<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03776331</url>
  </required_header>
  <id_info>
    <org_study_id>Vascular-Myelom</org_study_id>
    <nct_id>NCT03776331</nct_id>
  </id_info>
  <brief_title>Vascular Functions in Myeloma Patients During Anti-tumor Therapy</brief_title>
  <official_title>Characterization of Vascular Functions in Myeloma Patients Before and During Anti-tumor Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Essen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital, Essen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Treatment options for multiple myeloma have increased significantly over the last years with&#xD;
      the approval of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). These&#xD;
      therapies have markedly improved overall survival for these patients to a median of 5-7&#xD;
      years. Due to the advanced age, the myeloma patient collective has a high prevalence of&#xD;
      pre-existing cardiovascular comorbidities. In addition, the primary disease process&#xD;
      contributes to cardiovascular complications. With the beginning of anti-tumor therapy, an&#xD;
      increased incidence of cardiovascular complications in myeloma patients can be determined.&#xD;
      This includes hypertension, left ventricular dysfunction, heart failure and both arterial and&#xD;
      venous thromboembolic events. The detailed mechanism by which proteasome inhibitors and&#xD;
      immunomodulatory agents lead to increased cardiovascular events is not established at this&#xD;
      time. Endothelial dysfunction, as a possible mechanism of cardiovascular toxicity, is&#xD;
      difficult to assess. Flow-mediated dilation (FMD) is an noninvasive method to measure&#xD;
      endothelial function by assessing the change in the vasodilatative reserve of the brachial&#xD;
      artery. Several independent recent investigations implicate that vascular (endothelial)&#xD;
      dysfunction precedes hypertension and heart failure. This has been related to a reduced level&#xD;
      of metabolites of the l-arginine-nitric oxide (NO) signaling pathway.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
        1. Anti-myeloma therapy exert vascular toxicity by limiting endothelial function.&#xD;
           Endothelial function, assessed by the change in the vasodilatative reserve of the&#xD;
           brachial artery (flow-mediated dilation = FMD) decreases after myeloma therapy.&#xD;
&#xD;
        2. Patients with multiple myeloma have a limited endothelial function compared to a healthy&#xD;
           control group.&#xD;
&#xD;
      A total of 40 myeloma patients will be examined. Measurements will be taken at baseline, 1&#xD;
      month and 6 month after myeloma therapy. Patients should not have received chemotherapy for&#xD;
      at least 3 months. Furthermore a healthy sex- and age-matched control group will be examined.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Treatment options for multiple myeloma have increased significantly over the last years with&#xD;
      the approval of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). These&#xD;
      therapies have markedly improved overall survival for these patients to a median of 5-7&#xD;
      years, many continue to live for more than 10 years. Due to the advanced age, the myeloma&#xD;
      patient collective has a high prevalence of pre-existing cardiovascular comorbidities. In&#xD;
      addition, the primary disease process contributes to cardiovascular complications. With the&#xD;
      beginning of anti-tumor therapy, an increased incidence of cardiovascular complications in&#xD;
      myeloma patients can be determined. This includes hypertension, left ventricular dysfunction,&#xD;
      heart failure and both arterial and venous thromboembolic events.&#xD;
&#xD;
      Proteasome inhibitors including bortezomib and carfilzomib, and immunomodulatory agents, e.g.&#xD;
      lenalidomide, represent cornerstone therapies for multiple myeloma. The most common therapy&#xD;
      choices are Bortezomib-based therapy (VCD, VC) and Carfilzomib-based therapy (KRD, KD).&#xD;
      Induction therapy is given 4-6 cycles followed by autologous hematopoietic cell&#xD;
      transplantation. Thereafter, many patients receive consolidation therapy. In patients not&#xD;
      eligible for autologous hematopoietic cell transplantation, a prolonged course of initial&#xD;
      chemotherapy is typically administered. The proteasome inhibitor Bortezomib is used&#xD;
      predominately in the front line setting, while second-generation carfilzomib is used in&#xD;
      relapsed/refractory disease.&#xD;
&#xD;
      Despite their efficacy, increased rates of cardiovascular complications occur in patients&#xD;
      exposed to these particular therapies. Higher incidences of cardiac adverse events including&#xD;
      hypertension, arrhythmia, heart failure, ischemic heart disease and cardiomyopathy has been&#xD;
      reported in patients receiving carfilzomib and bortezomib. Immunomodulatory agents are known&#xD;
      to increase the risk of venous thromboembolic disease particularly when combined with&#xD;
