Sarclisa

5 WARNINGS AND PRECAUTIONS Infusion-Related Reactions : In case of grade ≥2, interrupt SARCLISA and manage medically. Permanently discontinue for grade 4 infusion-related reactions or anaphylactic reaction. ( 5.1 ) Infections : SARCLISA can cause serious and fatal infections. Monitor patients for signs and symptoms of infection and treat appropriately. ( 5.2 ) Neutropenia : Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. SARCLISA dose delays and the use of colony-stimulating factor may be required to allow improvement of neutrophil count. ( 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 SARCLISA. ( 5.5 , 7.1 ) Interference with Serum Protein Electrophoresis and Immunofixation Tests: SARCLISA 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. ( 5.6 ) 5.1 Infusion-Related Reactions SARCLISA can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be life-threatening and fatal outcomes have been reported [see Adverse Reactions (6.2) ]. Severe signs and symptoms included cardiac arrest, hypertension, hypotension, bronchospasm, dyspnea, angioedema, and swelling. In clinical trials (ICARIA-MM, IKEMA, and IMROZ), in patients treated with SARCLISA (N=592), infusion-related reactions occurred in 206 patients (35%). Among these 206 patients, 92% experienced infusion-related reactions during the first infusion and 12% after the first cycle. The most common symptoms (≥5%) of an infusion-related reaction included dyspnea and cough. Grade 1 infusion-related reactions were reported in 6% of patients, grade 2 in 28%, and grade 3 or 4 in 1.2%. Anaphylactic reactions occurred in less than 1% of patients. The total incidence of SARCLISA infusion interruptions was less than 1% and the incidence of patients with at least one SARCLISA infusion interruption due to infusion-related reactions was 26%. The median time to first SARCLISA infusion interruption was 61 minutes (range 4 to 240 minutes). SARCLISA was discontinued in 1% of patients due to infusion-related reactions. To decrease the risk and severity of infusion-related reactions, premedicate patients prior to SARCLISA infusion with acetaminophen, H2 antagonists, diphenhydramine, or equivalent, and dexamethasone [see Dosage and Administration (2.2) ] . Monitor vital signs frequently during the entire SARCLISA infusion. For patients with grade ≥2 reactions, interrupt SARCLISA infusion and provide appropriate medical management. For patients with grade 2 or grade 3 reactions, if symptoms improve to grade ≤1, restart SARCLISA infusion at half of the initial infusion rate, with supportive care as needed, and closely monitor patients. 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 [see Dosage and Administration (2.5) ] . In case symptoms do not improve to grade ≤1 after interruption of SARCLISA infusion, persist or worsen despite appropriate medications, or require hospitalization, permanently discontinue SARCLISA and institute appropriate management. Permanently discontinue SARCLISA if an anaphylactic reaction or life-threatening (grade 4) infusion-related reaction occurs and institute appropriate management. 5.2 Infections SARCLISA can cause severe, life-threatening, or fatal infections. In patients who received SARCLISA at the recommended dose in ICARIA-MM, IKEMA, and IMROZ (N=592), serious infections, including opportunistic infections, occurred in 46% of patients, grade 3 or 4 infections occurred in 43%, and fatal infections occurred in 4.7%. The most common type of serious infection reported was pneumonia (32%). Monitor patients for signs and symptoms of infection prior to and during treatment with SARCLISA and treat appropriately. Administer prophylactic antimicrobials according to guidelines [see Dosage and Administration (2.2) ] . 5.3 Neutropenia SARCLISA can cause neutropenia. In clinical trials (ICARIA-MM, IKEMA, and IMROZ), in patients treated with SARCLISA (N=592), neutropenia based on laboratory values occurred in 81%, with grade 3 or 4 occurring in 52%. Neutropenic infections occurred in 12% of patients, with grade 3 or 4 in 4.9%, and febrile neutropenia in 4% [see Adverse Reactions (6.1) ] . Monitor complete blood cell counts periodically during treatment. If needed, use antibacterial and antiviral prophylaxis during treatment [see Dosage and Administration (2.2) ] . Monitor patients with neutropenia for signs of infection. In case of grade 4 neutropenia delay SARCLISA dose until neutrophil count recovery to at least 1 × 10 9 /L, and provide supportive care with growth factors, according to institutional guidelines. No dose reductions of SARCLISA are recommended. 