Interventional, no-randomized, open-label, and single arm multicentre study of apixaban for the prevention of thromboembolic events during induction therapy in transplant-eligible patients with newly diagnosed multiple myeloma who receive bortezomib, thalidomide, and dexamethasone (VTD) during the induction phase of therapy prior to autologous stem cell transplantation (ASCT). The current study is designed to evaluate the efficacy and safety of apixaban during the induction period. Efficacy will be defined as a composite endpoint of acute symptomatic proximal and distal deep venous thrombosis, pulmonary embolism, VTE related deaths, and acute ischemic stroke.
This study is designed to test the efficacy and safety of the oral anti factor Xa apixaban 2.5 mg given twice daily as a prophylaxis of VTE in transplant-eligible patients with multiple myeloma during the induction therapy with VTD. Induction therapy prior to ASCT will consist in no less than 4 and no more than 6 cycles of VTD, depending on treatment response. Duration of each cycle is 4 weeks if there is not any disease or treatment-related complication; therefore, treatment duration will be around 4-6 months. Daily Prophylaxis with apixaban will continue up to a maximum of 14 days after the last dose of thalidomide. In addition, there will be an additional observation period of 14 (± 7) days, starting the day after the last dose of study medication (until 28 days after the end of the last cycle of VTD).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
60
Apixaban will be started simultaneously with anti myeloma treatment on day 1 of cycle 1 of VTD, and continues for 4 to 6 months depending on the number of induction cycles administered to the patient
Hospital Clinico Universitario
Valencia, Spain
Hospital Universitario Doctor Peset
Valencia, Spain
Hospital Universitario y Politécnico La Fe
Valencia, Spain
Hospital General Universitario
Valencia, Spain
Venous thromboembolism (VTE)- related death
i.e. death for which VTE can not be excluded as a cause
Time frame: Cycle 1 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Venous thromboembolism (VTE)- related death
i.e. death for which VTE can not be excluded as a cause
Time frame: Cycle 2 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Venous thromboembolism (VTE)- related death
i.e. death for which VTE can not be excluded as a cause
Time frame: Cycle 3 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Venous thromboembolism (VTE)- related death
i.e. death for which VTE can not be excluded as a cause
Time frame: Cycle 4 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Venous thromboembolism (VTE)- related death
i.e. death for which VTE can not be excluded as a cause
Time frame: Cycle 5 Day 1(each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Venous thromboembolism (VTE)- related death
i.e. death for which VTE can not be excluded as a cause
Time frame: Cycle 6 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Venous thromboembolism (VTE)- related death
i.e. death for which VTE can not be excluded as a cause
Time frame: Cycle 4 Day 29 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Venous thromboembolism (VTE)- related death
i.e. death for which VTE can not be excluded as a cause
Time frame: Cycle 6 Day 29 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Venous thromboembolism (VTE)- related death
i.e. death for which VTE can not be excluded as a cause
Time frame: Cycle 4 Day 43 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Venous thromboembolism (VTE)- related death
i.e. death for which VTE can not be excluded as a cause
Time frame: Cycle 6 Day 43 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Venous thromboembolism (VTE)- related death
i.e. death for which VTE can not be excluded as a cause
Time frame: 14 days after last dose of apixaban
Symptomatic deep-vein thrombosis (DVT)
Lower extremity DVT: erythema (redness of the skin), warmth, pain, swelling, tenderness
Time frame: Cycle 1 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Symptomatic deep-vein thrombosis (DVT)
Lower extremity DVT: erythema (redness of the skin), warmth, pain, swelling, tenderness
Time frame: Cycle 2 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Symptomatic deep-vein thrombosis (DVT)
Lower extremity DVT: erythema (redness of the skin), warmth, pain, swelling, tenderness
Time frame: Cycle 3 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Symptomatic deep-vein thrombosis (DVT)
Lower extremity DVT: erythema (redness of the skin), warmth, pain, swelling, tenderness
Time frame: Cycle 4 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Symptomatic deep-vein thrombosis (DVT)
Lower extremity DVT: erythema (redness of the skin), warmth, pain, swelling, tenderness
Time frame: Cycle 5 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Symptomatic deep-vein thrombosis (DVT)
Lower extremity DVT: erythema (redness of the skin), warmth, pain, swelling, tenderness
Time frame: Cycle 6 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Symptomatic deep-vein thrombosis (DVT)
Lower extremity DVT: erythema (redness of the skin), warmth, pain, swelling, tenderness
Time frame: Cycle 4 Day 29 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Symptomatic deep-vein thrombosis (DVT)
Lower extremity DVT: erythema (redness of the skin), warmth, pain, swelling, tenderness
Time frame: Cycle 6 Day 29 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Symptomatic deep-vein thrombosis (DVT)
Lower extremity DVT: erythema (redness of the skin), warmth, pain, swelling, tenderness
Time frame: Cycle 4 Day 43 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Symptomatic deep-vein thrombosis (DVT)
Lower extremity DVT: erythema (redness of the skin), warmth, pain, swelling, tenderness
Time frame: Cycle 6 Day 43 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Symptomatic deep-vein thrombosis (DVT)
Lower extremity DVT: erythema (redness of the skin), warmth, pain, swelling, tenderness
Time frame: 14 days after last dose of apixaban
Pulmonary embolism (PE)
Pleuritic chest pain, dyspnea (shortness of breath), cough, hemoptysis (expectoration of blood or blood-stained sputum), syncope (fainting), lightheadedness/dizziness, tachypnea (rapid breathing), tachycardia (fast heart rate).
