Sarclisa Escena

5 WARNINGS AND PRECAUTIONS Hypersensitivity and Other Administration Reactions: In case of grade ≥2 systemic administration reaction (SAR), interrupt SARCLISA ESCENA and manage medically. In case of grade 4 SAR, permanently discontinue SARCLISA ESCENA. ( 5.1 ) Neutropenia : Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. SARCLISA ESCENA dose delays and the use of colony-stimulating factor may be required to allow improvement of neutrophil count. ( 5.2 ) Infections : SARCLISA ESCENA may cause serious and fatal infections. Monitor patients for signs and symptoms of infection and treat appropriately. ( 5.3 ) Second Primary Malignancies (SPM) : Monitor patients for the development of second primary malignancies. ( 5.4 ) Laboratory Test Interference : Interference with Serological Testing (Indirect Antiglobulin Test): Type and screen patients prior to starting treatment. Inform blood banks that a patient has received isatuximab-irfc. ( 5.5 , 7.1 ) Interference with Serum Protein Electrophoresis and Immunofixation Tests: isatuximab-irfc may interfere with the assays used to monitor M-protein, which may impact the determination of complete response. ( 5.5 , 7.1 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Hypersensitivity and Other Administration Reactions SARCLISA ESCENA can cause both systemic administration-related reactions (SARs), including severe or life-threatening reactions, and local injection-site reactions. Systemic Administration Reactions In a pooled safety population of 411 patients with multiple myeloma who received SARCLISA ESCENA in combination with pomalidomide and dexamethasone (Pd), with carfilzomib and dexamethasone (Kd), and with bortezomib, lenalidomide, and dexamethasone (VRd) (IRAKLIA, IZALCO, and IsaSoCut, respectively, N=411), SARs occurred in 3.2% (Grade 1: 2.2%, Grade 2: 0.7%, Grade 3: 0.2%) of patients. SARs occurred at the first administration in 1.9% of patients and at subsequent administrations in 1.5% of patients. The median time to onset was 4 hours (range: 12 minutes to 3 days). The most frequently reported symptoms of SARs (all below 1%) were pyrexia and dyspnea, and Grade ≥3 symptoms was dyspnea (not collected in IsaSoCut study) [see Dosage and Administration (2.3) and Adverse Reactions (6.1) ] . In multiple myeloma clinical trials with intravenous isatuximab-irfc, anaphylactic reactions occurred in <1% of patients. To decrease the risk and severity of SARs, premedicate patients prior to SARCLISA ESCENA administration with leukotriene receptor antagonists (at cycle 1 only), acetaminophen, diphenhydramine, or equivalent, and dexamethasone [see Dosage and Administration (2.2) ] . In case of grade 2 SAR during SARCLISA ESCENA administration, stop current administration and do not complete it. Administer additional premedication, as needed, for subsequent SARCLISA ESCENA administration. In case of grade 3 SAR during SARCLISA ESCENA administration, stop current administration and do not complete it. SARCLISA ESCENA administration may be resumed at the next planned administration. In case of a third occurrence of a grade 3 SAR, permanently discontinue SARCLISA ESCENA treatment. In case of grade 4 SAR, permanently discontinue SARCLISA ESCENA treatment. Injection Site Reactions In clinical trials of SARCLISA ESCENA in combination with Pd, Kd, or VRd (IRAKLIA, IZALCO, and IsaSoCut, respectively, N=411), injection site reactions (ISRs) with SARCLISA ESCENA administration were reported in 9% (8% Grade 1 and 1.5% Grade 2) of patients and in 0.86% of injections. Among the SARCLISA ESCENA injections with ISRs, 82% occurred the day of the administration and 4.2% were delayed by at least 3 days. With SARCLISA ESCENA-Pd and SARCLISA ESCENA-Kd, 5% of patients experienced symptoms of ISR (not collected in IsaSoCut study). The most frequent (≥1%) symptoms of ISR were injection site erythema (3.3%), injection site swelling (2.1%), and injection site pain (1.5%). In case of grade 2 ISR during administration of SARCLISA ESCENA, interrupt it and resume it only after recovery to grade ≤1 with pauses during the administration (if using OBDS) or a slower administration (if manual injection). If the Grade 2 ISR occurs after the administration, continue SARCLISA ESCENA treatment after recovery to grade ≤1. In case of grade 3 or 4 ISR, permanently discontinue SARCLISA ESCENA treatment. In case SARCLISA ESCENA administration using CirCLIQ OBDS needs to be paused, please refer to the OBDS Instruction For Use (IFU). 