5.4 Second Primary Malignancies The incidence of second primary malignancies, during treatment and post-treatment, is increased in patients treated with SARCLISA-containing regimens. In clinical trials (ICARIA-MM, IKEMA, and IMROZ), in patients treated with SARCLISA (N=592), second primary malignancies occurred in 71 patients (12%). In ICARIA-MM, at a median follow-up time of 52 months, second primary malignancies occurred in 7% of patients in the Isa-Pd arm and in 2% of patients in the Pd arm. In IKEMA study, at a median follow-up time of 57 months, second primary malignancies occurred in 10% of patients in the Isa-Kd arm and in 8% of patients in the Kd arm. In IMROZ study, at a median follow-up time of 60 months, second primary malignancies occurred in 16% of patients in the Isa-VRd arm and in 9% of patients in the VRd arm. The most common (≥1%) second primary malignancies in ICARIA-MM, IKEMA, and IMROZ (N=592) included skin cancers (7% with SARCLISA-containing regimens and 3.1% with comparative regimens) and solid tumors other than skin cancer (4.6% with SARCLISA-containing regimens and 2.9% with comparative regimens). Patients with non-melanoma skin cancer continued treatment after resection of the skin cancer, except 2 patients on the Isa-VRd arm and 1 patient on the VRd arm of the IMROZ study. Monitor patients for the development of second primary malignancies. 5.5 Laboratory Test Interference Interference with Serological Testing (Indirect Antiglobulin Test) SARCLISA 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 approximately 6 months after the last infusion of SARCLISA. The indirect antiglobulin test was positive during Isa-Pd treatment in 68% of the tested patients, and during Isa-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 SARCLISA treatment. Before the first SARCLISA infusion, conduct blood type and screen tests on SARCLISA-treated patients. Consider phenotyping prior to starting SARCLISA treatment. If treatment with SARCLISA has already started, inform the blood bank that the patient is receiving SARCLISA and SARCLISA 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 SARCLISA is an IgG kappa monoclonal antibody that can be incidentally detected on both serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the accuracy of the determination of complete response in some patients with IgG kappa myeloma protein [see Drug Interactions (7.1) ] . 5.6 Embryo-Fetal Toxicity Based on the mechanism of action, SARCLISA can cause fetal harm when administered to a pregnant woman. SARCLISA may cause fetal immune cell depletion and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use an effective method of contraception during treatment with SARCLISA and for 5 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] . The combination of SARCLISA 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 are also described in other sections of the labeling: Infusion-Related Reactions [see Warnings and Precautions (5.1) ] Infections [see Warnings and Precautions (5.2) ] Neutropenia [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, infusion-related reactions, pneumonia, and diarrhea. The most common hematology laboratory abnormalities (≥80%) are decreased hemoglobin, decreased neutrophils, decreased lymphocytes, and decreased platelets. ( 6.1 ) In combination with carfilzomib and dexamethasone : The most common adverse reactions (≥20%) are upper respiratory tract infection, infusion-related reactions, fatigue, hypertension, diarrhea, pneumonia, dyspnea, insomnia, bronchitis, cough, and back pain. The most common hematology laboratory abnormalities (≥80%) are decreased hemoglobin, decreased lymphocytes, and decreased platelets. ( 6.1 ) In combination with bortezomib, lenalidomide and dexamethasone : The most common adverse reactions (≥20%) are upper respiratory