria (see section 4.4). This interference may persist for at least 6 months after the last administration of isatuximab. In patients with persistent very good partial response, where isatuximab interference is suspected, consider using a validated isatuximab-specific IFE assay (Sebia Hydrashift) to distinguish isatuximab from any remaining endogenous M-protein in the patient's serum, to facilitate determination of a complete response.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception

Women of childbearing potential treated with isatuximab should use effective contraception during treatment and for 7 months after cessation of treatment.

Pregnancy

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

Breast-feeding

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

FertilityNo human and animal data are available to determine potential effects of isatuximab on fertility in males and females (see section 5.3).

4.7. Effects on ability to drive and use machines

Isatuximab has minor to moderate influence on the ability to drive and use machines. Fatigue and dizziness have been reported in patients taking isatuximab and this should be taken into account when driving or using machines.

4.8. Undesirable effects

Summary of the safety profile

In ICARIA-MM, the most frequent adverse reactions are neutropenia (46.7%), infusion reactions (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 patients treated with Isa-Pd. Adverse reactions with a fatal outcome during treatment were reported in 7.9% of patients treated with Isa-Pd (those occurring in more than 1% of patients were pneumonia occurring in 1.3% of patients and other infections occurring in 2.0% of patients).

In IKEMA, the most frequent adverse reactions 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%). Serious adverse reactions occurred in 59.3% of patients receiving Isa-Kd. The most frequent serious adverse reaction is pneumonia (21.5%). Permanent discontinuation of treatment because of adverse reactions was reported in 8.5% of patients treated with Isa-Kd. Adverse reactions with a fatal outcome during treatment were reported in 3.4% of patients treated with Isa-Kd (those occurring in more than 1% of patients were pneumonia and cardiac failure both occurring in 1.1% of patients).

In IMROZ, the most frequent adverse reactions are diarrhoea (54.8%), peripheral sensory neuropathy (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 an adverse 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 patients receiving 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 in 22.8% of patients treated with Isa-VRd.

In GMMG-HD7, during the induction period, the most frequent adverse reactions are polyneuropathy (18.8%), neutropenia (16.1%), and infusion-related reactions (12.4%). Serious adverse reactions occurred in 35.2% of patients receiving Isa-VRd. The most frequent serious adverse reactions are pneumonia (3.6%), pyrexia (3.3%), and diarrhoea (2.1%). Adverse reactions with a fatal outcome during treatment (Grade 5 TEAEs) were reported in 1.2% of patients treated with Isa-VRd (due to Covid-19, pneumonia influenza, septic shock, and haemorrhage intracranial, each reported in 0.3% of patients). Permanent discontinuation of treatment because of adverse reactions was reported in 3% of patients treated with Isa-VRd.

Tabulated list of adverse reactions

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); frequency not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions 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 5: Adverse reactions reported in patients with multiple myeloma treated with isatuximab in combination with pomalidomide and dexamethasone

System organ class

Preferred term

Adverse reaction

Frequency

Incidence

(N = 244)

Any Grade

Grade ≥3

Infections and infestations

Pneumonia a b

Very common

34.8%

27.9%

Upper respiratory tract infection

Very common

40.2%

3.3%

Bronchitis

Very common

20.9%

3.7%

Herpes zoster

Common

2.5%

0.4%

Neoplasms benign, malignant and unspecified (incl cysts and polyps) c

Skin cancer

Common

4.9%

1.6%

Solid tumours (non-skin cancer)

