ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Cardiac Toxicities [see Warnings and Precautions (5.1)] Acute Renal Failure [see Warnings and Precautions (5.2)] Tumor Lysis Syndrome [see Warnings and Precautions (5.3)] Pulmonary Toxicity [see Warnings and Precautions (5.4)] Pulmonary Hypertension [see Warnings and Precautions (5.5)] Dyspnea [see Warnings and Precautions (5.6)] Hypertension [see Warnings and Precautions (5.7)] Venous Thrombosis [see Warnings and Precautions (5.8)] Infusion-Related Reactions [see Warnings and Precautions (5.9)] Hemorrhage [see Warnings and Precautions (5.10)] Thrombocytopenia [see Warnings and Precautions (5.11)] Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions (5.12)] Thrombotic Microangiopathy [see Warnings and Precautions (5.13)] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.14)] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.15)] Cardiac Toxicities [see Warnings and Precautions (5.1)] Acute Renal Failure [see Warnings and Precautions (5.2)] Tumor Lysis Syndrome [see Warnings and Precautions (5.3)] Pulmonary Toxicity [see Warnings and Precautions (5.4)] Pulmonary Hypertension [see Warnings and Precautions (5.5)] Dyspnea [see Warnings and Precautions (5.6)] Hypertension [see Warnings and Precautions (5.7)] Venous Thrombosis [see Warnings and Precautions (5.8)] Infusion-Related Reactions [see Warnings and Precautions (5.9)] Hemorrhage [see Warnings and Precautions (5.10)] Thrombocytopenia [see Warnings and Precautions (5.11)] Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions (5.12)] Thrombotic Microangiopathy [see Warnings and Precautions (5.13)] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.14)] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.15)] The most common adverse reactions occurring in at least 20% of patients treated with Kyprolis in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral. (6) The most common adverse reactions occurring in at least 20% of patients treated with Kyprolis in the combination therapy trials: anemia, diarrhea, fatigue, hypertension, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, dyspnea, and insomnia. (6)To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. The most common adverse reactions occurring in at least 20% of patients treated with Kyprolis in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral. (6). The most common adverse reactions occurring in at least 20% of patients treated with Kyprolis in the combination therapy trials: anemia, diarrhea, fatigue, hypertension, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, dyspnea, and insomnia. (6). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety population described in the Warnings and Precautions reflect exposure to Kyprolis in 1789 patients administered in combination with other drugs in ASPIRE, ENDEAVOR, A.R.R.O.W., and CANDOR. The most common adverse reactions occurring in at least 20% of patients who received Kyprolis in combination were anemia, diarrhea, fatigue, hypertension, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, dyspnea, and insomnia.. Kyprolis in Combination with Lenalidomide and Dexamethasone The safety of Kyprolis 20/27 mg/m2 twice weekly in combination with lenalidomide and dexamethasone (KRd) was evaluated in ASPIRE [see Clinical Studies (14.1)]. The median number of cycles initiated was 22 cycles for the KRd arm and 14 cycles for the Rd arm.Deaths due to adverse reactions within 30 days of the last dose of any therapy in the KRd arm occurred in 45/392 (12%) patients compared with 42/389 (11%) patients who died due to adverse reactions within 30 days of the last dose of any Rd therapy. The most frequent cause of deaths occurring in patients (%) in the two arms (KRd versus Rd) included infection 12 (3%) versus 11 (3%), cardiac 10 (3%) versus (2%), and other adverse reactions 23 (6%) versus 22 (6%).Serious adverse reactions were reported in 65% of the patients in the KRd arm and 57% of the patients in the Rd arm. The most frequent serious adverse reactions reported in the KRd arm as compared with the Rd arm were pneumonia (17% versus 13%), respiratory tract infection (4% versus 2%), pyrexia (4% versus 3%), and pulmonary embolism (3% versus 2%).Discontinuation due to any adverse reaction occurred in 33% in the KRd arm versus 30% in the Rd arm. Adverse reactions leading to discontinuation of Kyprolis occurred in 12% of patients and the most common reactions included pneumonia (1%), myocardial infarction (0.8%), and upper respiratory tract infection (0.8%). The incidence of cardiac failure events was 7% in the KRd arm versus 4% in the Rd arm.Table 12 summarizes the adverse reactions in the first 12 cycles in ASPIRE.Table 12: Adverse Reactions (>= 10%) Occurring in Cycles 1-12 in Patients Who Received KRd (20/27 mg/m2 Regimen) in ASPIREAdverse ReactionsKRd(N 392)n (%)Rd(N 389)n (%)Any Grade>= Grade 3Any Grade>= Grade 3KRd Kyprolis, lenalidomide, and dexamethasone; Rd lenalidomide and dexamethasoneBlood and Lymphatic System Disorders Anemia138 (35)53 (14)127 (33)47 (12) Neutropenia124 (32)104 (27)115 (30)89 (23) Thrombocytopenia100 (26)58 (15)75 (19)39 (10)Gastrointestinal Disorders Diarrhea119 (30)8 (2)106 (27)12 (3) Constipation68 (17)0 (0)55 (14)1 (0) Nausea63 (16)1 (0)43 (11)3 (1)General Disorders and Administration Site Conditions Fatigue113 (29)23 (6)107 (28)20 (5) Pyrexia93 (24)5 (1)64 (17)1 (0) Edema peripheral59 (15)3 (1)48 (12)2 (1) Asthenia54 (14)11 (3)49 (13)7 (2)Infections Upper respiratory tract infection87 (22)7 (2)54 (14)4 (1) Bronchitis55 (14)5 (1)40 (10)2 (1) Viral upper respiratory tract infection55 (14)0 (0)44 (11)0 (0) PneumoniaPneumonia includes pneumonia and bronchopneumonia. 54 (14)35 (9)43 (11)27 (7)Metabolism and Nutrition Disorders Hypokalemia78 (20)22 (6)35 (9)12 (3) Hypocalcemia55 (14)10 (3)39 (10)5 (1) Hyperglycemia43 (11)18 (5)33 (9)15 (4)Musculoskeletal and Connective Tissue Disorders Muscle spasms92 (24)3 (1)75 (19)3 (1) Back pain41 (11)4 (1)54 (14)6 (2)Nervous System Disorders Peripheral neuropathiesPeripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. 43 (11)7 (2)39 (10)4 (1)Psychiatric Disorders Insomnia64 (16)6 (2)51 (13)8 (2)Respiratory, Thoracic and Mediastinal Disorders CoughCough includes cough and productive cough. 93 (24)2 (1)54 (14)0 (0) DyspneaDyspnea includes dyspnea and dyspnea exertional. 71 (18)8 (2)61 (16)6 (2)Skin and Subcutaneous Tissue Disorders Rash45 (12)5 (1)54 (14)5 (1)Vascular Disorders Embolic and thrombotic eventsEmbolic and thrombotic events, venous includes deep vein thrombosis, pulmonary embolism, thrombophlebitis superficial, thrombophlebitis, venous thrombosis limb, post thrombotic syndrome, venous thrombosis. 49 (13)16 (4)23 (6)9 (2) HypertensionHypertension includes hypertension, hypertensive crisis. 41 (11)12 (3)15 (4)4 (1)There were 274 (70%) patients in the KRd arm who received treatment beyond Cycle 12. There were no new clinically relevant adverse reactions that emerged in the later treatment cycles.. Adverse Reactions Occurring at Frequency of 10%Blood and lymphatic system disorders: febrile neutropenia, lymphopeniaCardiac disorders: cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, pericardial effusionEar and labyrinth disorders: deafness, tinnitusEye disorders: cataract, vision blurredGastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothacheGeneral disorders and administration site conditions: chills, infusion site reaction, multi-organ failure, painInfections: clostridium difficile colitis, influenza, lung infection, rhinitis, sepsis, urinary tract infection, viral infectionMetabolism and nutrition disorders: dehydration, hyperkalemia, hyperuricemia, hypoalbuminemia, hyponatremia, tumor lysis syndromeMusculoskeletal and connective tissue disorders: muscular weakness, myalgiaNervous system disorders: hypoesthesia, intracranial hemorrhage, paresthesiaPsychiatric disorders: anxiety, deliriumRenal and urinary disorders: renal failure, renal failure acute, renal impairmentRespiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary embolism, pulmonary edema, pulmonary hemorrhageSkin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritusVascular disorders: deep vein thrombosis, hemorrhage, hypotensionGrade and higher adverse reactions that occurred during Cycles 1-12 with substantial difference (>= 2%) between the two arms were neutropenia, thrombocytopenia, hypokalemia, and hypophosphatemia.Table 13 describes Grade 3-4 laboratory abnormalities reported in ASPIRE.Table 13: Grade 3-4 Laboratory Abnormalities (>= 10%) in Cycles 1-12 in Patients Who Received KRd (20/27 mg/m2 Regimen) in ASPIRELaboratory AbnormalityKRd(N 392)n (%)Rd(N 389)n (%)KRd Kyprolis, lenalidomide, and dexamethasone; Rd lenalidomide and dexamethasoneDecreased lymphocytes182 (46)119 (31)Decreased absolute neutrophil count152 (39)141 (36)Decreased phosphorus122 (31)106 (27)Decreased platelets101 (26)59 (15)Decreased total white blood cell count97 (25)71 (18)Decreased hemoglobin58 (15)68 (18)Increased glucose53 (14)30 (8)Decreased potassium41 (11)23 (6). Blood and lymphatic system disorders: febrile neutropenia, lymphopenia. Cardiac disorders: cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, pericardial effusion. Ear and labyrinth disorders: deafness, tinnitus. Eye disorders: cataract, vision blurred. Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache. General disorders and administration site conditions: chills, infusion site reaction, multi-organ failure, pain. Infections: clostridium difficile colitis, influenza, lung infection, rhinitis, sepsis, urinary tract infection, viral infection. Metabolism and nutrition disorders: dehydration, hyperkalemia, hyperuricemia, hypoalbuminemia, hyponatremia, tumor lysis syndrome. Musculoskeletal and connective tissue disorders: muscular weakness, myalgia. Nervous system disorders: hypoesthesia, intracranial hemorrhage, paresthesia. Psychiatric disorders: anxiety, delirium. Renal and urinary disorders: renal failure, renal failure acute, renal impairment. Respiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary embolism, pulmonary edema, pulmonary hemorrhage. Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus. Vascular disorders: deep vein thrombosis, hemorrhage, hypotension. Kyprolis in Combination with Dexamethasone The safety of Kyprolis in combination with dexamethasone was evaluated in two open-label, randomized trials (ENDEAVOR and A.R.R.O.W.).. ENDEAVORThe safety of Kyprolis 20/56 mg/m2 twice weekly in combination with dexamethasone (Kd) was evaluated in ENDEAVOR [see Clinical Studies (14.2)]. Patients received treatment for median duration of 48 weeks in the Kd arm and 27 weeks in the bortezomib/dexamethasone (Vd) arm.Deaths due to adverse reactions within 30 days of last study treatment occurred in 32/463 (7%) patients in the Kd arm and 21/456 (5%) patients in the Vd arm. The causes of death occurring in patients (%) in the two arms (Kd versus Vd) included cardiac (1%) versus (1%), infections (2%) versus (2%), disease progression (2%) versus (1%), pulmonary (1%) versus (< 1%), renal (< 1%) versus (0%), and other adverse reactions (2%) versus (< 1%).Serious adverse reactions were reported in 59% of the patients in the Kd arm and 40% of the patients in the Vd arm. In both arms, pneumonia was the most frequently reported serious adverse reaction (8% versus 9%).Discontinuation due to any adverse reaction occurred in 29% in the Kd arm versus 26% in the Vd arm. The most frequent adverse reaction leading to discontinuation was cardiac failure in the Kd arm (n 8, 2%) and peripheral neuropathy in the Vd arm (n 22, 5%). The incidence of cardiac failure events was 11% in the Kd arm versus 3% in the Vd arm.Adverse reactions in the first months of therapy that occurred at rate of 10% or greater in the Kd arm are presented in Table 14.Table 14: Adverse Reactions (>= 10% Occurring in Months 1-6 in Patients Who Received Kd (20/56 mg/m2 Regimen) in ENDEAVORAdverse Reactions Kd(N 463)n (%)Vd(N 456)n (%)Any GradeGrade >= 3Any GradeGrade >= 3Kd Kyprolis and dexamethasone; Vd bortezomib and dexamethasoneBlood and Lymphatic System Disorders Anemia161 (35)57 (12)112 (25)43 (9) ThrombocytopeniaThrombocytopenia includes platelet count decreased and thrombocytopenia. 125 (27)45 (10)112 (25)64 (14)Gastrointestinal Disorders Diarrhea117 (25)14 (3)149 (33)27 (6) Nausea70 (15)4 (1)68 (15)3 (1) Constipation60 (13)1 (0)113 (25)6 (1) Vomiting45 (10)5 (1)33 (7)3 (1)General Disorders and Administration Site Conditions Fatigue116 (25)14 (3)126 (28)25 (6) Pyrexia102 (22)9 (2)52 (11)3 (1) Asthenia73 (16)9 (2)65 (14)13 (3) Peripheral edema62 (13)3 (1)62 (14)3 (1)Infections Upper respiratory tract infection67 (15)4 (1)55 (12)3 (1) Bronchitis54 (12)5 (1)25 (6)2 (0)Musculoskeletal and Connective Tissue Disorders Muscle spasms70 (15)1 (0)23 (5)3 (1) Back pain64 (14)8 (2)61 (13)10 (2)Nervous System Disorders Headache67 (15)4 (1)39 (9)2 (0) Peripheral neuropathiesPeripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. See Clinical Studies (14.2). 56 (12)7 (2)170 (37)23 (5)Psychiatric Disorders Insomnia105 (23)5 (1)116 (25)10 (2)Respiratory, Thoracic and Mediastinal Disorders DyspneaDyspnea includes dyspnea and dyspnea exertional. 128 (28)23 (5)69 (15)8 (2) CoughCough includes cough and productive cough. 97 (21)0 (0)61 (13)2 (0)Vascular Disorders HypertensionHypertension includes hypertension, hypertensive crisis, and hypertensive emergency. 83 (18)30 (7)33 (7)12 (3)The event rate of >= Grade peripheral neuropathy in the Kd arm was 7% (95% CI: 5, 9) versus 35% (95% CI: 31, 39) in the Vd arm.. Adverse Reactions Occurring at Frequency of 10%Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy, thrombotic thrombocytopenic purpuraCardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, tachycardiaEar and labyrinth disorders: tinnitusEye disorders: cataract, vision blurredGastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothacheGeneral disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, painHepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemiaImmune system disorders: drug hypersensitivityInfections: bronchopneumonia, gastroenteritis, influenza, lung infection, nasopharyngitis, pneumonia, rhinitis, sepsis, urinary tract infection, viral infectionMetabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndromeMusculoskeletal and connective tissue disorders: muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgiaNervous system disorders: cerebrovascular accident, dizziness, hypoesthesia, paresthesia, posterior reversible encephalopathy syndromePsychiatric disorders: anxietyRenal and urinary disorders: renal failure, renal failure acute, renal impairmentRespiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary embolism, pulmonary edema, pulmonary hypertension, wheezingSkin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rashVascular disorders: deep vein thrombosis, flushing, hypotensionTable 15 describes Grade 3-4 laboratory abnormalities reported at rate of >= 10% in the Kd arm.Table 15: Grade 3-4 Laboratory Abnormalities (>= 10%) in Months 1-6 in Patients Who Received Kd (20/56 mg/m2 Regimen) in ENDEAVORLaboratory AbnormalityKd(N 463)n (%)Vd(N 456)n (%)Kd Kyprolis and dexamethasone; Vd bortezomib and dexamethasoneDecreased lymphocytes249 (54)180 (40)Increased uric acid244 (53)198 (43)Decreased hemoglobin79 (17)68 (15)Decreased platelets85 (18)77 (17)Decreased phosphorus74 (16)61 (13)Decreased creatinine clearanceCalculated using the Cockcroft-Gault formula. 65 (14)49 (11)Increased potassium55 (12)21 (5). Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy, thrombotic thrombocytopenic purpura. Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, tachycardia. Ear and labyrinth disorders: tinnitus. Eye disorders: cataract, vision blurred. Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache. General disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, pain. Hepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemia. Immune system disorders: drug hypersensitivity. Infections: bronchopneumonia, gastroenteritis, influenza, lung infection, nasopharyngitis, pneumonia, rhinitis, sepsis, urinary tract infection, viral infection. Metabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome. Musculoskeletal and connective tissue disorders: muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia. Nervous system disorders: cerebrovascular accident, dizziness, hypoesthesia, paresthesia, posterior reversible encephalopathy syndrome. Psychiatric disorders: anxiety. Renal and urinary disorders: renal failure, renal failure acute, renal impairment. Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary embolism, pulmonary edema, pulmonary hypertension, wheezing. Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash. Vascular disorders: deep vein thrombosis, flushing, hypotension. A.R.R.O.W.The safety of Kyprolis in combination with dexamethasone was evaluated in A.R.R.O.W. [see Clinical Studies (14.2)]. Patients received treatment for median duration of 38 weeks in the Kd 20/70 mg/m2 arm once weekly and 29.1 weeks in the Kd 20/27 mg/m2 twice weekly arm. The safety profile for the once weekly Kd 20/70 mg/m2 regimen was similar to the twice weekly Kd 20/27 mg/m2 regimen.Deaths due to adverse reactions within 30 days of last study treatment occurred in 22/238 (9%) patients in the Kd 20/70 mg/m2 arm and 18/235 (8%) patients in the Kd 20/27 mg/m2 arm. The most frequent fatal adverse reactions occurring in patients (%) in the two arms (once weekly Kd 20/70 mg/m2 versus twice weekly Kd 20/27 mg/m2) were sepsis (< 1%) versus (< 1%), septic shock (< 1%) versus (< 1%), and infection (< 1%) versus (0%).Serious adverse reactions were reported in 43% of the patients in the Kd 20/70 mg/m2 arm and 41% of the patients in the Kd 20/27 mg/m2 arm. In both arms, pneumonia was the most frequently reported serious adverse reaction (8% versus 7%).Discontinuation due to any adverse reaction occurred in 13% in the Kd 20/70 mg/m2 arm versus 12% in the Kd 20/27 mg/m2 arm. The most frequent adverse reaction leading to discontinuation was acute kidney injury (2% versus 2%). The incidence of cardiac failure events was 3.8% in the once weekly Kd 20/70 mg/m2 arm versus 5.1% in the twice weekly Kd 20/27 mg/m2 arm.Adverse reactions that occurred at rate of 10% or greater in either Kd arm are presented in Table 16.Table 16: Adverse Reactions in Patients Who Received Kd (>= 10% in either Kd Arm) in A.R.R.O.W.Adverse Reactions Once weekly Kd 20/70 mg/m2 (N 238)n (%)Twice weekly Kd 20/27 mg/m2 (N 235)n (%)Any Grade Grade >= 3Any Grade Grade >= 3Kd Kyprolis and dexamethasoneBlood and Lymphatic System Disorders AnemiaAnemia includes anemia, hematocrit decreased, and hemoglobin decreased. 64 (27)42 (18)76 (32)42 (18) ThrombocytopeniaThrombocytopenia includes platelet count decreased and thrombocytopenia. 53 (22)26 (11)41 (17)27 (12) NeutropeniaNeutropenia includes neutrophil count decreased and neutropenia. 30 (13)21 (9)27 (12)17 (7)Gastrointestinal Disorders Diarrhea44 (19)2 (1)47 (20)3 (1) Nausea34 (14)1 (< 1)26 (11)2 (1)General Disorders and Administration Site Conditions Pyrexia55 (23)2 (1)38 (16)4 (2) Fatigue48 (20)11 (5)47 (20)5 (2) Asthenia24 (10)3 (1)25 (11)2 (1) Peripheral edema18 (8)0 (0)25 (11)2 (1)Infections Respiratory tract infectionRespiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection, and viral upper respiratory tract infection. 70 (29)7 (3)79 (34)7 (3) Pneumonia28 (12)24 (10)20 (9)16 (7) Bronchitis27 (11)2 (1)25 (11)5 (2)Musculoskeletal and Connective Tissue Disorders Back pain28 (12)2 (1)28 (12)4 (2)Nervous System Disorders Headache25 (11)1 (< 1)23 (10)1 (< 1)Psychiatric Disorders Insomnia35 (15)2 (1)47 (20)0 (0)Respiratory, Thoracic and Mediastinal Disorders CoughCough includes cough and productive cough. 37 (16)2 (1)31 (13)0 (0) DyspneaDyspnea includes dyspnea and dyspnea exertional. 28 (12)1 (< 1)26 (11)2 (1)Vascular Disorders HypertensionHypertension includes hypertension and hypertensive crisis. 51 (21)13 (6)48 (20)12 (5). Adverse Reactions Occurring at Frequency of 10%Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathyCardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, pericardial effusion, tachycardiaEar and labyrinth disorders: tinnitusEye disorders: cataract, vision blurredGastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, toothache, vomitingGeneral disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, painHepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemiaInfections: clostridium difficile colitis, gastroenteritis, influenza, lung infection, nasopharyngitis, rhinitis, sepsis, septic shock, urinary tract infection, viral infectionMetabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndromeMusculoskeletal and connective tissue disorders: muscle spasms, muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgiaNervous system disorders: cerebrovascular accident, dizziness, paresthesia, peripheral neuropathyPsychiatric disorders: anxiety, deliriumRenal and urinary disorders: acute kidney injury, renal failure, renal impairmentRespiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary hemorrhage, pulmonary embolism, pulmonary hypertension, pulmonary edema, wheezingSkin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rashVascular disorders: deep vein thrombosis, flushing, hypotension. Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy. Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, pericardial effusion, tachycardia. Ear and labyrinth disorders: tinnitus. Eye disorders: cataract, vision blurred. Gastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, toothache, vomiting. General disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, pain. Hepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemia. Infections: clostridium difficile colitis, gastroenteritis, influenza, lung infection, nasopharyngitis, rhinitis, sepsis, septic shock, urinary tract infection, viral infection. Metabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome. Musculoskeletal and connective tissue disorders: muscle spasms, muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia. Nervous system disorders: cerebrovascular accident, dizziness, paresthesia, peripheral neuropathy. Psychiatric disorders: anxiety, delirium. Renal and urinary disorders: acute kidney injury, renal failure, renal impairment. Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary hemorrhage, pulmonary embolism, pulmonary hypertension, pulmonary edema, wheezing. Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash. Vascular disorders: deep vein thrombosis, flushing, hypotension. Kyprolis in Combination with Intravenous Daratumumab and Dexamethasone The safety of Kyprolis in combination with intravenous daratumumab and dexamethasone was evaluated in two trials (CANDOR and EQUULEUS).. CANDORThe safety of Kyprolis 20/56 mg/m2 twice weekly in combination with intravenous daratumumab and dexamethasone (DKd) was evaluated in CANDOR [see Clinical Studies (14.3)]. Patients received Kyprolis for median duration of 58 weeks in the DKd arm and 40 weeks in the Kd arm.Serious adverse reactions were reported in 56% of the patients in the DKd arm and 46% of the patients in the Kd arm. The most frequent serious adverse reactions reported in the DKd arm as compared with the Kd arm were pneumonia (14% versus 9%), pyrexia (4.2% versus 2.0%), influenza (3.9% versus 1.3%), sepsis (3.9% versus 1.3%), anemia (2.3% versus 0.7%), bronchitis (1.9% versus 0%) and diarrhea (1.6% versus 0%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 10% of 308 patients in the DKd arm compared with 5% of 153 patients in the Kd arm. The most frequent fatal adverse reaction (DKd versus Kd) was infection 4.5% versus 2.6%.Permanent discontinuation due to an adverse reaction in patients who received Kyprolis occurred in 21% of patients in the DKd arm versus 22% in the Kd arm. The most frequent adverse reactions leading to discontinuation of Kyprolis were cardiac failure (1.9%) and fatigue (1.9%) in the DKd arm and cardiac failure (2.0%), hypertension (2.0%) and acute kidney injury (2.0%) in the Kd arm. Interruption of Kyprolis due to adverse reactions occurred in 71% of patients in DKd arm versus 63% in the Kd arm. Dose reduction of Kyprolis due to adverse reactions occurred in 25% of patients in DKd arm versus 20% in the Kd arm.Infusion-related reactions that occurred following the first Kyprolis dose was 13% in the DKd arm versus 1% in the Kd arm. Table 17 summarizes the adverse reactions in CANDOR.Table 17: Adverse Reactions (>= 15%) in Patients Who Received either DKd or Kd (20/56 mg/m2 Regimen) in CANDORAdverse ReactionsTwice weekly DKd(N 308)Twice weekly Kd(N 153)All Grades (%)Grade or (%)All Grades (%)Grade or (%)DKd Kyprolis, daratumumab, and dexamethasone; Kd Kyprolis and dexamethasoneGeneral Disorders and Administration Site Conditions Infusion-related reactionThe incidence of infusion related reactions is based on group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within day after DKd or Kd administration. 4112285 FatigueFatigue includes fatigue and asthenia. 3211288 Pyrexia201.9150.7Infections Respiratory tract infectionRespiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. 40Includes fatal adverse reactions. 7293.3 Pneumonia18 13129 Bronchitis172.6121.3Blood and Lymphatic System Disorders ThrombocytopeniaThrombocytopenia includes platelet count decreased and thrombocytopenia. 37253016 AnemiaAnemia includes anemia, hematocrit decreased and hemoglobin decreased. 33173114Gastrointestinal Disorders Diarrhea323.9140.7 Nausea180130.7Vascular Disorders Hypertension31182813Respiratory, Thoracic and Mediastinal Disorders CoughCough includes productive cough and cough. 210210 Dyspnea203.9222.6Psychiatric Disorders Insomnia183.9112.0Musculoskeletal and Connective Tissue Disorders Back pain161.9101.3. Adverse Reactions Occurring at Frequency of 15%Blood and lymphatic system disorders: febrile neutropenia, thrombotic thrombocytopenic purpuraCardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiomyopathy, myocardial infarction, myocardial ischemia, tachycardiaEye disorders: cataractGastrointestinal disorders: abdominal pain, gastrointestinal hemorrhageGeneral disorders and administration site conditions: chest pain, malaiseInfections: gastroenteritis, influenza, lung infection, nasopharyngitis, sepsis, septic shock, urinary tract infection, viral infectionInvestigations: alanine aminotransferase increased, blood creatinine increased, C-reactive protein increased, ejection fraction decreasedMetabolism and nutrition disorders: dehydration, hyperglycemia, hyperkalemia, hypokalemia, hyponatremia, tumor lysis syndromeMusculoskeletal and connective tissue disorders: pain in extremityNervous system disorders: cerebrovascular accident, intracranial hemorrhage, posterior reversible encephalopathy syndrome, peripheral neuropathyPsychiatric disorders: anxietyRenal and urinary disorders: acute kidney injury, renal failure, renal impairmentRespiratory, thoracic and mediastinal disorders: acute respiratory failure, epistaxis, interstitial lung disease, pneumonitis, pulmonary embolism, pulmonary hypertension, pulmonary edemaSkin and subcutaneous tissue disorders: rashVascular disorders: deep vein thrombosis, hypertensive crisis. Blood and lymphatic system disorders: febrile neutropenia, thrombotic thrombocytopenic purpura. Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiomyopathy, myocardial infarction, myocardial ischemia, tachycardia. Eye disorders: cataract. Gastrointestinal disorders: abdominal pain, gastrointestinal hemorrhage. General disorders and administration site conditions: chest pain, malaise. Infections: gastroenteritis, influenza, lung infection, nasopharyngitis, sepsis, septic shock, urinary tract infection, viral infection. Investigations: alanine aminotransferase increased, blood creatinine increased, C-reactive protein increased, ejection fraction decreased. Metabolism and nutrition disorders: dehydration, hyperglycemia, hyperkalemia, hypokalemia, hyponatremia, tumor lysis syndrome. Musculoskeletal and connective tissue disorders: pain in extremity. Nervous system disorders: cerebrovascular accident, intracranial hemorrhage, posterior reversible encephalopathy syndrome, peripheral neuropathy. Psychiatric disorders: anxiety. Renal and urinary disorders: acute kidney injury, renal failure, renal impairment. Respiratory, thoracic and mediastinal disorders: acute respiratory failure, epistaxis, interstitial lung disease, pneumonitis, pulmonary embolism, pulmonary hypertension, pulmonary edema. Skin and subcutaneous tissue disorders: rash. Vascular disorders: deep vein thrombosis, hypertensive crisis. EQUULEUSThe safety of Kyprolis 20/70 mg/m2 once weekly in combination with intravenous daratumumab and dexamethasone (DKd) was evaluated in EQUULEUS [see Clinical Studies (14.3)]. Patients received Kyprolis for median duration of 66 weeks.Serious adverse reactions were reported in 48% of patients. The most frequent serious adverse reactions reported were pneumonia (4.7%), upper respiratory tract infection (4.7%), basal cell carcinoma (4.7%), influenza (3.5%), general physical health deterioration (3.5%) and hypercalcemia (3.5%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 3.5% of patients who died of general physical health deterioration, multi-organ failure secondary to pulmonary aspergillosis, and disease progression.Discontinuation of Kyprolis occurred in 19% of patients. The most frequent adverse reaction leading to discontinuation was asthenia (2%). Interruption of Kyprolis due to adverse reactions occurred in 77% of patients. Dose reduction of Kyprolis due to adverse reactions occurred in 31% of patients in DKd.Infusion-related reactions that occurred following the first Kyprolis dose was 11%. Pulmonary hypertension adverse reactions were reported in 4.7% of patients in EQUULEUS.Table 18 summarizes the adverse reactions in EQUULEUS.Table 18: Adverse Reactions (>= 15%) in Patients Who Received DKd (20/70 mg/m2 Regimen) in EQUULEUSAdverse Reactions Once weekly DKd(N 85)All Grades(%)Grade or 4(%)DKd Kyprolis, daratumumab, and dexamethasone; Kd Kyprolis and dexamethasoneBlood and Lymphatic System Disorders ThrombocytopeniaThrombocytopenia includes platelet count decreased and thrombocytopenia. 6832 AnemiaAnemia includes anemia, hematocrit decreased and hemoglobin decreased. 5221 NeutropeniaNeutropenia includes neutrophil count decreased and neutropenia. 3121 LymphopeniaLymphopenia includes lymphocyte count decreased and lymphopenia. 2925General Disorders and Administration Site Conditions FatigueFatigue includes fatigue and asthenia. 5418 Infusion-related reactionThe incidence of infusion related reactions is based on group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within day after DKd administration. 5312 Pyrexia371.2Infections Respiratory tract infectionRespiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. 533.5 Bronchitis190 Nasopharyngitis180 Influenza173.5Gastrointestinal Disorders Nausea421.2 Vomiting401.2 Diarrhea382.4 Constipation170Respiratory, Thoracic and Mediastinal Disorders Dyspnea353.5 CoughCough includes productive cough and cough. 330Vascular Disorders Hypertension3320Psychiatric Disorders Insomnia334.7Nervous System Disorders Headache271.2Musculoskeletal and Connective Tissue Disorders Back pain250 Pain in extremity150. Adverse Reactions Occurring at Frequency of 15%Blood and lymphatic system disorders: febrile neutropenia, thrombotic microangiopathyCardiac disorders: cardiac failure, myocardial ischemiaGastrointestinal disorders: abdominal painGeneral disorders and administration site conditions: multiple organ dysfunction syndromeInfections: pneumonia, sepsis, septic shockMetabolism and nutrition disorders: dehydration, hypercalcemiaRenal and urinary disorders: acute kidney injury, renal failure, renal impairmentRespiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary hypertensionVascular disorders: hypotension. Blood and lymphatic system disorders: febrile neutropenia, thrombotic microangiopathy. Cardiac disorders: cardiac failure, myocardial ischemia. Gastrointestinal disorders: abdominal pain. General disorders and administration site conditions: multiple organ dysfunction syndrome. Infections: pneumonia, sepsis, septic shock. Metabolism and nutrition disorders: dehydration, hypercalcemia. Renal and urinary disorders: acute kidney injury, renal failure, renal impairment. Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary hypertension. Vascular disorders: hypotension. Kyprolis in Combination with Subcutaneous Daratumumab and DexamethasoneThe safety of Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone was evaluated in PLEIADES [see Clinical Studies (14.3)].. PLEIADESThe safety of Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone (DKd) was evaluated in single-arm cohort of PLEIADES. Patients received Kyprolis as 30-minute IV infusion once weekly for three weeks (Days 1, 8, and 15), followed by 13-day rest period (Days 16 to 28) and continued until disease progression or unacceptable toxicity (N=66) in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Among these patients, 77% were exposed for months or longer and 27% were exposed for greater than one year.Serious adverse reactions occurred in 27% of patients who received Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Fatal adverse reactions occurred in 3% of patients who received Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone.Permanent discontinuation of Kyprolis due to an adverse reaction occurred in 6% of patients who received Kyprolis.Dosage interruptions due to an adverse reaction occurred in 46% of patients who received Kyprolis.The most common adverse reactions (>=20%) were upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea and edema peripheral.Table 19 summarizes the adverse reactions in patients who received Kyprolis with subcutaneous daratumumab and dexamethasone (DKd) in PLEIADES.Table 19: Adverse Reactions (>=10%) in Patients Who Received Kyprolis with Subcutaneous Daratumumab and Dexamethasone (DKd) in PLEIADESAdverse ReactionDKd(N=66) All Grades(%)Grade >=3(%)Infections and infestations Upper respiratory tract infectionUpper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, viral pharyngitis, and viral upper respiratory tract infection. 520 BronchitisBronchitis includes bronchitis, and bronchitis viral. 122Only Grade adverse reactions occurred. General disorders and administration site conditions FatigueFatigue includes asthenia, and fatigue. 392 Pyrexia212 Edema peripheralEdema peripheral includes generalized edema, edema peripheral, and peripheral swelling. 200Psychiatric disorders Insomnia336 Vascular disorders HypertensionHypertension includes blood pressure increased, and hypertension. 3221 Gastrointestinal disorders Diarrhea290 Nausea210 Vomiting150Respiratory, thoracic and mediastinal disorders CoughCough includes cough, and productive cough. 240 DyspneaDyspnea includes dyspnea, and dyspnea exertional. 232 Nervous system disorders Headache230 Peripheral sensory neuropathy110Musculoskeletal and connective tissue disorders Back pain172 Musculoskeletal chest pain110Clinically relevant adverse reactions in <10% of patients who received Kyprolis with subcutaneous daratumumab and dexamethasone include:Gastrointestinal disorders: abdominal pain, constipation, pancreatitisInfection and infestations: pneumonia, influenza, urinary tract infection, herpes zoster, sepsisMetabolism and nutrition disorders: hyperglycemia, decreased appetite, hypocalcemiaMusculoskeletal and connective tissue disorders: muscle spasms, arthralgiaNervous system disorders: paresthesia, dizziness, syncopeGeneral disorders and administration site conditions: injection site reaction, infusion reactions, chillsSkin and subcutaneous tissue disorders: rash, pruritusCardiac disorders: cardiac failureVascular disorders: hypotensionTable 20 summarizes the laboratory abnormalities in patients who received Kyprolis with subcutaneous daratumumab and dexamethasone in PLEIADES.Table 20: Select Laboratory Abnormalities (>=30%) Worsening from Baseline in Patients Who Received DKd in PLEIADESLaboratory AbnormalityDKdDenominator is based on the safety population treated with DKd (N=66). All Grades (%)Grades 3-4 (%)Decreased platelets8818Decreased lymphocytes8350Decreased leukocytes6818Decreased neutrophils5515Decreased hemoglobin476Decreased corrected calcium452Increased alanine aminotransferase (ALT)355. Gastrointestinal disorders: abdominal pain, constipation, pancreatitis. Infection and infestations: pneumonia, influenza, urinary tract infection, herpes zoster, sepsis. Metabolism and nutrition disorders: hyperglycemia, decreased appetite, hypocalcemia. Musculoskeletal and connective tissue disorders: muscle spasms, arthralgia. Nervous system disorders: paresthesia, dizziness, syncope. General disorders and administration site conditions: injection site reaction, infusion reactions, chills. Skin and subcutaneous tissue disorders: rash, pruritus. Cardiac disorders: cardiac failure. Vascular disorders: hypotension. Kyprolis in Patients who Received Monotherapy The safety of Kyprolis 20/27 mg/m2 as 10-minute infusion was evaluated in clinical trials consisting of 598 patients with relapsed and/or refractory myeloma [see Clinical Studies (14.2)]. Premedication with dexamethasone mg was required before each dose in Cycle and was optional for subsequent cycles. The median age was 64 years (range 32-87), and approximately 57% were male. The patients received median of (range 1-20) prior regimens. The median number of cycles initiated was (range 1-35).Deaths due to adverse reactions within 30 days of the last dose of Kyprolis occurred in 30/598 (5%) patients receiving Kyprolis monotherapy. These adverse reactions were related to cardiac disorders in 10 (2%) patients, infections in (1%) patients, renal disorders in (< 1%) patients, and other adverse reactions in (1%) patients.Serious adverse reactions were reported in 50% of patients in the pooled Kyprolis monotherapy studies (N 598). The most frequent serious adverse reactions were: pneumonia (8%), acute renal failure (5%), disease progression (4%), pyrexia (3%), hypercalcemia (3%), congestive heart failure (3%), multiple myeloma (3%), anemia (2%), and dyspnea (2%). In FOCUS, randomized trial comparing Kyprolis as single agent versus corticosteroids with optional oral cyclophosphamide for patients with relapsed and refractory multiple myeloma, mortality was higher in the patients treated with Kyprolis in comparison to the control arm in the subgroup of 48 patients >= 75 years of age. The most common cause of discontinuation due to an adverse reaction was acute renal failure (2%).Safety of Kyprolis monotherapy dosed at 20/56 mg/m2 by 30-minute infusion was evaluated in multicenter, open-label study in patients with relapsed and/or refractory multiple myeloma [see Clinical Studies (14.4)]. The patients received median of (range 1-10) prior regimens.Adverse reactions occurring with Kyprolis monotherapy are presented in Table 21.Table 21: Adverse Reactions (>= 20%) with Kyprolis MonotherapyAdverse Reactions20/56 mg/m2 by 30-minute infusion(N 24)20/27 mg/m2 by 2- to 10-minute infusion(N 598)All Gradesn (%)Grades 3-5n (%)All Gradesn (%)Grades 3-5n (%)Fatigue14 (58)2 (8)238 (40)25 (4)DyspneaDyspnea includes dyspnea and dyspnea exertional. 14 (58)2 (8)202 (34)21 (4)Pyrexia14 (58)0177 (30)11 (2)Thrombocytopenia13 (54)13 (54)220 (37)152 (25)Nausea13 (54)0211 (35)7 (1)Anemia10 (42)7 (29)291 (49)141 (24)HypertensionHypertension includes hypertension, hypertensive crisis, and hypertensive emergency. 10 (42)3 (13)90 (15)22 (4)Chills9 (38)073 (12)1 (< 1)Headache8 (33)0141 (24)7 (1)CoughCough includes cough and productive cough. (33)0134 (22)2 (< 1)Vomiting8 (33)0104 (17)4 (1)Lymphopenia8 (33)8 (33)85 (14)73 (12)Insomnia7 (29)075 (13)0Dizziness7 (29)064 (11)5 (1)Diarrhea6 (25)1 (4)160 (27)8 (1)Blood creatinine increased6 (25)1 (4)103 (17)15 (3)Peripheral edema5 (21)0118 (20)1 (< 1)Back pain5 (21)1 (4)115 (19)19 (3)Upper respiratory tract infection5 (21)1 (4)112 (19)15 (3)Decreased appetite5 (21)089 (15)2 (< 1)Muscle spasms5 (21)062 (10)2 (< 1)Chest pain5 (21)020 (3)1 (< 1). Adverse Reactions Occurring at Frequency of 20%Blood and lymphatic system disorders: febrile neutropenia, leukopenia, neutropeniaCardiac disorders: cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemiaEar and labyrinth disorders: tinnitusEye disorders: cataract, blurred visionGastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, gastrointestinal hemorrhage, toothacheGeneral disorders and administration site conditions: asthenia, infusion site reaction, multi-organ failure, painHepatobiliary disorders: hepatic failureInfections: bronchitis, bronchopneumonia, influenza, lung infection, pneumonia, nasopharyngitis, respiratory tract infection, rhinitis, sepsis, urinary tract infectionMetabolism and nutrition disorders: hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndromeMusculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, musculoskeletal chest pain, myalgia, pain in extremityNervous system disorders: hypoesthesia, intracranial hemorrhage, paresthesia, peripheral motor neuropathy, peripheral neuropathy, peripheral sensory neuropathyPsychiatric disorders: anxietyRenal and urinary disorders: acute renal failure, renal failure, renal impairmentRespiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary edema, pulmonary hemorrhageSkin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rashVascular disorders: embolic and thrombotic events, venous (including deep vein thrombosis and pulmonary embolism), hemorrhage, hypotensionGrade and higher adverse reactions occurring at an incidence of 1% include febrile neutropenia, cardiac arrest, cardiac failure congestive, pain, sepsis, urinary tract infection, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hyponatremia, hypophosphatemia, renal failure, renal failure acute, renal impairment, pulmonary edema, and hypotension.Table 22 describes Grade 3-4 laboratory abnormalities reported at rate of 10% for patients who received Kyprolis monotherapy.Table 22: Grade 3-4 Laboratory Abnormalities (> 10%) with Kyprolis MonotherapyLaboratory AbnormalityKyprolis20/56 mg/m2 (N 24)Kyprolis20/27 mg/m2 (N 598)Decreased lymphocytes15 (63)151 (25)Decreased platelets11 (46)184 (31)Decreased hemoglobin7 (29)132 (22)Decreased total white blood cell count3 (13)71 (12)Decreased sodium2 (8)69 (12)Decreased absolute neutrophil count2 (8)67 (11). Blood and lymphatic system disorders: febrile neutropenia, leukopenia, neutropenia. Cardiac disorders: cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia. Ear and labyrinth disorders: tinnitus. Eye disorders: cataract, blurred vision. Gastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, gastrointestinal hemorrhage, toothache. General disorders and administration site conditions: asthenia, infusion site reaction, multi-organ failure, pain. Hepatobiliary disorders: hepatic failure. Infections: bronchitis, bronchopneumonia, influenza, lung infection, pneumonia, nasopharyngitis, respiratory tract infection, rhinitis, sepsis, urinary tract infection. Metabolism and nutrition disorders: hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome. Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, musculoskeletal chest pain, myalgia, pain in extremity. Nervous system disorders: hypoesthesia, intracranial hemorrhage, paresthesia, peripheral motor neuropathy, peripheral neuropathy, peripheral sensory neuropathy. Psychiatric disorders: anxiety. Renal and urinary disorders: acute renal failure, renal failure, renal impairment. Respiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary edema, pulmonary hemorrhage. Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash. Vascular disorders: embolic and thrombotic events, venous (including deep vein thrombosis and pulmonary embolism), hemorrhage, hypotension. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of Kyprolis. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure: hemolytic uremic syndrome (HUS), hepatitis virus reactivation, gastrointestinal perforation, pericarditis, and cytomegalovirus infection, including chorioretinitis, pneumonitis, enterocolitis, viremia, intestinal obstruction, and acute pancreatitis.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1In Combination with Lenalidomide and Dexamethasone for Relapsed or Refractory Multiple Myeloma. ASPIRE (NCT01080391)ASPIRE was randomized, open-label, multicenter trial which evaluated the combination of Kyprolis with lenalidomide and dexamethasone (KRd) versus lenalidomide and dexamethasone alone (Rd) in patients with relapsed or refractory multiple myeloma who had received to lines of therapy (A line of therapy is planned course of treatment [including sequential induction, transplantation, consolidation, and/or maintenance] without an interruption for lack of efficacy, such as for relapse or progressive disease). Patients who had the following were excluded from the trial: refractory to bortezomib in the most recent regimen, refractory to lenalidomide and dexamethasone in the most recent regimen, not responding to any prior regimen, creatinine clearance 50 mL/min, ALT/AST 3.5 ULN and bilirubin 2 ULN, New York Heart Association Class III to IV congestive heart failure, or myocardial infarction within the last months.In the KRd arm, Kyprolis was evaluated at starting dose of 20 mg/m2, which was increased to 27 mg/m2 on Cycle 1, Day onward. Kyprolis was administered as 10-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle for Cycle through 12. Kyprolis was dosed on Days 1, 2, 15, and 16 of each 28-day cycle from Cycle 13 through 18. Dexamethasone 40 mg was administered orally or intravenously on Days 1, 8, 15 and 22 of each cycle. Lenalidomide was given 25 mg orally on Days to 21 of each 28-day cycle. The Rd treatment arm had the same regimen for lenalidomide and dexamethasone as the KRd treatment arm. Kyprolis was administered for maximum of 18 cycles unless discontinued early for disease progression or unacceptable toxicity. Lenalidomide and dexamethasone administration could continue until progression or unacceptable toxicity. Concurrent use of thromboprophylaxis and proton pump inhibitor were required for both arms and antiviral prophylaxis was required for the KRd arm.The 792 patients in ASPIRE were randomized 1:1 to the KRd or Rd arm. The demographics and baseline characteristics were well-balanced between the two arms (see Table 24). Only 53% of the patients had testing for genetic mutations; high-risk genetic mutation was identified for 12% of patients in the KRd arm and in 13% in the Rd arm.Table 24: Demographics and Baseline Characteristics in ASPIRECharacteristicsKRd(N 396)Rd(N 396)ECOG Eastern Cooperative Oncology Group; IgG immunoglobulin G; ISS International Staging System; KRd Kyprolis, lenalidomide, and dexamethasone; Rd lenalidomide and dexamethasoneAge, Median, Years (min, max)64 (38, 87)65 (31, 91)Age >= 75 Years, (%)43 (11)53 (13)Males, (%)215 (54)232 (59)Race, (%) White377 (95)377 (95) Black12 (3)11 (3) Other or Not Reported7 (2)8 (2)Number of Prior Regimens, (%) 1184 (46)157 (40) 2120 (30)139 (35) 3Including patients with prior regimens. 