SARCLISA 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).

SARCLISA should be administered by a healthcare professional, in an environment where
resuscitation facilities are available.
Premedication
Premedication should be used prior to SARCLISA infusion with the following medicinal products to
reduce the risk and severity of infusion reactions:
• 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.
• Acetaminophen 650 mg to 1000 mg oral (or equivalent).

• Diphenhydramine 25 mg to 50 mg intravenous or oral (or equivalent [e.g., cetirizine,
promethazine, dexchlorpheniramine]). The intravenous route 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 and before isatuximab and carfilzomib 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 4
administrations 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 of
neutropenia. In the event of grade 4 neutropenia, SARCLISA administration should be delayed until
neutrophil count improves to at least 1.0 x 109/L (see section 4.4).
Posology
The recommended dose of SARCLISA 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), according to the schedule in Table 1:

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

Cycles	Dosing schedule
Cycle 1	Days 1, 8, 15 and 22 (weekly)
Cycle 2 and beyond	Days 1, 15 (every 2 weeks)

Each treatment cycle consists of a 28-day period. Treatment is repeated until disease progression or
unacceptable toxicity.
For other medicinal products that are administered with SARCLISA, see section 5.1 and the respective
current 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 the
treatment interval.
Dose adjustments
No dose reduction of SARCLISA is recommended.
Administration adjustments should be made if patients experience infusion reactions (see “Method of
administration” below).
For other medicinal products that are administered with SARCLISA, the respective current summary
of product characteristics should be considered.
Special populations
Elderly
Based on population pharmacokinetic analysis, no dose adjustment is recommended in elderly
patients.
Patients with renal impairment
Based on population pharmacokinetic analysis and on clinical safety, no dose adjustment is
recommended in patients with mild to severe renal impairment (see section 5.2).

Patients with hepatic impairment
Based on population pharmacokinetic analysis, no dose adjustment is recommended in patients with
mild hepatic impairment. Data in patients with moderate and severe 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
The safety and efficacy of SARCLISA in children below 18 years of age have not been established.
No data are available.
Method of administration
SARCLISA is for intravenous use. For instructions on dilution of the medicinal product before
administration, see section 6.6.
Infusion rates
Following dilution, the SARCLISA infusion should be administered intravenously at the infusion rate
presented in Table 2 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 2: Infusion rates of SARCLISA administration

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), SARCLISA
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 2.
• 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 require
hospitalization or are life-threatening, treatment with SARCLISA should be permanently
discontinued and additional supportive therapy should be administered, as needed.

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

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
SARCLISA in ICARIA-MM, and in 45.8% of patients treated with Isa-Kd in IKEMA (see section
4.8). In ICARIA-MM, all infusion reactions started 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. 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 (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 be
used as both premedication and anti-myeloma treatment (see section 4.2). Vital signs should be
frequently monitored during the entire SARCLISA infusion. When required, interrupt SARCLISA
infusion and provide appropriate medical and supportive measures (see section 4.2). In case symptoms
do not improve to grade ≤1 after interruption of SARCLISA infusion, persist or worsen despite
appropriate medicinal products, require hospitalization or are life-threatening, permanently
discontinue SARCLISA and institute appropriate management.
Neutropenia
In patients treated with Isa-Pd, neutropenia occurred 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 occurred 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
(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 SARCLISA are
recommended. SARCLISA 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 SARCLISA (see section 4.8). Patients receiving
SARCLISA should be closely monitored for signs of infection and appropriate standard therapy
instituted. Antibiotics and antiviral prophylaxis can be considered during treatment.
Second primary malignancies
In ICARIA-MM, second primary malignancies (SPMs) were reported in 6 patients (3.9%) treated with
Isa-Pd and in 1 patient (0.7%) treated with Pd, and included skin cancer in 4 patients treated with Isa-
Pd and in 1 patient treated with Pd (see section 4.8). Patients continued treatment after resection of the
skin cancer. In IKEMA, SPMs were reported in 13 patients (7.3%) treated with Isa-Kd and in 6
patients (4.9%) treated with Kd. SPMs were skin cancers in 9 patients (5.1%) treated with Isa-Kd and
in 3 patients (2.5%) treated with Kd, and were solid tumours other than skin cancer in 5 patients
(2.8%) treated with Isa-Kd and in 4 patients (3.3%) treated with Kd. One patient (0.6%) 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. The overall

