KYPROLIS SIDE EFFECTS

Last updated on MDtodate: 10/6/2022

SIDE EFFECTS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Cardiac Toxicities
• Acute Renal Failure
• Tumor Lysis Syndrome
• Pulmonary Toxicity
• Pulmonary Hypertension
• Dyspnea
• Hypertension
• Venous Thrombosis
• Infusion-Related Reactions
• Hemorrhage
• Thrombocytopenia
• Hepatic Toxicity and Hepatic Failu
• Thrombotic Microangiopathy
• Posterior Reversible Encephalopathy Syndrome
• Progressive Multifocal Leukoencephalopathy

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  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. 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 12 summarizes the adverse reactions in the first 12 cycles in ASPIRE.

Table 1: 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 (%)
	Any Grade	≥ Grade 3	Any Grade	≥ Grade 3
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)
Pneumoniaa	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 neuropathiesb	43 (11)	7 (2)	39 (10)	4 (1)
Psychiatric Disorders
Insomnia	64 (16)	6 (2)	51 (13)	8 (2)
Respiratory, Thoracic and Mediastinal Disorders
Coughc	93 (24)	2 (1)	54 (14)	0 (0)
Dyspnead	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 eventse	49 (13)	16 (4)	23 (6)	9 (2)
Hypertensionf	41 (11)	12 (3)	15 (4)	4 (1)
KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone a Pneumonia includes pneumonia and bronchopneumonia. b Peripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. c Cough includes cough and productive cough. d Dyspnea includes dyspnea and dyspnea exertional. e Embolic and thrombotic events, venous includes deep vein thrombosis, pulmonary embolism, thrombophlebitis superficial, thrombophlebitis, venous thrombosis limb, post thrombotic syndrome, venous thrombosis. f Hypertension includes hypertension, hypertensive crisis.

 

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 2 describes Grade 3-4 laboratory abnormalities reported in ASPIRE.

Table 2: 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 (%)
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)
KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone

 

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. 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 3.

Table 3: 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 (%)
	Any Grade	Grade ≥ 3	Any Grade	Grade ≥ 3
Blood and Lymphatic System Disorders
Anemia	161 (35)	57 (12)	112 (25)	43 (9)
Thrombocytopeniaa	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 neuropathiesb,c	56 (12)	7 (2)	170 (37)	23 (5)
Psychiatric Disorders
Insomnia	105 (23)	5 (1)	116 (25)	10 (2)
Respiratory, Thoracic and Mediastinal Disorders
Dyspnead	128 (28)	23 (5)	69 (15)	8 (2)
Coughe	97 (21)	0 (0)	61 (13)	2 (0)
Vascular Disorders
Hypertensionf	83 (18)	30 (7)	33 (7)	12 (3)
Kd = Kyprolis and dexamethasone; Vd = bortezomib and dexamethasone a Thrombocytopenia includes platelet count decreased and thrombocytopenia. b Peripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. d Dyspnea includes dyspnea and dyspnea exertional. e Cough includes cough and productive cough. f Hypertension includes hypertension, hypertensive crisis, and hypertensive emergency.

 

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

Table 4: 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 (%)
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 clearancea	65 (14)	49 (11)
Increased potassium	55 (12)	21 (5)
Kd = Kyprolis and dexamethasone; Vd = bortezomib and dexamethasone a Calculated using the Cockcroft-Gault formula.

 

A.R.R.O.W.

The safety of Kyprolis in combination with dexamethasone was evaluated in A.R.R.O.W.  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 5.

Table 5: 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 ≥ 3	Any Grade	Grade ≥ 3
Blood and Lymphatic System Disorders
Anemiaa	64 (27)	42 (18)	76 (32)	42 (18)
Thrombocytopeniab	53 (22)	26 (11)	41 (17)	27 (12)
Neutropeniac	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 infectiond	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
Coughe	37 (16)	2 (1)	31 (13)	0 (0)
Dyspneaf	28 (12)	1 (< 1)	26 (11)	2 (1)
Vascular Disorders
Hypertensiong	51 (21)	13 (6)	48 (20)	12 (5)
Kd = Kyprolis and dexamethasone a Anemia includes anemia, hematocrit decreased, and hemoglobin decreased. b Thrombocytopenia includes platelet count decreased and thrombocytopenia. c Neutropenia includes neutrophil count decreased and neutropenia. d Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection, and viral upper respiratory tract infection. e Cough includes cough and productive cough. f Dyspnea includes dyspnea and dyspnea exertional. g Hypertension includes hypertension and hypertensive crisis.