5.2 Neutropenia Neutropenia was reported in patients receiving SARCLISA ESCENA subcutaneously in combination with Pd, Kd, or VRd. In clinical trials of SARCLISA ESCENA (IRAKLIA, IZALCO, and IsaSoCut, N=411), neutropenia occurred in 86% of patients based on laboratory value. Grade 3–4 neutropenia occurred in 66% of patients based on laboratory value. Febrile neutropenia was reported in 3.4% and neutropenic infections occurred in 13% of patients [see Adverse Reactions (6.1) ] . Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. In case of grade 4 neutropenia, delay or omit SARCLISA ESCENA dose until neutrophil count recovery to at least 1 × 10 9 /L, and provide supportive care with growth factors, according to institutional guidelines [see Dosage and Administration (2.3) ] . 5.3 Infections SARCLISA ESCENA can cause severe, life-threatening, or fatal infections. In patients who received SARCLISA ESCENA subcutaneously in combination with Pd, Kd, or VRd (IRAKLIA, IZALCO, and IsaSoCut, respectively, N=411), fatal infections occurred in 2.9% of patients, serious infections occurred in 29% of patients, and Grade ≥3 infections in 29% of patients. The most commonly reported infections (≥10%) were pneumonia (21%), upper respiratory tract infection (19%), and Covid-19 (12%). The most frequent serious infection (≥5%) was pneumonia (17%) [see Adverse Reactions (6.1) ]. Patients receiving SARCLISA ESCENA should be closely monitored for signs of infection and appropriate standard therapy instituted. Antibacterial and antiviral prophylaxis (such as herpes zoster prophylaxis) should be considered during treatment [see Dosage and Administration (2.3) ] . 5.4 Second Primary Malignancies Second primary malignancies were reported in 3.9% of patients in clinical trials with SARCLISA ESCENA in combination with Pd, Kd, and VRd (IRAKLIA, IZALCO, and IsaSoCut, respectively, N=411). Monitor patients for the development of second primary malignancies and initiate treatment as indicated. 5.5 Laboratory Test Interference Interference with Serological Testing (Indirect Antiglobulin Test) Isatuximab-irfc 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 administration of intravenous isatuximab-irfc. The indirect antiglobulin test was positive during intravenous isatuximab-irfc-Pd treatment in 68% of the tested patients, and during intravenous isatuximab-irfc-Kd treatment in 63% of patients. In patients with a positive indirect antiglobulin test, blood transfusions were administered without evidence of hemolysis. ABO/RhD typing was not affected by intravenous isatuximab-irfc treatment. Before the first isatuximab-irfc administration, conduct blood type and screen tests on isatuximab-treated patients. Consider phenotyping prior to starting isatuximab-irfc treatment. If treatment with isatuximab-irfc has already started, inform the blood bank that the patient is receiving isatuximab-irfc and isatuximab-irfc interference with blood compatibility testing can be resolved using dithiothreitol-treated RBCs. If an emergency transfusion is required, non–cross-matched ABO/RhD-compatible RBCs can be given as per local blood bank practices [see Drug Interactions (7.1) ] . Interference with Serum Protein Electrophoresis and Immunofixation Tests Isatuximab-irfc is an IgG kappa monoclonal antibody that can be incidentally detected on both serum protein electrophoresis and immunofixation assays (IFE) used for the clinical monitoring of endogenous M-protein. In patients with persistent very good partial response, where interference is suspected, consider using a validated isatuximab-specific IFE assay (Sebia Hydrashift) to remove isatuximab-irfc interference and specifically visualize any remaining serum M-protein, to facilitate determination of complete response. [see Drug Interactions (7.1) ] . 