tract infections, diarrhea, fatigue, peripheral sensory neuropathy, pneumonia, musculoskeletal pain, cataract, constipation, peripheral edema, rash, infusion-related reaction, insomnia, and COVID-19. The most common hematologic laboratory abnormalities (≥80%) are decreased hemoglobin, decreased leukocytes, decreased lymphocytes, decreased platelets, and decreased neutrophils. ( 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 (Isa-Pd) The safety of SARCLISA was evaluated in ICARIA-MM, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously, weekly in the first cycle and every two weeks thereafter, in combination with pomalidomide and dexamethasone (Isa-Pd) (n=152) or pomalidomide and dexamethasone (Pd) (n=149) [see Clinical Studies (14) ] . Among patients receiving Isa-Pd, 66% were exposed to SARCLISA for 6 months or longer and 24% were exposed for greater than 12 months or longer. Serious adverse reactions occurred in 62% of patients receiving Isa-Pd. Serious adverse reactions in >5% of patients who received Isa-Pd included pneumonia (26%), upper respiratory tract infections (7%), and febrile neutropenia (7%). Fatal adverse reactions occurred in 11% of patients (those that occurred in more than 1% of patients were pneumonia and other infections [3%]). Permanent treatment discontinuation due to an adverse reaction (grades 1–4) occurred in 7% of patients who received Isa-Pd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Pd were infections (2.6%). SARCLISA alone was discontinued in 3% of patients due to infusion-related reactions. Dosage interruptions due to an adverse reaction occurred in 31% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion-related reaction (28%). The most common adverse reactions (≥20%) were upper respiratory tract infection, infusion-related reactions, pneumonia, and diarrhea. Table 4 summarizes the adverse reactions in ICARIA-MM. Table 4: Adverse Reactions (≥10%) in Patients Receiving SARCLISA, Pomalidomide, and Dexamethasone with a Difference Between Arms of ≥5% Compared to Control Arm in ICARIA-MM Trial Adverse Reactions SARCLISA + Pomalidomide + Dexamethasone (Isa-Pd) Pomalidomide + Dexamethasone (Pd) (N=152) (N=149) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) CTCAE version 4.03 General disorders and administration site conditions Infusion-related reaction Infusion-related reaction includes infusion-related reaction, cytokine release syndrome, and drug hypersensitivity. 38 1.3 1.3 0 0 0 Infections Upper respiratory tract infection Upper respiratory tract infection includes bronchiolitis, bronchitis, bronchitis viral, chronic sinusitis, fungal pharyngitis, influenza-like illness, laryngitis, nasopharyngitis, parainfluenzae virus infection, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tracheitis, upper respiratory tract infection, and upper respiratory tract infection bacterial. 57 9 0 42 3.4 0 Pneumonia Pneumonia includes atypical pneumonia, bronchopulmonary aspergillosis, pneumonia, pneumonia haemophilus, pneumonia influenzal, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, candida pneumonia, pneumonia bacterial, haemophilus infection, lung infection, pneumonia fungal, and pneumocystis jirovecii pneumonia. 31 22 3.3 23 16 2.7 Blood and lymphatic system disorders Febrile neutropenia 12 11 1.3 2 1.3 0.7 Respiratory, thoracic and mediastinal disorders Dyspnea Dyspnea includes dyspnea, dyspnea exertional, and dyspnea at rest. 17 5 0 12 1.3 0 Gastrointestinal disorders Diarrhea 26 2 0 19 0.7 0 Nausea 15 0 0 9 0 0 Vomiting 12 1.3 0 3.4 0 0 Table 5 summarizes the hematology laboratory abnormalities in ICARIA-MM. Table 5: Hematology Laboratory Abnormalities During the Treatment Period in Patients Receiving Isa-Pd versus Pd in ICARIA-MM Laboratory Parameter SARCLISA + Pomalidomide + Dexamethasone (Isa-Pd) Pomalidomide + Dexamethasone (Pd) (N=152) (N=149) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) The denominator used to calculate the percentages was based on the safety population. Hemoglobin decreased 99 32 0 97 28 0 Neutrophils decreased 96 24 61 92 38 31 Lymphocytes decreased 92 42 13 92 35 8 Platelets decreased 84 14 16 79 9 15 Combination treatment with carfilzomib and dexamethasone (Isa-Kd) The safety of SARCLISA was evaluated in IKEMA, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously weekly in the first cycle, and every two weeks thereafter, in combination with carfilzomib and dexamethasone (Isa-Kd) (n=177) or carfilzomib and dexamethasone (Kd) (n=122) [see Clinical Studies (14) ] . Among patients receiving Isa-Kd, 68% were exposed to SARCLISA for 12 months or longer and 51% were exposed for greater than 18 months. Serious adverse reactions occurred in 59% of patients receiving Isa-Kd. The most frequent serious adverse reactions in >5% of patients who received Isa-Kd were pneumonia (25%) and upper respiratory tract infections (9%). Adverse reactions with a fatal outcome during treatment were reported in 3.4% of patients in the Isa-Kd group (those occurring in more than 1% of patients were pneumonia occurring in 1.7% and cardiac failure in 1.1% of patients). Permanent treatment discontinuation due to an adverse reaction (grades 1–4) occurred in 8% of patients who received Isa-Kd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Kd were infections (2.8%). SARCLISA alone was discontinued in 0.6% of patients due to infusion-related reactions. Dosage interruptions due to an adverse reaction occurred in 33% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion-related reaction (30%). The most common adverse reactions (≥20%) were upper respiratory tract infection, infusion-related reactions, fatigue, hypertension, diarrhea, pneumonia, dyspnea, insomnia, bronchitis, cough, and back pain. Table 6 summarizes the adverse reactions in IKEMA. Table 6: Adverse Reactions (≥10%) in Patients Receiving SARCLISA, Carfilzomib, and Dexamethasone with a Difference Between Arms of ≥5% Compared to Control Arm in IKEMA Adverse Reactions SARCLISA + Carfilzomib + Dexamethasone (Isa-Kd) Carfilzomib + Dexamethasone (Kd) (N=177) (N=122) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) General disorders and administration site conditions Infusion-related reaction Infusion-related reaction includes infusion-related reaction, cytokine release syndrome, and hypersensitivity. 46 0.6 0 3.3 0 0 Fatigue Fatigue includes fatigue and asthenia. 42 5 0 32 3.3 0 Infections Upper respiratory tract infection Upper respiratory tract infection includes acute sinusitis, chronic sinusitis, H1N1 influenza, H3N2 influenza, influenza, laryngitis, laryngitis viral, nasal herpes, nasopharyngitis, pharyngitis, pharyngotonsillitis, respiratory syncytial virus infection, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, tracheitis, upper respiratory tract infection, viral rhinitis, respiratory tract infection, respiratory tract infection viral, influenza like illness, parainfluenzae virus infection, respiratory tract infection bacterial, and viral upper respiratory tract infection. 67 9 0 57 7 0 Pneumonia Pneumonia includes atypical pneumonia, lower respiratory tract infection, lower respiratory tract infection viral, pneumocystis jirovecii pneumonia, pneumonia, pneumonia influenzal, pneumonia legionella, pneumonia pneumococcal, pneumonia respiratory syncytial viral, pneumonia streptococcal, pneumonia viral, pulmonary sepsis, and pulmonary tuberculosis. 36 19 3.4 30 15 2.5 Bronchitis Bronchitis includes bronchitis, bronchitis viral, respiratory syncytial virus bronchitis, bronchitis chronic, and tracheobronchitis. 24 2.3 0 13 0.8 0 Vascular disorders Hypertension Hypertension includes hypertension, blood pressure increased, and hypertensive crisis. 37 20 0.6 32 18 1.6 Respiratory, thoracic and mediastinal disorders Dyspnea Dyspnea includes dyspnea and dyspnea exertional. 29 5 0 24 0.8 0 Cough Cough includes cough, productive cough, and allergic cough. 