 

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. 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 6 summarizes the adverse reactions in CANDOR.

Table 6: 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)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
General Disorders and Administration Site Conditions
Infusion-related reactiona	41	12	28	5
Fatigueb	32	11	28	8
Pyrexia	20	1.9	15	0.7
Infections
Respiratory tract infectionc	40g	7	29	3.3
Pneumonia	18g	13	12	9
Bronchitis	17	2.6	12	1.3
Blood and lymphatic system disorders
Thrombocytopeniad	37	25	30	16
Anemiae	33	17	31	14
Gastrointestinal Disorders
Diarrhea	32	3.9	14	0.7
Diarrhea	18	0	13	0.7
Vascular Disorders
Hypertension	31	18	28	13
Respiratory, Thoracic and Mediastinal Disorders
Coughf	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
DKd = Kyprolis, daratumumab, and dexamethasone; Kd = Kyprolis and dexamethasone a 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. b Fatigue includes fatigue and asthenia. c Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. d Thrombocytopenia includes platelet count decreased and thrombocytopenia. e Anemia includes anemia, hematocrit decreased and hemoglobin decreased. f Cough includes productive cough and cough. g Includes fatal adverse reactions.

 

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 daratumumab and dexamethasone (DKd) was evaluated in EQUULEUS. 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 7 summarizes the adverse reactions in EQUULEUS.

Table 7: Adverse Reactions (≥ 15%) in Patients Who Received DKd (20/70 mg/m² Regimen) in EQUULEUS

Adverse Reactions	Once weekly DKd (N = 85)
	All Grades (%)	Grade 3 or 4 (%)
Blood and Lymphatic System Disorders
Thrombocytopeniaa	68	32
Anemiab	52	21
Neutropeniac	31	21
Lymphopeniad	29	25
General Disorders and Administration Site Conditions
Fatiguee	54	18
Infusion-related reactionf	53	12
Pyrexia	37	1.2
Infections
Respiratory tract infectiong	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
Coughh	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
DKd = Kyprolis, daratumumab, and dexamethasone; Kd = Kyprolis and dexamethasone a Thrombocytopenia includes platelet count decreased and thrombocytopenia. b Anemia includes anemia, hematocrit decreased and hemoglobin decreased. c Neutropenia includes neutrophil count decreased and neutropenia. d Lymphopenia includes lymphocyte count decreased and lymphopenia e Fatigue includes fatigue and asthenia. f 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. g Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. h Cough includes productive cough and cough.

 

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 Patients Who Received Monotherapy

The safety of Kyprolis 20/27 mg/m² as a 10-minute infusion was evaluated in clinical trials in which 598 patients with relapsed and/or refractory myeloma. 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. The patients received a median of 4 (range 1-10) prior regimens.

Adverse reactions occurring with Kyprolis monotherapy are presented in Table 8.

Table 8: 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)
	All Grades n (%)	Grades 3-5 n (%)	All Grades n (%)	Grades 3-5 n (%)
Fatigue	14 (58)	2 (8)	238 (40)	25 (4)
Dyspneaa	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)
Hypertensionb	10 (42)	3 (13)	90 (15)	22 (4)
Chills	9 (38)	0	73 (12)	1 (< 1)
Headache	8 (33)	0	141 (24)	7 (1)
Coughc	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)
a Dyspnea includes dyspnea and dyspnea exertional. b Hypertension includes hypertension, hypertensive crisis, and hypertensive emergency. c Cough includes cough and productive cough.

 

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

Table 9: 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)

 

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, and intestinal obstruction.