5.6 Embryo-Fetal Toxicity Based on its mechanism of action, isatuximab-irfc can cause fetal harm when administered to a pregnant woman. Isatuximab-irfc may cause fetal immune cell depletion and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with isatuximab-irfc and for 7 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] . The combination of isatuximab-irfc with pomalidomide or lenalidomide is contraindicated in pregnant women because pomalidomide or lenalidomide may cause birth defects and death of the unborn child. Refer to the pomalidomide or lenalidomide prescribing information on use during pregnancy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions from SARCLISA ESCENA are also described in other sections of the labeling: Hypersensitivity and Other Administration Reactions [see Warnings and Precautions (5.1) ] Neutropenia [see Warnings and Precautions (5.2) ] Infections [see Warnings and Precautions (5.3) ] Second Primary Malignancies [see Warnings and Precautions (5.4) ] In combination with pomalidomide and dexamethasone : The most common adverse reactions (≥20%) are upper respiratory tract infection, fatigue, pneumonia, musculoskeletal pain, and diarrhea. ( 6.1 ) In combination with carfilzomib and dexamethasone : The most common adverse reactions (≥20%) are upper respiratory tract infection and musculoskeletal pain. ( 6.1 ) In combination with bortezomib, lenalidomide and dexamethasone : The most common adverse reactions (≥20%) are peripheral neuropathy, constipation, diarrhea, fatigue, musculoskeletal pain, upper respiratory tract infections, injection site reaction, insomnia, edema, rash, and erythema. ( 6.1 ) The most common hematology laboratory abnormalities (≥40%) with SARCLISA ESCENA combination therapies are decreased neutrophils, decreased platelets, decreased hemoglobin, decreased leukocytes, and decreased lymphocytes. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Relapsed and/or Refractory Multiple Myeloma Combination treatment with pomalidomide and dexamethasone (SARCLISA ESCENA-Pd versus intravenous isatuximab-irfc-Pd) IRAKLIA The safety of SARCLISA ESCENA was evaluated in IRAKLIA, a randomized, open-label phase 3 clinical trial in patients with previously treated multiple myeloma. Patients received SARCLISA ESCENA 1,400 mg administered subcutaneously, weekly in the first cycle and every two weeks thereafter, in combination with pomalidomide and dexamethasone (SARCLISA ESCENA-Pd, n=263) or isatuximab-irfc administered intravenously in combination with pomalidomide and dexamethasone (intravenous isatuximab-irfc-Pd, n=264) [see Clinical Studies (14) ] . Among patients receiving SARCLISA ESCENA-Pd, 66% were exposed to SARCLISA ESCENA for 6 months or longer and 25% were exposed for greater than 12 months or longer. The median duration of the injection with OBDS was 13 minutes. Serious adverse reactions occurred in 53% of patients receiving SARCLISA ESCENA-Pd. Serious adverse reactions in ≥5% of patients who received SARCLISA ESCENA-Pd included pneumonia (20.5%). Fatal adverse reactions occurred in 4.9% of patients who received SARCLISA ESCENA-Pd, including pneumonia (1.5%), sepsis/septic shock (1.5%), death (0.8%), COVID-19, lower respiratory tract infection, hemorrhagic stroke, and sudden death (0.4% each). Permanent treatment discontinuation due to an adverse reaction occurred in 8% of patients who received SARCLISA ESCENA-Pd. Adverse reactions which resulted in permanent discontinuation of SARCLISA ESCENA-Pd in more than 1 patient included pneumonia, death, COVID-19, sepsis, anemia, and neutrophil count decreased. The most common adverse reactions (≥20%) were upper respiratory tract infection, fatigue, pneumonia, musculoskeletal pain, and diarrhea. The most common hematology laboratory abnormalities (≥40%) were decreased leukocytes, decreased neutrophils, decreased lymphocytes, decreased platelets, and decreased hemoglobin. Table 3 summarizes the adverse reactions in IRAKLIA. Table 3: Adverse Reactions (≥10%) in Patients Who Received SARCLISA ESCENA-Pd or Intravenous Isatuximab-irfc-Pd in IRAKLIA Adverse Reaction SARCLISA ESCENA-Pd (N=263) Intravenous isatuximab-irfc-Pd (N=264) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection Upper respiratory tract infection is a grouping of viral, bacterial, fungal, and pathogen unspecified infections. 39 4.2 37 3.4 Pneumonia Pneumonia is a grouping of pneumonia from viral, fungal, and bacterial origins. 27 Includes 5 patients (1.9%) with fatal pneumonia. 19 28 Includes 4 patients (1.5%) with fatal pneumonia. 