incidence of SPMs in all the SARCLISA-exposed patients is 3.6%. Physicians should carefully
evaluate patients before and during treatment as per IMWG guidelines for occurrence of SPM and
initiate treatment as indicated.
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). To avoid potential problems with RBC transfusion, patients
being treated with SARCLISA should have blood type and screen tests performed prior to the first
infusion. Phenotyping may be considered prior to starting SARCLISA treatment as per local practice.
If treatment with SARCLISA 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). There is currently no available information with regards to how long the interference with
the indirect Coombs test may persist after the last infusion of SARCLISA. Based on the half-life of
isatuximab, it is anticipated that isatuximab mediated positive indirect Coombs test may persist for
approximately 6 months after the last infusion.
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. 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 Mprotein.
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).
Elderly
Data are limited in the elderly population ≥ 85 years old (see section 4.2).

Isatuximab has no impact on the pharmacokinetics of pomalidomide or carfilzomib, 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). 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 Tests
Isatuximab may be detected by serum protein electrophoresis (SPE) and immunofixation (IFE) assays
used for the monitoring of M-protein, and could interfere with accurate response classification based
on International Myeloma Working Group (IMWG) criteria (see section 4.4).

Women of childbearing potential/Contraception

Women of childbearing potential treated with isatuximab should use effective contraception during
treatment and for 5 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 breastfeeding
if clinically needed.
Fertility
No human and animal data are available to determine potential effects of isatuximab on fertility in
males and females (see section 5.3).
For other medicinal products that are administered with isatuximab, refer to the respective current
summary of product characteristics.

 

SARCLISA has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile
In ICARIA-MM, the most frequent adverse reactions (>20%) 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 (≥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%). 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).
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 from the 152 patients who received Isa-Pd with a median duration
of exposure of 41 weeks in ICARIA-MM study (see section 5.1).
Table 3a: Adverse reactions reported in patients with multiple myeloma treated with isatuximab
in combination with pomalidomide and dexamethasone (ICARIA-MM)

The adverse reactions were reported from the 177 patients who received Isa-Kd with a median
duration of exposure of 80.0 weeks in IKEMA study (see section 5.1).
Table 4a: Adverse reactions reported in patients with multiple myeloma treated with isatuximab
in combination with carfilzomib and dexamethasone (IKEMA)

Description of selected adverse reactions
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 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. (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. (see section 4.4).
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 5: Haematology laboratory abnormalities in patients receiving isatuximab combined with
pomalidomide and dexamethasone–versus pomalidomide and dexamethasone (ICARIA-MM

Table 6: Haematology laboratory abnormalities in patients receiving isatuximab combined with
carfilzomib and dexamethasone versus carfilzomib and dexamethasone (IKEMA)

Immunogenicity
Across 9 clinical studies in multiple myeloma (MM) with isatuximab single agent and combination
therapies including ICARIA-MM and IKEMA (N=1018), the incidence of treatment emergent ADAs
was 1.9%. No effect of ADAs was observed on pharmacokinetics, safety or efficacy of isatuximab.
To report any side effect(s):
• Saudi Arabia:
The National Pharmacovigilance Centre (NPC):
o SFDA call center : 19999
o E-mail: npc.drug@sfda.gov.sa
o Website: https://ade.sfda.gov.sa/
• Sanofi- Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com