Time frame: Cycle 1 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Pulmonary embolism (PE)
Pleuritic chest pain, dyspnea (shortness of breath), cough, hemoptysis (expectoration of blood or blood-stained sputum), syncope (fainting), lightheadedness/dizziness, tachypnea (rapid breathing), tachycardia (fast heart rate).
Time frame: Cycle 2 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Pulmonary embolism (PE)
Pleuritic chest pain, dyspnea (shortness of breath), cough, hemoptysis (expectoration of blood or blood-stained sputum), syncope (fainting), lightheadedness/dizziness, tachypnea (rapid breathing), tachycardia (fast heart rate).
Time frame: Cycle 3 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Pulmonary embolism (PE)
Pleuritic chest pain, dyspnea (shortness of breath), cough, hemoptysis (expectoration of blood or blood-stained sputum), syncope (fainting), lightheadedness/dizziness, tachypnea (rapid breathing), tachycardia (fast heart rate).
Time frame: Cycle 4 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Pulmonary embolism (PE)
Pleuritic chest pain, dyspnea (shortness of breath), cough, hemoptysis (expectoration of blood or blood-stained sputum), syncope (fainting), lightheadedness/dizziness, tachypnea (rapid breathing), tachycardia (fast heart rate).
Time frame: Cycle 5 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Pulmonary embolism (PE)
Pleuritic chest pain, dyspnea (shortness of breath), cough, hemoptysis (expectoration of blood or blood-stained sputum), syncope (fainting), lightheadedness/dizziness, tachypnea (rapid breathing), tachycardia (fast heart rate).
Time frame: Cycle 6 Day 1 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Pulmonary embolism (PE)
Pleuritic chest pain, dyspnea (shortness of breath), cough, hemoptysis (expectoration of blood or blood-stained sputum), syncope (fainting), lightheadedness/dizziness, tachypnea (rapid breathing), tachycardia (fast heart rate).
Time frame: Cycle 4 Day 29 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Pulmonary embolism (PE)
Pleuritic chest pain, dyspnea (shortness of breath), cough, hemoptysis (expectoration of blood or blood-stained sputum), syncope (fainting), lightheadedness/dizziness, tachypnea (rapid breathing), tachycardia (fast heart rate).
Time frame: Cycle 6 Day 29 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Pulmonary embolism (PE)
Pleuritic chest pain, dyspnea (shortness of breath), cough, hemoptysis (expectoration of blood or blood-stained sputum), syncope (fainting), lightheadedness/dizziness, tachypnea (rapid breathing), tachycardia (fast heart rate).
Time frame: Cycle 4 Day 43 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Pulmonary embolism (PE)
Pleuritic chest pain, dyspnea (shortness of breath), cough, hemoptysis (expectoration of blood or blood-stained sputum), syncope (fainting), lightheadedness/dizziness, tachypnea (rapid breathing), tachycardia (fast heart rate).
Time frame: Cycle 6 Day 43 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Pulmonary embolism (PE)
Pleuritic chest pain, dyspnea (shortness of breath), cough, hemoptysis (expectoration of blood or blood-stained sputum), syncope (fainting), lightheadedness/dizziness, tachypnea (rapid breathing), tachycardia (fast heart rate).