20 COVID-19 COVID-19 is a grouping of Coronavirus infections. 14 Includes 1 patient (0.4%) with fatal COVID-19. 4.6 18 4.2 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes: Arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain. 23 2.3 24 3 Gastrointestinal disorders Diarrhea 20 4.6 20 0.8 Constipation 14 0 13 0 General disorders and administration site conditions Fatigue Fatigue includes: fatigue, asthenia, malaise 29 4.9 22 1.5 Edema peripheral 8 0 12 1.1 Systemic administration reaction 1.5 0.4 25 1.1 Psychiatric disorders Insomnia 15 2.7 15 4.5 Table 4 summarizes the laboratory abnormalities in IRAKLIA. Table 4: Laboratory Abnormalities That Worsened (≥30%) From Baseline in Patients Who Received SARCLISA ESCENA-Pd versus Intravenous Isatuximab-irfc-Pd in IRAKLIA Laboratory Abnormality SARCLISA ESCENA-Pd (N=263) Intravenous isatuximab-irfc-Pd (N=264) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) 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. Hematology Leukocytes decreased 98 62 90 56 Neutrophils decreased 97 85 93 74 Lymphocytes decreased 92 49 85 41 Platelets decreased 77 26 73 23 Hemoglobin decreased 56 13 47 13 Chemistry Calcium decreased 48 0.8 49 0.4 Magnesium decreased 43 0.4 47 0 Albumin decreased 40 1.9 39 1.9 Alanine aminotransferase increased 34 1.9 35 0.8 Sodium decreased 33 6 31 4.2 Creatinine increased 32 5 23 2.7 Alkaline phosphatase increased 30 0.8 26 0 Combination treatment with carfilzomib and dexamethasone (SARCLISA ESCENA-Kd) IZALCO The safety of SARCLISA ESCENA was evaluated in IZALCO, a randomized, open-label phase 2 clinical trial in patients with previously treated multiple myeloma. In IZALCO, patients received SARCLISA ESCENA 1,400 mg subcutaneously weekly in the first cycle, and every two weeks thereafter, in combination with carfilzomib and dexamethasone (SARCLISA ESCENA-Kd) (n=74). SARCLISA ESCENA was administered either by CirCLIQ OBDS or by manual administration [see Clinical Studies (14) ] . In IZALCO, 77% of patients were exposed to SARCLISA ESCENA for 6 months or longer and 7% were exposed for greater than 12 months. Serious adverse reactions occurred in 41% of patients receiving SARCLISA ESCENA-Kd. Serious adverse reactions in ≥5% of patients included pneumonia (11%). Fatal adverse reaction occurred in 5.4% of patients who received SARCLISA ESCENA-Kd, including meningitis (1.4%), acute pulmonary edema (1.4%), acute respiratory distress syndrome (1.4%), and death from unknown cause (1.4%). Permanent treatment discontinuation due to an adverse reaction occurred in 8% of patients who received SARCLISA ESCENA-Kd. Adverse reactions which resulted in permanent discontinuation of SARCLISA ESCENA-Kd in 1 patient each included lower respiratory tract infection, meningitis, acute pulmonary edema, acute respiratory distress syndrome, erythema multiforme, and death. The most common adverse reactions (≥20%) were upper respiratory tract infection and musculoskeletal pain. The most common hematology laboratory abnormalities (≥40%) were decreased platelets, decreased lymphocytes, decreased leukocytes, decreased hemoglobin, and decreased neutrophils. Table 5 summarizes the adverse reactions in IZALCO. Table 5: Adverse Reactions (≥10%) in Patients Who Received SARCLISA ESCENA-Kd in IZALCO SARCLISA ESCENA-Kd (N=74) Adverse Reaction All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection Upper respiratory tract infection is a grouping of bacterial, viral, and pathogen unspecified infections. 54 1.4 Pneumonia Pneumonia is a grouping of pneumonia from fungal, viral, and pathogen unspecified origins. 18 10 COVID-19 12 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes: Arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain. 20 1.4 Vascular disorders Hypertension 14 4.1 Psychiatric disorders Insomnia 12 2.7 Gastrointestinal disorders Diarrhea 11 0 General disorders and administration site conditions Pyrexia 11 1.4 Clinically relevant adverse reactions in <10% of patients who received SARCLISA ESCENA in combination with carfilzomib and dexamethasone included cardiac failure. Table 6 summarizes the laboratory abnormalities in IZALCO. Table 6: Laboratory Abnormalities That Worsened (≥30%) From Baseline in Patients Who Received SARCLISA ESCENA-Kd in IZALCO Laboratory Abnormality SARCLISA