92 (23)100 (25)Prior Transplantation, (%)217 (55)229 (58)ECOG Performance Status, (%) 0165 (42)175 (44) 1191 (48)186 (47) 240 (10)35 (9)ISS Stage at Study Baseline, (%) I167 (42)154 (39) II148 (37)153 (39) III73 (18)82 (21) Unknown8 (2)7 (2)Creatinine Clearance mL/min, Median (min, max)79 (39, 212)79 (30, 208) 30 to 50, (%)19 (5)32 (8) 50 to 80, (%)185 (47)170 (43)Refractory to Last Therapy, (%)110 (28)119 (30)Refractory at Any Time to, (%): Bortezomib60 (15)58 (15) Lenalidomide29 (7)28 (7) Bortezomib immunomodulatory agent24 (6)27 (7)Patients in the KRd arm demonstrated improved PFS compared with those in the Rd arm (HR 0.69, with 2-sided P-value 0.0001) as determined using standard International Myeloma Working Group (IMWG)/European Blood and Marrow Transplantation (EBMT) response criteria by an Independent Review Committee (IRC). The median PFS was 26.3 months in the KRd arm versus 17.6 months in the Rd arm (see Table 25 and Figure 1).A pre-planned overall survival (OS) analysis was performed after 246 deaths in the KRd arm and 267 deaths in the Rd arm. The median follow-up was approximately 67 months. statistically significant advantage in OS was observed in patients in the KRd arm compared to patients in the Rd arm (see Table 25 and Figure 2).Table 25: Efficacy Outcomes in ASPIREEligible patients had 1-3 prior lines of therapy. Combination TherapyKRd(N 396)Rd(N 396)CI confidence interval; CR complete response; HR hazard ratio; KRd Kyprolis, lenalidomide, and dexamethasone; ORR overall response rate; PFS progression-free survival; PR partial response; Rd lenalidomide and dexamethasone; sCR stringent CR; VGPR very good partial responsePFSAs determined by an Independent Review Committee. MedianBased on Kaplan-Meier estimates., Months (95% CI)26.3 (23.3, 30.5)17.6 (15.0, 20.6) HR (95% CI)Based on stratified Coxs model. 0.69 (0.57, 0.83) P-value (2-sided)The P-value was derived using stratified log-rank test. 0.0001Overall Survival Median, Months (95% CI)48.3 (42.4, 52.8)40.4 (33.6, 44.4) HR (95% CI) 0.79 (0.67, 0.95) P-value (2-sided) 0.0091Overall Response with response345264 ORR (%) (95% CI)Exact confidence interval. 87 (83, 90)67 (62, 71) P-value (2-sided)The P-value was derived using Cochran Mantel Haenszel test. 0.0001Response Category, (%) sCR56 (14)17 (4) CR70 (18)20 (5) VGPR151 (38)123 (31) PR68 (17)104 (26)The median duration of response (DOR) was 28.6 months (95% CI: 24.9, 31.3) for the 345 patients achieving response in the KRd arm and 21.2 months (95% CI: 16.7, 25.8) for the 264 patients achieving response in the Rd arm. The median time to response was month (range to 14 months) in the KRd arm and month (range to 16 months) in the Rd arm.Figure 1: Kaplan-Meier Curve of Progression-Free Survival in ASPIRECI confidence interval; EBMT European Blood and Marrow Transplantation; HR hazard ratio; IMWG International Myeloma Working Group; KRd Kyprolis, lenalidomide, and dexamethasone; mo months; PFS progression-free survival; Rd lenalidomide and dexamethasone armNote: The response and PD outcomes were determined using standard objective IMWG/EBMT response criteria.Figure 2: Kaplan-Meier Curve of Overall Survival in ASPIRECI confidence interval; HR hazard ratio; KRd Kyprolis, lenalidomide, and dexamethasone; mo months; OS overall survival; Rd lenalidomide and dexamethasone arm. Figure 1. Figure 2. 14.2In Combination with Dexamethasone for Relapsed or Refractory Multiple Myeloma. The efficacy of Kyprolis in combination with dexamethasone was evaluated in two open-label randomized trials (ENDEAVOR and A.R.R.O.W.).. ENDEAVOR (NCT01568866)ENDEAVOR was randomized, open-label, multicenter trial of Kyprolis and dexamethasone (Kd) versus bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma who had received to lines of therapy. total of 929 patients were enrolled and randomized (464 in the Kd arm; 465 in the Vd arm). Randomization was stratified by prior proteasome inhibitor therapy (yes versus no), prior lines of therapy (1 versus or 3), current International Staging System stage (1 versus or 3), and planned route of bortezomib administration. Patients were excluded if they had less than PR to all prior regimens; creatinine clearance 15 mL/min; hepatic transaminases >= x ULN; or left-ventricular ejection fraction 40% or other significant cardiac conditions.This trial evaluated Kyprolis at starting dose of 20 mg/m2, which was increased to 56 mg/m2 on Cycle 1, Day onward. Kyprolis was administered twice weekly as 30-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle. In the Vd arm, bortezomib was dosed at 1.3 mg/m2 intravenously or subcutaneously on Days 1, 4, 8, and 11 of 21-day cycle, and dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle. Concurrent use of thromboprophylaxis was optional, and prophylaxis with an antiviral agent and proton pump inhibitor was required. Of the 465 patients in the Vd arm, 381 received bortezomib subcutaneously. Treatment continued until disease progression or unacceptable toxicity.The demographics and baseline characteristics are summarized in Table 26.Table 26: Demographics and Baseline Characteristics in ENDEAVORCharacteristicsKd(N 464)Vd(N 465)ECOG Eastern Cooperative Oncology Group; FISH Fluorescence in situ hybridization; ISS International Staging System; Kd Kyprolis and dexamethasone; Vd bortezomib and dexamethasoneAge, Years Median (min, max)65 (35, 89)65 (30, 88) 65, (%)223 (48)210 (45) 65 74, (%)164 (35)189 (41) >= 75, (%)77 (17)66 (14)Sex, (%) Female224 (48)236 (51) Male240 (52)229 (49)Race, (%) White353 (76)361 (78) Black7 (2)9 (2) Asian56 (12)57 (12) Other or Not Reported48 (10)38 (8)ECOG Performance Status, (%) 0221 (48)232 (50) 1210 (45)203 (44) 233 (7)30 (6)Creatinine Clearance (mL/min) Median (min, max)73 (14, 185)72 (12, 208) 30, (%)28 (6)28 (6) 30 < 50, (%)57 (12)71 (15) 50 < 80, (%)186 (40)177 (38) >= 80, (%)193 (42)189 (41)FISH, (%) High-risk97 (21)113 (24) Standard-risk284 (61)291 (63) Unknown-risk83 (18)61 (13)ISS Stage at Study Baseline, (%) ISS I219 (47)212 (46) ISS II138 (30)153 (33) ISS III107 (23)100 (22)Number of Prior Regimens, (%) 1232 (50)231 (50) 2158 (34)144 (31) 374 (16)88 (19) 40 (0)2 (0.4)Prior Therapies, (%)464 (100)465 (100) Bortezomib250 (54)252 (54) Transplant for Multiple Myeloma266 (57)272 (59) Thalidomide212 (46)249 (54) Lenalidomide177 (38)178 (38) Bortezomib immunomodulatory agent159 (34)168 (36)Refractory to last prior therapy, (%)Refractory disease not achieving minimal response or better, progressing during therapy, or progressing within 60 days after completion of therapy. 184 (40)189 (41)The efficacy of Kyprolis was evaluated by PFS as determined by an IRC using IMWG response criteria. The trial showed median PFS of 18.7 months in the Kd arm versus 9.4 months in the Vd arm (see Table 27 and Figure 3).CI confidence interval; HR hazard ratio; Kd Kyprolis and dexamethasone; mo months; PFS progression-free survival; Vd bortezomib and dexamethasoneFigure 3: Kaplan-Meier Plot of Progression-Free Survival in ENDEAVOROther endpoints included OS and overall response rate (ORR).A pre-planned OS analysis was performed after 189 deaths in the Kd arm and 209 deaths in the Vd arm. The median follow-up was approximately 37 months. significantly longer OS was observed in patients in the Kd arm compared to patients in the Vd arm (HR 0.79; 95% CI: 0.65, 0.96; P-value 0.01). Results are provided in Table 27 and Figure 4.Table 27: Summary of Key Results in ENDEAVOR (Intent-to-Treat Population)Eligible patients had 1-3 prior lines of therapy. Kd(N 464)Vd(N 465)CI confidence interval; CR complete response; HR= hazard ratio; Kd Kyprolis and dexamethasone; ORR overall response rate; PFS progression-free survival; PR partial response; sCR stringent CR; Vd bortezomib and dexamethasone; VGPR very good partial response; NE non-estimablePFSPFS and ORR were determined by an Independent Review Committee. Number of events (%)171 (37)243 (52) MedianBased on Kaplan-Meier estimates., Months (95% CI)18.7 (15.6, NE)9.4 (8.4, 10.4) HR (Kd/Vd) (95% CI)Based on stratified Coxs model. 0.53 (0.44, 0.65) P-value (1-sided)P-value was derived using stratified log-rank test. 0.0001Overall Survival Number of deaths (%)189 (41)209 (45) Median, Months (95% CI)47.6 (42.5, NE)40.0 (32.6, 42.3) HR (Kd/Vd) (95% CI) 0.79 (0.65, 0.96) P-value (1-sided) 0.01Overall Response with Response357291 ORR (%) (95% CI)Exact confidence interval. 77 (73, 81)63 (58, 67) P-value (1-sided)The P-value was derived using Cochran Mantel Haenszel test. 0.0001Response Category, (%) sCR8 (2)9 (2) CR50 (11)20 (4) VGPR194 (42)104 (22) PRIncludes one patient in each arm with confirmed PR which may not have been the best response. 105 (23)158 (34)Figure 4: Kaplan-Meier Plot of Overall Survival in ENDEAVORCI confidence interval; HR hazard ratio; Kd Kyprolis and dexamethasone; mo month; OS overall survival; Vd bortezomib and dexamethasoneThe median DOR in subjects achieving PR or better was 21.3 months (95% CI: 21.3, not estimable) in the Kd arm and 10.4 months (95% CI: 9.3, 13.8) in the Vd arm. The median time to response was month (range 1 to months) in both arms.. Figure 3. Figure 4. A.R.R.O.W. (NCT02412878)A.R.R.O.W. was randomized, open-label, multicenter superiority trial of Kyprolis and dexamethasone (Kd) once weekly (20/70 mg/m2) versus Kd twice weekly (20/27 mg/m2) in patients with relapsed and refractory multiple myeloma who had received to prior lines of therapy. Patients were excluded if they had less than PR to at least one prior line; creatinine clearance 30 mL/min; hepatic transaminases >= x ULN; or left-ventricular ejection fraction 40% or other significant cardiac conditions. total of 478 patients were enrolled and randomized (240 in 20/70 mg/m2 arm; 238 in 20/27 mg/m2 arm). Randomization was stratified by current International Staging System stage (stage versus stages or 3), refractory to bortezomib treatment (yes versus no), and age (< 65 versus >= 65 years).Arm of this trial evaluated Kyprolis at starting dose of 20 mg/m2, which was increased to 70 mg/m2 on Cycle 1, Day onward. Arm Kyprolis was administered once weekly as 30-minute infusion on Days 1, and 15, of each 28-day cycle. Arm of this trial evaluated Kyprolis at starting dose of 20 mg/m2, which was increased to 27 mg/m2 on Cycle 1, Day onward. Arm Kyprolis was administered twice weekly as 10-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. In both regimens, dexamethasone 40 mg was administered orally or intravenously on Days 1, 8, 15 for all cycles and on Day 22 for cycles to only. Concurrent use of thromboprophylaxis was optional, prophylaxis with an antiviral agent was recommended, and prophylaxis with proton pump inhibitor was required. Treatment continued until disease progression or unacceptable toxicity.The demographics and baseline characteristics are summarized in Table 28.Table 28: Demographics and Baseline Characteristics in A.R.R.O.W.CharacteristicsOnce weekly Kd 20/70 mg/m2 (N 240)Twice weekly Kd 20/27 mg/m2 (N 238)ECOG Eastern Cooperative Oncology Group; FISH Fluorescence in situ hybridization; ISS International Staging System; Kd Kyprolis and dexamethasoneAge, Years Median (min, max)66 (39, 85)66 (35, 83) 65, (%)104 (43)104 (44) 65 74, (%)90 (38)102 (43) >= 75, (%)46 (19)32 (13)Sex, (%) Female108 (45)110 (46) Male132 (55)128 (54)Race, (%) White200 (83)202 (85) Black3 (1)2 (1) Asian30 (13)15 (6) Other or Not Reported7 (3)19 (8)ECOG Performance Status, (%) 0118 (49)118 (50) 1121 (50)120 (50) 21 (0.4)0 (0)Creatinine Clearance (mL/min) Median (min, max)70.80 (28, 212)73.20 (29, 181) 30, (%)2 (1)1 (0.4) 30 < 50, (%)48 (20)34 (14) 50 < 80, (%)91 (38)111 (47) >= 80, (%)99 (41)91 (38)FISH, (%) High-risk34 (14)47 (20) Standard-risk47 (20)53 (22) Unknown-risk159 (66)138 (58)ISS Stage at Study Baseline, (%) ISS I94 (39)99 (42) ISS II80 (33)81 (34) ISS III63 (26)54 (23)Number of Prior Regimens, (%) 2116 (48)125 (53) 3124 (52)112 (47) >30 (0)1 (0.4)Prior Therapies, (%) Bortezomib236 (98)237 (100) Transplantation146 (61)157 (66) Thalidomide119 (50)119 (50) Lenalidomide207 (86)194 (82)The efficacy of Kyprolis was evaluated by PFS using IMWG response criteria. Efficacy results are provided in Table 29 and Figure 5.Figure 5: Kaplan-Meier Plot of Progression-Free Survival in A.R.R.O.W.CI confidence interval; HR hazard ratio; Kd Kyprolis and dexamethasone; PFS progression-free survivalTable 29: Summary of Key Results in A.R.R.O.W. (Intent-to-Treat Population) Once weekly Kd 20/70 mg/m2 (N 240)Twice weekly Kd 20/27 mg/m2 (N 238)CI confidence interval; CR complete response; HR hazard ratio; Kd Kyprolis and dexamethasone; ORR overall response rate; PFS progression-free survival; PR partial response; sCR stringent complete response; VGPR very good partial responsePFS Number of events, (%)126 (52.5)148 (62.2) Median, Months (95% CI)11.2 (8.6, 13.0)7.6 (5.8, 9.2) HR (95% CI)0.69 (0.54, 0.88) P-value (1-sided)0.0014Overall ResponseOverall response is defined as achieving best overall response of PR, VGPR, CR or sCR. with Response15197 ORR (%) (95% CI)62.9 (56.5, 69.0)40.8 (34.5, 47.3) P-value (1-sided)< 0.0001Response Category, (%) sCR4 (1.7)0 (0.0) CR13 (5.4)4 (1.7) VGPR65 (27.1)28 (11.8) PR69 (28.8)65 (27.3)The median DOR in subjects achieving PR or better was 15 months (95% CI: 12.2, not estimable) in the Kd 20/70 mg/m2 arm and 13.8 months (95% CI: 9.5, not estimable) in the Kd 20/27 mg/m2 arm. The median time to response was 1.1 months in the Kd 20/70 mg/m2 arm and 1.9 months in the Kd 20/27 mg/m2 arm.Kyprolis is not approved for twice weekly 20/27 mg/m2 administration in combination with dexamethasone alone.. Figure 5. 14.3In Combination with Daratumumab and Dexamethasone for Relapsed or Refractory Multiple Myeloma. The efficacy of Kyprolis in combination with daratumumab and dexamethasone or daratumumab and hyaluronidase-fihj and dexamethasone (DKd) was evaluated in three open-label clinical trials (CANDOR, EQUULEUS, and PLEIADES).. CANDOR (NCT03158688)CANDOR was randomized, open-label, multicenter trial which evaluated the combination of Kyprolis 20/56 mg/m2 twice weekly with intravenous daratumumab and dexamethasone (DKd) versus Kyprolis 20/56 mg/m2 twice weekly and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma who had received to prior lines of therapy. Patients who had the following were excluded from the trial: known moderate or severe persistent asthma within the past years, known chronic obstructive pulmonary disease (COPD) with FEV1 50% of predicted normal, and active congestive heart failure. Randomization was stratified by the ISS (stage or vs stage 3) at screening, prior proteasome inhibitor exposure (yes vs no), number of prior lines of therapy (1 vs >= 2), or prior cluster differentiation antigen 38 (CD38) antibody therapy (yes vs no).Kyprolis was administered intravenously over 30 minutes at dose of 20 mg/m2 in Cycle on Days and 2; at dose of 56 mg/m2 in Cycle on Days 8, 9, 15 and 16; and on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle thereafter. Dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15 and 16 and then 40 mg orally or intravenously on Day 22 of each 28-day cycle. In the DKd arm, daratumumab was administered intravenously at dose of mg/kg in Cycle on Days and 2. Thereafter, daratumumab was administered intravenously at dose of 16 mg/kg on Days 8, 15 and 22 of Cycle 1; Days 1, and 15 and 22 of Cycle 2; Days and 15 of Cycles to 6; and Day for the remaining cycles or until disease progression. For patients >75 years on reduced dexamethasone dose of 20 mg, the entire 20 mg dose was given as daratumumab pre-infusion medication on days when daratumumab was administered. Dosing of dexamethasone was otherwise split across days when Kyprolis was administered in both study arms. Treatment was continued in both arms until disease progression or unacceptable toxicity.A total of 466 patients were randomized; 312 to the DKd arm and 154 to the Kd arm. The demographics and baseline characteristics are summarized in Table 30.Table 30: Demographics and Baseline Characteristics in CANDORCharacteristicsDKd(N 312)Kd (N 154)DKd Kyprolis, daratumumab, and dexamethasone; ECOG Eastern Cooperative Oncology Group; FISH Fluorescence in situ hybridization; ISS International Staging System; Kd Kyprolis and dexamethasoneAge at randomization (years) Median (min, max)64 (29, 84)65 (35, 83)Age group n (%) 18 64 years163 (52)77 (50) 65 74 years121 (39)55 (36) 75 years and older28 (9)22 (14)Sex n (%) Male177 (57)91 (59) Female135 (43)63 (41)Race n (%) Asian46 (15)20 (13) Black or African American7 (2.2)2 (1.3) White243 (78)123 (80) Other16 (5)9 (6)Geographic region n (%) North America21 (7)12 (8) Europe207 (66)103 (67) Asia Pacific84 (27)39 (25)ECOG performance status n (%) or 1295 (95)147 (95) 215 (4.8)7 (4.5) Missing2 (0.6)0 (0.0)Risk group as determined by FISH n (%) High risk48 (15)26 (17) Standard risk104 (33)52 (34) Unknown160 (51)76 (49)ISS stage per x RS at screening n (%) or II252 (81)127 (82) III60 (19)27 (17)Number of prior regimens n (%)Subjects with number of prior regimens 3 was in the DKd arm and in Kd arm. 1144 (46)70 (45) 299 (32)46 (30) 369 (22)37 (24)Prior Therapies Lenalidomide123 (39)74 (48) Refractory to lenalidomide99 (32)55 (36) Bortezomib287 (92)134 (87) Prior CD38 antibody therapy n (%)1 (0.3)0 (0.0) Prior stem cell transplant (ASCT) n (%)195 (62)75 (49)Efficacy was assessed by an IRC evaluation of PFS using the IMWG response criteria. Efficacy results are provided in Table 31 and Figure 6. The median duration of response has not been reached for the DKd arm and was 16.6 months (13.9, NE) for the Kd arm. The median (min, max) time to response was 1.0 (1, 14) months for the DKd arm and 1.0 (1, 10) months for the Kd arm.Figure 6: Kaplan-Meier Plot of Progression-Free Survival in CANDORCI confidence interval; DKd Kyprolis, daratumumab and dexamethasone; HR hazard ratio; Kd= Kyprolis and dexamethasoneTable 31: Summary of Key Results in CANDOR (Intent-to-Treat Population) DKd(N 312)Kd(N 154)CI confidence interval; CR complete response; HR hazard ratio; DKd Kyprolis, daratumumab, and dexamethasone; Kd Kyprolis and dexamethasone; ORR overall response rate; PFS progression-free survival; PR partial response; MRD [-] CR minimal residual disease negative-complete response; NE non-estimable; VGPR very good partial response PFS Number of events (%)110 (35%)68 (44%) Median, Months (95% CI)NE (NE, NE)15.8 (12.1, NE) HR (95% CI)0.63 (0.46, 0.85) P-value (1-sided)The P-value was derived using stratified log-rank test 0.0014Overall Response with Response263115 ORR (%) (95% CI)84%(80%, 88%)75%(67%, 81%) P-value (1-sided)The P-value was derived using stratified Cochran Mantel-Haenszel Chi-Squared test 0.0040 CR89 (28%)16 (10%) VGPR127 (41%)59 (38%) PR47 (15%)40 (26%)MRD [-] CR rate at 12 months (%)MRD [-] CR (at 10-5 level) is defined as achievement of CR per IMWG-URC and MRD[-] status as assessed by the next-generation sequencing assay (ClonoSEQ) at the 12 months landmark (from months to 13 months window) (95% CI)39 (12%)(9%, 17%)2 (1.3%)(0.2%, 4.6%) P-value (1-sided) 0.0001MRD [-] CRMRD[-]CR (at 10-5 level) is defined as achievement of CR per IMWG-URC and MRD[-] status as assessed by the next-generation sequencing assay (ClonoSEQ) at any timepoint during the trial 43 (14%)5 (3.2%). Figure 6. EQUULEUS (NCT01998971)EQUULEUS was an open-label, multi-cohort trial which evaluated the combination of Kyprolis with intravenous daratumumab and dexamethasone in patients with relapsed or refractory multiple myeloma who had received to prior lines of therapy. Patients who had the following were excluded from the trial: known moderate or severe persistent asthma within the past years, known chronic obstructive pulmonary disease (COPD) with FEV1 50% of predicted normal, or active congestive heart failure (defined as New York Heart Association Class III-IV).Kyprolis was administered intravenously over 30 minutes once weekly at dose of 20 mg/m2 on Cycle Day and escalated to dose of 70 mg/m2 on Cycle 1, Days and 15; and on Days 1, 8, and 15 of each 28-day cycle. Ten patients were administered daratumumab at dose of 16 mg/kg intravenously on Cycle 1, Day and the remaining patients were administered daratumumab at dose of mg/kg intravenously on Cycle 1, Days and 2. Thereafter, daratumumab was administered intravenously at dose of 16 mg/kg on Days 8, 15 and 22 of Cycle 1; Days 1, 8, 15 and 22 of Cycle 2; Days and 15 of Cycles to 6; and then Day for the remaining cycles of each 28-day cycle. In Cycles and 2, dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15, 16, 22 and 23; in cycles to 6, dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 15 and 16 and at dose of 40 mg on Day and 22; and in cycles and thereafter, dexamethasone 20 mg was administered orally or intravenously on Days and and at dose of 40 mg on Days 8, 15, and 22. For patients 75 years of age, dexamethasone 20 mg was administered orally or intravenously weekly after the first week. Treatment continued until disease progression or unacceptable toxicity.The EQUULEUS trial enrolled 85 patients. The demographics and baseline characteristics are summarized in Table 32.Table 32: Demographics and Baseline Characteristics in DKd 20/70 mg/m2 Regimen of EQUULEUS (Combination Therapy for Relapsed or Refractory Multiple Myeloma)CharacteristicsNumber of Patients (%)ECOG Eastern Cooperative Oncology Group; FISH Fluorescence in situ hybridization; PI proteasome inhibitor; IMiD immunomodulatory agent. Age (years) Median (min, max)66 (38, 85)Age group n (%) 65 years36 (42) 65 < 75 years41 (48) >= 75 years8 (9)Sex n (%) Male46 (54) Female39 (46)Race n (%) Asian3 (3.5) Black or African American3 (3.5) White68 (80)ECOG Score, (%) 032 (38) 146 (54) 27 (8)FISH, (%) N67 Standard Risk54 (81) High Risk13 (19)Number of Prior regimens 120 (23) 240 (47) 323 (27) 32 (2.4)Prior Therapies Bortezomib85 (100) Lenalidomide81 (95) Prior stem cell transplant (ASCT)62 (73) Refractory to lenalidomide51 (60) Refractory to both PI and IMiD25 (29)Efficacy results were based on overall response rate using IMWG criteria. Efficacy results are provided in Table 33. The median time to response was 0.95 months (range: 0.9, 14.3). The median duration of response was 28 months (95% CI: 20.5, not estimable).Table 33: Summary of Key Results in EQUULEUS (Intent-to-Treat Population) Study Patientsn (%)CI confidence interval; sCR stringent complete response; CR complete response; ORR overall response rate; PR partial response; VGPR very good partial response Overall Response with Response69 ORR (%) (95% CI)81% (71, 89)Response category, (%) sCR18 (21%) CR12 (14%) VGPR28 (33%) PR11 (13%). PLEIADES (NCT03412565)The efficacy of Kyprolis with daratumumab and hyaluronidase-fihj plus dexamethasone (DKd) was evaluated in single-arm cohort of PLEIADES, multi-cohort, open-label trial. This cohort enrolled patients with relapsed or refractory multiple myeloma excluding patients with left ventricular ejection fraction (LVEF) less than 40%, myocardial infarction within months, uncontrolled cardiac arrhythmia, or uncontrolled hypertension (systolic blood pressure >159 mmHg or diastolic >99 mmHg despite optimal treatment). Patients received Kyprolis administered by IV infusion at dose of 20 mg/m2 on Cycle Day and if dose of 20 mg/m2 was tolerated Kyprolis was administered at dose of 70 mg/m2 as 30-minute IV infusion on Cycle Day and Day 15, and then Day 1, and 15 of each cycle; daratumumab and hyaluronidase-fihj1,800 mg/30,000 units administered subcutaneously once weekly from Weeks to 8, once every weeks from Weeks to 24 and once every weeks starting with Week 25 until disease progression or unacceptable toxicity; and dexamethasone 40 mg per week (or reduced dose of 20 mg per week for patients >=75 years or BMI <18.5). The major efficacy outcome measure was ORR. total of 66 patients received the DKd regimen. The median age was 61 years (range: 42, 84); 52% were male; 73% were White and 3% Black or African American; and 68% had ISS Stage I, 18% had ISS Stage II, and 14% had ISS Stage III disease. total of 79% of patients had prior ASCT; 91% of patients received prior PI. All patients received prior line of therapy with exposure to lenalidomide and 62% of patients were refractory to lenalidomide.Efficacy results are summarized in Table 34. At median follow-up of 9.2 months, the median duration of response had not been reached and an estimated 85.2% (95% CI: 72.5, 92.3) maintained response for at least months and 82.5% (95% CI: 68.9, 90.6) maintained response for at least months.Table 34: Efficacy Results from PLEIADES in Patients Who Received DKdDKd(N=66)CI confidence intervalOverall response rate (sCR+CR+VGPR+PR), (%)Based on treated patients 56 (84.8%)95% CI (%) (73.9%, 92.5%) Stringent complete response (sCR)11 (16.7%) Complete response (CR)14 (21.2%) Very good partial response (VGPR)26 (39.4%) Partial response (PR)5 (7.6%). 