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)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared 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 2,239 patients administered in combination with other drugs in ASPIRE, ENDEAVOR, A.R.R.O.W., CANDOR, IKEMA, EQUULEUS, and PLEIADES. The most common adverse reactions occurring in at least 20% of patients who received Kyprolis in combination were anemia, diarrhea, hypertension, fatigue, upper respiratory tract infection, thrombocytopenia, pyrexia, 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 9 (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 8 summarizes the adverse reactions in the first 12 cycles in ASPIRE.

Table 8: Adverse Reactions (≥ 10%) Occurring in Cycles 1–12 in Patients Who Received KRd (20/27 mg/m2 Regimen) in ASPIRE
Adverse Reactions	KRd (N = 392) n (%)		Rd (N = 389) n (%)
Adverse Reactions	Any Grade	≥ Grade 3	Any Grade	≥ Grade 3
KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone
* Pneumonia includes pneumonia and bronchopneumonia. † Peripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. ‡ Cough includes cough and productive cough. § Dyspnea includes dyspnea and dyspnea exertional. ¶ Embolic and thrombotic events, venous includes deep vein thrombosis, pulmonary embolism, thrombophlebitis superficial, thrombophlebitis, venous thrombosis limb, post thrombotic syndrome, venous thrombosis. # Hypertension includes hypertension, hypertensive crisis.
Blood and Lymphatic System Disorders
Anemia	138 (35)	53 (14)	127 (33)	47 (12)
Neutropenia	124 (32)	104 (27)	115 (30)	89 (23)
Thrombocytopenia	100 (26)	58 (15)	75 (19)	39 (10)
Gastrointestinal Disorders
Diarrhea	119 (30)	8 (2)	106 (27)	12 (3)
Constipation	68 (17)	0 (0)	55 (14)	1 (0)
Nausea	63 (16)	1 (0)	43 (11)	3 (1)
General Disorders and Administration Site Conditions
Fatigue	113 (29)	23 (6)	107 (28)	20 (5)
Pyrexia	93 (24)	5 (1)	64 (17)	1 (0)
Edema peripheral	59 (15)	3 (1)	48 (12)	2 (1)
Asthenia	54 (14)	11 (3)	49 (13)	7 (2)
Infections
Upper respiratory tract infection	87 (22)	7 (2)	54 (14)	4 (1)
Bronchitis	55 (14)	5 (1)	40 (10)	2 (1)
Viral upper respiratory tract infection	55 (14)	0 (0)	44 (11)	0 (0)
Pneumonia*	54 (14)	35 (9)	43 (11)	27 (7)
Metabolism and Nutrition Disorders
Hypokalemia	78 (20)	22 (6)	35 (9)	12 (3)
Hypocalcemia	55 (14)	10 (3)	39 (10)	5 (1)
Hyperglycemia	43 (11)	18 (5)	33 (9)	15 (4)
Musculoskeletal and Connective Tissue Disorders
Muscle spasms	92 (24)	3 (1)	75 (19)	3 (1)
Back pain	41 (11)	4 (1)	54 (14)	6 (2)
Nervous System Disorders
Peripheral neuropathies†	43 (11)	7 (2)	39 (10)	4 (1)
Psychiatric Disorders
Insomnia	64 (16)	6 (2)	51 (13)	8 (2)
Respiratory, Thoracic and Mediastinal Disorders
Cough‡	93 (24)	2 (1)	54 (14)	0 (0)
Dyspnea§	71 (18)	8 (2)	61 (16)	6 (2)
Skin and Subcutaneous Tissue Disorders
Rash	45 (12)	5 (1)	54 (14)	5 (1)
Vascular Disorders
Embolic and thrombotic events¶	49 (13)	16 (4)	23 (6)	9 (2)
Hypertension#	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 a Frequency of < 10%

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

Grade 3 and higher adverse reactions that occurred during Cycles 1–12 with a substantial difference (≥ 2%) between the two arms were neutropenia, thrombocytopenia, hypokalemia, and hypophosphatemia.

