Cardiovascular Complications of Carfilzomib Treatment

Accumulating evidence supports the hypothesis of a pathophysiological role of the Ubiquitin Proteasome System (UPS) in the process of atherosclerosis and vascular function. However the data are contradicting in respect to the direction of this association and therefore the net effect of UPS activity on the cardiovascular system is not known. Inhibitors of UPS are currently standard of care for patients with multiple myeloma (MM). Heart failure and hypertension have been reported in studies of carfilzomib, an irreversible 2nd generation proteasome inhibitor, both as a single agent and in combination with other drugs but their potential vascular toxicity is not adequately studied. Furthermore, as the role of the UPS has not been studied yet clinically but only in experimental and autopsy based studies, assessment of UPS inhibition in humans would facilitate understanding of the UPS-mediated pathophysiologic mechanisms in human atherosclerosis. Thus, this project may stimulate further research on the role of UPS in atherogenesis and potential new therapeutic approaches on vascular dysfunction may arise. We designed the following project in order to investigate the acute and chronic effect of Carfilzomib (CFZ) on cardiovascular function. Patients with an indication to receive CFZ will be recruited to be followed in the Clinical Therapeutics Department in pre-specified timepoints. Functional and structural measurements including markers of arterial stiffness and subclinical atherosclerosis will be performed using non-invasive well-validated techniques. Blood pressure will be also evaluated using 24h hour ambulatory monitoring. Evaluation of cardiac function will be performed at baseline and thereafter at 6 months or earlier if a suspicious event occurs necessitating evaluation of cardiac function. In parallel and at each time point, the activity of UPS and intracellular levels of ubiquitin conjugates will be measured in peripheral blood mononuclear cells (PBMCs) and red blood cells (RBCs) using enzymatic proteasome activity assays and western blot techniques, respectively.

This is an observational, non interventional, prospective study. Patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy and who receive carfilzomib with dexamethasone according to the approved dose and schedule will be included in this observational study. No specific treatment intervention related to the study is going to be performed. No specific harms or benefits are expected due to study investigations.

Objectives and Purpose: The present study will assess patients with multiple myeloma receiving the proteasome inhibitor carfilzomib (CFZ), in order to investigate, in vivo, a wide spectrum of human atherosclerosis indices, from cardiovascular risk factors to subclinical atherosclerosis at multiple successive stages in a human model under conditions of global UPS inhibition, and correlate with cardiovascular complications associated with carfilzomib therapy, in patients receiving carfilzomib with dexamethasone.

Primary objective: To investigate cardiovascular complications and the role of the UPS inhibition on atheromatosis and vascular function and inflammation, in patients with relapsed or refractory myeloma who are receiving carfilzomib and dexamethasone.

Secondary objective(s): To outline the clinical significance of carfilzomib toxicity in hemodynamic parameters and vascular function and structure in humans

Duration of the study: Patients will receive therapy until disease progression or as per physician's decision regarding the patient's best interest and according to the approved indications. Study accrual and collection of data will be completed in two years. The study can be terminated for any reason and at any time by the Sponsor.

Population: The study will include patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy (2) and who according to physicians' decision are treated with carfilzomib dexamethasone in the approved indication, doses and schedule. Briefly, patients aged 18 years or older with relapsed or refractory multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 to 2, at last one prior treatments, will be included.

Carfilzomib treatment: According to the approved indications patients will be given carfilzomib at a dose of 20 mg/m2 on days 1 and 2 of cycle 1; and thereafter at a dose of 56 mg/m2, in a 30 min intravenous infusion, on days 1,2,8,9,15 and 16. Dexamethasone (40mg IV) will be administered 24-48 hours before first CFZ infusion in order to assess the individual vascular effects of each drug separately; subsequently dexamethasone will be given IV at a dose of 20 mg on days 1,2,8,9,15 and 16, and orally on days 22 and 23 of a 28-day cycle. The rationale for using these doses is based on the results of the ENDEAVOR study and the approved indications and dosing of KYPROLIS. Intravenous hydration (250-500 mL before and after dose administration) is going to be given during cycle 1 and at the investigator's discretion thereafter.

Sample size: This is an observational study with non interventional design. Sample size calculation is made on the basis of previous data indicating that at least 2% absolute difference in Flow mediated dilatation (FMD) (corresponding to 20-30% relative difference) is considered significant and clinically relevant. With the null hypothesis being that CFZ/Dex therapy is associated with \<10% relative difference in FMD and the alternative hypothesis being that a ≥30% difference is considered as significant, and with an a=0.05, a sample of 40 patients is required for 90% power of detecting these differences (all tests are 2-sided). A dropout rate of 15% is assumed. A total number of 46 patients is thus calculated to be enrolled.

