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.

Sex

All

Minimum age

18 Years

Maximum age

90 Years

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

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