Table 9 describes Grade 3–4 laboratory abnormalities reported in ASPIRE.

Table 9: Grade 3–4 Laboratory Abnormalities (≥ 10%) in Cycles 1-12 in Patients Who Received KRd (20/27 mg/m2 Regimen) in ASPIRE
Laboratory Abnormality	KRd (N = 392) n (%)	Rd (N = 389) n (%)
KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone
Decreased lymphocytes	182 (46)	119 (31)
Decreased absolute neutrophil count	152 (39)	141 (36)
Decreased phosphorus	122 (31)	106 (27)
Decreased platelets	101 (26)	59 (15)
Decreased total white blood cell count	97 (25)	71 (18)
Decreased hemoglobin	58 (15)	68 (18)
Increased glucose	53 (14)	30 (8)
Decreased potassium	41 (11)	23 (6)

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.).

ENDEAVOR

The 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 a 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 4 (1%) versus 5 (1%), infections 8 (2%) versus 8 (2%), disease progression 7 (2%) versus 4 (1%), pulmonary 3 (1%) versus 2 (< 1%), renal 1 (< 1%) versus 0 (0%), and other adverse reactions 9 (2%) versus 2 (< 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 6 months of therapy that occurred at a rate of 10% or greater in the Kd arm are presented in Table 10.

Table 10: Adverse Reactions (≥ 10% ) Occurring in Months 1–6 in Patients Who Received Kd (20/56 mg/m2 Regimen) in ENDEAVOR
Adverse Reactions	Kd (N = 463) n (%)		Vd (N = 456) n (%)
Adverse Reactions	Any Grade	Grade ≥ 3	Any Grade	Grade ≥ 3
Kd = Kyprolis and dexamethasone; Vd = bortezomib and dexamethasone
* Thrombocytopenia includes platelet count decreased and thrombocytopenia. † Peripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. ‡ See Clinical Studies (14.2). § Dyspnea includes dyspnea and dyspnea exertional. ¶ Cough includes cough and productive cough. # Hypertension includes hypertension, hypertensive crisis, and hypertensive emergency.
Blood and Lymphatic System Disorders
Anemia	161 (35)	57 (12)	112 (25)	43 (9)
Thrombocytopenia*	125 (27)	45 (10)	112 (25)	64 (14)
Gastrointestinal Disorders
Diarrhea	117 (25)	14 (3)	149 (33)	27 (6)
Nausea	70 (15)	4 (1)	68 (15)	3 (1)
Constipation	60 (13)	1 (0)	113 (25)	6 (1)
Vomiting	45 (10)	5 (1)	33 (7)	3 (1)
General Disorders and Administration Site Conditions
Fatigue	116 (25)	14 (3)	126 (28)	25 (6)
Pyrexia	102 (22)	9 (2)	52 (11)	3 (1)
Asthenia	73 (16)	9 (2)	65 (14)	13 (3)
Peripheral edema	62 (13)	3 (1)	62 (14)	3 (1)
Infections
Upper respiratory tract infection	67 (15)	4 (1)	55 (12)	3 (1)
Bronchitis	54 (12)	5 (1)	25 (6)	2 (0)
Musculoskeletal and Connective Tissue Disorders
Muscle spasms	70 (15)	1 (0)	23 (5)	3 (1)
Back pain	64 (14)	8 (2)	61 (13)	10 (2)
Nervous System Disorders
Headache	67 (15)	4 (1)	39 (9)	2 (0)
Peripheral neuropathies†,‡	56 (12)	7 (2)	170 (37)	23 (5)
Psychiatric Disorders
Insomnia	105 (23)	5 (1)	116 (25)	10 (2)
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea§	128 (28)	23 (5)	69 (15)	8 (2)
Cough¶	97 (21)	0 (0)	61 (13)	2 (0)
Vascular Disorders
Hypertension#	83 (18)	30 (7)	33 (7)	12 (3)

The event rate of ≥ Grade 2 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 a Frequency of < 10%

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

Table 11 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥ 10% in the Kd arm.