14.4Monotherapy for Relapsed or Refractory Multiple Myeloma. Study PX-171-007 (NCT00531284)Study PX-171-007 was multicenter, open-label, dose escalation, single-arm trial that evaluated the safety of Kyprolis monotherapy as 30-minute infusion in patients with relapsed or refractory multiple myeloma after or more lines of therapy. Patients were excluded if they had creatinine clearance 20 mL/min; ALT >= x upper limit of normal (ULN), bilirubin >= 1.5 ULN; New York Heart Association Class III or IV congestive heart failure; or other significant cardiac conditions. total of 24 subjects with multiple myeloma were enrolled at the maximum tolerated dose level of 20/56 mg/m2. Kyprolis was administered twice weekly for consecutive weeks (Days 1, 2, 8, 9, 15, and 16) of 28-day cycle. In Cycle 13 onward, the Day and Kyprolis doses could be omitted. Patients received Kyprolis at starting dose of 20 mg/m2 on Days and of Cycle 1, which was increased to 56 mg/m2 for all subsequent doses. Dexamethasone mg orally or intravenously was required prior to each Kyprolis dose in Cycle and was optional in subsequent cycles. Treatment was continued until disease progression or unacceptable toxicity.Efficacy was evaluated by ORR and DOR. ORR by investigator assessment was 50% (95% CI: 29, 71) per IMWG criteria (see Table 35). The median DOR in subjects who achieved PR or better was 8.0 months (Range: 1.4, 32.5).Table 35: Response Categories in Study PX-171-007 (20/56 mg/m2 Monotherapy Regimen)CharacteristicsStudy PatientsEligible patients had or more prior lines of therapy. (%)CI confidence interval; CR complete response; PR partial response; sCR stringent complete response; VGPR very good partial responseNumber of Patients (%)24 (100)Overall ResponsePer investigator assessment. 12 (50) 95% CIExact confidence interval. (29, 71)Response Category sCR1 (4) CR0 (0) VGPR4 (17) PR7 (29). Study PX-171-003 A1 (NCT00511238)Study PX-171-003 A1 was single-arm, multicenter clinical trial of Kyprolis monotherapy by up to 10-minute infusion. Eligible patients were those with relapsed and refractory multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) and had <= 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. Patients were excluded from the trial if they were refractory to all prior therapies or had total bilirubin >= x ULN; creatinine clearance 30 mL/min; New York Heart Association Class III to IV congestive heart failure; symptomatic cardiac ischemia; myocardial infarction within the last months; peripheral neuropathy Grade or 4, or peripheral neuropathy Grade with pain; active infections requiring treatment; or pleural effusion.Kyprolis was administered intravenously up to 10 minutes on two consecutive days each week for three weeks, followed by 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for maximum of 12 cycles. Patients received 20 mg/m2 at each dose in Cycle 1, and 27 mg/m2 in subsequent cycles. Dexamethasone mg orally or intravenously was administered prior to Kyprolis doses in the first and second cycles.A total of 266 patients were enrolled. Baseline patient and disease characteristics are summarized in Table 36.Table 36: Demographics and Baseline Characteristics in Study PX-171-003 A1 (20/27 mg/m2 Monotherapy Regimen)CharacteristicsNumber of Patients (%)FISH Fluorescence in situ hybridization; ISS International Staging SystemPatient Characteristics Enrolled patients266 (100) Median age, years (range)63 (37, 87) Age group, 65 >= 65 (years)146 (55) 120 (45) Sex (male female)155 (58) 111 (42) Race (White Black Asian Other)190 (71) 53 (20) 6 (2) 17 (6)Disease Characteristics Number of Prior Regimens (median)5Range: 1, 20. Prior Transplantation198 (74) Refractory Status to Most Recent TherapyCategories for refractory status are derived by programmatic assessment using available laboratory data. Refractory: Progression during most recent therapy198 (74) Refractory: Progression within 60 days after completion of most recent therapy38 (14) Refractory: <= 25% response to treatment16 (6) Relapsed: Progression after 60 days post treatment14 (5) Years since diagnosis, median (range)5.4 (0.5, 22.3) Plasma cell involvement (< 50% >= 50% unknown)143 (54) 106 (40) 17 (6)ISS Stage at Study Baseline I76 (29) II102 (38) III81 (31) Unknown7 (3)Cytogenetics or FISH analyses Normal/Favorable159 (60) Poor Prognosis75 (28) Unknown32 (12) Creatinine clearance 30 mL/min6 (2)Efficacy was evaluated by ORR as determined by IRC assessment using IMWG criteria. Efficacy results are provided in Table 37. The median DOR was 7.8 months (95% CI: 5.6, 9.2).Table 37: Response Categories in Study PX-171-003 A1 (20/27 mg/m2 Monotherapy Regimen)CharacteristicsStudy PatientsEligible patients had or more prior lines of therapy and were refractory to the last regimen. (%)CI confidence interval; CR complete response; PR partial response; VGPR very good partial responseNumber of Patients (%)266 (100)Overall ResponseAs assessed by the Independent Review Committee. 61 (23) 95% CIExact confidence interval. (18, 28)Response Category CR1 (< 1) VGPR13 (5) PR47 (18). Study PX-171-004 Part (NCT00530816)Study PX-171-004 Part was single-arm, multicenter clinical trial of Kyprolis monotherapy by up to 10-minute infusion. Eligible patients were those with relapsed or refractory multiple myeloma who were bortezomib-naive, had received one to three prior lines of therapy and had <= 25% response or progression during therapy or within 60 days after completion of therapy. Patients were excluded from the trial if they were refractory to standard first-line therapy or had total bilirubin >= x ULN; creatinine clearance 30 mL/min; New York Heart Association Class III to IV congestive heart failure; symptomatic cardiac ischemia; myocardial infarction within the last months; active infections requiring treatment; or pleural effusion.Kyprolis was administered intravenously up to 10 minutes on two consecutive days each week for three weeks, followed by 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for maximum of 12 cycles. Patients received 20 mg/m2 at each dose in Cycle 1, and 27 mg/m2 in subsequent cycles. Dexamethasone mg orally or intravenously was administered prior to Kyprolis doses in the first and second cycles.A total of 70 patients were treated with this 20/27 mg/m2 regimen. Baseline patient and disease characteristics are summarized in Table 38.Table 38: Demographics and Baseline Characteristics in Study PX-171-004 Part (20/27 mg/m2 Monotherapy Regimen)CharacteristicsNumber of Patients (%)FISH Fluorescence in situ hybridization; ISS International Staging SystemPatient Characteristics Enrolled patients70 (100) Median age, years (range)66 (45, 85) Age group, 65 >= 65 (years)31 (44) 39 (56) Sex (male female)44 (63) 26 (37) Race (White Black Asian Hispanic Other)52 (74) 12 (17) 3 (4) 2 (3) 1 (1)Disease Characteristics Number of Prior Regimens (median)2Range: 1, 4. Prior Transplantation47 (67) Refractory Status to Most Recent TherapyCategories for refractory status are derived by programmatic assessment using available laboratory data. Refractory: Progression during most recent therapy28 (40) Refractory: Progression within 60 days after completion of most recent therapy7 (10) Refractory: <= 25% response to treatment10 (14) Relapsed: Progression after 60 days post treatment23 (33) No Signs of Progression2 (3) Years since diagnosis, median (range)3.6 (0.7, 12.2) Plasma cell involvement (< 50% >= 50% unknown)54 (77) 14 (20) 1 (1) ISS Stage at Study Baseline, (%) I28 (40) II25 (36) III16 (23) Unknown1 (1) Cytogenetics or FISH analyses Normal/Favorable57 (81) Poor Prognosis10 (14) Unknown3 (4) Creatinine clearance 30 mL/min1 (1)Efficacy was evaluated by ORR as determined by IRC assessment using IMWG criteria. Efficacy results are provided in Table 39. The median DOR was not reached.Table 39: Response Categories in Study PX-171-004 Part (20/27 mg/m2 Monotherapy Regimen)CharacteristicsStudy PatientsEligible patients had 1-3 prior lines of therapy and were refractory to the last regimen. (%)CI confidence interval; CR complete response; PR partial response; VGPR very good partial responseNumber of Patients (%)70 (100)Overall ResponseAs assessed by an Independent Review Committee. 35 (50) 95% CIExact confidence interval. (38, 62)Response Category CR1 (1) VGPR18 (26) PR16 (23).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety population described in the Warnings and Precautions reflect exposure to Kyprolis in 1789 patients administered in combination with other drugs in ASPIRE, ENDEAVOR, A.R.R.O.W., and CANDOR. The most common adverse reactions occurring in at least 20% of patients who received Kyprolis in combination were anemia, diarrhea, fatigue, hypertension, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, dyspnea, and insomnia.. Kyprolis in Combination with Lenalidomide and Dexamethasone The safety of Kyprolis 20/27 mg/m2 twice weekly in combination with lenalidomide and dexamethasone (KRd) was evaluated in ASPIRE [see Clinical Studies (14.1)]. The median number of cycles initiated was 22 cycles for the KRd arm and 14 cycles for the Rd arm.Deaths due to adverse reactions within 30 days of the last dose of any therapy in the KRd arm occurred in 45/392 (12%) patients compared with 42/389 (11%) patients who died due to adverse reactions within 30 days of the last dose of any Rd therapy. The most frequent cause of deaths occurring in patients (%) in the two arms (KRd versus Rd) included infection 12 (3%) versus 11 (3%), cardiac 10 (3%) versus (2%), and other adverse reactions 23 (6%) versus 22 (6%).Serious adverse reactions were reported in 65% of the patients in the KRd arm and 57% of the patients in the Rd arm. The most frequent serious adverse reactions reported in the KRd arm as compared with the Rd arm were pneumonia (17% versus 13%), respiratory tract infection (4% versus 2%), pyrexia (4% versus 3%), and pulmonary embolism (3% versus 2%).Discontinuation due to any adverse reaction occurred in 33% in the KRd arm versus 30% in the Rd arm. Adverse reactions leading to discontinuation of Kyprolis occurred in 12% of patients and the most common reactions included pneumonia (1%), myocardial infarction (0.8%), and upper respiratory tract infection (0.8%). The incidence of cardiac failure events was 7% in the KRd arm versus 4% in the Rd arm.Table 12 summarizes the adverse reactions in the first 12 cycles in ASPIRE.Table 12: Adverse Reactions (>= 10%) Occurring in Cycles 1-12 in Patients Who Received KRd (20/27 mg/m2 Regimen) in ASPIREAdverse ReactionsKRd(N 392)n (%)Rd(N 389)n (%)Any Grade>= Grade 3Any Grade>= Grade 3KRd Kyprolis, lenalidomide, and dexamethasone; Rd lenalidomide and dexamethasoneBlood and Lymphatic System Disorders Anemia138 (35)53 (14)127 (33)47 (12) Neutropenia124 (32)104 (27)115 (30)89 (23) Thrombocytopenia100 (26)58 (15)75 (19)39 (10)Gastrointestinal Disorders Diarrhea119 (30)8 (2)106 (27)12 (3) Constipation68 (17)0 (0)55 (14)1 (0) Nausea63 (16)1 (0)43 (11)3 (1)General Disorders and Administration Site Conditions Fatigue113 (29)23 (6)107 (28)20 (5) Pyrexia93 (24)5 (1)64 (17)1 (0) Edema peripheral59 (15)3 (1)48 (12)2 (1) Asthenia54 (14)11 (3)49 (13)7 (2)Infections Upper respiratory tract infection87 (22)7 (2)54 (14)4 (1) Bronchitis55 (14)5 (1)40 (10)2 (1) Viral upper respiratory tract infection55 (14)0 (0)44 (11)0 (0) PneumoniaPneumonia includes pneumonia and bronchopneumonia. 54 (14)35 (9)43 (11)27 (7)Metabolism and Nutrition Disorders Hypokalemia78 (20)22 (6)35 (9)12 (3) Hypocalcemia55 (14)10 (3)39 (10)5 (1) Hyperglycemia43 (11)18 (5)33 (9)15 (4)Musculoskeletal and Connective Tissue Disorders Muscle spasms92 (24)3 (1)75 (19)3 (1) Back pain41 (11)4 (1)54 (14)6 (2)Nervous System Disorders Peripheral neuropathiesPeripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. 43 (11)7 (2)39 (10)4 (1)Psychiatric Disorders Insomnia64 (16)6 (2)51 (13)8 (2)Respiratory, Thoracic and Mediastinal Disorders CoughCough includes cough and productive cough. 93 (24)2 (1)54 (14)0 (0) DyspneaDyspnea includes dyspnea and dyspnea exertional. 71 (18)8 (2)61 (16)6 (2)Skin and Subcutaneous Tissue Disorders Rash45 (12)5 (1)54 (14)5 (1)Vascular Disorders Embolic and thrombotic eventsEmbolic and thrombotic events, venous includes deep vein thrombosis, pulmonary embolism, thrombophlebitis superficial, thrombophlebitis, venous thrombosis limb, post thrombotic syndrome, venous thrombosis. 49 (13)16 (4)23 (6)9 (2) HypertensionHypertension includes hypertension, hypertensive crisis. 41 (11)12 (3)15 (4)4 (1)There were 274 (70%) patients in the KRd arm who received treatment beyond Cycle 12. There were no new clinically relevant adverse reactions that emerged in the later treatment cycles.. Adverse Reactions Occurring at Frequency of 10%Blood and lymphatic system disorders: febrile neutropenia, lymphopeniaCardiac disorders: cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, pericardial effusionEar and labyrinth disorders: deafness, tinnitusEye disorders: cataract, vision blurredGastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothacheGeneral disorders and administration site conditions: chills, infusion site reaction, multi-organ failure, painInfections: clostridium difficile colitis, influenza, lung infection, rhinitis, sepsis, urinary tract infection, viral infectionMetabolism and nutrition disorders: dehydration, hyperkalemia, hyperuricemia, hypoalbuminemia, hyponatremia, tumor lysis syndromeMusculoskeletal and connective tissue disorders: muscular weakness, myalgiaNervous system disorders: hypoesthesia, intracranial hemorrhage, paresthesiaPsychiatric disorders: anxiety, deliriumRenal and urinary disorders: renal failure, renal failure acute, renal impairmentRespiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary embolism, pulmonary edema, pulmonary hemorrhageSkin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritusVascular disorders: deep vein thrombosis, hemorrhage, hypotensionGrade and higher adverse reactions that occurred during Cycles 1-12 with substantial difference (>= 2%) between the two arms were neutropenia, thrombocytopenia, hypokalemia, and hypophosphatemia.Table 13 describes Grade 3-4 laboratory abnormalities reported in ASPIRE.Table 13: Grade 3-4 Laboratory Abnormalities (>= 10%) in Cycles 1-12 in Patients Who Received KRd (20/27 mg/m2 Regimen) in ASPIRELaboratory AbnormalityKRd(N 392)n (%)Rd(N 389)n (%)KRd Kyprolis, lenalidomide, and dexamethasone; Rd lenalidomide and dexamethasoneDecreased lymphocytes182 (46)119 (31)Decreased absolute neutrophil count152 (39)141 (36)Decreased phosphorus122 (31)106 (27)Decreased platelets101 (26)59 (15)Decreased total white blood cell count97 (25)71 (18)Decreased hemoglobin58 (15)68 (18)Increased glucose53 (14)30 (8)Decreased potassium41 (11)23 (6). Blood and lymphatic system disorders: febrile neutropenia, lymphopenia. Cardiac disorders: cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, pericardial effusion. Ear and labyrinth disorders: deafness, tinnitus. Eye disorders: cataract, vision blurred. Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache. General disorders and administration site conditions: chills, infusion site reaction, multi-organ failure, pain. Infections: clostridium difficile colitis, influenza, lung infection, rhinitis, sepsis, urinary tract infection, viral infection. Metabolism and nutrition disorders: dehydration, hyperkalemia, hyperuricemia, hypoalbuminemia, hyponatremia, tumor lysis syndrome. Musculoskeletal and connective tissue disorders: muscular weakness, myalgia. Nervous system disorders: hypoesthesia, intracranial hemorrhage, paresthesia. Psychiatric disorders: anxiety, delirium. Renal and urinary disorders: renal failure, renal failure acute, renal impairment. Respiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary embolism, pulmonary edema, pulmonary hemorrhage. Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus. Vascular disorders: deep vein thrombosis, hemorrhage, hypotension. Kyprolis in Combination with Dexamethasone The safety of Kyprolis in combination with dexamethasone was evaluated in two open-label, randomized trials (ENDEAVOR and A.R.R.O.W.).. ENDEAVORThe safety of Kyprolis 20/56 mg/m2 twice weekly in combination with dexamethasone (Kd) was evaluated in ENDEAVOR [see Clinical Studies (14.2)]. Patients received treatment for median duration of 48 weeks in the Kd arm and 27 weeks in the bortezomib/dexamethasone (Vd) arm.Deaths due to adverse reactions within 30 days of last study treatment occurred in 32/463 (7%) patients in the Kd arm and 21/456 (5%) patients in the Vd arm. The causes of death occurring in patients (%) in the two arms (Kd versus Vd) included cardiac (1%) versus (1%), infections (2%) versus (2%), disease progression (2%) versus (1%), pulmonary (1%) versus (< 1%), renal (< 1%) versus (0%), and other adverse reactions (2%) versus (< 1%).Serious adverse reactions were reported in 59% of the patients in the Kd arm and 40% of the patients in the Vd arm. In both arms, pneumonia was the most frequently reported serious adverse reaction (8% versus 9%).Discontinuation due to any adverse reaction occurred in 29% in the Kd arm versus 26% in the Vd arm. The most frequent adverse reaction leading to discontinuation was cardiac failure in the Kd arm (n 8, 2%) and peripheral neuropathy in the Vd arm (n 22, 5%). The incidence of cardiac failure events was 11% in the Kd arm versus 3% in the Vd arm.Adverse reactions in the first months of therapy that occurred at rate of 10% or greater in the Kd arm are presented in Table 14.Table 14: Adverse Reactions (>= 10% Occurring in Months 1-6 in Patients Who Received Kd (20/56 mg/m2 Regimen) in ENDEAVORAdverse Reactions Kd(N 463)n (%)Vd(N 456)n (%)Any GradeGrade >= 3Any GradeGrade >= 3Kd Kyprolis and dexamethasone; Vd bortezomib and dexamethasoneBlood and Lymphatic System Disorders Anemia161 (35)57 (12)112 (25)43 (9) ThrombocytopeniaThrombocytopenia includes platelet count decreased and thrombocytopenia. 125 (27)45 (10)112 (25)64 (14)Gastrointestinal Disorders Diarrhea117 (25)14 (3)149 (33)27 (6) Nausea70 (15)4 (1)68 (15)3 (1) Constipation60 (13)1 (0)113 (25)6 (1) Vomiting45 (10)5 (1)33 (7)3 (1)General Disorders and Administration Site Conditions Fatigue116 (25)14 (3)126 (28)25 (6) Pyrexia102 (22)9 (2)52 (11)3 (1) Asthenia73 (16)9 (2)65 (14)13 (3) Peripheral edema62 (13)3 (1)62 (14)3 (1)Infections Upper respiratory tract infection67 (15)4 (1)55 (12)3 (1) Bronchitis54 (12)5 (1)25 (6)2 (0)Musculoskeletal and Connective Tissue Disorders Muscle spasms70 (15)1 (0)23 (5)3 (1) Back pain64 (14)8 (2)61 (13)10 (2)Nervous System Disorders Headache67 (15)4 (1)39 (9)2 (0) Peripheral neuropathiesPeripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. See Clinical Studies (14.2). 56 (12)7 (2)170 (37)23 (5)Psychiatric Disorders Insomnia105 (23)5 (1)116 (25)10 (2)Respiratory, Thoracic and Mediastinal Disorders DyspneaDyspnea includes dyspnea and dyspnea exertional. 128 (28)23 (5)69 (15)8 (2) CoughCough includes cough and productive cough. 97 (21)0 (0)61 (13)2 (0)Vascular Disorders HypertensionHypertension includes hypertension, hypertensive crisis, and hypertensive emergency. 83 (18)30 (7)33 (7)12 (3)The event rate of >= Grade peripheral neuropathy in the Kd arm was 7% (95% CI: 5, 9) versus 35% (95% CI: 31, 39) in the Vd arm.. Adverse Reactions Occurring at Frequency of 10%Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy, thrombotic thrombocytopenic purpuraCardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, tachycardiaEar and labyrinth disorders: tinnitusEye disorders: cataract, vision blurredGastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothacheGeneral disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, painHepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemiaImmune system disorders: drug hypersensitivityInfections: bronchopneumonia, gastroenteritis, influenza, lung infection, nasopharyngitis, pneumonia, rhinitis, sepsis, urinary tract infection, viral infectionMetabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndromeMusculoskeletal and connective tissue disorders: muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgiaNervous system disorders: cerebrovascular accident, dizziness, hypoesthesia, paresthesia, posterior reversible encephalopathy syndromePsychiatric disorders: anxietyRenal and urinary disorders: renal failure, renal failure acute, renal impairmentRespiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary embolism, pulmonary edema, pulmonary hypertension, wheezingSkin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rashVascular disorders: deep vein thrombosis, flushing, hypotensionTable 15 describes Grade 3-4 laboratory abnormalities reported at rate of >= 10% in the Kd arm.Table 15: Grade 3-4 Laboratory Abnormalities (>= 10%) in Months 1-6 in Patients Who Received Kd (20/56 mg/m2 Regimen) in ENDEAVORLaboratory AbnormalityKd(N 463)n (%)Vd(N 456)n (%)Kd Kyprolis and dexamethasone; Vd bortezomib and dexamethasoneDecreased lymphocytes249 (54)180 (40)Increased uric acid244 (53)198 (43)Decreased hemoglobin79 (17)68 (15)Decreased platelets85 (18)77 (17)Decreased phosphorus74 (16)61 (13)Decreased creatinine clearanceCalculated using the Cockcroft-Gault formula. 65 (14)49 (11)Increased potassium55 (12)21 (5). Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy, thrombotic thrombocytopenic purpura. Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, tachycardia. Ear and labyrinth disorders: tinnitus. Eye disorders: cataract, vision blurred. Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache. General disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, pain. Hepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemia. Immune system disorders: drug hypersensitivity. Infections: bronchopneumonia, gastroenteritis, influenza, lung infection, nasopharyngitis, pneumonia, rhinitis, sepsis, urinary tract infection, viral infection. Metabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome. Musculoskeletal and connective tissue disorders: muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia. Nervous system disorders: cerebrovascular accident, dizziness, hypoesthesia, paresthesia, posterior reversible encephalopathy syndrome. Psychiatric disorders: anxiety. Renal and urinary disorders: renal failure, renal failure acute, renal impairment. Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary embolism, pulmonary edema, pulmonary hypertension, wheezing. Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash. Vascular disorders: deep vein thrombosis, flushing, hypotension. A.R.R.O.W.The safety of Kyprolis in combination with dexamethasone was evaluated in A.R.R.O.W. [see Clinical Studies (14.2)]. Patients received treatment for median duration of 38 weeks in the Kd 20/70 mg/m2 arm once weekly and 29.1 weeks in the Kd 20/27 mg/m2 twice weekly arm. The safety profile for the once weekly Kd 20/70 mg/m2 regimen was similar to the twice weekly Kd 20/27 mg/m2 regimen.Deaths due to adverse reactions within 30 days of last study treatment occurred in 22/238 (9%) patients in the Kd 20/70 mg/m2 arm and 18/235 (8%) patients in the Kd 20/27 mg/m2 arm. The most frequent fatal adverse reactions occurring in patients (%) in the two arms (once weekly Kd 20/70 mg/m2 versus twice weekly Kd 20/27 mg/m2) were sepsis (< 1%) versus (< 1%), septic shock (< 1%) versus (< 1%), and infection (< 1%) versus (0%).Serious adverse reactions were reported in 43% of the patients in the Kd 20/70 mg/m2 arm and 41% of the patients in the Kd 20/27 mg/m2 arm. In both arms, pneumonia was the most frequently reported serious adverse reaction (8% versus 7%).Discontinuation due to any adverse reaction occurred in 13% in the Kd 20/70 mg/m2 arm versus 12% in the Kd 20/27 mg/m2 arm. The most frequent adverse reaction leading to discontinuation was acute kidney injury (2% versus 2%). The incidence of cardiac failure events was 3.8% in the once weekly Kd 20/70 mg/m2 arm versus 5.1% in the twice weekly Kd 20/27 mg/m2 arm.Adverse reactions that occurred at rate of 10% or greater in either Kd arm are presented in Table 16.Table 16: Adverse Reactions in Patients Who Received Kd (>= 10% in either Kd Arm) in A.R.R.O.W.Adverse Reactions Once weekly Kd 20/70 mg/m2 (N 238)n (%)Twice weekly Kd 20/27 mg/m2 (N 235)n (%)Any Grade Grade >= 3Any Grade Grade >= 3Kd Kyprolis and dexamethasoneBlood and Lymphatic System Disorders AnemiaAnemia includes anemia, hematocrit decreased, and hemoglobin decreased. 64 (27)42 (18)76 (32)42 (18) ThrombocytopeniaThrombocytopenia includes platelet count decreased and thrombocytopenia. 53 (22)26 (11)41 (17)27 (12) NeutropeniaNeutropenia includes neutrophil count decreased and neutropenia. 30 (13)21 (9)27 (12)17 (7)Gastrointestinal Disorders Diarrhea44 (19)2 (1)47 (20)3 (1) Nausea34 (14)1 (< 1)26 (11)2 (1)General Disorders and Administration Site Conditions Pyrexia55 (23)2 (1)38 (16)4 (2) Fatigue48 (20)11 (5)47 (20)5 (2) Asthenia24 (10)3 (1)25 (11)2 (1) Peripheral edema18 (8)0 (0)25 (11)2 (1)Infections Respiratory tract infectionRespiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection, and viral upper respiratory tract infection. 70 (29)7 (3)79 (34)7 (3) Pneumonia28 (12)24 (10)20 (9)16 (7) Bronchitis27 (11)2 (1)25 (11)5 (2)Musculoskeletal and Connective Tissue Disorders Back pain28 (12)2 (1)28 (12)4 (2)Nervous System Disorders Headache25 (11)1 (< 1)23 (10)1 (< 1)Psychiatric Disorders Insomnia35 (15)2 (1)47 (20)0 (0)Respiratory, Thoracic and Mediastinal Disorders CoughCough includes cough and productive cough. 37 (16)2 (1)31 (13)0 (0) DyspneaDyspnea includes dyspnea and dyspnea exertional. 28 (12)1 (< 1)26 (11)2 (1)Vascular Disorders HypertensionHypertension includes hypertension and hypertensive crisis. 51 (21)13 (6)48 (20)12 (5). Adverse Reactions Occurring at Frequency of 10%Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathyCardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, pericardial effusion, tachycardiaEar and labyrinth disorders: tinnitusEye disorders: cataract, vision blurredGastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, toothache, vomitingGeneral disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, painHepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemiaInfections: clostridium difficile colitis, gastroenteritis, influenza, lung infection, nasopharyngitis, rhinitis, sepsis, septic shock, urinary tract infection, viral infectionMetabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndromeMusculoskeletal and connective tissue disorders: muscle spasms, muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgiaNervous system disorders: cerebrovascular accident, dizziness, paresthesia, peripheral neuropathyPsychiatric disorders: anxiety, deliriumRenal and urinary disorders: acute kidney injury, renal failure, renal impairmentRespiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary hemorrhage, pulmonary embolism, pulmonary hypertension, pulmonary edema, wheezingSkin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rashVascular disorders: deep vein thrombosis, flushing, hypotension. Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy. Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, pericardial effusion, tachycardia. Ear and labyrinth disorders: tinnitus. Eye disorders: cataract, vision blurred. Gastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, toothache, vomiting. General disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, pain. Hepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemia. Infections: clostridium difficile colitis, gastroenteritis, influenza, lung infection, nasopharyngitis, rhinitis, sepsis, septic shock, urinary tract infection, viral infection. Metabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome. Musculoskeletal and connective tissue disorders: muscle spasms, muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia. Nervous system disorders: cerebrovascular accident, dizziness, paresthesia, peripheral neuropathy. Psychiatric disorders: anxiety, delirium. Renal and urinary disorders: acute kidney injury, renal failure, renal impairment. Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary hemorrhage, pulmonary embolism, pulmonary hypertension, pulmonary edema, wheezing. Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash. Vascular disorders: deep vein thrombosis, flushing, hypotension. Kyprolis in Combination with Intravenous Daratumumab and Dexamethasone The safety of Kyprolis in combination with intravenous daratumumab and dexamethasone was evaluated in two trials (CANDOR and EQUULEUS).. CANDORThe safety of Kyprolis 20/56 mg/m2 twice weekly in combination with intravenous daratumumab and dexamethasone (DKd) was evaluated in CANDOR [see Clinical Studies (14.3)]. Patients received Kyprolis for median duration of 58 weeks in the DKd arm and 40 weeks in the Kd arm.Serious adverse reactions were reported in 56% of the patients in the DKd arm and 46% of the patients in the Kd arm. The most frequent serious adverse reactions reported in the DKd arm as compared with the Kd arm were pneumonia (14% versus 9%), pyrexia (4.2% versus 2.0%), influenza (3.9% versus 1.3%), sepsis (3.9% versus 1.3%), anemia (2.3% versus 0.7%), bronchitis (1.9% versus 0%) and diarrhea (1.6% versus 0%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 10% of 308 patients in the DKd arm compared with 5% of 153 patients in the Kd arm. The most frequent fatal adverse reaction (DKd versus Kd) was infection 4.5% versus 2.6%.Permanent discontinuation due to an adverse reaction in patients who received Kyprolis occurred in 21% of patients in the DKd arm versus 22% in the Kd arm. The most frequent adverse reactions leading to discontinuation of Kyprolis were cardiac failure (1.9%) and fatigue (1.9%) in the DKd arm and cardiac failure (2.0%), hypertension (2.0%) and acute kidney injury (2.0%) in the Kd arm. Interruption of Kyprolis due to adverse reactions occurred in 71% of patients in DKd arm versus 63% in the Kd arm. Dose reduction of Kyprolis due to adverse reactions occurred in 25% of patients in DKd arm versus 20% in the Kd arm.Infusion-related reactions that occurred following the first Kyprolis dose was 13% in the DKd arm versus 1% in the Kd arm. Table 17 summarizes the adverse reactions in CANDOR.Table 17: Adverse Reactions (>= 15%) in Patients Who Received either DKd or Kd (20/56 mg/m2 Regimen) in CANDORAdverse ReactionsTwice weekly DKd(N 308)Twice weekly Kd(N 153)All Grades (%)Grade or (%)All Grades (%)Grade or (%)DKd Kyprolis, daratumumab, and dexamethasone; Kd Kyprolis and dexamethasoneGeneral Disorders and Administration Site Conditions Infusion-related reactionThe incidence of infusion related reactions is based on group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within day after DKd or Kd administration. 4112285 FatigueFatigue includes fatigue and asthenia. 3211288 Pyrexia201.9150.7Infections Respiratory tract infectionRespiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. 40Includes fatal adverse reactions. 7293.3 Pneumonia18 13129 Bronchitis172.6121.3Blood and Lymphatic System Disorders ThrombocytopeniaThrombocytopenia includes platelet count decreased and thrombocytopenia. 37253016 AnemiaAnemia includes anemia, hematocrit decreased and hemoglobin decreased. 33173114Gastrointestinal Disorders Diarrhea323.9140.7 Nausea180130.7Vascular Disorders Hypertension31182813Respiratory, Thoracic and Mediastinal Disorders CoughCough includes productive cough and cough. 210210 Dyspnea203.9222.6Psychiatric Disorders Insomnia183.9112.0Musculoskeletal and Connective Tissue Disorders Back pain161.9101.3. Adverse Reactions Occurring at Frequency of 15%Blood and lymphatic system disorders: febrile neutropenia, thrombotic thrombocytopenic purpuraCardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiomyopathy, myocardial infarction, myocardial ischemia, tachycardiaEye disorders: cataractGastrointestinal disorders: abdominal pain, gastrointestinal hemorrhageGeneral disorders and administration site conditions: chest pain, malaiseInfections: gastroenteritis, influenza, lung infection, nasopharyngitis, sepsis, septic shock, urinary tract infection, viral infectionInvestigations: alanine aminotransferase increased, blood creatinine increased, C-reactive protein increased, ejection fraction decreasedMetabolism and nutrition disorders: dehydration, hyperglycemia, hyperkalemia, hypokalemia, hyponatremia, tumor lysis syndromeMusculoskeletal and connective tissue disorders: pain in extremityNervous system disorders: cerebrovascular accident, intracranial hemorrhage, posterior reversible encephalopathy syndrome, peripheral neuropathyPsychiatric disorders: anxietyRenal and urinary disorders: acute kidney injury, renal failure, renal impairmentRespiratory, thoracic and mediastinal disorders: acute respiratory failure, epistaxis, interstitial lung disease, pneumonitis, pulmonary embolism, pulmonary hypertension, pulmonary edemaSkin and subcutaneous tissue disorders: rashVascular disorders: deep vein thrombosis, hypertensive crisis. Blood and lymphatic system disorders: febrile neutropenia, thrombotic thrombocytopenic purpura. Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiomyopathy, myocardial infarction, myocardial ischemia, tachycardia. Eye disorders: cataract. Gastrointestinal disorders: abdominal pain, gastrointestinal hemorrhage. General disorders and administration site conditions: chest pain, malaise. Infections: gastroenteritis, influenza, lung infection, nasopharyngitis, sepsis, septic shock, urinary tract infection, viral infection. Investigations: alanine aminotransferase increased, blood creatinine increased, C-reactive protein increased, ejection fraction decreased. Metabolism and nutrition disorders: dehydration, hyperglycemia, hyperkalemia, hypokalemia, hyponatremia, tumor lysis syndrome. Musculoskeletal and connective tissue disorders: pain in extremity. Nervous system disorders: cerebrovascular accident, intracranial hemorrhage, posterior reversible encephalopathy syndrome, peripheral neuropathy. Psychiatric disorders: anxiety. Renal and urinary disorders: acute kidney injury, renal failure, renal impairment. Respiratory, thoracic and mediastinal disorders: acute respiratory failure, epistaxis, interstitial lung disease, pneumonitis, pulmonary embolism, pulmonary hypertension, pulmonary edema. Skin and subcutaneous tissue disorders: rash. Vascular disorders: deep vein thrombosis, hypertensive crisis. EQUULEUSThe safety of Kyprolis 20/70 mg/m2 once weekly in combination with intravenous daratumumab and dexamethasone (DKd) was evaluated in EQUULEUS [see Clinical Studies (14.3)]. Patients received Kyprolis for median duration of 66 weeks.Serious adverse reactions were reported in 48% of patients. The most frequent serious adverse reactions reported were pneumonia (4.7%), upper respiratory tract infection (4.7%), basal cell carcinoma (4.7%), influenza (3.5%), general physical health deterioration (3.5%) and hypercalcemia (3.5%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 3.5% of patients who died of general physical health deterioration, multi-organ failure secondary to pulmonary aspergillosis, and disease progression.Discontinuation of Kyprolis occurred in 19% of patients. The most frequent adverse reaction leading to discontinuation was asthenia (2%). Interruption of Kyprolis due to adverse reactions occurred in 77% of patients. Dose reduction of Kyprolis due to adverse reactions occurred in 31% of patients in DKd.Infusion-related reactions that occurred following the first Kyprolis dose was 11%. Pulmonary hypertension adverse reactions were reported in 4.7% of patients in EQUULEUS.Table 18 summarizes the adverse reactions in EQUULEUS.Table 18: Adverse Reactions (>= 15%) in Patients Who Received DKd (20/70 mg/m2 Regimen) in EQUULEUSAdverse Reactions Once weekly DKd(N 85)All Grades(%)Grade or 4(%)DKd Kyprolis, daratumumab, and dexamethasone; Kd Kyprolis and dexamethasoneBlood and Lymphatic System Disorders ThrombocytopeniaThrombocytopenia includes platelet count decreased and thrombocytopenia. 6832 AnemiaAnemia includes anemia, hematocrit decreased and hemoglobin decreased. 5221 NeutropeniaNeutropenia includes neutrophil count decreased and neutropenia. 3121 LymphopeniaLymphopenia includes lymphocyte count decreased and lymphopenia. 2925General Disorders and Administration Site Conditions FatigueFatigue includes fatigue and asthenia. 5418 Infusion-related reactionThe incidence of infusion related reactions is based on group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within day after DKd administration. 5312 Pyrexia371.2Infections Respiratory tract infectionRespiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. 533.5 Bronchitis190 Nasopharyngitis180 Influenza173.5Gastrointestinal Disorders Nausea421.2 Vomiting401.2 Diarrhea382.4 Constipation170Respiratory, Thoracic and Mediastinal Disorders Dyspnea353.5 CoughCough includes productive cough and cough. 330Vascular Disorders Hypertension3320Psychiatric Disorders Insomnia334.7Nervous System Disorders Headache271.2Musculoskeletal and Connective Tissue Disorders Back pain250 Pain in extremity150. Adverse Reactions Occurring at Frequency of 15%Blood and lymphatic system disorders: febrile neutropenia, thrombotic microangiopathyCardiac disorders: cardiac failure, myocardial ischemiaGastrointestinal disorders: abdominal painGeneral disorders and administration site conditions: multiple organ dysfunction syndromeInfections: pneumonia, sepsis, septic shockMetabolism and nutrition disorders: dehydration, hypercalcemiaRenal and urinary disorders: acute kidney injury, renal failure, renal impairmentRespiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary hypertensionVascular disorders: hypotension. Blood and lymphatic system disorders: febrile neutropenia, thrombotic microangiopathy. Cardiac disorders: cardiac failure, myocardial ischemia. Gastrointestinal disorders: abdominal pain. General disorders and administration site conditions: multiple organ dysfunction syndrome. Infections: pneumonia, sepsis, septic shock. Metabolism and nutrition disorders: dehydration, hypercalcemia. Renal and urinary disorders: acute kidney injury, renal failure, renal impairment. Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary hypertension. Vascular disorders: hypotension. Kyprolis in Combination with Subcutaneous Daratumumab and DexamethasoneThe safety of Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone was evaluated in PLEIADES [see Clinical Studies (14.3)].. PLEIADESThe safety of Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone (DKd) was evaluated in single-arm cohort of PLEIADES. Patients received Kyprolis as 30-minute IV infusion once weekly for three weeks (Days 1, 8, and 15), followed by 13-day rest period (Days 16 to 28) and continued until disease progression or unacceptable toxicity (N=66) in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Among these patients, 77% were exposed for months or longer and 27% were exposed for greater than one year.Serious adverse reactions occurred in 27% of patients who received Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Fatal adverse reactions occurred in 3% of patients who received Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone.Permanent discontinuation of Kyprolis due to an adverse reaction occurred in 6% of patients who received Kyprolis.Dosage interruptions due to an adverse reaction occurred in 46% of patients who received Kyprolis.The most common adverse reactions (>=20%) were upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea and edema peripheral.Table 19 summarizes the adverse reactions in patients who received Kyprolis with subcutaneous daratumumab and dexamethasone (DKd) in PLEIADES.Table 19: Adverse Reactions (>=10%) in Patients Who Received Kyprolis with Subcutaneous Daratumumab and Dexamethasone (DKd) in PLEIADESAdverse ReactionDKd(N=66) All Grades(%)Grade >=3(%)Infections and infestations Upper respiratory tract infectionUpper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, viral pharyngitis, and viral upper respiratory tract infection. 520 BronchitisBronchitis includes bronchitis, and bronchitis viral. 122Only Grade adverse reactions occurred. General disorders and administration site conditions FatigueFatigue includes asthenia, and fatigue. 392 Pyrexia212 Edema peripheralEdema peripheral includes generalized edema, edema peripheral, and peripheral swelling. 200Psychiatric disorders Insomnia336 Vascular disorders HypertensionHypertension includes blood pressure increased, and hypertension. 3221 Gastrointestinal disorders Diarrhea290 Nausea210 Vomiting150Respiratory, thoracic and mediastinal disorders CoughCough includes cough, and productive cough. 240 DyspneaDyspnea includes dyspnea, and dyspnea exertional. 232 Nervous system disorders Headache230 Peripheral sensory neuropathy110Musculoskeletal and connective tissue disorders Back pain172 Musculoskeletal chest pain110Clinically relevant adverse reactions in <10% of patients who received Kyprolis with subcutaneous daratumumab and dexamethasone include:Gastrointestinal disorders: abdominal pain, constipation, pancreatitisInfection and infestations: pneumonia, influenza, urinary tract infection, herpes zoster, sepsisMetabolism and nutrition disorders: hyperglycemia, decreased appetite, hypocalcemiaMusculoskeletal and connective tissue disorders: muscle spasms, arthralgiaNervous system disorders: paresthesia, dizziness, syncopeGeneral disorders and administration site conditions: injection site reaction, infusion reactions, chillsSkin and subcutaneous tissue disorders: rash, pruritusCardiac disorders: cardiac failureVascular disorders: hypotensionTable 20 summarizes the laboratory abnormalities in patients who received Kyprolis with subcutaneous daratumumab and dexamethasone in PLEIADES.Table 20: Select Laboratory Abnormalities (>=30%) Worsening from Baseline in Patients Who Received DKd in PLEIADESLaboratory AbnormalityDKdDenominator is based on the safety population treated with DKd (N=66). All Grades (%)Grades 3-4 (%)Decreased platelets8818Decreased lymphocytes8350Decreased leukocytes6818Decreased neutrophils5515Decreased hemoglobin476Decreased corrected calcium452Increased alanine aminotransferase (ALT)355. Gastrointestinal disorders: abdominal pain, constipation, pancreatitis. Infection and infestations: pneumonia, influenza, urinary tract infection, herpes zoster, sepsis. Metabolism and nutrition disorders: hyperglycemia, decreased appetite, hypocalcemia. Musculoskeletal and connective tissue disorders: muscle spasms, arthralgia. Nervous system disorders: paresthesia, dizziness, syncope. General disorders and administration site conditions: injection site reaction, infusion reactions, chills. Skin and subcutaneous tissue disorders: rash, pruritus. Cardiac disorders: cardiac failure. Vascular disorders: hypotension. Kyprolis in Patients who Received Monotherapy The safety of Kyprolis 20/27 mg/m2 as 10-minute infusion was evaluated in clinical trials consisting of 598 patients with relapsed and/or refractory myeloma [see Clinical Studies (14.2)]. Premedication with dexamethasone mg was required before each dose in Cycle and was optional for subsequent cycles. The median age was 64 years (range 32-87), and approximately 57% were male. The patients received median of (range 1-20) prior regimens. The median number of cycles initiated was (range 1-35).Deaths due to adverse reactions within 30 days of the last dose of Kyprolis occurred in 30/598 (5%) patients receiving Kyprolis monotherapy. These adverse reactions were related to cardiac disorders in 10 (2%) patients, infections in (1%) patients, renal disorders in (< 1%) patients, and other adverse reactions in (1%) patients.Serious adverse reactions were reported in 50% of patients in the pooled Kyprolis monotherapy studies (N 598). The most frequent serious adverse reactions were: pneumonia (8%), acute renal failure (5%), disease progression (4%), pyrexia (3%), hypercalcemia (3%), congestive heart failure (3%), multiple myeloma (3%), anemia (2%), and dyspnea (2%). In FOCUS, randomized trial comparing Kyprolis as single agent versus corticosteroids with optional oral cyclophosphamide for patients with relapsed and refractory multiple myeloma, mortality was higher in the patients treated with Kyprolis in comparison to the control arm in the subgroup of 48 patients >= 75 years of age. The most common cause of discontinuation due to an adverse reaction was acute renal failure (2%).Safety of Kyprolis monotherapy dosed at 20/56 mg/m2 by 30-minute infusion was evaluated in multicenter, open-label study in patients with relapsed and/or refractory multiple myeloma [see Clinical Studies (14.4)]. The patients received median of (range 1-10) prior regimens.Adverse reactions occurring with Kyprolis monotherapy are presented in Table 21.Table 21: Adverse Reactions (>= 20%) with Kyprolis MonotherapyAdverse Reactions20/56 mg/m2 by 30-minute infusion(N 24)20/27 mg/m2 by 2- to 10-minute infusion(N 598)All Gradesn (%)Grades 3-5n (%)All Gradesn (%)Grades 3-5n (%)Fatigue14 (58)2 (8)238 (40)25 (4)DyspneaDyspnea includes dyspnea and dyspnea exertional. 14 (58)2 (8)202 (34)21 (4)Pyrexia14 (58)0177 (30)11 (2)Thrombocytopenia13 (54)13 (54)220 (37)152 (25)Nausea13 (54)0211 (35)7 (1)Anemia10 (42)7 (29)291 (49)141 (24)HypertensionHypertension includes hypertension, hypertensive crisis, and hypertensive emergency. 