23 0 0 15 0 0 Gastrointestinal disorders Diarrhea 36 2.8 0 29 2.5 0 Vomiting 15 1.1 0 9 0.8 0 Table 7 summarizes the hematology laboratory abnormalities in IKEMA. Table 7: Hematology Laboratory Abnormalities During the Treatment Period in Patients Receiving Isa-Kd versus Kd in IKEMA Laboratory Parameter SARCLISA + Carfilzomib + Dexamethasone (Isa-Kd) Carfilzomib + Dexamethasone (Kd) (N=177) (N=122) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) The denominator used to calculate the percentage was based on the safety population. Hemoglobin decreased 99 22 0 99 20 0 Lymphocytes decreased 94 52 17 95 43 14 Platelets decreased 94 19 11 88 16 8 Neutrophils decreased 55 18 1.7 43 7 0.8 Newly Diagnosed Multiple Myeloma not Eligible for Autologous Stem Cell Transplant Combination treatment with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) The safety of SARCLISA was evaluated in IMROZ, a randomized, open-label clinical trial in patients with newly diagnosed multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously on day 1, 8, 15, 22, and 29 in the first 42-day cycle, followed by every two weeks from cycle 2 to 4 (42-day cycles), followed by every two weeks from cycle 5 to 17 (28-day cycles), and then on day 1 from cycle 18 and onwards (28-day cycles), in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) (n=263) or bortezomib, lenalidomide, and dexamethasone (VRd) (n= 181) [see Clinical Studies (14) ] . In IMROZ, median duration of exposure to treatment was 53 (range: 0.5–69) months in patients treated with Isa-VRd and 31 (range 0.6–67) months in patients treated with VRd. Serious adverse reactions occurred in 71% of patients receiving Isa-VRd. The serious adverse reaction in > 5% of patients who received Isa-VRd was pneumonia (30%). Fatal adverse reactions occurred in 11% of patients with Isa-VRd (those occurring in more than 1% of patients were pneumonia (5%). Permanent discontinuation of treatment due to an adverse reaction occurred in 22.8% of patients treated with Isa-VRd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-VRd were infections (8%). SARCLISA alone was discontinued in 2.3% of patients. Dosage interruptions due to an adverse reaction occurred in 21% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion related reaction (21%). The most common adverse reactions (≥20%) were upper respiratory tract infections, diarrhea, fatigue, peripheral sensory neuropathy, pneumonia, musculoskeletal pain, cataract, constipation, peripheral edema, rash, infusion-related reaction, insomnia, and COVID-19. The most common hematologic laboratory abnormalities (≥80%) were decreased hemoglobin, decreased leukocytes, decreased lymphocytes, decreased platelets, and decreased neutrophils. Table 8 summarizes the adverse reactions in IMROZ. Table 8: Adverse Reactions (≥ 20%) in Patients Receiving SARCLISA, Bortezomib, Lenalidomide, and Dexamethasone in IMROZ IMROZ study Adverse Reactions SARCLISA + Bortezomib + Lenalidomide + Dexamethasone (N=263) Bortezomib + Lenalidomide + Dexamethasone (N=181) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection Includes other related terms 65 4.6 57 Includes 1 patient (0.6%) with fatal URTI. 6 Pneumonia Pneumonia includes Atypical pneumonia, Bronchopulmonary aspergillosis, COVID-19 pneumonia, Lower respiratory tract infection, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia aspiration, Pneumonia bacterial, Pneumonia influenzal, Pneumonia klebsiella, Pneumonia legionella, Pneumonia parainfluenzae viral, Pneumonia pneumococcal, Pneumonia pseudomonal, Pneumonia respiratory syncytial viral, Pneumonia viral, Pulmonary sepsis. 45 Includes 14 patients (5%) with fatal pneumonia. 26 31 Includes 4 patients (2.2%) with fatal pneumonia. 19 COVID-19 COVID-19 includes COVID-19 infections other than COVID-19 pneumonia. 22 0.8 17 Includes 2 patients (1.1%) with fatal COVID-19. 1.7 General disorders and administration site conditions Fatigue Fatigue includes Fatigue, Asthenia, or Malaise. 55 11 50 9 Edema peripheral 33 0 33 1.1 Infusion-related reaction 24 0.4 1.1 0 Gastrointestinal disorders Diarrhea 55 8 49 8 Constipation 36 2.3 41 1.7 Nervous system disorders Peripheral sensory neuropathy 54 7 61 6 Eye disorders Cataract 38 16 25 11 Musculoskeletal and connective tissue disorders Musculoskeletal pain 38 4.2 33 3.3 Skin and subcutaneous tissue disorders Rash Rash includes Dermatitis, Dermatitis acneiform, Dermatitis allergic, Dermatitis atopic, Dermatitis exfoliative generalized, Drug eruption, Rash, Rash erythematous, Rash macular, Rash maculo-papular, Rash pruritic, Rash pustular, Skin exfoliation, Skin hyperpigmentation, Skin lesion, Skin reaction, and Toxic skin eruption. 