      dexamethasone or other chemotherapy. Furthermore, increased incidence of myocardial&#xD;
      infarction (MI) and cerebrovascular events has been demonstrated in patients treated with&#xD;
      lenalidomide. The mechanism of PI- and IMiD-associated cardiotoxicity is not fully&#xD;
      elucidated. PIs inhibit proteasome activity, leading to the accumulation of abnormal proteins&#xD;
      which in turn activates apoptotic pathways in myeloma cells. IMiDs bind cereblon, a component&#xD;
      of the E3 ubiquitin ligase which promotes proteasome-mediated degradation of the&#xD;
      transcription factors, IKZF1 and IKZF. It is unclear if the protein degradation properties of&#xD;
      these drugs contribute to cardiotoxicity, although clinical features of the toxicity suggest&#xD;
      endothelial cell injury and dysfunction. It is possible that CV events may be augmented when&#xD;
      these two classes of medications are co-administered and further enhanced by the additional&#xD;
      endothelial stress conferred by steroids. The detailed mechanism by which proteasome&#xD;
      inhibitors and immunomodulatory agents lead to increased cardiovascular events is not&#xD;
      established at this time.&#xD;
&#xD;
      Endothelial dysfunction, as a possible mechanism of cardiovascular toxicity, is difficult to&#xD;
      assess. Flow-mediated dilation (FMD) is an noninvasive method to measure endothelial function&#xD;
      by assessing the change in the vasodilatative reserve of the brachial artery. Several&#xD;
      independent recent investigations implicate that vascular (endothelial) dysfunction precedes&#xD;
      hypertension and heart failure. This has been related to a reduced level of metabolites of&#xD;
      the l-arginine-nitric oxide (NO) signaling pathway.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
        1. Anti-myeloma therapy exert vascular toxicity by limiting endothelial function.&#xD;
           Endothelial function, assessed by the change in the vasodilatative reserve of the&#xD;
           brachial artery (flow-mediated dilation = FMD) decreases after myeloma therapy.&#xD;
&#xD;
        2. Patients with multiple myeloma have a limited endothelial function compared to a healthy&#xD;
           control group.&#xD;
&#xD;
      Study design:&#xD;
&#xD;
      A total of 40 myeloma patients will be examined. Measurements will be taken at baseline, 1&#xD;
      month 6 month after myeloma therapy. Patients should not have received chemotherapy for at&#xD;
      least 3 months. Furthermore a healthy sex- and age-matched control group will be examined.&#xD;
&#xD;
      Primary endpoint:&#xD;
&#xD;
      • Endothelial function, assessed by the change in the vasodilatative reserve of the brachial&#xD;
      artery (flow-mediated dilation = FMD), between baseline and 1 month data&#xD;
&#xD;
      Secondary endpoints:&#xD;
&#xD;
        -  Endothelial function, assessed by the vasodilatative reserve of the brachial artery&#xD;
           (flow-mediated dilation = FMD) between baseline data in myeloma patients and control&#xD;
           group&#xD;
&#xD;
        -  Change of left ventricular pump function (3D-EF, global longitudinal strain)&#xD;
&#xD;
        -  Alteration of echocardiographic parameters of diastolic dysfunction&#xD;
&#xD;
        -  Change in dyspnea symptoms (NYHA Classification)&#xD;
&#xD;
        -  Modification of cardiac biomarkers (NT-pro BNP, Troponin)&#xD;
&#xD;
        -  Change of circulating NO-Pool&#xD;
&#xD;
        -  Change in metabolomics (Biobank)&#xD;
&#xD;
        -  Change in arterial stiffness and augmentation index&#xD;
&#xD;
        -  Change of quality of life rated according to Medical Outcomes Short-Form Survey, SF-36,&#xD;
           Minnesota Living With Heart Failure Questionnaire&#xD;
&#xD;
        -  Change in blood pressure&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">December 28, 2018</start_date>
  <completion_date type="Anticipated">March 28, 2020</completion_date>
  <primary_completion_date type="Anticipated">December 28, 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Change of endothelial function, assessed by the change in the vasodilatative reserve of the brachial artery (flow-mediated dilation = FMD)</measure>
    <time_frame>between baseline and 1 month data</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change of endothelial function, assessed by the change in the vasodilatative reserve of the brachial artery (flow-mediated dilation = FMD)</measure>
    <time_frame>between baseline and 6 month data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of endothelial function, assessed by the change in the vasodilatative reserve of the brachial artery (flow-mediated dilation = FMD)</measure>
    <time_frame>between 1 and 6 month data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of endothelial function, assessed by the vasodilatative reserve of the brachial artery (flow-mediated dilation = FMD) between baseline data in myeloma patients and control group</measure>