10 (42)3 (13)90 (15)22 (4)Chills9 (38)073 (12)1 (< 1)Headache8 (33)0141 (24)7 (1)CoughCough includes cough and productive cough. (33)0134 (22)2 (< 1)Vomiting8 (33)0104 (17)4 (1)Lymphopenia8 (33)8 (33)85 (14)73 (12)Insomnia7 (29)075 (13)0Dizziness7 (29)064 (11)5 (1)Diarrhea6 (25)1 (4)160 (27)8 (1)Blood creatinine increased6 (25)1 (4)103 (17)15 (3)Peripheral edema5 (21)0118 (20)1 (< 1)Back pain5 (21)1 (4)115 (19)19 (3)Upper respiratory tract infection5 (21)1 (4)112 (19)15 (3)Decreased appetite5 (21)089 (15)2 (< 1)Muscle spasms5 (21)062 (10)2 (< 1)Chest pain5 (21)020 (3)1 (< 1). Adverse Reactions Occurring at Frequency of 20%Blood and lymphatic system disorders: febrile neutropenia, leukopenia, neutropeniaCardiac disorders: cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemiaEar and labyrinth disorders: tinnitusEye disorders: cataract, blurred visionGastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, gastrointestinal hemorrhage, toothacheGeneral disorders and administration site conditions: asthenia, infusion site reaction, multi-organ failure, painHepatobiliary disorders: hepatic failureInfections: bronchitis, bronchopneumonia, influenza, lung infection, pneumonia, nasopharyngitis, respiratory tract infection, rhinitis, sepsis, urinary tract infectionMetabolism and nutrition disorders: hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndromeMusculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, musculoskeletal chest pain, myalgia, pain in extremityNervous system disorders: hypoesthesia, intracranial hemorrhage, paresthesia, peripheral motor neuropathy, peripheral neuropathy, peripheral sensory neuropathyPsychiatric disorders: anxietyRenal and urinary disorders: acute renal failure, renal failure, renal impairmentRespiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary edema, pulmonary hemorrhageSkin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rashVascular disorders: embolic and thrombotic events, venous (including deep vein thrombosis and pulmonary embolism), hemorrhage, hypotensionGrade and higher adverse reactions occurring at an incidence of 1% include febrile neutropenia, cardiac arrest, cardiac failure congestive, pain, sepsis, urinary tract infection, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hyponatremia, hypophosphatemia, renal failure, renal failure acute, renal impairment, pulmonary edema, and hypotension.Table 22 describes Grade 3-4 laboratory abnormalities reported at rate of 10% for patients who received Kyprolis monotherapy.Table 22: Grade 3-4 Laboratory Abnormalities (> 10%) with Kyprolis MonotherapyLaboratory AbnormalityKyprolis20/56 mg/m2 (N 24)Kyprolis20/27 mg/m2 (N 598)Decreased lymphocytes15 (63)151 (25)Decreased platelets11 (46)184 (31)Decreased hemoglobin7 (29)132 (22)Decreased total white blood cell count3 (13)71 (12)Decreased sodium2 (8)69 (12)Decreased absolute neutrophil count2 (8)67 (11). Blood and lymphatic system disorders: febrile neutropenia, leukopenia, neutropenia. Cardiac disorders: cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia. Ear and labyrinth disorders: tinnitus. Eye disorders: cataract, blurred vision. Gastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, gastrointestinal hemorrhage, toothache. General disorders and administration site conditions: asthenia, infusion site reaction, multi-organ failure, pain. Hepatobiliary disorders: hepatic failure. Infections: bronchitis, bronchopneumonia, influenza, lung infection, pneumonia, nasopharyngitis, respiratory tract infection, rhinitis, sepsis, urinary tract infection. Metabolism and nutrition disorders: hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome. Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, musculoskeletal chest pain, myalgia, pain in extremity. Nervous system disorders: hypoesthesia, intracranial hemorrhage, paresthesia, peripheral motor neuropathy, peripheral neuropathy, peripheral sensory neuropathy. Psychiatric disorders: anxiety. Renal and urinary disorders: acute renal failure, renal failure, renal impairment. Respiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary edema, pulmonary hemorrhage. Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash. Vascular disorders: embolic and thrombotic events, venous (including deep vein thrombosis and pulmonary embolism), hemorrhage, hypotension.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. For injection: 10 mg, 30 mg and 60 mg as lyophilized cake or powder in single-dose vial for reconstitution.. For injection: 10 mg, 30 mg or 60 mg lyophilized powder in single-dose vial for reconstitution. (3).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Geriatric Use: In the Kyprolis clinical trials, the incidence of adverse reactions was greater in patients >= 75 years of age. (8.5)Hepatic Impairment: Reduce the dose of Kyprolis by 25% in patients with mild or moderate hepatic impairment. (2.4)Patients on Hemodialysis: Administer Kyprolis after the hemodialysis procedure. (2.1)Lactation: Advise women not to breastfeed. (8.2). Geriatric Use: In the Kyprolis clinical trials, the incidence of adverse reactions was greater in patients >= 75 years of age. (8.5). Hepatic Impairment: Reduce the dose of Kyprolis by 25% in patients with mild or moderate hepatic impairment. (2.4). Patients on Hemodialysis: Administer Kyprolis after the hemodialysis procedure. (2.1). Lactation: Advise women not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryKyprolis can cause fetal harm based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)]. There are no available data on Kyprolis use in pregnant women to evaluate for drug-associated risks. Kyprolis caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (see Data). Advise pregnant women of the potential risk to the fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.. Data. Animal DataCarfilzomib administered intravenously to pregnant rats and rabbits during the period of organogenesis was not teratogenic at doses up to mg/kg/day in rats and 0.8 mg/kg/day in rabbits. In rabbits, there was an increase in pre-implantation loss at >= 0.4 mg/kg/day and an increase in early resorptions and post-implantation loss and decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on BSA.. 8.2 Lactation. Risk SummaryThere are no data on the presence of Kyprolis in human milk, the effects on the breastfed child, or the effects of the drug on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with Kyprolis and for weeks after treatment.. 8.3 Females and Males of Reproductive Potential. Based on its mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingConduct pregnancy testing on females of reproductive potential prior to initiating Kyprolis treatment.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with Kyprolis and for months following the last dose.. MalesAdvise males with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for months following the last dose.. InfertilityBased on the mechanism of action, Kyprolis may have an effect on either male or female fertility [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. There are no data on the effect of Kyprolis on human fertility.. 8.4 Pediatric Use. The safety and effectiveness of Kyprolis in pediatric patients have not been established.. 8.5 Geriatric Use. Of the 2,387 patients in clinical studies of Kyprolis, 51% were 65 years and older, while 14% were 75 years and older. The incidence of serious adverse reactions was 49% in patients 65 years of age, 58% in patients 65 to 74 years of age, and 63% in patients >= 75 years of age. Of the 308 patients in CANDOR who received DKd, 47% of patients were 65 years and older, while 9% were 75 years and older. Fatal adverse reactions in the DKd arm of CANDOR occurred in 6% of patients <65 years of age, 14% of patients between 65 to 74 years of age, and 14% of patients >= 75 years of age [see Adverse Reactions (6.1)]. No overall differences in effectiveness were observed between older and younger patients. 8.6 Hepatic Impairment. Reduce the dose of Kyprolis by 25% in patients with mild (total bilirubin to 1.5 ULN and any AST or total bilirubin <= ULN and AST ULN) or moderate (total bilirubin 1.5 to x ULN and any AST) hepatic impairment. recommended dosage of Kyprolis has not been established for patients with severe hepatic impairment (total bilirubin 3 ULN and any AST) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].The incidence of serious adverse reactions was higher in patients with mild, moderate, and severe hepatic impairment combined (22/35 or 63%) than in patients with normal hepatic function (3/11 or 27%) [see Warnings and Precautions (5.12), Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Cardiac Toxicities: Monitor for signs and symptoms of cardiac failure or ischemia. Withhold Kyprolis and evaluate promptly. (5.1)Acute Renal Failure: Monitor serum creatinine regularly. (5.2)Tumor Lysis Syndrome (TLS): Administer pre-treatment hydration. (2.1) Monitor for TLS, including uric acid levels and treat promptly. (5.3)Pulmonary Toxicity, including Acute Respiratory Distress Syndrome, Acute Respiratory Failure, and Acute Diffuse Infiltrative Pulmonary Disease: Withhold Kyprolis and evaluate promptly. (5.4)Pulmonary Hypertension: Withhold Kyprolis and evaluate. (5.5)Dyspnea: For severe or life-threatening dyspnea, withhold Kyprolis and evaluate. (5.6)Hypertension, including Hypertensive Crisis: Monitor blood pressure regularly. If hypertension cannot be controlled, interrupt treatment with Kyprolis. (5.7)Venous Thrombosis: Thromboprophylaxis is recommended. (5.8)Infusion-related Reactions: Premedicate with dexamethasone. (2.1, 5.9)Hemorrhage: Fatal or serious cases of hemorrhage may occur, including gastrointestinal, pulmonary, and intracranial hemorrhage. Promptly evaluate signs and symptoms of blood loss. (5.10)Thrombocytopenia: Monitor platelet counts; interrupt or reduce Kyprolis dosing as clinically indicated. (2.3, 5.11)Hepatic Toxicity and Hepatic Failure: Monitor liver enzymes regularly. Withhold Kyprolis if suspected. (5.12)Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue Kyprolis if suspected. (5.13)Posterior Reversible Encephalopathy Syndrome (PRES): Consider neuro-radiological imaging (MRI) for onset of visual or neurological symptoms; discontinue Kyprolis if suspected. (5.14)Progressive Multifocal Leukoencephalopathy: Consider PML if new or worsening neurologic manifestations. Discontinue Kyprolis in patients who develop PML. (5.15) Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients (5.16)Embryo-Fetal Toxicity: Kyprolis can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to fetus and to use effective contraception. (5.17, 8.1). Cardiac Toxicities: Monitor for signs and symptoms of cardiac failure or ischemia. Withhold Kyprolis and evaluate promptly. (5.1). Acute Renal Failure: Monitor serum creatinine regularly. (5.2). Tumor Lysis Syndrome (TLS): Administer pre-treatment hydration. (2.1) Monitor for TLS, including uric acid levels and treat promptly. (5.3). Pulmonary Toxicity, including Acute Respiratory Distress Syndrome, Acute Respiratory Failure, and Acute Diffuse Infiltrative Pulmonary Disease: Withhold Kyprolis and evaluate promptly. (5.4). Pulmonary Hypertension: Withhold Kyprolis and evaluate. (5.5). Dyspnea: For severe or life-threatening dyspnea, withhold Kyprolis and evaluate. (5.6). Hypertension, including Hypertensive Crisis: Monitor blood pressure regularly. If hypertension cannot be controlled, interrupt treatment with Kyprolis. (5.7). Venous Thrombosis: Thromboprophylaxis is recommended. (5.8). Infusion-related Reactions: Premedicate with dexamethasone. (2.1, 5.9). Hemorrhage: Fatal or serious cases of hemorrhage may occur, including gastrointestinal, pulmonary, and intracranial hemorrhage. Promptly evaluate signs and symptoms of blood loss. (5.10). Thrombocytopenia: Monitor platelet counts; interrupt or reduce Kyprolis dosing as clinically indicated. (2.3, 5.11). Hepatic Toxicity and Hepatic Failure: Monitor liver enzymes regularly. Withhold Kyprolis if suspected. (5.12). Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue Kyprolis if suspected. (5.13). Posterior Reversible Encephalopathy Syndrome (PRES): Consider neuro-radiological imaging (MRI) for onset of visual or neurological symptoms; discontinue Kyprolis if suspected. (5.14). Progressive Multifocal Leukoencephalopathy: Consider PML if new or worsening neurologic manifestations. Discontinue Kyprolis in patients who develop PML. (5.15). Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients (5.16). Embryo-Fetal Toxicity: Kyprolis can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to fetus and to use effective contraception. (5.17, 8.1). 5.1Cardiac Toxicities. New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Some events occurred in patients with normal baseline ventricular function. In clinical studies with Kyprolis, these events occurred throughout the course of Kyprolis therapy. Death due to cardiac arrest has occurred within one day of Kyprolis administration. In randomized, open-label, multicenter trials for combination therapies, the incidence of cardiac failure events was 8% and that of arrythmias was 8% (majority of which were atrial fibrillation and sinus tachycardia) [see Adverse Reactions (6.1)]. Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold Kyprolis for Grade or cardiac adverse reactions until recovery and consider whether to restart Kyprolis at dose level reduction based on benefit/risk assessment [see Dosage and Administration (2.3)].While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure [see Dosage and Administration (2.1)].In patients >= 75 years of age, the risk of cardiac failure is increased compared to younger patients. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications; for these patients, complete comprehensive medical assessment (including blood pressure control and fluid management) prior to starting treatment with Kyprolis and remain under close follow-up [see Use in Specific Populations (8.5)].. 5.2Acute Renal Failure. Cases of acute renal failure have occurred in patients receiving Kyprolis. Some of these events have been fatal. Renal insufficiency (including renal failure) has occurred in approximately 9% of patients who received Kyprolis. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy. The risk of fatal renal failure was greater in patients with baseline reduced estimated creatinine clearance (calculated using Cockcroft-Gault equation).Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3)].. 5.3Tumor Lysis Syndrome. Cases of TLS, including fatal outcomes, have been reported in patients who received Kyprolis. Patients with multiple myeloma and high tumor burden should be considered to be at greater risk for TLS.Administer oral and intravenous fluids before administration of Kyprolis in Cycle and in subsequent cycles as needed. Consider uric acid-lowering drugs in patients at risk for TLS. Monitor for TLS during treatment and manage promptly, including interruption of Kyprolis until TLS is resolved [see Dosage and Administration (2.1)].. 5.4Pulmonary Toxicity. Acute Respiratory Distress Syndrome (ARDS) and acute respiratory failure have occurred in approximately 2% of patients who received Kyprolis. In addition, acute diffuse infiltrative pulmonary disease, such as pneumonitis and interstitial lung disease, occurred in approximately 2% of patients who received Kyprolis. Some events were fatal.In the event of drug-induced pulmonary toxicity, discontinue Kyprolis.. 5.5Pulmonary Hypertension. Pulmonary arterial hypertension was reported in approximately 2% of patients who received Kyprolis, with Grade or greater in less than 1%.Evaluate with cardiac imaging and/or other tests as indicated. Withhold Kyprolis for pulmonary hypertension until resolved or returned to baseline and consider whether to restart Kyprolis based on benefit/risk assessment.. 5.6Dyspnea. Dyspnea was reported in 25% of patients treated with Kyprolis, with Grade or greater in 4%.Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade or dyspnea until resolved or returned to baseline. Consider whether to restart Kyprolis based on benefit/risk assessment [see Warnings and Precautions (5.1, 5.4) and Adverse Reactions (6.1)].. 5.7Hypertension. Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. In ASPIRE, the incidence of hypertension events was 17% in the KRd arm versus 9% in the Rd arm. In ENDEAVOR, the incidence of hypertension events was 34% in the Kd arm versus 11% in the Vd arm. In CANDOR, the incidence of hypertension events was 31% in the DKd arm versus 28% in the Kd arm. Some of these events have been fatal.Optimize blood pressure prior to starting Kyprolis. Monitor blood pressure regularly in all patients while on Kyprolis. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on benefit/risk assessment.. 5.8Venous Thrombosis. Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. In ASPIRE, with thromboprophylaxis used in both arms, the incidence of venous thromboembolic events in the first 12 cycles was 13% in the KRd arm versus 6% in the Rd arm. In ENDEAVOR, the incidence of venous thromboembolic events in months 1-6 was 9% in the Kd arm versus 2% in the Vd arm. With Kyprolis monotherapy, the incidence of venous thromboembolic events was 2%.Provide thromboprophylaxis for patients being treated with Kyprolis in combination with lenalidomide and dexamethasone; with dexamethasone; or with intravenous daratumumab and dexamethasone. Select the thromboprophylaxis regimen based on the patients underlying risks. For patients using oral contraceptives or hormonal contraception associated with risk of thrombosis, consider non-hormonal contraception during treatment when Kyprolis is administered in combination [see Use in Specific Populations (8.3)].. 5.9Infusion-Related Reactions. Infusion-related reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Administer dexamethasone prior to Kyprolis to reduce the incidence and severity of infusion-related reactions [see Dosage and Administration (2.1, 2.2), Adverse Reactions (6.1)]. 5.10Hemorrhage. Fatal or serious cases of hemorrhage have been reported in patients treated with Kyprolis [see Adverse Reactions (6.1)]. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. The bleeding can be spontaneous and intracranial hemorrhage has occurred without trauma. Hemorrhage has been reported in patients having either low or normal platelet counts. Hemorrhage has also been reported in patients who were not on antiplatelet therapy or anticoagulation.Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3)].. 5.11Thrombocytopenia. Kyprolis causes thrombocytopenia with platelet nadirs observed between Day and Day 15 of each 28-day cycle, with recovery to baseline platelet count usually by the start of the next cycle [see Adverse Reactions (6.1)]. Thrombocytopenia was reported in approximately 32% of patients in clinical trials with Kyprolis. Hemorrhage may occur [see Adverse Reactions (6.1), Warnings and Precautions (5.10)].Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3)].. 5.12Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been reported (2%) during treatment with Kyprolis. Kyprolis can cause increased serum transaminases [see Adverse Reactions (6.1)].Monitor liver enzymes regularly, regardless of baseline values. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3)].. 5.13Thrombotic Microangiopathy. Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received Kyprolis. Some of these events have been fatal.Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Kyprolis and evaluate. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known.. 5.14Posterior Reversible Encephalopathy Syndrome Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving Kyprolis. PRES, formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS), is neurological disorder which can present with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological disturbances, along with hypertension, and the diagnosis is confirmed by neuro-radiological imaging (MRI).Discontinue Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.. 5.15 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), which can be fatal, has been reported with Kyprolis. In addition to Kyprolis, other possible contributory factors include prior or concurrent immunosuppressive therapy that may cause immunosuppression. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue Kyprolis and initiate evaluation for PML including neurology consultation. 5.16 Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients. In CLARION, clinical trial of 955 transplant-ineligible patients with newly diagnosed multiple myeloma randomized to Kyprolis (20/36 mg/m2 by 30-minute infusion twice weekly for four of each six-week cycle), melphalan and prednisone (KMP) or bortezomib, melphalan and prednisone (VMP), higher incidence of fatal adverse reactions (7% versus 4%) and serious adverse reactions (50% versus 42%) were observed in the KMP arm compared to patients in the VMP arm, respectively. Patients in the KMP arm were observed to have higher incidence of any grade adverse reactions involving cardiac failure (11% versus 4%), hypertension (25% versus 8%), acute renal failure (14% versus 6%), and dyspnea (18% versus 9%). This study did not meet its primary outcome measure of superiority in progression-free survival (PFS) for the KMP arm. Kyprolis in combination with melphalan and prednisone is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.. 5.17 Embryo-Fetal Toxicity. Based on the mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to pregnant woman. Carfilzomib administered intravenously to pregnant rabbits during organogenesis at dose approximately 40% of the clinical dose of 27 mg/m2 based on BSA caused post-implantation loss and decrease in fetal weight.Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with Kyprolis and for months following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Kyprolis and for months following the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2Animal Toxicology and/or Pharmacology. Cardiovascular ToxicityMonkeys administered single bolus intravenous dose of carfilzomib at mg/kg (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on BSA) experienced hypotension, increased heart rate, and increased serum levels of troponin-T.. Chronic AdministrationRepeated bolus intravenous administration of carfilzomib at >= mg/kg/dose in rats and mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) systems. The dose of mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m2 based on BSA. The dose of mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on BSA.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with carfilzomib.Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay.Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-month monkey chronic toxicity studies.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Carfilzomib is tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors.. 12.2 Pharmacodynamics. Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like (CT-L) activity when measured in blood hour after the first dose. Doses of carfilzomib >= 15 mg/m2 with or without lenalidomide and dexamethasone induced >= 80% inhibition of the CT-L activity of the proteasome. In addition, carfilzomib, 20 mg/m2 intravenously as single agent, resulted in mean inhibition of the low molecular mass polypeptide (LMP2) and multicatalytic endopeptidase complex-like (MECL1) subunits of the proteasome ranging from 26% to 32% and 41% to 49%, respectively. Proteasome inhibition was maintained for >= 48 hours following the first dose of carfilzomib for each week of dosing.. 