Table 11: Grade 3–4 Laboratory Abnormalities (≥ 10%) in Months 1–6 in Patients Who Received Kd (20/56 mg/m2 Regimen) in ENDEAVOR
Laboratory Abnormality	Kd (N = 463) n (%)	Vd (N = 456) n (%)
Kd = Kyprolis and dexamethasone; Vd = bortezomib and dexamethasone
* Calculated using the Cockcroft-Gault formula.
Decreased lymphocytes	249 (54)	180 (40)
Increased uric acid	244 (53)	198 (43)
Decreased hemoglobin	79 (17)	68 (15)
Decreased platelets	85 (18)	77 (17)
Decreased phosphorus	74 (16)	61 (13)
Decreased creatinine clearance*	65 (14)	49 (11)
Increased potassium	55 (12)	21 (5)

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 a 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 2 (< 1%) versus 2 (< 1%), septic shock 2 (< 1%) versus 1 (< 1%), and infection 2 (< 1%) versus 0 (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 a rate of 10% or greater in either Kd arm are presented in Table 12.

Table 12: 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 (%)
Adverse Reactions	Any Grade	Grade ≥ 3	Any Grade	Grade ≥ 3
Kd = Kyprolis and dexamethasone
* Anemia includes anemia, hematocrit decreased, and hemoglobin decreased. † Thrombocytopenia includes platelet count decreased and thrombocytopenia. ‡ Neutropenia includes neutrophil count decreased and neutropenia. § Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection, and viral upper respiratory tract infection. ¶ Cough includes cough and productive cough. # Dyspnea includes dyspnea and dyspnea exertional. Þ Hypertension includes hypertension and hypertensive crisis.
Blood and Lymphatic System Disorders
Anemia*	64 (27)	42 (18)	76 (32)	42 (18)
Thrombocytopenia†	53 (22)	26 (11)	41 (17)	27 (12)
Neutropenia‡	30 (13)	21 (9)	27 (12)	17 (7)
Gastrointestinal Disorders
Diarrhea	44 (19)	2 (1)	47 (20)	3 (1)
Nausea	34 (14)	1 (< 1)	26 (11)	2 (1)
General Disorders and Administration Site Conditions
Pyrexia	55 (23)	2 (1)	38 (16)	4 (2)
Fatigue	48 (20)	11 (5)	47 (20)	5 (2)
Asthenia	24 (10)	3 (1)	25 (11)	2 (1)
Peripheral edema	18 (8)	0 (0)	25 (11)	2 (1)
Infections
Respiratory tract infection§	70 (29)	7 (3)	79 (34)	7 (3)
Pneumonia	28 (12)	24 (10)	20 (9)	16 (7)
Bronchitis	27 (11)	2 (1)	25 (11)	5 (2)
Musculoskeletal and Connective Tissue Disorders
Back pain	28 (12)	2 (1)	28 (12)	4 (2)
Nervous System Disorders
Headache	25 (11)	1 (< 1)	23 (10)	1 (< 1)
Psychiatric Disorders
Insomnia	35 (15)	2 (1)	47 (20)	0 (0)
Respiratory, Thoracic and Mediastinal Disorders
Cough¶	37 (16)	2 (1)	31 (13)	0 (0)
Dyspnea#	28 (12)	1 (< 1)	26 (11)	2 (1)
Vascular Disorders
HypertensionÞ	51 (21)	13 (6)	48 (20)	12 (5)

Adverse Reactions Occurring at a Frequency of < 10%

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).

CANDOR

The 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 a 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 13 summarizes the adverse reactions in CANDOR.