ESCENA-Kd (N=74) All Grades (%) Grade 3 or 4 (%) 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. Hematology Lymphocytes decreased 85 56 Platelets decreased 85 19 Leukocytes decreased 59 15 Hemoglobin decreased 56 14 Neutrophils decreased 47 15 Chemistry Calcium decreased 55 1.4 Sodium decreased 44 5 Magnesium decreased 33 0 Alkaline phosphatase increased 33 0 Albumin decreased 32 1.4 Newly Diagnosed Multiple Myeloma not Eligible for Autologous Stem Cell Transplant Combination treatment with bortezomib, lenalidomide, and dexamethasone (SARCLISA ESCENA-VRd) IsaSoCut The safety of SARCLISA ESCENA was evaluated in IsaSoCut, a multicenter, open-label single-arm, phase 2 clinical trial in patients with newly diagnosed multiple myeloma who are not eligible for stem cell transplantation. Patients received SARCLISA ESCENA 1,400 mg administered subcutaneously with CirCLIQ OBDS in combination with bortezomib, lenalidomide, and dexamethasone (SARCLISA ESCENA-VRd) [see Clinical Studies (14) ] . Among patients receiving SARCLISA ESCENA-VRd, 97% were exposed to SARCLISA ESCENA for 6 months or longer and 50% were exposed for 12 months or longer. Serious adverse reactions occurred in 45% of patients who received SARCLISA ESCENA-VRd. Serious adverse reactions >5% of patients included pneumonia (8%). Fatal adverse reactions occurred in 2.7% of patients who received SARCLISA ESCENA-VRd, including cardio-respiratory arrest (1.4%) and myocardial infarction (1.4%). Permanent treatment discontinuation due to an adverse reaction occurred in 4.1% of patients who received SARCLISA ESCENA-VRd. Adverse reactions which resulted in permanent discontinuation of SARCLISA ESCENA-VRd in 1 patient each included pyelonephritis, cardio-respiratory arrest, and myocardial infarction. The most common adverse reactions (≥20%) were peripheral neuropathy, constipation, diarrhea, fatigue, musculoskeletal pain, upper respiratory tract infections, injection site reaction, insomnia, edema, rash, and erythema. The most common hematology laboratory abnormalities (≥40%) were decreased lymphocytes, decreased leukocytes, decreased platelets, decreased neutrophils, and decreased hemoglobin. Table 7 summarizes the adverse reactions in IsaSoCut. Table 7: Adverse Reactions (≥10%) in Patients Who Received SARCLISA ESCENA-VRd in IsaSoCut SARCLISA ESCENA-VRd (N=74) Adverse Reaction All Grades (%) Grade 3 or 4 (%) Nervous system disorders Peripheral neuropathy Peripheral neuropathy included the grouping of paresthesias, dysesthesias, hypoesthesias, and peripheral neuropathies (sensory and motor). 59 5 Gastrointestinal disorders Constipation 43 2.7 Diarrhea 41 0 Nausea 15 0 Vomiting 11 0 Abdominal pain Abdominal pain refers to the grouping of gastrointestinal and abdominal pains (excluding oral and throat). 11 0 General disorders and administration site conditions Fatigue Fatigue is a grouping of asthenic conditions. 37 2.7 Injection site reaction 27 0 Edema Edema is a grouping of the following terms: eyelid edema, face edema, generalized edema, localized edema, edema, and edema peripheral. 20 1.4 Pyrexia 11 0 Infections and infestations Upper respiratory tract infections Upper respiratory tract infections is a grouping of viral and pathogen unspecified infections. 30 0 COVID-19 COVID-19 is a grouping of Coronavirus infections. 18 5 Pneumonia Pneumonia is a grouping of pneumonia from bacterial and viral origins. 15 8 Bronchitis 14 0 Influenza 12 0 Urinary tract infection Urinary tract infection is a grouping of genitourinary tract infections (bacterial origin or pathogen unspecified). 12 0 Psychiatric disorders Insomnia 26 0 Skin and subcutaneous tissue disorders Rash Rash is a grouping of the following terms: drug eruption, eczema, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. 20 2.7 Erythema 20 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain is a grouping of the following terms: arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain. 32 2.7 Back pain 16 0 Muscle spasms 14 0 Vascular disorders Hypotension Hypotension is a grouping of the following terms: hypotension and orthostatic hypotension. 16 2.7 Investigations Weight decreased 14 0 Clinically relevant adverse reactions in <10% of patients who received SARCLISA ESCENA in combination with bortezomib, lenalidomide, and dexamethasone included systemic administration reactions. Table 8 summarizes the laboratory abnormalities in IsaSoCut. Table 8: Laboratory Abnormalities That Worsened (≥30%) From Baseline in Patients Who Received SARCLISA ESCENA-VRd in IsaSoCut Laboratory Abnormality SARCLISA ESCENA-VRd (N=74) All Grades (%) Grade 3 or 4 (%) 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. Hematology Lymphocytes decreased 92 64 Leukocytes decreased 92 30 Platelets decreased 82 26 Neutrophils decreased 76 49 Hemoglobin decreased 41 8 Chemistry Alkaline phosphatase increased 42 0