12.3 Pharmacokinetics. Carfilzomib at doses between 20 mg/m2 and 70 mg/m2 administered as 30-minute infusion resulted in dose-dependent increases in maximum plasma concentrations (Cmax) and area under the curve over time to infinity (AUC0-INF) in patients with multiple myeloma. dose-dependent increase in Cmax and AUC0-INF was also observed between carfilzomib 20 mg/m2 and 56 mg/m2 as 2- to 10-minute infusion in patients with relapsed or refractory multiple myeloma. 30-minute infusion resulted in similar AUC0-INF, but 2- to 3-fold lower Cmax than that observed with 2- to 10-minute infusion at the same dose. There was no evidence of carfilzomib accumulation following repeated administration of carfilzomib 70 mg/m2 as 30-minute once weekly infusion or 15 and 20 mg/m2 as 2- to 10-minute twice weekly infusion.Table 23 lists the estimated mean average daily area under the curve in the first cycle (AUCC1,avg), average daily area under the curve at steady-state (AUCss) and Cmax at the highest dose in the first cycle (Cmax,C1) for the different dosing regimens.Table 23: Carfilzomib Exposure Parameters for Different Dosing RegimensEstimated Parameters (%CV)20/27 mg/m2 twice weekly with 2- to 10-minute infusion20/56 mg/m2 twice weekly with 30-minute infusion20/70 mg/m2 once weekly with 30-minute infusionCV Coefficient of variationAUCC1,avg (nghr/mL)95 (40)170 (35)114 (36)AUCss (nghr/mL)111 (34)228 (28)150 (35)Cmax,C1 (ng/mL)1282 (17)1166 (29)1595 (36). DistributionThe mean steady-state volume of distribution of 20 mg/m2 dose of carfilzomib was 28 L. Carfilzomib is 97% bound to human plasma proteins over the concentration range of 0.4 to micromolar in vitro.. EliminationCarfilzomib has half-life of <= hour on Day of Cycle following intravenous doses >= 15 mg/m2. The half-life was similar when administered either as 30-minute infusion or 2- to 10-minute infusion. The systemic clearance ranged from 151 to 263 L/hour.. MetabolismCarfilzomib is rapidly metabolized. Peptidase cleavage and epoxide hydrolysis were the principal pathways of metabolism. Cytochrome P450 (CYP)-mediated mechanisms contribute minor role in overall carfilzomib metabolism.. ExcretionApproximately 25% of the administered dose of carfilzomib was excreted in urine as metabolites in 24 hours. Urinary and fecal excretion of the parent compound was negligible (0.3% of total dose).. Specific PopulationsAge (35-89 years), sex, race or ethnicity (80% White, 11% Black, 6% Asians, 3% Hispanics), and mild to severe renal impairment (creatinine clearance 15-89 mL/min) did not have clinically meaningful effects on the pharmacokinetics of carfilzomib.. Patients with Hepatic ImpairmentCompared to patients with normal hepatic function, patients with mild (total bilirubin to 1.5 ULN and any AST or total bilirubin <= ULN and AST ULN) and moderate (total bilirubin 1.5 to x ULN and any AST) hepatic impairment had approximately 50% higher carfilzomib AUC. The pharmacokinetics of carfilzomib has not been evaluated in patients with severe hepatic impairment (total bilirubin 3 ULN and any AST).. Patients with Renal ImpairmentRelative to patients with normal renal function, ESRD patients on hemodialysis showed 33% higher carfilzomib AUC. Since hemodialysis clearance of Kyprolis concentrations has not been studied, the drug should be administered after the hemodialysis procedure.. Drug Interaction Studies. Clinical Studies. Effect of Carfilzomib on Sensitive CYP3A Substrate: Midazolam (a sensitive CYP3A substrate) pharmacokinetics was not affected by concomitant administration of carfilzomib.. In Vitro Studies. Effect of Carfilzomib on Cytochrome P450 (CYP) Enzymes: Carfilzomib showed direct and time-dependent inhibition of CYP3A but did not induce CYP1A2 and CYP3A4 in vitro.. Effect of Transporters on Carfilzomib: Carfilzomib is P-glycoprotein (P-gp) substrate in vitro.. Effect of Carfilzomib on Transporters: Carfilzomib inhibits P-gp in vitro. However, given that Kyprolis is administered intravenously and is extensively metabolized, the pharmacokinetics of Kyprolis is unlikely to be affected by P-gp inhibitors or inducers.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Carfilzomib is proteasome inhibitor. The chemical name for carfilzomib is (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide. Carfilzomib has the following structure:Carfilzomib is crystalline substance with molecular weight of 719.9. The molecular formula is C40H57N5O7. Carfilzomib is practically insoluble in water and very slightly soluble in acidic conditions.Kyprolis for injection, for intravenous use is sterile, white to off-white lyophilized powder in single-dose vial. Each 10 mg vial contains 10 mg of carfilzomib, 500 mg sulfobutylether beta-cyclodextrin, and 9.6 mg anhydrous citric acid and sodium hydroxide for pH adjustment (target pH 3.5). Each 30 mg vial contains 30 mg of carfilzomib, 1500 mg sulfobutylether beta-cyclodextrin, and 28.8 mg anhydrous citric acid and sodium hydroxide for pH adjustment (target pH 3.5). Each 60 mg vial contains 60 mg of carfilzomib, 3000 mg sulfobutylether beta-cyclodextrin, 57.7 mg citric acid, and sodium hydroxide for pH adjustment (target pH 3.5).. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Hydrate prior to and following Kyprolis as needed. (2.1) Premedicate prior to all Cycle doses and if infusion-related reactions develop or reappear. (2.1) The recommended dosing regimens are as follows. See Full Prescribing Information for additional dosage information. (2.2)RegimenDosageInfusion TimeKyprolis and Dexamethasone (Kd) or Kyprolis, Daratumumab and Dexamethasone (DKd) or Daratumumab and hyaluronidase-fihj and Dexamethasone (DKd)20/70 mg/m2 once weekly30 minutesKd or Daratumumab and Dexamethasone (DKd) or Daratumumab and hyaluronidase-fihj and Dexamethasone (DKd) or Monotherapy20/56 mg/m2 twice weekly30 minutesKyprolis, Lenalidomide and Dexamethasone (KRd) orMonotherapy20/27 mg/m2 twice weekly10 minutes. Hydrate prior to and following Kyprolis as needed. (2.1). Premedicate prior to all Cycle doses and if infusion-related reactions develop or reappear. (2.1). The recommended dosing regimens are as follows. See Full Prescribing Information for additional dosage information. (2.2). 2.1Administration Precautions. HydrationAdequate hydration is required prior to dosing in Cycle 1, especially in patients at high-risk of tumor lysis syndrome (TLS) or renal toxicity. Consider hydration with both oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid prior to each dose in Cycle 1). If needed, give an additional 250 mL to 500 mL of intravenous fluids following Kyprolis administration. Continue oral and/or intravenous hydration, as needed, in subsequent cycles.Monitor patients for evidence of volume overload and adjust hydration to individual patient needs, especially in patients with or at risk for cardiac failure [see Warnings and Precautions (5.1, 5.3)].. Electrolyte MonitoringMonitor serum potassium levels regularly during treatment with Kyprolis [see Adverse Reactions (6.1)].. Premedications and Concomitant MedicationsPremedicate with the recommended dose of dexamethasone for monotherapy or dexamethasone administered as part of the combination therapy [see Dosage and Administration (2.2)]. Administer dexamethasone orally or intravenously at least 30 minutes but no more than hours prior to all doses of Kyprolis during Cycle to reduce the incidence and severity of infusion-related reactions [see Warnings and Precautions (5.9)]. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.Provide thromboprophylaxis for patients being treated with Kyprolis in combination with other therapies [see Warnings and Precautions (5.8)].Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation [see Adverse Reactions (6.1)].. Dose CalculationFor patients with body surface area (BSA) of 2.2 m2 or less, calculate the Kyprolis dose using actual BSA. Dose adjustments do not need to be made for weight changes of 20% or less.For patients with BSA greater than 2.2 m2, calculate the Kyprolis dose using BSA of 2.2 m2.. 2.2Recommended Dosage. Kyprolis in Combination with Lenalidomide and DexamethasoneAdminister Kyprolis intravenously as 10-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle in combination with lenalidomide and dexamethasone until Cycle 12 as shown in Table [see Clinical Studies (14.1)]. The recommended starting dose of Kyprolis is 20 mg/m2 on Cycle 1, Days and 2. If tolerated, escalate the dose to 27 mg/m2 on Cycle 1, Day 8. From Cycle 13, administer Kyprolis on Days 1, 2, 15, 16 until Cycle 18. Discontinue Kyprolis after Cycle 18. Continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity occurs. Refer to the Prescribing Information for lenalidomide and dexamethasone for additional dosage information.Table 1: Kyprolis 20/27 mg/m2 Twice Weekly (10-Minute Infusion) in Combination with Lenalidomide and DexamethasoneCycle 1Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Days 23-28Kyprolis (mg/m2)2020-2727-2727---Dexamethasone (mg)40--40--40--40-Lenalidomide25 mg daily on Days 1-21--Cycles to 12Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Days 23-28Kyprolis (mg/m2)2727-2727-2727---Dexamethasone (mg)40--40--40--40-Lenalidomide25 mg daily on Days 1-21--Cycles 13 and laterKyprolis is administered through Cycle 18; lenalidomide and dexamethasone continue thereafter. Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Days23-28Kyprolis (mg/m2)2727----2727---Dexamethasone (mg)40--40--40--40-Lenalidomide25 mg daily on Days 1-21--. Once weekly 20/70 mg/m2 regimen by 30-minute infusionAdminister Kyprolis intravenously as 30-minute infusion on Days 1, 8, and 15 of each 28-day cycle in combination with dexamethasone until disease progression or unacceptable toxicity as shown in Table [see Clinical Studies (14.2)]. The recommended starting dose of Kyprolis is 20 mg/m2 on Cycle 1, Day 1. If tolerated, escalate the dose to 70 mg/m2 on Cycle 1, Day 8. Administer dexamethasone 30 minutes to hours before Kyprolis. Refer to Prescribing Information for dexamethasone for additional dosage information.Table 2: Kyprolis 20/70 mg/m2 Once Weekly (30-Minute Infusion) in Combination with DexamethasoneCycle 1Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Day23Days24-28Kyprolis (mg/m2)20--70--70-----Dexamethasone (mg)40--40--40--40--Cycles to 9Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Day23Days24-28Kyprolis (mg/m2)70--70--70-----Dexamethasone (mg)40--40--40--40--Cycles 10 and laterWeek 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Day23Days24-28Kyprolis (mg/m2)70--70--70-----Dexamethasone (mg)40--40--40-----. Kyprolis in Combination with Dexamethasone. Twice weekly 20/56 mg/m2 regimen by 30-minute infusionAdminister Kyprolis intravenously as 30-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle in combination with dexamethasone until disease progression or unacceptable toxicity as shown in Table [see Clinical Studies (14.2)]. The recommended starting dose of Kyprolis is 20 mg/m2 on Cycle 1, Days and 2. If tolerated, escalate the dose to 56 mg/m2 on Cycle 1, Day 8. Administer dexamethasone 30 minutes to hours before Kyprolis. Refer to the Prescribing Information for dexamethasone for additional dosage information.Table 3: Kyprolis 20/56 mg/m2 Twice Weekly (30-Minute Infusion) in Combination with DexamethasoneCycle 1Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Day23Days24-28Kyprolis (mg/m2)2020-5656-5656----Dexamethasone (mg)2020-2020-2020-2020-Cycles and laterWeek 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Day23Days24-28Kyprolis (mg/m2)5656-5656-5656----Dexamethasone (mg)2020-2020-2020-2020-. Kyprolis in Combination with Daratumumab and Dexamethasone or Daratumumab and Hyaluronidase-fihj and Dexamethasone. Twice weekly 20/56 mg/m2 regimen by 30-minute infusionAdminister Kyprolis intravenously as 30-minute infusion on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle in combination the daratumumab and dexamethasone or daratumumab and hyaluronidase-fihj and dexamethasone until disease progression or unacceptable toxicity as shown in Table [see Clinical Studies (14.3)]. The recommended starting dose of Kyprolis is 20 mg/m2 on Cycle 1, Days and 2. If tolerated, escalate the dose to 56 mg/m2 on Cycle 1, Day and thereafter. Administer dexamethasone 30 minutes to hours before Kyprolis and to hours before daratumumab or daratumumab and hyaluronidase-fihj. Refer to the Prescribing Information for daratumumab, daratumumab and hyaluronidase-fihj, and dexamethasone for additional dosage information.Table 4: Kyprolis 20/56 mg/m2 Twice Weekly (30-Minute Infusion) in Combination with Daratumumab or Daratumumab and hyaluronidase-fihj and Dexamethasone Cycle 1Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Day23Days24-28Kyprolis (mg/m2)2020-5656-5656----Dexamethasone (mg)For patients 75 years of age, administer 20 mg of dexamethasone orally or intravenously weekly after the first week. 2020-2020-2020-2020- with intravenous daratumumabDaratumumab intravenous (mg/kg)88-16--16--16-- OR with subcutaneous daratumumabDaratumumab and hyaluronidase-fihj (mg/units)1,800/30,000--1,800/30,000--1,800/30,000--1,800/30,000-- Cycle 2Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Day23Days24-28Kyprolis (mg/m2)5656-5656-5656----Dexamethasone (mg) 2020-2020-2020-2020- with intravenous daratumumabDaratumumabintravenous (mg/kg)16--16--16--16-- OR with subcutaneous daratumumabDaratumumab and hyaluronidase-fihj (mg/units)1,800/30,000--1,800/30,000--1,800/30,000--1,800/30,000-- Cycles 3-6Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Day23Days24-28Kyprolis (mg/m2)5656-5656-5656----Dexamethasone (mg) 2020-2020-2020-40-- with intravenous daratumumabDaratumumabintravenous (mg/kg)16-----16----- OR with subcutaneous daratumumabDaratumumab and hyaluronidase-fihj (mg/units)1,800/30,000-----1,800/30,000----- Cycles and onwardsWeek 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Day23Days24-28Kyprolis (mg/m2)5656-5656-5656----Dexamethasone (mg) 2020-2020-2020-40-- with intravenous daratumumabDaratumumab intravenous (mg/kg)16----------- OR with subcutaneous daratumumabDaratumumab and hyaluronidase-fihj (mg/units)1,800/30,000-----------. Once weekly 20/70 mg/m2 regimen by 30-minute infusionAdminister Kyprolis intravenously as 30-minute infusion on Days 1, and 15 of each 28-day cycle in combination with daratumumab and dexamethasone or daratumumab and hyaluronidase-fihj and dexamethasone until disease progression or unacceptable toxicity as shown in Table [see Clinical Studies (14.3)]. The recommended starting dose of Kyprolis is 20 mg/m2 on Cycle 1, Day 1. If tolerated, escalate the dose to 70 mg/m2 on Cycle 1, Day and thereafter. Administer dexamethasone 30 minutes to hours before Kyprolis and to hours before daratumumab or daratumumab and hyaluronidase-fihj. Refer to the Prescribing Information for daratumumab, daratumumab and hyaluronidase-fihj, and dexamethasone for additional dosage information.Table 5: Kyprolis 20/70 mg/m2 Once Weekly (30-Minute Infusion) in Combination with Daratumumab or Daratumumab and hyaluronidase-fihj and DexamethasoneCycle 1Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Day23Days24-28Kyprolis (mg/m2)20--70--70-----Dexamethasone (mg)For patients 75 years of age, administer 20 mg of dexamethasone orally or intravenously weekly after the first week. 2020-2020-2020-2020-with intravenous daratumumabDaratumumab intravenous (mg/kg)88-16--16--16--OR with subcutaneous daratumumabDaratumumab and hyaluronidase-fihj (mg/units)1,800/30,000--1,800/30,000--1,800/30,000--1,800/30,000--Cycle 2Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Day23Days24-28Kyprolis (mg/m2)70--70--70-----Dexamethasone (mg) 2020-2020-2020-2020-with intravenous daratumumabDaratumumabintravenous (mg/kg)16--16--16--16--OR with subcutaneous daratumumabDaratumumab and hyaluronidase-fihj (mg/units)1,800/30,000--1,800/30,000--1,800/30,000--1,800/30,000--Cycles 3-6Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Day23Days24-28Kyprolis (mg/m2)70--70--70-----Dexamethasone (mg) 2020-40--2020-40--with intravenous daratumumabDaratumumabintravenous (mg/kg)16-----16----- OR with subcutaneous daratumumabDaratumumab and hyaluronidase-fihj subcutaneous (mg/units)1,800/30,000-----1,800/30,000----- Cycles and onwardsWeek 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Day22Day23Days24-28Kyprolis (mg/m2)70--70--70-----Dexamethasone (mg) 2020-40--40--40-- with intravenous daratumumabDaratumumab intravenous (mg/kg)16----------- OR with subcutaneous daratumumabDaratumumab and hyaluronidase (mg/units)1,800/30,000-----------. Kyprolis Monotherapy. 20/27 mg/m2 twice weekly regimen by 10-minute infusionAdminister Kyprolis intravenously as 10-minute infusion [see Clinical Studies (14.4)]. In Cycles through 12, administer Kyprolis on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle as shown in Table 6. From Cycle 13, administer Kyprolis on Days 1, 2, 15 and 16 of each 28-day cycle. Premedicate with dexamethasone mg orally or intravenously 30 minutes to hours before each Kyprolis dose in Cycle 1, then as needed to minimize infusion-related reactions [see Dosage and Administration (2.1)]. The recommended starting dose of Kyprolis is 20 mg/m2 in Cycle on Days and 2. If tolerated, escalate the dose to 27 mg/m2 on Day of Cycle and thereafter. Continue Kyprolis until disease progression or unacceptable toxicity.Table 6: Kyprolis Monotherapy 20/27 mg/m2 Twice Weekly (10-Minute Infusion)Cycle 1Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Days22-28Kyprolis (mg/m2)Dexamethasone premedication is required for each Kyprolis dose in Cycle 1.2020-2727-2727--Cycles to 12Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Days22-28Kyprolis (mg/m2)2727-2727-2727--Cycles 13 and laterWeek 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Days22-28Kyprolis (mg/m2)2727----2727--. 20/56 mg/m2 twice weekly regimen by 30-minute infusionAdminister Kyprolis intravenously as 30-minute infusion [see Clinical Studies (14.4)]. In Cycles through 12, administer Kyprolis on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle as shown in Table 7. From Cycle 13, administer Kyprolis on Days 1, 2, 15 and 16 of each 28-day cycle. Premedicate with dexamethasone mg orally or intravenously 30 minutes to hours before each Kyprolis dose in Cycle 1, then as needed to minimize infusion-related reactions [see Dosage and Administration (2.1)]. The recommended starting dose of Kyprolis is 20 mg/m2 in Cycle on Days and 2. If tolerated, escalate the dose to 56 mg/m2 on Day of Cycle 1. Continue Kyprolis until disease progression or unacceptable toxicity.Table 7: Kyprolis Monotherapy 20/56 mg/m2 Twice Weekly (30-Minute Infusion)Cycle 1Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Days22-28Kyprolis (mg/m2)Dexamethasone premedication is required for each Kyprolis dose in Cycle 1. 2020-5656-5656--Cycles to 12Week 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Days22-28Kyprolis (mg/m2)5656-5656-5656--Cycles 13 and laterWeek 1Week 2Week 3Week 4Day1Day2Days3-7Day8Day9Days10-14Day15Day16Days17-21Days22-28Kyprolis (mg/m2)5656----5656--. 2.3Dosage Modifications for Adverse Reactions. Recommended actions and dosage modifications for Kyprolis are presented in Table 8. Dose level reductions are presented in Table 9. See the lenalidomide, intravenous daratumumab, and dexamethasone Prescribing Information respectively for recommended dosage modifications associated with each product.Table 8: Dosage Modifications for Adverse ReactionsSee Table for dose level reductions. ANC absolute neutrophil countHematologic Toxicity[see Warnings and Precautions (5.11), Adverse Reactions (6.1)]Recommended ActionANC less than 0.5 109/LWithhold doseIf recovered to greater than or equal to 0.5 109/L, continue at the same dose level For subsequent drops to less than 0.5 109/L, follow the same recommendations as above and consider dose level reduction when restarting Kyprolis Febrile neutropenia: ANC less than 0.5 109/L and an oral temperature more than 38.5C or two consecutive readings of more than 38.0C for hoursWithhold doseIf ANC returns to baseline grade and fever resolves, resume at the same dose level Platelets less than 10 109/L or evidence of bleeding with thrombocytopeniaWithhold doseIf recovered to greater than or equal to 10 109/L and/or bleeding is controlled, continue at the same dose level For subsequent drops to less than 10 109/L, follow the same recommendations as above and consider dose level reduction when restarting Kyprolis Renal Toxicity [see Warnings and Precautions (5.2)]Recommended ActionSerum creatinine greater than or equal to x baseline, orCreatinine clearance less than 15 mL/min, or creatinine clearance decreases to less than or equal to 50% of baseline, or need for hemodialysis Withhold dose and continue monitoring renal function (serum creatinine or creatinine clearance)If attributable to Kyprolis, resume when renal function has recovered to within 25% of baseline; start at dose level reduction If not attributable to Kyprolis, dosing may be resumed at the discretion of the healthcare provider For patients on hemodialysis receiving Kyprolis, the dose is to be administered after the hemodialysis procedureOther Non-hematologic Toxicity [see Adverse Reactions (6.1)].Recommended ActionAll other severe or life-threateningGrade and 4. non-hematological toxicitiesWithhold until resolved or returned to baselineConsider restarting the next scheduled treatment at dose level reduction Table 9: Dose Level Reductions for Adverse ReactionsRegimen DoseFirst Dose ReductionSecond Dose ReductionThird Dose ReductionNote: Infusion times remain unchanged during dose reduction(s).Kyprolis and DexamethasoneORKyprolis, Daratumumab and Dexamethasone (once weekly) 70 mg/m2 56 mg/m2 45 mg/m2 36 mg/m2 If toxicity persists, discontinue Kyprolis treatment. Kyprolis and DexamethasoneORKyprolis, Daratumumab, and DexamethasoneORKyprolis Monotherapy (twice weekly) 56 mg/m2 45 mg/m2 36 mg/m2 27 mg/m2 Kyprolis, Lenalidomide, and DexamethasoneORKyprolis Monotherapy (twice weekly)27 mg/m2 20 mg/m2 15 mg/m2 --. ANC less than 0.5 109/L. Withhold doseIf recovered to greater than or equal to 0.5 109/L, continue at the same dose level If recovered to greater than or equal to 0.5 109/L, continue at the same dose level. For subsequent drops to less than 0.5 109/L, follow the same recommendations as above and consider dose level reduction when restarting Kyprolis Febrile neutropenia: ANC less than 0.5 109/L and an oral temperature more than 38.5C or two consecutive readings of more than 38.0C for hours. Withhold doseIf ANC returns to baseline grade and fever resolves, resume at the same dose level If ANC returns to baseline grade and fever resolves, resume at the same dose level. Platelets less than 10 109/L or evidence of bleeding with thrombocytopenia. Withhold doseIf recovered to greater than or equal to 10 109/L and/or bleeding is controlled, continue at the same dose level If recovered to greater than or equal to 10 109/L and/or bleeding is controlled, continue at the same dose level. For subsequent drops to less than 10 109/L, follow the same recommendations as above and consider dose level reduction when restarting Kyprolis Serum creatinine greater than or equal to x baseline, or. Creatinine clearance less than 15 mL/min, or creatinine clearance decreases to less than or equal to 50% of baseline, or need for hemodialysis. Withhold dose and continue monitoring renal function (serum creatinine or creatinine clearance)If attributable to Kyprolis, resume when renal function has recovered to within 25% of baseline; start at dose level reduction If not attributable to Kyprolis, dosing may be resumed at the discretion of the healthcare provider If attributable to Kyprolis, resume when renal function has recovered to within 25% of baseline; start at dose level reduction If not attributable to Kyprolis, dosing may be resumed at the discretion of the healthcare provider. For patients on hemodialysis receiving Kyprolis, the dose is to be administered after the hemodialysis procedure. All other severe or life-threateningGrade and 4. non-hematological toxicities. Withhold until resolved or returned to baseline. Consider restarting the next scheduled treatment at dose level reduction 2.4Dosage Modifications for Hepatic Impairment. For patients with mild (total bilirubin to 1.5 ULN and any AST or total bilirubin <= ULN and AST ULN) or moderate (total bilirubin 1.5 to x ULN and any AST) hepatic impairment, reduce the dose of Kyprolis by 25% [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].. 