Studied parameters History record: A detailed history will be obtained from every subject and all possible risk factors that could be associated with an increased risk of cardiac and vascular adverse events including thorough clinical examination along with ECG and cardiac echocardiography to ensure that every patient has an ejection fraction ≥40% thus being eligible for enrollment.

Assessment of arterial stiffness: Arterial stiffness in the aorta by measurement of pulse wave velocity (PWV).

Central blood pressures and reflected waves in the aorta: Non-invasive estimation of aortic pressure waveforms and reflected waves by pulse wave analysis (PWA) will be performed. The following indices are measured: a. augmentation index (AI, percentage) normalized for the heart rate of 75 bpm, expressed as a percentage of the aortic pulse pressure, b. central systolic and diastolic pressures (cBP), c. time to the beginning of the reflected wave (in milliseconds) and d. blood pressure amplification calculated as the ratio of peripheral pulse pressure: central pulse pressure.

Endothelial function by ultrasound measurement of endothelium-dependent flow-mediated dilatation (FMD): Endothelial function will be assessed by Flow Mediated Dilatation (FMD)

Carotid and Femoral Intima-Media Thickness (IMT): Carotid intima-media thickness (ccIMT) will be measured at the distal 1.0 cm of the common carotid proximal to the bifurcation. Femoral IMT (fIMT) will be measured on each side, scanning a 1cm-long arterial segment proximal to the femoral bifurcation, defined as the common femoral artery segment and the average value of IMT of the far wall will be estimated.

Ankle Brachial Index (ABI): The ABI is a simple, non-invasive diagnostic test for lower-extremity peripheral arterial disease (PAD) with high validity of the test for stenosis ≥50% in leg arteries (sensitivity ≈95% and specificity ≈100%).

All the above mentioned vascular measurements will be performed at each time point, that is on baseline and days 1,2,8,9,15 and 16 of cycle 1 and on days 1,2 of cycle 2 and 3 before and 2 hours after drug administration. The B-Mode ultrasound of the carotid and femoral arteries will only be performed at baseline. On cycle 6 all vascular measurements will be repeated to assess the chronic effect of proteasome inhibition on vascular function and atherosclerosis.

24-hour Ambulatory Blood Pressure Monitoring (ABPM): Patients will have their blood pressure monitored for 24 hours during the 1st day of cycles 1, 2, 3 and 6.

Cardiac Ultrasonography: Study participants will undergo a baseline echocardiographic examination before the initiation of the treatment.

Study of Proteasome activity: In order to examine the molecular and cellular effects of therapeutic inhibitors in blood cells of MM patients, we will proceed to isolation of Red Blood Cells (RBCs) and Peripheral Blood Mononuclear Cells (PBMCs). The blood samples which will be used in this research will be collected between specific time points of therapeutic proteasomal inhibitors administration. The first day of the treatment (no drug administration) will be used as a control time point.

Eligibility Criteria:
Inclusion Criteria:

* Males and females at least 18 years of age
* Voluntary written informed consent before performance of any study-related procedure
* Documented relapsed or refractory multiple myeloma in need of therapy, after at least one previous line of therapy for myeloma
* Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2
* Willingness and ability to participate in study procedures

Exclusion Criteria:

* Anti-myeloma treatment within 2 weeks prior to Cycle 1, Day 1
* Cumulative dose of corticosteroids greater than or equal to the equivalent of 140mg prednisone for ≥4 days or a dose of corticosteroids greater than or equal to the equivalent of 40 mg/day of dexamethasone for ≥4 days within the 2-week period prior to Cycle 1, Day 1
* Previous allogeneic stem cell transplant; or Autologous Stem Cell Transplantation (ASCT) within 12 weeks before Cycle 1, Day 1
* Clinical signs of meningeal involvement of multiple myeloma
* Clinically significant cardiac disease, including:

  1. Myocardial infarction within 6 months, or unstable or uncontrolled condition (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV)
  2. Cardiac arrhythmia (CTCAE Grade 2 or higher) or clinically significant ECG abnormalities
  3. ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) \>470 msec
* Known active hepatitis B, or C.
* Known HIV infection.
* Prior or concurrent malignancy, except for the following:

  1. Adequately treated basal cell or squamous cell skin cancer.
  2. Any cancer (other than in-situ) from which the subject has been disease-free for 3 years prior to study entry.
* Any of the following laboratory test results during Screening:

  1. Absolute neutrophil count ≤1.0 × 109/L;
  2. Hemoglobin level ≤7.5 g/dL (≤5 mmol/L);
  3. Platelet count \<75 × 109/L in patients in whom \<50% of bone marrow nucleated cells are plasma cells and \<50x109/L in patients in whom more than 50% of bone marrow nucleated cells are plasma cells;
  4. Alanine aminotransferase level ≥2.5 times the upper limit of normal (ULN);
* Pregnant or nursing women