Common

2.9%

1.6%

Haematology malignancy

Uncommon

0.4%

0.4%

Blood and lymphatic system disorders

Neutropenia

Very common

52.5%

51.6%

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 disorders

Anaphylactic reaction d

Uncommon

0.3%

0.3%

Metabolism and nutrition disorders

Decreased appetite

Very common

11.5%

1.2%

Cardiac disorders

Atrial fibrillation

Common

5.7%

2.5%

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Very common

25.8%

5.7%

Gastrointestinal disorders

Diarrhoea

Very common

34.0%

2.5%

Nausea

Very common

22.1%

0%

Vomiting

Very common

14.8%

0.8%

Investigations

Weight decreased

Common

4.9%

0%

Injury, poisoning and procedural complications

Infusion reaction b

Very common

39.3%

2.0%

a The term pneumonia is a grouping of the following terms: atypical pneumonia, bronchopulmonary aspergillosis, pneumonia, pneumonia haemophilus, pneumonia influenza, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, pneumonia bacterial, haemophilus infection, lung infection, pneumonia fungal and pneumocystis jirovecii pneumonia.

b See “Description of selected adverse reactions”.

c Based on second primary malignancies reported during study treatment period and during post-treatment period.

d Based on post-marketing experience, anaphylactic reactions including fatal cases have been reported.

Table 6 a: Adverse reactions reported in patients with multiple myeloma treated with isatuximab in combination with carfilzomib and dexamethasone

System organ class

Preferred term

Adverse reaction

Frequency

Incidence

(N = 177)

Any Grade

Grade ≥3

Infections and infestations

Pneumonia b c

Very common

28.8%

20.9%

Upper respiratory tract infection

Very common

36.2%

3.4%

Bronchitis

Very common

22.6%

2.3%

Herpes zoster

Common

2.3%

0.6%

Neoplasms benign, malignant and unspecified (incl cysts and polyps) d

Skin cancers

Common

7.3%

1.7%

Solid tumours (non-skin cancer)

Common

4.0%

3.4%

Blood and lymphatic system disorders

Anaemia

Common

5.1%

4.5%

Neutropenia

Common

4.5%

4.0%

Thrombocytopenia

Common

2.8%

2.3%

Lymphopenia

Not known

–

–

Immune system disorders

Anaphylactic reaction e

Uncommon

0.3%

0.3%

Vascular disorders

Hypertension

Very common

36.7%

20.3%

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Very common

27.7%

5.1%

Cough

Very common

19.8%

0%

Gastrointestinal disorders

Diarrhoea

Very common

36.2%

2.8%

Vomiting

Very common

15.3%

1.1%

General disorders and administration site conditions

Fatigue

Very common

28.2%

3.4%

Injury, poisoning and procedural complications

Infusion reaction c

Very common

45.8%

0.6%

a 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 jirovecii pneumonia, 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 malignancies reported during study treatment period and during post-treatment period.

e Based on post-marketing experience, anaphylactic reactions including fatal cases have been reported.

Table 7: Adverse reactions reported in patients with newly diagnosed multiple myeloma, transplant ineligible, treated with isatuximab in combination with bortezomib, lenalidomide, and dexamethasone

System organ class

Preferred term

Adverse reaction

Frequency

Incidence

(N = 336)

Any Grade

Grade ≥3

Infections and infestations

Pneumonia a

Very common

34.2%

24.1%

Bronchitis

Very common

22.6%

3.0%

Covid-19

Very common

19.9%

1.2%

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Skin cancer

Common

8.0%

2.7%

Solid tumours (non-skin cancer)

Common

5.7%

3.6%

Haematology malignancy

Uncommon

0.9%

0.3%

Blood and lymphatic system disorders

Neutropenia

Very common

28.0%

27.1%

Thrombocytopenia

Very common

13.4%

10.7%

Anaemia

Common

6.3%

2.7%

Lymphopenia

Not known

–

–

Immune system disorders

Anaphylactic reaction b

Uncommon

0.3%

0.3%

Eye disorders

Cataract

Very common

36.0%

13.1%

Gastrointestinal disorders

Diarrhoea

Very common

56.8%

8.3%

Vomiting

Common

9.5%

0.3%

General disorders and administration site conditions

Fatigue

Very common

32.7%

6.5%

Injury, poisoning and procedural complications

Infusion reaction

Very common

27.4%

0.6%

a The term pneumonia is a grouping of the following terms: Atypical pneumonia, Bronchopulmonary aspergillosis, Covid-19 pneumonia, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia bacterial, Pneumonia haemophilus, Pneumonia influenza, Pneumonia klebsiella, Pneumonia legionella, Pneumonia pneumococcal, Pneumonia pseudomonal, Pneumonia respiratory syncytial viral, Pneumonia viral, Pulmonary sepsis, Tuberculosis.