Table 13: Adverse Reactions (≥ 15%) in Patients Who Received either DKd or Kd (20/56 mg/m2 Regimen) in CANDOR
Adverse Reactions	Twice weekly DKd (N = 308)		Twice weekly Kd (N = 153)
Adverse Reactions	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
DKd = Kyprolis, daratumumab, and dexamethasone; Kd = Kyprolis and dexamethasone
* The incidence of infusion related reactions is based on a 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 1 day after DKd or Kd administration. † Fatigue includes fatigue and asthenia. ‡ Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. § Includes fatal adverse reactions. ¶ Thrombocytopenia includes platelet count decreased and thrombocytopenia. # Anemia includes anemia, hematocrit decreased and hemoglobin decreased. Þ Cough includes productive cough and cough.
General Disorders and Administration Site Conditions
Infusion-related reaction*	41	12	28	5
Fatigue†	32	11	28	8
Pyrexia	20	1.9	15	0.7
Infections
Respiratory tract infection‡	40§	7	29	3.3
Pneumonia	18§	13	12	9
Bronchitis	17	2.6	12	1.3
Blood and Lymphatic System Disorders
Thrombocytopenia¶	37	25	30	16
Anemia#	33	17	31	14
Gastrointestinal Disorders
Diarrhea	32	3.9	14	0.7
Nausea	18	0	13	0.7
Vascular Disorders
Hypertension	31	18	28	13
Respiratory, Thoracic and Mediastinal Disorders
CoughÞ	21	0	21	0
Dyspnea	20	3.9	22	2.6
Psychiatric Disorders
Insomnia	18	3.9	11	2.0
Musculoskeletal and Connective Tissue Disorders
Back pain	16	1.9	10	1.3

Adverse Reactions Occurring at a Frequency of < 15%

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

EQUULEUS

The 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 a 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 14 summarizes the adverse reactions in EQUULEUS.

Table 14: Adverse Reactions (≥ 15%) in Patients Who Received DKd (20/70 mg/m2 Regimen) in EQUULEUS
Adverse Reactions	Once weekly DKd (N = 85)
Adverse Reactions	All Grades (%)	Grade 3 or 4 (%)
DKd = Kyprolis, daratumumab, and dexamethasone; Kd = Kyprolis and dexamethasone
* Thrombocytopenia includes platelet count decreased and thrombocytopenia. † Anemia includes anemia, hematocrit decreased and hemoglobin decreased. ‡ Neutropenia includes neutrophil count decreased and neutropenia. § Lymphopenia includes lymphocyte count decreased and lymphopenia. ¶ Fatigue includes fatigue and asthenia. # The incidence of infusion related reactions is based on a 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 1 day after DKd administration. Þ Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. ß Cough includes productive cough and cough.
Blood and Lymphatic System Disorders
Thrombocytopenia*	68	32
Anemia†	52	21
Neutropenia‡	31	21
Lymphopenia§	29	25
General Disorders and Administration Site Conditions
Fatigue¶	54	18
Infusion-related reaction#	53	12
Pyrexia	37	1.2
Infections
Respiratory tract infectionÞ	53	3.5
Bronchitis	19	0
Nasopharyngitis	18	0
Influenza	17	3.5
Gastrointestinal Disorders
Nausea	42	1.2
Vomiting	40	1.2
Diarrhea	38	2.4
Constipation	17	0
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea	35	3.5
Coughß	33	0
Vascular Disorders
Hypertension	33	20
Psychiatric Disorders
Insomnia	33	4.7
Nervous System Disorders
Headache	27	1.2
Musculoskeletal and Connective Tissue Disorders
Back pain	25	0
Pain in extremity	15	0

Adverse Reactions Occurring at a Frequency of < 15%

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 Dexamethasone

The safety of Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone was evaluated in PLEIADES [see Clinical Studies (14.3)].