2.5Recommended Dosage for End Stage Renal Disease. For patients with end stage renal disease who are on hemodialysis, administer Kyprolis after the hemodialysis procedure.. 2.6Preparation and Administration. Kyprolis vials contain no antimicrobial preservatives and are intended for single-dose only. The reconstituted solution contains carfilzomib at concentration of mg/mL.Read the complete preparation instructions prior to reconstitution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.. Reconstitution/Preparation Steps:Remove vial from refrigerator just prior to use.Calculate the dose (mg/m2) and number of vials of Kyprolis required using the patients BSA at baseline. Aseptically reconstitute each Kyprolis vial only with Sterile Water for Injection, USP using the volumes described in Table 10. Use 21-gauge or larger needle (0.8 mm or smaller external diameter needle) to reconstitute each vial by slowly injecting Sterile Water for Injection, USP through the stopper and directing the Sterile Water for Injection, USP onto the INSIDE WALL OF THE VIAL to minimize foaming. There is no data to support the use of closed system transfer devices with Kyprolis. Table 10: Reconstitution VolumesStrengthAmount of Sterile Water for Injection, USP required for reconstitution10 mg vial5 mL30 mg vial15 mL60 mg vial29 mL Gently swirl and/or invert the vial slowly for about minute, or until complete dissolution. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow the solution to settle in the vial until foaming subsides (approximately minutes) and the solution is clear.Visually inspect for particulate matter and discoloration prior to administration. The reconstituted product should be clear, colorless solution and should not be administered if any discoloration or particulate matter is observed.Discard any unused portion left in the vial. DO NOT pool unused portions from the vials. DO NOT administer more than one dose from vial. Administer Kyprolis directly by intravenous infusion or in 50 mL to 100 mL intravenous bag containing 5% Dextrose Injection, USP. Do not administer as an intravenous push or bolus.When administering in an intravenous bag, use 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle) to withdraw the calculated dose from the vial and dilute into 50 mL or 100 mL intravenous bag containing only 5% Dextrose Injection, USP (based on the calculated total dose and infusion time).Flush the intravenous administration line with normal saline or 5% Dextrose Injection, USP immediately before and after Kyprolis administration.Do not mix Kyprolis with or administer as an infusion with other medicinal products.The stabilities of reconstituted Kyprolis under various temperature and container conditions are shown in Table 11.Table 11: Stability of Reconstituted KyprolisStorage Conditions of Reconstituted KyprolisStabilityTotal time from reconstitution to administration should not exceed 24 hours. per ContainerVialSyringeIntravenous Bag (D5W5% Dextrose Injection, USP.)Refrigerated 2C to 8C (36F to 46F)24 hours24 hours24 hoursRoom Temperature 15C to 30C (59F to 86F)4 hours4 hours4 hours. Remove vial from refrigerator just prior to use.. Calculate the dose (mg/m2) and number of vials of Kyprolis required using the patients BSA at baseline. Aseptically reconstitute each Kyprolis vial only with Sterile Water for Injection, USP using the volumes described in Table 10. Use 21-gauge or larger needle (0.8 mm or smaller external diameter needle) to reconstitute each vial by slowly injecting Sterile Water for Injection, USP through the stopper and directing the Sterile Water for Injection, USP onto the INSIDE WALL OF THE VIAL to minimize foaming. There is no data to support the use of closed system transfer devices with Kyprolis. Table 10: Reconstitution VolumesStrengthAmount of Sterile Water for Injection, USP required for reconstitution10 mg vial5 mL30 mg vial15 mL60 mg vial29 mL Gently swirl and/or invert the vial slowly for about minute, or until complete dissolution. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow the solution to settle in the vial until foaming subsides (approximately minutes) and the solution is clear.. Visually inspect for particulate matter and discoloration prior to administration. The reconstituted product should be clear, colorless solution and should not be administered if any discoloration or particulate matter is observed.. Discard any unused portion left in the vial. DO NOT pool unused portions from the vials. DO NOT administer more than one dose from vial.. Administer Kyprolis directly by intravenous infusion or in 50 mL to 100 mL intravenous bag containing 5% Dextrose Injection, USP. Do not administer as an intravenous push or bolus.. When administering in an intravenous bag, use 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle) to withdraw the calculated dose from the vial and dilute into 50 mL or 100 mL intravenous bag containing only 5% Dextrose Injection, USP (based on the calculated total dose and infusion time).. Flush the intravenous administration line with normal saline or 5% Dextrose Injection, USP immediately before and after Kyprolis administration.. Do not mix Kyprolis with or administer as an infusion with other medicinal products.. Image.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Based on its mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingConduct pregnancy testing on females of reproductive potential prior to initiating Kyprolis treatment.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with Kyprolis and for months following the last dose.. MalesAdvise males with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for months following the last dose.. InfertilityBased on the mechanism of action, Kyprolis may have an effect on either male or female fertility [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. There are no data on the effect of Kyprolis on human fertility.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 2,387 patients in clinical studies of Kyprolis, 51% were 65 years and older, while 14% were 75 years and older. The incidence of serious adverse reactions was 49% in patients 65 years of age, 58% in patients 65 to 74 years of age, and 63% in patients >= 75 years of age. Of the 308 patients in CANDOR who received DKd, 47% of patients were 65 years and older, while 9% were 75 years and older. Fatal adverse reactions in the DKd arm of CANDOR occurred in 6% of patients <65 years of age, 14% of patients between 65 to 74 years of age, and 14% of patients >= 75 years of age [see Adverse Reactions (6.1)]. No overall differences in effectiveness were observed between older and younger patients.

HEPATIC IMPAIRMENT SUBSECTION.

8.6 Hepatic Impairment. Reduce the dose of Kyprolis by 25% in patients with mild (total bilirubin to 1.5 ULN and any AST or total bilirubin <= ULN and AST ULN) or moderate (total bilirubin 1.5 to x ULN and any AST) hepatic impairment. recommended dosage of Kyprolis has not been established for patients with severe hepatic impairment (total bilirubin 3 ULN and any AST) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].The incidence of serious adverse reactions was higher in patients with mild, moderate, and severe hepatic impairment combined (22/35 or 63%) than in patients with normal hepatic function (3/11 or 27%) [see Warnings and Precautions (5.12), Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedKyprolis (carfilzomib) is supplied as: An individually packaged single-dose vial containing 10 mg of carfilzomib as white to off-white lyophilized cake or powder: NDC 76075-103-01.An individually packaged single-dose vial containing 30 mg of carfilzomib as white to off-white lyophilized cake or powder: NDC 76075-102-01.An individually packaged single-dose vial containing 60 mg of carfilzomib as white to off-white lyophilized cake or powder: NDC 76075-101-01.. An individually packaged single-dose vial containing 10 mg of carfilzomib as white to off-white lyophilized cake or powder: NDC 76075-103-01.. An individually packaged single-dose vial containing 30 mg of carfilzomib as white to off-white lyophilized cake or powder: NDC 76075-102-01.. An individually packaged single-dose vial containing 60 mg of carfilzomib as white to off-white lyophilized cake or powder: NDC 76075-101-01.. Storage and HandlingUnopened vials should be stored refrigerated 2C to 8C (36F to 46F). Retain in original package to protect from light.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Kyprolis is proteasome inhibitor that is indicated:for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination withLenalidomide and dexamethasone; orDexamethasone; orDaratumumab and dexamethasone; or Daratumumab and hyaluronidase-fihj and dexamethasone (1, 14) as single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. (1, 14). for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination withLenalidomide and dexamethasone; orDexamethasone; orDaratumumab and dexamethasone; or Daratumumab and hyaluronidase-fihj and dexamethasone (1, 14) Lenalidomide and dexamethasone; or. Dexamethasone; or. Daratumumab and dexamethasone; or Daratumumab and hyaluronidase-fihj and dexamethasone (1, 14). as single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. (1, 14). 1.1Relapsed or Refractory Multiple Myeloma. Kyprolis is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with:Lenalidomide and dexamethasone; orDexamethasone; orDaratumumab and dexamethasone; orDaratumumab and hyaluronidase-fihj and dexamethasone.Kyprolis is indicated as single agent for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.. Kyprolis is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with:Lenalidomide and dexamethasone; orDexamethasone; orDaratumumab and dexamethasone; orDaratumumab and hyaluronidase-fihj and dexamethasone.. Lenalidomide and dexamethasone; or. Dexamethasone; or. Daratumumab and dexamethasone; or. Daratumumab and hyaluronidase-fihj and dexamethasone.. Kyprolis is indicated as single agent for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Discuss the following with patients prior to treatment with Kyprolis:. Cardiac Toxicities: Advise patients of the risks and symptoms of cardiac failure and ischemia [see Warnings and Precautions (5.1)].. Dehydration: Counsel patients to avoid dehydration, since patients receiving Kyprolis therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dehydration [see Warnings and Precautions (5.3)].. Respiratory: Advise patients that they may experience cough or shortness of breath (dyspnea) during treatment with Kyprolis. This most commonly occurs within day of dosing. Advise patients to contact their healthcare provider if they experience shortness of breath [see Warnings and Precautions (5.6)].. Venous Thrombosis: Inform patients of the risk of venous thromboembolism and discuss the options for prophylaxis. Advise patients to seek immediate medical attention for symptoms of venous thrombosis or embolism [see Warnings and Precautions (5.8)].. Infusion-Related Reactions: Advise patients of the risk of infusion-related reactions and discuss the common signs and symptoms of infusion-related reactions with the patients [see Warnings and Precautions (5.9)].. Bleeding: Inform patients that they may bruise or bleed more easily or that it may take longer to stop bleeding and to report to their healthcare provider any prolonged, unusual or excessive bleeding. Instruct patients on the signs of occult bleeding [see Warnings and Precautions (5.10)].. Hepatic: Inform patients of the risk of developing hepatic failure. Advise patients to contact their healthcare provider for symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.12)].. Other: Inform patients to contact their healthcare provider if they experience neurologic symptoms such as headaches, confusion, dizziness or loss of balance, difficulty talking or walking, decreased strength or weakness on one side of the body, seizures, or visual loss [see Warnings and Precautions (5) and Adverse Reactions (6)].. Driving/Operating Machines: Advise patients that Kyprolis may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms [see Adverse Reactions (6.1)].. Embryo-Fetal Toxicity: Advise females of the potential risk to the fetus. Advise females of reproductive potential to inform their healthcare provider immediately of known or suspected pregnancy. Advise female patients to use effective contraceptive during treatment with Kyprolis and for months following the last dose. Advise male patients with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for months following the last dose [see Warnings and Precautions (5.17), Use in Specific Populations (8.1, 8.3)].. Lactation: Advise patients to avoid breastfeeding while receiving Kyprolis and for weeks after the last dose [see Use in Specific Populations (8.2)].. Concomitant Medications: Advise patients to discuss with their healthcare provider any medication they are currently taking prior to starting treatment with Kyprolis, or prior to starting any new medication(s) during treatment with Kyprolis.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of Kyprolis in human milk, the effects on the breastfed child, or the effects of the drug on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with Kyprolis and for weeks after treatment.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Carfilzomib is tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with carfilzomib.Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay.Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-month monkey chronic toxicity studies.. 13.2Animal Toxicology and/or Pharmacology. Cardiovascular ToxicityMonkeys administered single bolus intravenous dose of carfilzomib at mg/kg (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on BSA) experienced hypotension, increased heart rate, and increased serum levels of troponin-T.. Chronic AdministrationRepeated bolus intravenous administration of carfilzomib at >= mg/kg/dose in rats and mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) systems. The dose of mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m2 based on BSA. The dose of mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on BSA.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia, and lymphopenia has been reported following dose of 200 mg of Kyprolis administered in error.There is no known specific antidote for Kyprolis overdosage. In the event of overdose, monitor patients for adverse reactions and provide supportive care as appropriate.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. Single-Dose VialNDC 76075-103-01AMGEN(R) Kyprolis(R) (carfilzomib) for Injection10 mg/vial10 mg/vialSingle-dose vial. Discard unused portion.Reconstitution: Reconstitute with mL Sterile Water for Injection, USP.Dilution: May be further diluted with 5% Dextrose Injection, USP.For Intravenous Administration OnlyRx Only PRINCIPAL DISPLAY PANEL Single-Dose Vial NDC 76075-103-01 AMGEN(R) Kyprolis(R) (carfilzomib) for Injection 10 mg/vial 10 mg/vial Single-dose vial. Discard unused portion. Reconstitution: Reconstitute with mL Sterile Water for Injection, USP. Dilution: May be further diluted with 5% Dextrose Injection, USP. For Intravenous Administration Only Rx Only.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Kyprolis in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like (CT-L) activity when measured in blood hour after the first dose. Doses of carfilzomib >= 15 mg/m2 with or without lenalidomide and dexamethasone induced >= 80% inhibition of the CT-L activity of the proteasome. In addition, carfilzomib, 20 mg/m2 intravenously as single agent, resulted in mean inhibition of the low molecular mass polypeptide (LMP2) and multicatalytic endopeptidase complex-like (MECL1) subunits of the proteasome ranging from 26% to 32% and 41% to 49%, respectively. Proteasome inhibition was maintained for >= 48 hours following the first dose of carfilzomib for each week of dosing.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Carfilzomib at doses between 20 mg/m2 and 70 mg/m2 administered as 30-minute infusion resulted in dose-dependent increases in maximum plasma concentrations (Cmax) and area under the curve over time to infinity (AUC0-INF) in patients with multiple myeloma. dose-dependent increase in Cmax and AUC0-INF was also observed between carfilzomib 20 mg/m2 and 56 mg/m2 as 2- to 10-minute infusion in patients with relapsed or refractory multiple myeloma. 30-minute infusion resulted in similar AUC0-INF, but 2- to 3-fold lower Cmax than that observed with 2- to 10-minute infusion at the same dose. There was no evidence of carfilzomib accumulation following repeated administration of carfilzomib 70 mg/m2 as 30-minute once weekly infusion or 15 and 20 mg/m2 as 2- to 10-minute twice weekly infusion.Table 23 lists the estimated mean average daily area under the curve in the first cycle (AUCC1,avg), average daily area under the curve at steady-state (AUCss) and Cmax at the highest dose in the first cycle (Cmax,C1) for the different dosing regimens.Table 23: Carfilzomib Exposure Parameters for Different Dosing RegimensEstimated Parameters (%CV)20/27 mg/m2 twice weekly with 2- to 10-minute infusion20/56 mg/m2 twice weekly with 30-minute infusion20/70 mg/m2 once weekly with 30-minute infusionCV Coefficient of variationAUCC1,avg (nghr/mL)95 (40)170 (35)114 (36)AUCss (nghr/mL)111 (34)228 (28)150 (35)Cmax,C1 (ng/mL)1282 (17)1166 (29)1595 (36). DistributionThe mean steady-state volume of distribution of 20 mg/m2 dose of carfilzomib was 28 L. Carfilzomib is 97% bound to human plasma proteins over the concentration range of 0.4 to micromolar in vitro.. EliminationCarfilzomib has half-life of <= hour on Day of Cycle following intravenous doses >= 15 mg/m2. The half-life was similar when administered either as 30-minute infusion or 2- to 10-minute infusion. The systemic clearance ranged from 151 to 263 L/hour.. MetabolismCarfilzomib is rapidly metabolized. Peptidase cleavage and epoxide hydrolysis were the principal pathways of metabolism. Cytochrome P450 (CYP)-mediated mechanisms contribute minor role in overall carfilzomib metabolism.. ExcretionApproximately 25% of the administered dose of carfilzomib was excreted in urine as metabolites in 24 hours. Urinary and fecal excretion of the parent compound was negligible (0.3% of total dose).. Specific PopulationsAge (35-89 years), sex, race or ethnicity (80% White, 11% Black, 6% Asians, 3% Hispanics), and mild to severe renal impairment (creatinine clearance 15-89 mL/min) did not have clinically meaningful effects on the pharmacokinetics of carfilzomib.. Patients with Hepatic ImpairmentCompared to patients with normal hepatic function, patients with mild (total bilirubin to 1.5 ULN and any AST or total bilirubin <= ULN and AST ULN) and moderate (total bilirubin 1.5 to x ULN and any AST) hepatic impairment had approximately 50% higher carfilzomib AUC. The pharmacokinetics of carfilzomib has not been evaluated in patients with severe hepatic impairment (total bilirubin 3 ULN and any AST).. Patients with Renal ImpairmentRelative to patients with normal renal function, ESRD patients on hemodialysis showed 33% higher carfilzomib AUC. Since hemodialysis clearance of Kyprolis concentrations has not been studied, the drug should be administered after the hemodialysis procedure.. Drug Interaction Studies. Clinical Studies. Effect of Carfilzomib on Sensitive CYP3A Substrate: Midazolam (a sensitive CYP3A substrate) pharmacokinetics was not affected by concomitant administration of carfilzomib.. In Vitro Studies. Effect of Carfilzomib on Cytochrome P450 (CYP) Enzymes: Carfilzomib showed direct and time-dependent inhibition of CYP3A but did not induce CYP1A2 and CYP3A4 in vitro.. Effect of Transporters on Carfilzomib: Carfilzomib is P-glycoprotein (P-gp) substrate in vitro.. Effect of Carfilzomib on Transporters: Carfilzomib inhibits P-gp in vitro. However, given that Kyprolis is administered intravenously and is extensively metabolized, the pharmacokinetics of Kyprolis is unlikely to be affected by P-gp inhibitors or inducers.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of Kyprolis. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure: hemolytic uremic syndrome (HUS), hepatitis virus reactivation, gastrointestinal perforation, pericarditis, and cytomegalovirus infection, including chorioretinitis, pneumonitis, enterocolitis, viremia, intestinal obstruction, and acute pancreatitis.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryKyprolis can cause fetal harm based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)]. There are no available data on Kyprolis use in pregnant women to evaluate for drug-associated risks. Kyprolis caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (see Data). Advise pregnant women of the potential risk to the fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.. Data. Animal DataCarfilzomib administered intravenously to pregnant rats and rabbits during the period of organogenesis was not teratogenic at doses up to mg/kg/day in rats and 0.8 mg/kg/day in rabbits. In rabbits, there was an increase in pre-implantation loss at >= 0.4 mg/kg/day and an increase in early resorptions and post-implantation loss and decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on BSA.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1.1)11/2021Dosage and Administration (2.2)11/2021.

SPL UNCLASSIFIED SECTION.

1.1Relapsed or Refractory Multiple Myeloma. Kyprolis is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with:Lenalidomide and dexamethasone; orDexamethasone; orDaratumumab and dexamethasone; orDaratumumab and hyaluronidase-fihj and dexamethasone.Kyprolis is indicated as single agent for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.. Kyprolis is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with:Lenalidomide and dexamethasone; orDexamethasone; orDaratumumab and dexamethasone; orDaratumumab and hyaluronidase-fihj and dexamethasone.. Lenalidomide and dexamethasone; or. Dexamethasone; or. Daratumumab and dexamethasone; or. Daratumumab and hyaluronidase-fihj and dexamethasone.. Kyprolis is indicated as single agent for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

STORAGE AND HANDLING SECTION.

Storage and HandlingUnopened vials should be stored refrigerated 2C to 8C (36F to 46F). Retain in original package to protect from light.