    <time_frame>baseline data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of left ventricular pump function (3D-EF)</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of left ventricular pump function (global longitudinal strain)</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alteration of grade of diastolic dysfunction</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
    <description>Assesed by E, E/A, E/e', IVRT, DT, e', e'/a', TEI index, sPAP, according to ASE/EACVI GUIDELINES AND STANDARDS, Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging, Sherif et al, 2016, J Am Soc Echocardiogr, 2016</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in dyspnea symptoms (NYHA Classification)</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in concentration of Troponin</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in concentration of NT-pro BNP</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in circulating arginine-nitric oxide (NO) metabolites</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
    <description>Levels of arginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-monomethylarginine (MMA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in levels of circulating arginine</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in leves of circulating citrulline</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in levels of circulating ornithine</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in levels of circulating asymmetric dimethylarginine (ADMA)</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in levels of circulating symmetric dimethylarginine (SDMA)</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in levels of circulating N-monomethylarginine (MMA)</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in pulse wave velocity as a parameter of arterial stiffness</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in augmentation index</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
    <description>Augmentation index (AIx), the pressure difference between the shoulder on the pressure wave and systolic pressure expressed as a ratio of pulse pressure is widely used as a proxy of wave reflection</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of quality of life rated according to Minnesota Living With Heart Failure Questionnaire</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
    <description>The questionnaire is comprised of 21 important physical, emotional and socioeconomic ways heart failure can adversely affect a patient's life. After receiving brief standardized instructions, the patient marks a 0 (zero) to 5 scale to indicate how much each itemized adverse of heart failure has prevented the patient from living as he or she wanted to live during the past 4 weeks. The questionnaire is simply scored by summation of all 21 responses.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of quality of life rated according to Medical Outcomes Short-Form Survey</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
    <description>The SF-36 consists of 36 questions and is a general health questionnaire that provides information about the health status of the patient through 8 different dimensions. He makes statements about:&#xD;
General Health Perception, Physical Health, Restricted physical role function, Physical pain, Vitality, Mental Healt, Restricted emotional role function, Social functioning. For the evaluation of the SF-36 questionnaire v1.0 you first recode all answers in predefined points using a recoding table. Then you calculate the average score of all questions of the respective health dimension, e.g. physical health, so you have 8 average points for the 8 dimensions. These 8 scores now describe the health status of the patient in their respective dimensions, which can then be assessed using comparison charts.&#xD;
The possible score ranges from 0 to 100 points. 0 points represent the greatest possible restriction of health, while 100 points represent the absence of health restrictions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in blood pressure (systolic, diastolic and MAD)</measure>
    <time_frame>between baseline and 1 month data/baseline and 6 month data/1 and 6 month data</time_frame>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">96</enrollment>
  <condition>Cardiooncology</condition>
  <condition>Myeloma</condition>
  <condition>Endothelial Dysfunction</condition>
  <arm_group>
    <arm_group_label>Myeloma Patients</arm_group_label>
  </arm_group>
  <arm_group>
    <arm_group_label>Controll group</arm_group_label>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Flow mediated dilation</intervention_name>
    <description>Measurement of the change in the vasodilatative reserve of the brachial artery</description>
    <arm_group_label>Controll group</arm_group_label>
    <arm_group_label>Myeloma Patients</arm_group_label>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood tissue&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        The cohorts will be selected of the population of patients of the university clinic of&#xD;