<table width="80%"><caption>Table 3: Adverse Reactions (&#x2265;10%) in Patients Who Received SARCLISA ESCENA-Pd or Intravenous Isatuximab-irfc-Pd in IRAKLIA</caption><col width="20%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th rowspan="2" styleCode="Lrule Rrule">Adverse Reaction</th><th colspan="2" styleCode="Rrule">SARCLISA ESCENA-Pd (N=263) </th><th colspan="2" styleCode="Rrule">Intravenous isatuximab-irfc-Pd (N=264) </th></tr><tr><th align="center" styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3 or 4 (%)</th><th styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3 or 4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Infections and infestations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection <footnote ID="K1558">Upper respiratory tract infection is a grouping of viral, bacterial, fungal, and pathogen unspecified infections.</footnote></td><td styleCode="Rrule">39</td><td styleCode="Rrule">4.2</td><td styleCode="Rrule">37</td><td styleCode="Rrule">3.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pneumonia <footnote ID="K1577">Pneumonia is a grouping of pneumonia from viral, fungal, and bacterial origins.</footnote></td><td styleCode="Rrule">27 <footnote ID="K1582">Includes 5 patients (1.9%) with fatal pneumonia.</footnote></td><td styleCode="Rrule">19</td><td styleCode="Rrule">28 <footnote ID="K1590">Includes 4 patients (1.5%) with fatal pneumonia.</footnote></td><td styleCode="Rrule">20</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">COVID-19 <footnote ID="K1600">COVID-19 is a grouping of Coronavirus infections.</footnote></td><td styleCode="Rrule">14 <footnote ID="K1605">Includes 1 patient (0.4%) with fatal COVID-19.</footnote></td><td styleCode="Rrule">4.6</td><td styleCode="Rrule">18</td><td styleCode="Rrule">4.2</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Musculoskeletal pain <footnote ID="K1629">Musculoskeletal pain includes: Arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain.</footnote></td><td styleCode="Rrule">23</td><td styleCode="Rrule">2.3</td><td styleCode="Rrule">24</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">20</td><td styleCode="Rrule">4.6</td><td styleCode="Rrule">20</td><td styleCode="Rrule">0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue <footnote ID="K1698">Fatigue includes: fatigue, asthenia, malaise</footnote></td><td styleCode="Rrule">29</td><td styleCode="Rrule">4.9</td><td styleCode="Rrule">22</td><td styleCode="Rrule">1.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Edema peripheral</td><td styleCode="Rrule">8</td><td styleCode="Rrule">0</td><td styleCode="Rrule">12</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Systemic administration reaction</td><td styleCode="Rrule">1.5</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">25</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric disorders</content></td></tr><tr><td styleCode="Lrule Rrule">Insomnia</td><td styleCode="Rrule">15</td><td styleCode="Rrule">2.7</td><td styleCode="Rrule">15</td><td styleCode="Rrule">4.5</td></tr></tbody></table>