PLEIADES

The safety of Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone (DKd) was evaluated in a single-arm cohort of PLEIADES. Patients received Kyprolis as a 30-minute IV infusion once weekly for three weeks (Days 1, 8, and 15), followed by a 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 6 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 15 summarizes the adverse reactions in patients who received Kyprolis with subcutaneous daratumumab and dexamethasone (DKd) in PLEIADES.

Table 15: Adverse Reactions (≥10%) in Patients Who Received Kyprolis with Subcutaneous Daratumumab and Dexamethasone (DKd) in PLEIADES
Adverse Reaction	DKd (N=66)
Adverse Reaction	All Grades (%)	Grade ≥3 (%)
* Upper 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. † Bronchitis includes bronchitis, and bronchitis viral. ‡ Only Grade 3 adverse reactions occurred. § Fatigue includes asthenia, and fatigue. ¶ Edema peripheral includes generalized edema, edema peripheral, and peripheral swelling. # Hypertension includes blood pressure increased, and hypertension. Þ Cough includes cough, and productive cough. ß Dyspnea includes dyspnea, and dyspnea exertional.
Infections and infestations
Upper respiratory tract infection*	52	0
Bronchitis†	12	2‡
General disorders and administration site conditions
Fatigue§	39	2‡
Pyrexia	21	2‡
Edema peripheral¶	20	0
Psychiatric disorders
Insomnia	33	6‡
Vascular disorders
Hypertension#	32	21‡
Gastrointestinal disorders
Diarrhea	29	0
Nausea	21	0
Vomiting	15	0
Respiratory, thoracic and mediastinal disorders
CoughÞ	24	0
Dyspneaß	23	2‡
Nervous system disorders
Headache	23	0
Peripheral sensory neuropathy	11	0
Musculoskeletal and connective tissue disorders
Back pain	17	2‡
Musculoskeletal chest pain	11	0

Clinically relevant adverse reactions in <10% of patients who received Kyprolis with subcutaneous daratumumab and dexamethasone include:

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

Table 16 summarizes the laboratory abnormalities in patients who received Kyprolis with subcutaneous daratumumab and dexamethasone in PLEIADES.

Table 16: Select Laboratory Abnormalities (≥30%) Worsening from Baseline in Patients Who Received DKd in PLEIADES
Laboratory Abnormality	DKd*
Laboratory Abnormality	All Grades (%)	Grades 3-4 (%)
* Denominator is based on the safety population treated with DKd (N=66).
Decreased platelets	88	18
Decreased lymphocytes	83	50
Decreased leukocytes	68	18
Decreased neutrophils	55	15
Decreased hemoglobin	47	6
Decreased corrected calcium	45	2
Increased alanine aminotransferase (ALT)	35	5

Kyprolis in Combination with Isatuximab and Dexamethasone

The safety of Kyprolis in combination with isatuximab and dexamethasone was evaluated in IKEMA, a randomized, open-label clinical trial in patients with previously treated multiple myeloma [see Clinical Studies (14.4)]. Patients received Kyprolis 20/56 mg/m2 twice weekly in combination with isatuximab and dexamethasone (Isa-Kd) (n=177) or Kyprolis and dexamethasone (Kd) (n=122). Among patients receiving Isa-Kd, the median exposure to Kyprolis was 65 weeks.

Serious adverse reactions occurred in 59% of patients receiving Isa-Kd. The most frequent serious adverse reactions in >5% of patients who received Isa-Kd were pneumonia (25%) and upper respiratory tract infections (9%). Adverse reactions with a fatal outcome during treatment were reported in 3.4% of patients in the Isa-Kd group (those occurring in more than 1% of patients were pneumonia occurring in 1.7% and cardiac failure in 1.1% of patients).

Permanent treatment discontinuation due to an adverse reaction (grades 1-4) occurred in 8% of patients who received Isa-Kd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Kd were infections (2.8%).