32 5 34 5 Psychiatric disorders Insomnia 22 3.8 24 2.2 Table 9 summarizes the hematology laboratory abnormalities in IMROZ. Table 9: Hematology Laboratory Abnormalities During the Treatment Period in Patients Receiving Isa-VRd Versus VRd in IMROZ Laboratory parameter SARCLISA + Bortezomib + Lenalidomide + Dexamethasone The denominator used to calculate the rate is based on the number of patients with a baseline value and at least one post-baseline value. Bortezomib + Lenalidomide + Dexamethasone All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Decreased hemoglobin 99 17 98 16 Decreased leukocytes 97 32 88 17 Decreased lymphocytes 95 60 92 53 Decreased platelets 95 30 85 28 Decreased neutrophils 87 54 80 37 Description of Selected Adverse Reactions Cardiac failure In IKEMA, cardiac failure (including cardiac failure, cardiac failure congestive, cardiac failure acute, cardiac failure chronic, left ventricular failure, and pulmonary edema) was reported in 7% of patients with the Isa-Kd group (grade ≥3 in 4%) and in 7% of patients with the Kd group (grade ≥3 in 4.1%). Serious cardiac failure was observed in 4% of patients in the Isa-Kd group and in 3.3% of patients in the Kd group. See the current prescribing information for carfilzomib for more information. 6.2 Postmarketing Experience The following adverse reactions have been identified with postapproval use of SARCLISA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders : Anaphylactic reactions including fatal cases.

<table width="90%" ID="table4"><caption>Table 4: Adverse Reactions (&#x2265;10%) in Patients Receiving SARCLISA, Pomalidomide, and Dexamethasone with a Difference Between Arms of &#x2265;5% Compared to Control Arm in ICARIA-MM Trial</caption><col width="25%" align="left" valign="middle"/><col width="12%" align="center" valign="middle"/><col width="13%" align="center" valign="middle"/><col width="12%" align="center" valign="middle"/><col width="13%" align="center" valign="middle"/><col width="12%" align="center" valign="middle"/><col width="13%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" valign="top">Adverse Reactions</th><th styleCode="Rrule" valign="top" colspan="3">SARCLISA + Pomalidomide + Dexamethasone (Isa-Pd)</th><th styleCode="Rrule" valign="top" colspan="3">Pomalidomide + Dexamethasone (Pd)</th></tr><tr><th styleCode="Lrule Rrule" valign="top"/><th styleCode="Botrule Rrule" valign="bottom" colspan="3">(N=152)</th><th styleCode="Botrule Rrule" valign="bottom" colspan="3">(N=149)</th></tr><tr><th styleCode="Lrule Rrule" valign="top"/><th styleCode="Rrule" valign="top">All Grades (%)</th><th styleCode="Rrule" valign="top">Grade 3 (%)</th><th styleCode="Rrule" valign="top">Grade 4 (%)</th><th styleCode="Rrule" valign="top">All Grades (%)</th><th styleCode="Rrule" valign="top">Grade 3 (%)</th><th styleCode="Rrule" valign="top">Grade 4 (%)</th></tr></thead><tfoot><tr><td align="left" valign="top" colspan="7"> CTCAE version 4.03</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="bold">General disorders and administration site conditions</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Infusion-related reaction<footnote>Infusion-related reaction includes infusion-related reaction, cytokine release syndrome, and drug hypersensitivity.</footnote></td><td styleCode="Rrule">38</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="bold">Infections</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection<footnote>Upper respiratory tract infection includes bronchiolitis, bronchitis, bronchitis viral, chronic sinusitis, fungal pharyngitis, influenza-like illness, laryngitis, nasopharyngitis, parainfluenzae virus infection, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tracheitis, upper respiratory tract infection, and upper respiratory tract infection bacterial.</footnote></td><td styleCode="Rrule">57</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0</td><td styleCode="Rrule">42</td><td styleCode="Rrule">3.4</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pneumonia<footnote>Pneumonia includes atypical pneumonia, bronchopulmonary aspergillosis, pneumonia, pneumonia haemophilus, pneumonia influenzal, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, candida pneumonia, pneumonia bacterial, haemophilus infection, lung infection, pneumonia fungal, and pneumocystis jirovecii pneumonia.