b Based on post-marketing experience, anaphylactic reactions including fatal cases have been reported.

MedDRA 26.0

Table 8: Adverse reactions reported during induction period in patients with newly diagnosed multiple myeloma, transplant eligible, treated with isatuximab in combination with bortezomib, lenalidomide, and dexamethasone

System organ class

Preferred term

Adverse reaction

Frequency

Incidence

(N = 330)

Any Grade

Grade ≥3

Infections and infestations

Pneumonia a b

Common

5.5%

4.8%

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Solid tumours (non-skin cancer)

Uncommon

0.3%

0.3%

Blood and lymphatic system disorders

Neutropenia

Very common

16.1%

16.1%

Anaemia

Common

3.6%

3.6%

Thrombocytopenia

Common

4.5%

4.5%

Lymphopenia

Common

3.3%

3.3%

Immune system disorders

Anaphylactic reaction c

Uncommon

0.3%

0.3%

Investigations

Neutrophil count decreased

Common

7.3%

7.3%

Injury, poisoning and procedural complications

Infusion reaction b

Very common

12.7%

0.9%

a The term pneumonia is a grouping of the following terms: Pneumonia, Pneumonia influenza, Atypical pneumonia, Pneumonia fungal.

b See “Description of selected adverse reactions”.

c Based on post-marketing experience, anaphylactic reactions including fatal cases have been reported.

Description of selected adverse reactions

Infusion reactions

In ICARIA-MM, infusion reactions were reported in 58 patients (38.2%) treated with isatuximab. All patients who experienced infusion reactions, experienced them during the 1st infusion of isatuximab, 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 and resolved the same day in 98% of the infusions. Signs and symptoms of Grade 3 or 4 infusion reactions included dyspnoea, hypertension, and bronchospasm.

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

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

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

In IMROZ, infusion reactions were reported in 63 patients (24.0%) treated with Isa-VRd. Grade 1 IRs were reported in 1.9%, Grade 2 in 21.3%, Grade 3 in 0.4%, and Grade 4 in 0.4% of the patients treated with Isa-VRd. The IRs started on the infusion day in all patients, mostly during the first isatuximab infusion, 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 with isatuximab infusion interruptions because of infusion reactions was 20.9%. The median time to isatuximab infusion interruption was 66.0 minutes. Isatuximab was discontinued in 0.8% of patients due to infusion reactions.

In GMMG-HD7, during the induction period, infusion reactions were reported in 42 patients (12.7%) treated with Isa-VRd. Grade 1 infusion reactions were not collected in the study. Grade 2 infusion reactions were reported in 11.8%, Grade 3 in 0.6% and Grade 4 in 0.3% of the patients treated with Isa-VRd. All infusion reactions resolved. The incidence of patients with isatuximab infusion interruptions because of infusion reactions was 7.6%. Isatuximab was discontinued in 0.3% of patients due to infusion reactions (see sections 4.2 and 4.4).