Dosage interruptions due to an adverse reaction occurred in 4% of patients who received Kyprolis in the Isa-Kd group. The most frequent adverse reactions requiring dosage interruption in patients who received Kyprolis in the Isa-Kd group were administration site extravasation (1.1%) and infusion site extravasation (1.1%).

Dose reductions or omissions of Kyprolis due to an adverse reaction in the Isa-Kd group occurred in 67% of patients. Adverse reactions which required dose reductions or omissions in >10% of patients who received Kyprolis in the Isa-Kd group were upper respiratory tract infection (12.4%) and hypertension (11.9%).

The most common adverse reactions (≥20%) were upper respiratory tract infection, infusion-related reactions, fatigue, hypertension, diarrhea, pneumonia, dyspnea, insomnia, bronchitis, cough and back pain.

Table 17 summarizes the adverse reactions in IKEMA.

Table 17: Adverse Reactions (≥10%) in Patients Who Received Kyprolis with Isatuximab and Dexamethasone (Isa-Kd) in IKEMA
Adverse Reactions	Isa-Kd (N = 177)		Kd (N = 122)
Adverse Reactions	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Isa-Kd = Kyprolis, isatuximab, and dexamethasone
* Upper respiratory tract infection includes acute sinusitis, chronic sinusitis, H1N1 influenza, H3N2 influenza, influenza, laryngitis, laryngitis viral, nasal herpes, nasopharyngitis, pharyngitis, pharyngotonsillitis, respiratory syncytial virus infection, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, tracheitis, upper respiratory tract infection, viral rhinitis, respiratory tract infection, respiratory tract infection viral, influenza like illness, parainfluenzae virus infection, respiratory tract infection bacterial, and viral upper respiratory tract infection. † Pneumonia includes atypical pneumonia, lower respiratory tract infection, lower respiratory tract infection viral, pneumocystis jirovecii pneumonia, pneumonia, pneumonia influenzal, pneumonia legionella, pneumonia pneumococcal, pneumonia respiratory syncytial viral, pneumonia streptococcal, pneumonia viral, pulmonary sepsis, and pulmonary tuberculosis. ‡ Bronchitis includes bronchitis, bronchitis viral, respiratory syncytial virus bronchitis, bronchitis chronic, and tracheobronchitis. § Infusion-related reaction includes infusion-related reaction, cytokine release syndrome, and hypersensitivity. ¶ Fatigue includes fatigue and asthenia. # Hypertension includes hypertension, blood pressure increased, and hypertensive crisis. Þ Dyspnea includes dyspnea and dyspnea exertional. ß Cough includes cough, productive cough, and allergic cough.
Infections
Upper respiratory tract infection*	67	9	57	7
Pneumonia†	36	22	30	18
Bronchitis‡	24	2.3	13	0.8
General Disorders and Administration Site Conditions
Infusion-related reaction§	46	0.6	3.3	0
Fatigue¶	42	5	32	3.3
Vascular Disorders
Hypertension#	37	21	32	20
Gastrointestinal Disorders
Diarrhea	36	2.8	29	2.5
Vomiting	15	1.1	9	0.8
Respiratory, Thoracic and Mediastinal Disorders
DyspneaÞ	29	5	24	0.8
Coughß	23	0	15	0

Table 18 summarizes the laboratory abnormalities in patients who received Kyprolis with isatuximab and dexamethasone versus Kyprolis with dexamethasone in IKEMA.

