ASH Clinical News ACN_5.1_Digital - Page 17

C K Most Common Adverse Reactions (≥ 10% in the KRd Arm) Occurring in Cycles 1–12 (20/27 mg/m 2 Regimen in Combination with Lenalidomide and Dexamethasone) RIGHT 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. 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) Laboratory Abnormalities Table 10 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥ 10% in the KRd arm for patients who received combination therapy. Safety Experience with Kyprolis in Combination with Dexamethasone in Patients with Multiple Myeloma The safety of Kyprolis in combination with dexamethasone was evaluated in two open-label, randomized trials (ENDEAVOR and A.R.R.O.W.). ENDEAVOR evaluated patients with relapsed or refractory multiple myeloma. Patients received treatment for a median duration of 48 weeks in the twice weekly Kyprolis/dexamethasone (Kd) 20/56 mg/m 2 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 vs. 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 events 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 treatment arms, pneumonia was the most commonly reported serious adverse reaction (8% vs. 9%). In patients treated with Kyprolis, 52% were 65 and over and 17% were 75 and over. The incidence of serious adverse events was 54% in patients < 65 years of age, 60% in patients 65 to 74 years of age, and 69% in patients ≥ 75 years of age. Discontinuation due to any adverse reaction occurred in 29% in the Kd arm versus 26% in the Vd arm. The most common 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. 87 (22) 7 (2) 54 (14) 4 (1) Most Common Adverse Reactions (≥ 10% in the Kd Arm) Occurring in Months 1–6 (20/56 mg/m 2 Regimen in Combination with Dexamethasone) KRd Arm (N = 392), n (%) Adverse Reactions by Body System Rd Arm (N = 389), n (%) Any Grade ≥ Grade 3 Any Grade ≥ Grade 3 138 (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) 119 (30) 8 (2) 106 (27) 12 (3) Blood and Lymphatic System Disorders Anemia Gastrointestinal Disorders Diarrhea Constipation 68 (17) 0 (0) 55 (14) 1 (0) Nausea 63 (16) 1 (0) 43 (11) 3 (1) General Disorders and Administration Site Conditions Infections and Infestations Upper respiratory tract infection Bronchitis 55 (14) 5 (1) 40 (10) 2 (1) Viral upper respiratory tract infection 55 (14) 0 (0) 44 (11) 0 (0) Pneumonia a 54 (14) 35 (9) 43 (11) 27 (7) Hypokalemia 78 (20) 22 (6) 35 (9) 12 (3) Anemia Hypocalcemia 55 (14) 10 (3) 39 (10) 5 (1) Thrombocytopenia Hyperglycemia 43 (11) 18 (5) 33 (9) 15 (4) Metabolism and Nutrition Disorders Kd (N = 463), n (%) Adverse Reaction by Body System Vd (N = 456), n (%) Any Grade ≥ Grade 3 Any Grade ≥ Grade 3 161 (35) 57 (12) 112 (25) 43 (9) 125 (27) 45 (10) 112 (25) 64 (14) 27 (6) Blood and Lymphatic System Disorders Musculoskeletal and Connective Tissue Disorders a Gastrointestinal Disorders Diarrhea 117 (25) 14 (3) 149 (33) Muscle spasms 92 (24) 3 (1) 75 (19) 3 (1) Nausea 70 (15) 4 (1) 68 (15) 3 (1) Back pain 41 (11) 4 (1) 54 (14) 6 (2) Constipation 60 (13) 1 (0) 113 (25) 6 (1) Vomiting 45 (10) 5 (1) 33 (7) 3 (1) 43 (11) 7 (2) 39 (10) 4 (1) 64 (16) 6 (2) 51 (13) 8 (2) 25 (6) Nervous System Disorders Peripheral neuropathies b Psychiatric Disorders Insomnia Respiratory, Thoracic, and Mediastinal Disorders Cough c 93 (24) 2 (1) 54 (14) 0 (0) Dyspnea d 71 (18) 8 (2) 61 (16) 6 (2) 45 (12) 5 (1) 54 (14) 5 (1) Skin and Subcutaneous Tissue Disorders Rash Vascular Disorders Embolic and thrombotic events e 49 (13) 16 (4) 23 (6) 9 (2) Hypertension f 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 include 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 and infestations: 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 General Disorders and Administration Site Conditions Fatigue 116 (25) 14 (3) 126 (28) 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) Upper respiratory tract infection 67 (15) 4 (1) 55 (12) 3 (1) Bronchitis 54 (12) 5 (1) 25 (6) 2 (0) Infections and Infestations 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) 67 (15) 4 (1) 39 (9) 2 (0) 56 (12) 7 (2) 170 (37) 23 (5) 105 (23) 5 (1) 116 (25) 10 (2) Nervous System Disorders Headache Peripheral neuropathies b Psychiatric Disorders Insomnia Respiratory, Thoracic, and Mediastinal Disorders Dyspnea c 123 (27) 23 (5) 66 (15) 8 (2) Cough 97 (21) 0 (0) 61 (13) 2 (0) 83 (18) 30 (7) 33 (7) 12 (3) d Vascular Disorders Hypertension e Kd = Kyprolis and dexamethasone; Vd = bortezomib and dexamethasone. a Thrombocytopenia includes platelet count decreased and thrombocytopenia. b Peripheral neuropathies include peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. c Dyspnea includes dyspnea and dyspnea exertional. d Cough includes cough and productive cough. e 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 310408gi401_PI_Kng df