</footnote></td><td styleCode="Rrule">31</td><td styleCode="Rrule">22</td><td styleCode="Rrule">3.3</td><td styleCode="Rrule">23</td><td styleCode="Rrule">16</td><td styleCode="Rrule">2.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="bold">Blood and lymphatic system disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Febrile neutropenia</td><td styleCode="Rrule">12</td><td styleCode="Rrule">11</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">2</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspnea<footnote>Dyspnea includes dyspnea, dyspnea exertional, and dyspnea at rest.</footnote></td><td styleCode="Rrule">17</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0</td><td styleCode="Rrule">12</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">26</td><td styleCode="Rrule">2</td><td styleCode="Rrule">0</td><td styleCode="Rrule">19</td><td styleCode="Rrule">0.7</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">12</td><td styleCode="Rrule">1.3</td><td styleCode="Rrule">0</td><td styleCode="Rrule">3.4</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="90%" ID="table5"><caption>Table 5: Hematology Laboratory Abnormalities During the Treatment Period in Patients Receiving Isa-Pd versus Pd in ICARIA-MM </caption><col width="25%" align="left" valign="top"/><col width="12%" align="center" valign="top"/><col width="13%" align="center" valign="top"/><col width="12%" align="center" valign="top"/><col width="13%" align="center" valign="top"/><col width="12%" align="center" valign="top"/><col width="13%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Laboratory Parameter</th><th styleCode="Rrule" colspan="3">SARCLISA + Pomalidomide + Dexamethasone (Isa-Pd)</th><th styleCode="Rrule" colspan="3">Pomalidomide + Dexamethasone (Pd)</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Botrule Rrule" colspan="3">(N=152)</th><th styleCode="Botrule Rrule" colspan="3">(N=149)</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3 (%)</th><th styleCode="Rrule">Grade 4 (%)</th><th styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3 (%)</th><th styleCode="Rrule">Grade 4 (%)</th></tr></thead><tfoot><tr><td align="left" valign="top" colspan="7">The denominator used to calculate the percentages was based on the safety population.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hemoglobin decreased </td><td styleCode="Rrule">99</td><td styleCode="Rrule">32</td><td styleCode="Rrule">0</td><td styleCode="Rrule">97</td><td styleCode="Rrule">28</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutrophils decreased</td><td styleCode="Rrule">96</td><td styleCode="Rrule">24</td><td styleCode="Rrule">61</td><td styleCode="Rrule">92</td><td styleCode="Rrule">38</td><td styleCode="Rrule">31</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Lymphocytes decreased</td><td styleCode="Rrule">92</td><td styleCode="Rrule">42</td><td styleCode="Rrule">13</td><td styleCode="Rrule">92</td><td styleCode="Rrule">35</td><td styleCode="Rrule">8</td></tr><tr><td styleCode="Lrule Rrule">Platelets decreased</td><td styleCode="Rrule">84</td><td styleCode="Rrule">14</td><td styleCode="Rrule">16</td><td styleCode="Rrule">79</td><td styleCode="Rrule">9</td><td styleCode="Rrule">15</td></tr></tbody></table>

<table width="90%" ID="table6"><caption>Table 6: Adverse Reactions (&#x2265;10%) in Patients Receiving SARCLISA, Carfilzomib, and Dexamethasone with a Difference Between Arms of &#x2265;5% Compared to Control Arm in IKEMA</caption><col width="25%" align="left" valign="top"/><col width="12%" align="center" valign="top"/><col width="13%" align="center" valign="top"/><col width="12%" align="center" valign="top"/><col width="13%" align="center" valign="top"/><col width="12%" align="center" valign="top"/><col width="13%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" valign="top">Adverse Reactions</th><th styleCode="Rrule" valign="top" colspan="3">SARCLISA + Carfilzomib + Dexamethasone (Isa-Kd)</th><th styleCode="Rrule" valign="top" colspan="3">Carfilzomib + Dexamethasone (Kd)</th></tr><tr><th styleCode="Lrule Rrule" valign="top"/><th styleCode="Botrule