Signs and symptoms
There has been no experience of overdosage 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 SARCLISA overdose. In the event of overdose, monitor the
patients for signs or symptoms of adverse reactions and take all appropriate measures immediately.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC38.
Mechanism of action
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 myeloma
cells.
In vitro, isatuximab acts through IgG Fc-dependent mechanisms including: antibody dependent cell
mediated cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), and complement
dependent cytotoxicity (CDC). Furthermore, isatuximab can also trigger tumour cell death by
induction of apoptosis via an Fc-independent mechanism.
In vitro, isatuximab blocks the enzymatic activity of CD38 which catalyses the synthesis and
hydrolysis of cyclic ADP-ribose (cADPR), a calcium mobilizing agent. Isatuximab inhibits the

cADPR production from extracellular nicotinamide adenine dinucleotide (NAD) in multiple myeloma
cells.
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+ Tcells
and TREG (CD3+, CD4+, CD25+, CD127-) was observed in peripheral blood of patients treated
with isatuximab monotherapy.
In multiple myeloma patients, SARCLISA monotherapy induced clonal expansion of the T-cell
receptor repertoire indicating an adaptive immune response.
The combination of isatuximab and pomalidomide in vitro enhances cell lysis of CD38 expressing
multiple myeloma cells by effector cells (ADCC), and by direct tumour cell killing compared to that
of isatuximab alone. In vivo animal experiments using a human multiple myeloma xenograft model in
mice demonstrated that the combination of isatuximab and pomalidomide results in enhanced
antitumour activity compared to the activity of isatuximab or pomalidomide alone.
Clinical efficacy and safety
ICARIA-MM (EFC14335)
The efficacy and safety of SARCLISA in combination with pomalidomide and dexamethasone were
evaluated 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 at
least two prior therapies including lenalidomide and a proteasome inhibitor with disease progression
on or within 60 days after the end of the previous therapy. Patients with primary refractory disease
were excluded.
A total of 307 patients were randomised in a 1:1 ratio to receive either SARCLISA in combination
with 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 disease
progression or unacceptable toxicity. SARCLISA 10 mg/kg was administered as an I.V. infusion
weekly in the first cycle and every two weeks thereafter. Pomalidomide 4 mg was taken orally once
daily from day 1 to day 21 of each 28-day cycle. Dexamethasone (oral/intravenous) 40 mg (20 mg for
patients ≥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 treatment
groups, with some minor imbalances. The median patient age was 67 years (range 36-86), 19.9% of
patients were ≥75 years. ECOG PS was 0 in 35.7% of patients in the isatuximab arm and 45.1% in the
comparator arm, 1 in 53.9% in the isatuximab arm and 44.4% in the comparator arm, and 2 in 10.4%
in the isatuximab arm and 10.5% in the comparator arm, 10.4% of patients in the isatuximab arm
versus 10.5% in the comparator arm entered the study with a history of COPD or asthma, and 38.6%
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) had high-risk
chromosomal abnormalities at study entry; del(17p), t(4;14) and t(14;16) were present in 12.1%
(9.1% in the isatuximab arm and 15.0% in the comparator arm), 8.5% (7.8% in the isatuximab 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 prior
proteasome inhibitor, all patients received prior lenalidomide, and 56.4% of patients received prior
stem 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, and
59% 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 improvement
in PFS represented a 40.4% reduction in the risk of disease progression or death in patients treated
with Isa-Pd.
Efficacy results are presented in Table 7 and Kaplan-Meier curves for PFS and OS are provided in
Figures 1 and 2:
Table 7: Efficacy of SARCLISA in combination with pomalidomide and dexamethasone versus
pomalidomide and dexamethasone in the treatment of multiple myeloma (intent-to-treat
analysis)

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 in patients >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 to 0.977), 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 lenalidomide at 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 with
daratumumab (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. With a median duration of follow-up of 11.56 months in the Isa-Pd group and 11.73 months
in the Pd group, median overall survival was not reached for either treatment group. The hazard ratio
for OS was 0.687 (95% CI: 0.461-1.023, p-value=0.0631).