Time frame: 14 days after last dose of apixaban
Asymptomatic proximal DVT as detected by systematic compression ultrasound
Diagnostic assessment of DVT. Presence of any one of the following will be considered diagnostic for the presence of DVT: 1. New or previously undocumented non-compressibility of one or more proximal venous segments (popliteal vein or higher) of the legs on compression ultrasound. 2. Constant intraluminal filing defect(s) in two or more views on contrast venography in one or more venous segments in the legs or pelvis, or involving the inferior vena cava.
Time frame: Cycle 4 Day 43 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Asymptomatic proximal DVT as detected by systematic compression ultrasound
Diagnostic assessment of DVT. Presence of any one of the following will be considered diagnostic for the presence of DVT: 1. New or previously undocumented non-compressibility of one or more proximal venous segments (popliteal vein or higher) of the legs on compression ultrasound. 2. Constant intraluminal filing defect(s) in two or more views on contrast venography in one or more venous segments in the legs or pelvis, or involving the inferior vena cava.
Time frame: Cycle 6 Day 43 (each cycle is 28 days. Treatment will finish on cycle 4 or 6. Treatment with Apixaban will continue until 14 days after cycle 4/6)
Major bleeding event
Defined as a bleeding event that is acute clinically overt bleeding accompanied by one or more of the following: * A decrease in hemoglobin (Hb) of 2 g/dL or more over a 24-hour period. * A transfusion of 2 or more units of packed red blood cells. * Bleeding that occurs in at least one of the following critical sites: intracranial, intra-spinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, an operated joint and requires re-operation or intervention, intramuscular with compartment syndrome, retroperitoneal. * Bleeding that is fatal.
Time frame: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 4/ 6 Day 29, Cycle 4/6 Day 43, Day 14 after end of treatment (each cycle is 28 days. Treatment with Apixaban will continue until 14 days after cycle 4 or 6)
Clinically relevant non-major bleeding event
Defined as a bleeding event that is: * Acute clinically overt bleeding. * Does not satisfy additional criteria required for the bleeding event to be defined as a major bleeding event and meets at least one of the following criteria: * Epistaxis: need to medical attention from a physician or visits an emergency room, requires an intervention, persists for 5 minutes or more. * Gastrointestinal bleed: vomit containing frank blood or coffee ground material which tests positive for blood, endoscopically confirmed bleeding, frank blood per rectum or melena stools. * Hematuria: overt spontaneous bleeding, bleeding persists for 24 hours or more after instrumentation. * Bruising/ecchymosis: any bruise, which is assessed as "unusual". * Hematoma: presence of a hematoma is demonstrated radiographically, and a drop-in hemoglobin is present with no external evidence of bleeding. * Hemoptysis: expectoration of blood or blood-stained sputum.
Time frame: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 4/ 6 Day 29, Cycle 4/6 Day 43, Day 14 after end of treatment (each cycle is 28 days. Treatment with Apixaban will continue until 14 days after cycle 4 or 6)
Fatal Bleeding Event
Defined as a bleeding event that determines is the primary cause of death or contributes directly to death.
Time frame: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 4/ 6 Day 29, Cycle 4/6 Day 43, Day 14 after end of treatment (each cycle is 28 days. Treatment with Apixaban will continue until 14 days after cycle 4 or 6)
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Liver injury event
Potential or suspected cases of liver injury including but not limited to liver test abnormalities (elevation of ALT, AST, GGT, alkaline phosphatase and total bilirrubin), jaundice, hepatitis or cholestasis events.
Time frame: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 4/ 6 Day 29, Cycle 4/6 Day 43, Day 14 after end of treatment (each cycle is 28 days. Treatment with Apixaban will continue until 14 days after cycle 4 or 6)
Serious adverse events
A Serious Adverse Event is any untoward medical occurrence that: * Results in death. * Is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe). * Requires inpatient hospitalization or prolongation of existing hospitalization * Results in persistent or significant disability/incapacity. * Is a congenital anomaly/birth defect. * Is an important medical event (defined as a medical event(s) that may require medical intervention to prevent one of a serious outcome listed above). * Overdose. * Second primary malignancies.
Time frame: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 4/ 6 Day 29, Cycle 4/6 Day 43, Day 14 after end of treatment (each cycle is 28 days. Treatment with Apixaban will continue until 14 days after cycle 4 or 6)
Symptomatic DVT or PE occurring during the 90 days of follow-up period
Symptomatic DTV or PE as defined aforementioned, assessed 90 days after the last dose of the study drug.
Time frame: Day +90 follow-up
Death occurring during the 90 days of follow-up period
All cause of mortality occurring during the 90 days after the last dose of the study drug.
Time frame: Day +90 follow-up