Table 18: Hematology Laboratory Abnormalities During the Treatment Period in Patients Who Received Isa-Kd versus Kd in IKEMA
Laboratory Abnormality	Isa-Kd* (N=177)		Kd (N=122)
Laboratory Abnormality	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
* Denominator is based on the safety population.
Hemoglobin decreased	99	22	99	20
Lymphocytes decreased	94	69	95	57
Platelets decreased	94	30	88	24
Neutrophils decreased	55	20	43	8

Kyprolis in Patients who Received Monotherapy

The safety of Kyprolis 20/27 mg/m2 as a 10-minute infusion was evaluated in clinical trials consisting of 598 patients with relapsed and/or refractory myeloma [see Clinical Studies (14.5)]. Premedication with dexamethasone 4 mg was required before each dose in Cycle 1 and was optional for subsequent cycles. The median age was 64 years (range 32–87), and approximately 57% were male. The patients received a median of 5 (range 1–20) prior regimens. The median number of cycles initiated was 4 (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 8 (1%) patients, renal disorders in 4 (< 1%) patients, and other adverse reactions in 8 (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, a randomized trial comparing Kyprolis as a 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 a multicenter, open-label study in patients with relapsed and/or refractory multiple myeloma [see Clinical Studies (14.5)]. The patients received a median of 4 (range 1–10) prior regimens.

Adverse reactions occurring with Kyprolis monotherapy are presented in Table 19.

Table 19: Adverse Reactions (≥ 20%) with Kyprolis Monotherapy
Adverse Reactions	20/56 mg/m2 by 30-minute infusion (N = 24)		20/27 mg/m2 by 2- to 10-minute infusion (N = 598)
Adverse Reactions	All Grades n (%)	Grades 3-5 n (%)	All Grades n (%)	Grades 3-5 n (%)
* Dyspnea includes dyspnea and dyspnea exertional. † Hypertension includes hypertension, hypertensive crisis, and hypertensive emergency. ‡ Cough includes cough and productive cough.
Fatigue	14 (58)	2 (8)	238 (40)	25 (4)
Dyspnea*	14 (58)	2 (8)	202 (34)	21 (4)
Pyrexia	14 (58)	0	177 (30)	11 (2)
Thrombocytopenia	13 (54)	13 (54)	220 (37)	152 (25)
Nausea	13 (54)	0	211 (35)	7 (1)
Anemia	10 (42)	7 (29)	291 (49)	141 (24)
Hypertension†	10 (42)	3 (13)	90 (15)	22 (4)
Chills	9 (38)	0	73 (12)	1 (< 1)
Headache	8 (33)	0	141 (24)	7 (1)
Cough‡	8 (33)	0	134 (22)	2 (< 1)
Vomiting	8 (33)	0	104 (17)	4 (1)
Lymphopenia	8 (33)	8 (33)	85 (14)	73 (12)
Insomnia	7 (29)	0	75 (13)	0
Dizziness	7 (29)	0	64 (11)	5 (1)
Diarrhea	6 (25)	1 (4)	160 (27)	8 (1)
Blood creatinine increased	6 (25)	1 (4)	103 (17)	15 (3)
Peripheral edema	5 (21)	0	118 (20)	1 (< 1)
Back pain	5 (21)	1 (4)	115 (19)	19 (3)
Upper respiratory tract infection	5 (21)	1 (4)	112 (19)	15 (3)
Decreased appetite	5 (21)	0	89 (15)	2 (< 1)
Muscle spasms	5 (21)	0	62 (10)	2 (< 1)
Chest pain	5 (21)	0	20 (3)	1 (< 1)

Adverse Reactions Occurring at a Frequency of < 20%

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

Grade 3 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 20 describes Grade 3–4 laboratory abnormalities reported at a rate of > 10% for patients who received Kyprolis monotherapy.

Table 20: Grade 3–4 Laboratory Abnormalities (> 10%) with Kyprolis Monotherapy
Laboratory Abnormality	Kyprolis 20/56 mg/m2 (N = 24)	Kyprolis 20/27 mg/m2 (N = 598)
Decreased lymphocytes	15 (63)	151 (25)
Decreased platelets	11 (46)	184 (31)
Decreased hemoglobin	7 (29)	132 (22)
Decreased total white blood cell count	3 (13)	71 (12)
Decreased sodium	2 (8)	69 (12)
Decreased absolute neutrophil count	2 (8)	67 (11)

6.2 Postmarketing Experience

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