Infections

In ICARIA-MM, the incidence of Grade 3 or higher infections was 42.8%. Pneumonia was the most commonly reported severe infection with Grade 3 reported in 21.7% of patients in the Isa-Pd group compared to 16.1% in the Pd group, and Grade 4 in 3.3% of patients in the Isa-Pd group compared to 2.7% in the Pd group. Discontinuations from treatment due to infection were reported in 2.6% of patients in the Isa-Pd group compared to 5.4% in the Pd group. Fatal infections were reported in 3.3% of patients in the Isa-Pd group and 4.0% in the Pd group. In IKEMA, the incidence of Grade 3 or 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 was discontinued due to infection in 2.8% of patients in the Isa-Kd group compared to 4.9% in the Kd group. Fatal infections were reported in 2.3% of patients in the Isa-Kd group and 0.8% in the Kd group. In IMROZ, the incidence of Grade 3 or higher infections was 44.9% in the Isa-VRd group and 38.1% in the VRd group. Pneumonia was the most commonly reported severe infection with Grade 3 reported in 25.1% of patients in the Isa-VRd group compared to 15.5% in the VRd group, Grade 4 in 2.3% of patients in the Isa-VRd group compared to 3.9% in the VRd group. Grade 5 pneumonia, based on preferred term, occurred in 1.5% of patients in the Isa-VRd group compared to 1.1% in the VRd group. 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 in the Isa-VRd group and 4.4% in the VRd group. In GMMG-HD7, during the induction period, the incidence of Grade 3 or higher infections was 13% in the Isa-VRd group and 10.1% in the VRd group. Pneumonia was the most commonly reported severe infection with Grade ≥3 reported in 3.9% of patients in the Isa-VRd group compared to 2.1% in the VRd group. Discontinuations from treatment due to infection were reported in 0.3% of patients in the Isa-VRd group compared to 0.9% in the VRd group (see section 4.4).

In relapsed and refractory multiple myeloma clinical studies, herpes zoster was reported in 2.0% of patients. In ICARIA-MM, the incidence of herpes zoster was 4.6% in the Isa-Pd group compared to 0.7% in the Pd group, and in IKEMA, incidence was 2.3% in the Isa-Kd group compared to 1.6% in the 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 to 5.5% in the VRd group. In GMMG-HD7, during the induction period, the incidence of herpes zoster was 0.9% in the Isa-VRd group compared to 0.3% 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% of patients 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 in 3.3% of patients in the Kd group. Cardiac failure with a fatal outcome during treatment was reported in 1.1% of patients in the Isa-Kd group and not reported in the Kd group (see the current prescribing information for carfilzomib).

Haematology laboratory values

Table 9: Haematology laboratory abnormalities in patients receiving isatuximab combined with pomalidomide and dexamethasone versus pomalidomide and dexamethasone (ICARIA-MM)

Laboratory parameter

Isatuximab + Pomalidomide + Dexamethasone

(N = 152)

Pomalidomide + Dexamethasone

(N = 147)

All Grades

Grade 3

Grade 4

All Grades

Grade 3

Grade 4

Anaemia

99.3%

31.6%

0%

98.6%

27.9%

0%

Neutropenia

96.1%

24.3%

60.5%

93.2%

38.8%

31.3%

Lymphopenia

92.1%

42.1%

12.5%

93.2%

35.4%

8.2%

Thrombocytopenia

83.6%

14.5%

16.4%

80.3%

9.5%

15.0%

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

Table 10: Haematology laboratory abnormalities in patients receiving isatuximab combined with carfilzomib and dexamethasone versus carfilzomib and dexamethasone (IKEMA)

Laboratory parameter

Isatuximab + Carfilzomib + Dexamethasone

(N = 177)

Carfilzomib + Dexamethasone

(N = 122)

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%

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 1 evaluation of the laboratory test during the considered observation period.

Table 11: Haematology laboratory abnormalities in patients receiving isatuximab combined with bortezomib, lenalidomide, and dexamethasone versus bortezomib, lenalidomide, and dexamethasone (IMROZ and TCD13983)

Laboratory parameter

Isatuximab + Bortezomib +

Lenalidomide + Dexamethasone

(N = 336)

Bortezomib + Lenalidomide + Dexamethasone

(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 the laboratory test during the considered observation period.

CTCAE version: 4.03.