<table width="80%"><caption>Table 4: Laboratory Abnormalities That Worsened (&#x2265;30%) From Baseline in Patients Who Received SARCLISA ESCENA-Pd versus Intravenous Isatuximab-irfc-Pd in IRAKLIA</caption><col width="20%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th rowspan="2" styleCode="Lrule Rrule">Laboratory Abnormality</th><th colspan="2" styleCode="Rrule">SARCLISA ESCENA-Pd (N=263) </th><th colspan="2" styleCode="Rrule">Intravenous isatuximab-irfc-Pd (N=264) </th></tr><tr><th align="center" styleCode="Rrule">All Grades (%) </th><th styleCode="Rrule">Grade 3 or 4 (%) </th><th styleCode="Rrule">All Grades (%) </th><th styleCode="Rrule">Grade 3 or 4 (%) </th></tr></thead><tfoot><tr><td align="left" colspan="5">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.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Hematology</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Leukocytes decreased</td><td styleCode="Rrule">98</td><td styleCode="Rrule">62</td><td styleCode="Rrule">90</td><td styleCode="Rrule">56</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutrophils decreased</td><td styleCode="Rrule">97</td><td styleCode="Rrule">85</td><td styleCode="Rrule">93</td><td styleCode="Rrule">74</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Lymphocytes decreased</td><td styleCode="Rrule">92</td><td styleCode="Rrule">49</td><td styleCode="Rrule">85</td><td styleCode="Rrule">41</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Platelets decreased</td><td styleCode="Rrule">77</td><td styleCode="Rrule">26</td><td styleCode="Rrule">73</td><td styleCode="Rrule">23</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hemoglobin decreased</td><td styleCode="Rrule">56</td><td styleCode="Rrule">13</td><td styleCode="Rrule">47</td><td styleCode="Rrule">13</td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule"><content styleCode="bold">Chemistry</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Calcium decreased</td><td styleCode="Rrule">48</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">49</td><td styleCode="Rrule">0.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Magnesium decreased</td><td styleCode="Rrule">43</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">47</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Albumin decreased</td><td styleCode="Rrule">40</td><td styleCode="Rrule">1.9</td><td styleCode="Rrule">39</td><td styleCode="Rrule">1.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Alanine aminotransferase increased</td><td styleCode="Rrule">34</td><td styleCode="Rrule">1.9</td><td styleCode="Rrule">35</td><td styleCode="Rrule">0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Sodium decreased</td><td styleCode="Rrule">33</td><td styleCode="Rrule">6</td><td styleCode="Rrule">31</td><td styleCode="Rrule">4.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Creatinine increased</td><td styleCode="Rrule">32</td><td styleCode="Rrule">5</td><td styleCode="Rrule">23</td><td styleCode="Rrule">2.7</td></tr><tr><td styleCode="Lrule Rrule">Alkaline phosphatase increased</td><td styleCode="Rrule">30</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">26</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="80%"><caption>Table 5: Adverse Reactions (&#x2265;10%) in Patients Who Received SARCLISA ESCENA-Kd in IZALCO</caption><col width="33%" align="left" valign="top"/><col width="34%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule"/><th colspan="2" styleCode="Rrule">SARCLISA ESCENA-Kd (N=74) </th></tr><tr><th align="center" styleCode="Lrule Rrule">Adverse Reaction</th><th styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3 or 4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Infections and infestations</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection <footnote ID="K2142">Upper respiratory tract infection is a grouping of bacterial, viral, and pathogen unspecified infections.</footnote></td><td styleCode="Rrule">54</td><td styleCode="Rrule">1.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pneumonia <footnote ID="K2155">Pneumonia is a grouping of pneumonia from fungal, viral, and pathogen unspecified origins.</footnote></td><td styleCode="Rrule">18</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">COVID-19</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Musculoskeletal pain <footnote ID="K2190">Musculoskeletal pain includes: Arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain.</footnote></td><td styleCode="Rrule">20</td><td styleCode="Rrule">1.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Vascular disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension</td><td styleCode="Rrule">14</td><td styleCode="Rrule">4.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Insomnia</td><td styleCode="Rrule">12</td><td styleCode="Rrule">2.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">11</td><td styleCode="Rrule">1.4</td></tr></tbody></table>