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

IKEMA (EFC15246)
The efficacy and safety of SARCLISA in combination with carfilzomib and dexamethasone were
evaluated 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 to
three prior therapies. Patients with primary refractory disease, who had previously been treated with
carfilzomib, or who were refractory to previous anti-CD38 monoclonal antibody treatment were
excluded.
A total of 302 patients were randomized in a 3:2 ratio to receive either SARCLISA in combination
with 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 or
unacceptable toxicity. SARCLISA 10 mg/kg was administered as an I.V. infusion weekly in the first
cycle and every two weeks thereafter. Carfilzomib was administered as an I.V. infusion at the dose of
20 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/m²
on days 1, 2, 8, 9, 15 and 16 for subsequent cycles of each 28-day cycle. Dexamethasone (IV on the
days of isatuximab and/ or carfilzomib infusions, and PO on the other days) 20 mg was given on days
1, 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 treatment
groups. 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 renal
impairment (eGFR<60 mL/min/1.73 m2) was 24.0% in the Isa-Kd group versus 14.6% in the Kd
group. 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 at study
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 1
prior line of therapy. Overall, 89.7% of patients received prior proteasome inhibitors, 78.1% received
prior immunomodulators (including 43.4% who received prior lenalidomide), and 61.3 % received
prior stem cell transplantation. Overall, 33.1% of patients were refractory to prior proteasome
inhibitors, 45.0% were refractory to prior immunomodulators (including 32.8% refractory to
lenalidomide), 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 for
the Kd group.
Progression-free survival (PFS) was the primary efficacy endpoint of IKEMA. The improvement in
PFS represented a 46.9% reduction in the risk of disease progression or death in patients treated with
Isa-Kd compared to patients treated with Kd.
Efficacy results are presented in Table 8 and Kaplan-Meier curves for PFS are provided in the Figure
3:

Table 8: Efficacy of SARCLISA in combination with carfilzomib and dexamethasone versus
carfilzomib and dexamethasone in the treatment of multiple myeloma (intent-to-treat analysis)

PFS improvements in the Isa-Kd group were observed in patients with high -risk cytogenetics (central
laboratory assessment, HR = 0.724; 95% CI: 0.361 to 1.451), with gain (1q21) chromosomal
abnormality (HR=0.569; 95% CI: 0.330 to 0.981), ≥65 years (HR =0.429; 95% CI: 0.248 to 0.742),
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 not
reached (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 with
daratumumab (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 Kd
group. With a median follow-up time of 20.73 months, 17.3% patients in the Isa-Kd arm and 20.3%
patients in the Kd arm had died.

Cutoff date = 07 February 2020.
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 in the 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 4 patients in
the Isa-Kd group and the 3 patients in the Kd group with severe renal impairment at baseline (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-Kd group and 33.3% of patients
in the Kd group.
Paediatric population
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 malignant
neoplasms of the haematopoietic and lymphoid tissue. See section 4.2 for information on paediatric
use.

The pharmacokinetics of isatuximab were assessed in 476 patients with multiple myeloma treated with
isatuximab intravenous infusion as a single agent or in combination with pomalidomide and

dexamethasone, 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 by
every 2 weeks.
Isatuximab displays nonlinear pharmacokinetics with target-mediated drug disposition due to its
binding 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 weeks
schedule, while no deviation to the dose proportionality is observed between 5 and 20 mg/kg
following every week for 4 weeks followed by every 2 weeks schedule. This is due to the high
contribution 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 for 4
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 trial performed in relapsed and/or refractory multiple
myeloma patients treated with isatuximab in combination with pomalidomide and dexamethasone, the
mean (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-based volume
administration method for isatuximab infusion to the fixed volume infusion method resulted in
changes in the tmax, the change had a limited impact on pharmacokinetics exposure with comparable
simulated Cmax at steady state (283 μg/mL vs 284 μg/mL) and Ctrough at 4 weeks (119 μg/mL vs
119 μg/mL) for a patient with median weight (76 kg). Also for other patient weight groups, Cmax and
Ctrough were comparable. In IKEMA, clinical trial performed in relapsed and/or refractory multiple
myeloma patients treated with isatuximab in combination with carfilzomib and dexamethasone, the
mean (CV%) predicted maximum plasma concentration Cmax and AUC at steady state were 655 μg/mL
(30.8%) and 159,000 μg.h/mL (37.1%), respectively.
The pharmacokinetics of isatuximab and pomalidomide, or of isatuximab and carfilzomib, were not
influenced by their co-administration.
Distribution
The estimated total volume of distribution of isatuximab is 8.75 L.
Metabolism
As a large protein, isatuximab is expected to be metabolized by non-saturable proteolytic catabolism
processes.
Elimination
Isatuximab is eliminated by two parallel pathways, a nonlinear target-mediated pathway
predominating at low concentrations, and a nonspecific linear pathway predominating at higher
concentrations. In the therapeutic plasma concentrations range, the linear pathway is predominant and
decreases over time by 50% to a steady state value of 9.55 mL/h (0.229 L/day). This is associated with
a terminal half-life of 28 days.
Specific populations
Age
The population pharmacokinetic analyses of 476 patients aged 36 to 85 years showed comparable
exposure to isatuximab in patients <75 years old (n=406) versus ≥ 75 years old (n=70).
Gender
The population pharmacokinetic analysis with 207 female (43.5%) and 269 male (56.5%) patients
showed no clinically meaningful effect of gender on isatuximab pharmacokinetics.