Table 12: Haematology laboratory abnormalities in patients receiving isatuximab combined with bortezomib, lenalidomide, and dexamethasone versus bortezomib, lenalidomide, and dexamethasone during induction period (GMMG-HD7)

Laboratory parameter

Isatuximab + Bortezomib +

Lenalidomide + Dexamethasone

(N = 330)

Bortezomib + Lenalidomide + Dexamethasone

(N = 328)

All Grades

Grade 3

Grade 4

All Grades

Grade 3

Grade 4

Anaemia

80.0%

1.6%

0%

79.7%

0.9%

0%

Neutropenia

30.9%

3.1%

2.8%

22.9%

2.5%

1.9%

Lymphopenia

54.4%

15.6%

2.2%

67.4%

18.7%

5.1%

Thrombocytopenia

21.6%

0.6%

0.9%

20.3%

0.3%

0%

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

Elderly patients

Of the total number of patients in clinical studies of isatuximab, 42.7% (763 patients) were less than 65, 43.2% (772 patients) were 65 – 74, and 14.1% (252 patients) were 75 or older. Differences in safety were observed between older versus younger age groups. Grade ≥3 TEAEs were reported in 64.7% of patients less than 65, 79.7% of patients 65 – 74 and 76.6% of patients 75 or older, Grade 5 TEAEs were reported in 5.6% 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, 59.3% of patients 65 – 74, and 61.1% of patients 75 or older. TEAEs leading to definitive treatment discontinuation were reported in 6.4% of patients less than 65, 14.4% of patients 65 – 74, and 15.9% of patients 75 or older.

In the IMROZ study, no Grade 5 TEAEs were reported in patients less than 65, they were reported in 10.7% of patients 65 – 74, and in 13.2% of patients 75 or older. In GMMG-HD7 study, only patients until 70 years of age were included. During the induction period, Grade ≥3 TEAEs were reported in 59.7% of patients less than 65 and in 77.8% of patients 65 or older, TEAEs leading to definitive treatment discontinuation were reported in 1.6% of patients less than 65 and 8.3% of patients 65 or older, and Grade 5 TEAEs were reported in 0.8% of patients less than 65 and in 2.8% of patients 65 or older.

Immunogenicity

Across 9 clinical studies (N = 1023) in relapsed or refractory multiple myeloma (RRMM) with isatuximab single agent and combination therapies including ICARIA-MM and IKEMA, the incidence of treatment emergent anti-drug antibodies (ADAs) was <2%. No effect of ADAs was observed on pharmacokinetics, safety or efficacy of isatuximab. Across 3 clinical studies (N = 383) in newly diagnosed multiple myeloma (NDMM) with isatuximab in combination therapy with bortezomib, lenalidomide, and dexamethasone, including IMROZ and GMMG-HD7, ADA incidence ranged from 9.1% to 21.6%. In IMROZ and GMMG-HD7, 60% (15 out of 25) and 50% (4 out of 8) of the treatment-induced ADA were neutralising, respectively. In NDMM, a trend to lower exposure was observed in ADA-positive patients. No effect of ADAs was observed on efficacy of isatuximab. No conclusions can be drawn on safety due to the small subgroup of ADA positive patients.

Paediatric population

In a Phase 2 single-arm study conducted in 67 paediatric patients with relapsed or refractory acute lymphoblastic leukaemia or acute myeloid leukaemia, all evaluable for safety, Grade ≥3 TEAEs were reported in 79.1% of patients. The most common Grade ≥3 TEAEs occurring in >10% of patients included febrile neutropenia (41.8%), septic shock (11.9%), and stomatitis (10.4%). The addition of isatuximab to standard chemotherapies did not modify the expected safety profile observed with standard chemotherapies in this paediatric population and was consistent with isatuximab safety profile for adults with multiple myeloma in ICARIA and IKEMA studies (see section 4.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Signs and symptoms

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

Management

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