Rrule" valign="bottom" colspan="3">(N=177)</th><th styleCode="Botrule Rrule" valign="bottom" colspan="3">(N=122)</th></tr><tr><th styleCode="Lrule Rrule" valign="top"/><th styleCode="Rrule" valign="top">All Grades (%)</th><th styleCode="Rrule" valign="top">Grade 3 (%)</th><th styleCode="Rrule" valign="top">Grade 4 (%)</th><th styleCode="Rrule" valign="top">All Grades (%)</th><th styleCode="Rrule" valign="top">Grade 3 (%)</th><th styleCode="Rrule" valign="top">Grade 4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td align="left" valign="top" colspan="7" styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administration site conditions</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Infusion-related reaction<footnote>Infusion-related reaction includes infusion-related reaction, cytokine release syndrome, and hypersensitivity.</footnote></td><td styleCode="Rrule">46</td><td styleCode="Rrule">0.6</td><td styleCode="Rrule">0</td><td styleCode="Rrule">3.3</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue<footnote>Fatigue includes fatigue and asthenia.</footnote></td><td styleCode="Rrule">42</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0</td><td styleCode="Rrule">32</td><td styleCode="Rrule">3.3</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="bold">Infections</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection<footnote>Upper respiratory tract infection includes acute sinusitis, chronic sinusitis, H1N1 influenza, H3N2 influenza, influenza, laryngitis, laryngitis viral, nasal herpes, nasopharyngitis, pharyngitis, pharyngotonsillitis, respiratory syncytial virus infection, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, tracheitis, upper respiratory tract infection, viral rhinitis, respiratory tract infection, respiratory tract infection viral, influenza like illness, parainfluenzae virus infection, respiratory tract infection bacterial, and viral upper respiratory tract infection. </footnote></td><td styleCode="Rrule">67</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0</td><td styleCode="Rrule">57</td><td styleCode="Rrule">7</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pneumonia<footnote>Pneumonia includes atypical pneumonia, lower respiratory tract infection, lower respiratory tract infection viral, pneumocystis jirovecii pneumonia, pneumonia, pneumonia influenzal, pneumonia legionella, pneumonia pneumococcal, pneumonia respiratory syncytial viral, pneumonia streptococcal, pneumonia viral, pulmonary sepsis, and pulmonary tuberculosis.</footnote></td><td styleCode="Rrule">36</td><td styleCode="Rrule">19</td><td styleCode="Rrule">3.4</td><td styleCode="Rrule">30</td><td styleCode="Rrule">15</td><td styleCode="Rrule">2.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Bronchitis<footnote>Bronchitis includes bronchitis, bronchitis viral, respiratory syncytial virus bronchitis, bronchitis chronic, and tracheobronchitis.</footnote></td><td styleCode="Rrule">24</td><td styleCode="Rrule">2.3</td><td styleCode="Rrule">0</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="bold">Vascular disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension<footnote>Hypertension includes hypertension, blood pressure increased, and hypertensive crisis.</footnote></td><td styleCode="Rrule">37</td><td styleCode="Rrule">20</td><td styleCode="Rrule">0.6</td><td styleCode="Rrule">32</td><td styleCode="Rrule">18</td><td styleCode="Rrule">1.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspnea<footnote>Dyspnea includes dyspnea and dyspnea exertional.</footnote></td><td styleCode="Rrule">29</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0</td><td styleCode="Rrule">24</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough<footnote>Cough includes cough, productive cough, and allergic cough.</footnote></td><td styleCode="Rrule">23</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">36</td><td styleCode="Rrule">2.8</td><td styleCode="Rrule">0</td><td styleCode="Rrule">29</td><td styleCode="Rrule">2.5</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">15</td><td styleCode="Rrule">1.1</td><td styleCode="Rrule">0</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0.8</td><td styleCode="Rrule">0</td></tr></tbody></table>