Race
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 isatuximab
pharmacokinetics.
Weight
Based on a population pharmacokinetics analysis using data from 476 patients, the clearance of
isatuximab increased with increasing body weight, supporting the body-weight based dosing.
Hepatic Impairment
No formal studies of isatuximab in patients with hepatic impairment have been conducted. Out of the
476 patients of the population pharmacokinetic analyses, 65 patients presented with mild hepatic
impairment [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 ULN
and any AST). Mild hepatic impairment had no clinically meaningful effect on the pharmacokinetics
of isatuximab. The effect of moderate (total bilirubin >1.5 times to 3 times ULN and any AST) and
severe hepatic impairment (total bilirubin >3 times ULN and any AST) on isatuximab
pharmacokinetics is unknown. However, since isatuximab is a monoclonal antibody, it is not expected
to be cleared via hepatic-enzyme mediated metabolism and as such, variation in hepatic function is not
expected to affect the elimination of isatuximab (see section 4.2).
Renal Impairment
No formal studies of isatuximab in patients with renal impairment have been conducted. The
population 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), 163 patients
with moderate renal impairment (30 mL/min/1.73 m2≤ e-GFR < 60 mL/min/1.73 m2) and 12 patients
with severe renal impairment (e-GFR <30 mL/min/1.73 m2). Analyses suggested no clinically
meaningful effect of mild to severe renal impairment on isatuximab pharmacokinetics compared to
normal renal function.
Paediatric population
Isatuximab was not evaluated in patients under 18 years of age.

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

Sucrose
Histidine hydrochloride monohydrate
Histidine
Polysorbate 80
Water for injections

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

Unopened Vial 3 years After dilution Chemical and physical in-use stability of SARCLISA infusion solution has been demonstrated for 48 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 used immediately, in-use storage times and conditions prior use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated 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 closed
with ETFE (copolymer of ethylene and tetrafluoroethylene)-coated bromobutyl stopper. The vials are
crimped with an aluminium seal with a grey flip-off button. The fill volume has been established to
ensure 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 closed
with ETFE (copolymer of ethylene and tetrafluoroethylene)-coated bromobutyl stopper. The vials are
crimped with an aluminium seal with a blue flip-off button. The fill volume has been established to
ensure 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 section
4.2). 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 do
not contain any particles and are not discoloured.
• Do not shake vials.
• The volume of diluent equal to the required volume of SARCLISA concentrate should be
removed from a 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection or glucose
5% 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.
Administration
• The infusion solution must be administered by intravenous infusion using an intravenous
tubing infusion set (in PE, PVC with or without DEHP, polybutadiene (PBD) or polyurethane
(PU)) with an in-line filter (polyethersulfone (PES), polysulfone or nylon).
• The infusion solution should be administered for a period of time that will depend on the
infusion rate (see section 4.2).
• No protection from light is required for the prepared infusion bag in a standard artificial light
environment.
• Do not infuse SARCLISA solution concomitantly in the same intravenous line with other
agents.
Disposal
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.