        Essen&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Included in the study are myeloma patients with planned bortezomib, carfilzomib and&#xD;
        lenalidomide-based chemotherapy and 20 subjects from a healthy normal population.&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  written consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Severe pulmonary, valvular, or congenital heart disease with clinical dyspnoea&#xD;
             symptoms&#xD;
&#xD;
          -  Life expectancy less than 6 months&#xD;
&#xD;
          -  Unstable angina pectoris or indication for coronary revascularization&#xD;
&#xD;
          -  Valvular disease (aortic valve and mitral regurgitation greater than moderate, and&#xD;
             aortic valve or mitral valve stenosis greater than moderate)&#xD;
&#xD;
          -  Atrial fibrillation or flutter&#xD;
&#xD;
          -  Chronic renal insufficiency (Cockcroft-Gault GFR &lt;30 mL / min)&#xD;
&#xD;
          -  Severe cirrhosis (Child-Pugh B and C)&#xD;
&#xD;
          -  Current or future indication for therapy with organic nitrates&#xD;
&#xD;
          -  Leading non-cardiac cause of clinical dyspnea symptoms, such as high-grade obesity or&#xD;
             lung disease in need of glucocorticoid therapy or oxygen therapy&#xD;
&#xD;
          -  Other cause of clinical dyspnea symptoms, such as high-grade obesity or lung disease&#xD;
             with need for glucocorticoid therapy or oxygen therapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Matthias Totzeck</last_name>
    <role>Principal Investigator</role>
    <affiliation>Universitätsklinikum Essen AOeR</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Matthias Totzeck</last_name>
    <phone>004920172384805</phone>
    <email>matthias.totzeck@uk-essen.de</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Lena Hinrichs</last_name>
    <phone>015144531284</phone>
    <email>lena.hinrichs@uk-essen.de</email>
  </overall_contact_backup>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>November 10, 2018</study_first_submitted>
  <study_first_submitted_qc>December 13, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 14, 2018</study_first_posted>
  <last_update_submitted>December 17, 2018</last_update_submitted>
  <last_update_submitted_qc>December 17, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 19, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital, Essen</investigator_affiliation>
    <investigator_full_name>Fadi Al-Rashid</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Myeloma</keyword>
  <keyword>Flow mediated dilation</keyword>
  <keyword>Endothelial Dysfunction</keyword>
  <keyword>Proteasome inhibitors</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Myeloma</mesh_term>
    <mesh_term>Neoplasms, Plasma Cell</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03776331
org study id: Vascular-Myelom
nct id: NCT03776331
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Treatment options for multiple myeloma have increased significantly over the last years with
      the approval of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). These
      therapies have markedly improved overall survival for these patients to a median of 5-7
      years. Due to the advanced age, the myeloma patient collective has a high prevalence of
      pre-existing cardiovascular comorbidities. In addition, the primary disease process
      contributes to cardiovascular complications. With the beginning of anti-tumor therapy, an
      increased incidence of cardiovascular complications in myeloma patients can be determined.
      This includes hypertension, left ventricular dysfunction, heart failure and both arterial and
      venous thromboembolic events. The detailed mechanism by which proteasome inhibitors and
      immunomodulatory agents lead to increased cardiovascular events is not established at this
      time. Endothelial dysfunction, as a possible mechanism of cardiovascular toxicity, is
      difficult to assess. Flow-mediated dilation (FMD) is an noninvasive method to measure
      endothelial function by assessing the change in the vasodilatative reserve of the brachial
      artery. Several independent recent investigations implicate that vascular (endothelial)
      dysfunction precedes hypertension and heart failure. This has been related to a reduced level
      of metabolites of the l-arginine-nitric oxide (NO) signaling pathway.

      Hypothesis:

        1. Anti-myeloma therapy exert vascular toxicity by limiting endothelial function.
           Endothelial function, assessed by the change in the vasodilatative reserve of the
           brachial artery (flow-mediated dilation = FMD) decreases after myeloma therapy.

        2. Patients with multiple myeloma have a limited endothelial function compared to a healthy
           control group.

      A total of 40 myeloma patients will be examined. Measurements will be taken at baseline, 1
      month and 6 month after myeloma therapy. Patients should not have received chemotherapy for
      at least 3 months. Furthermore a healthy sex- and age-matched control group will be examined.
Treatment options for multiple myeloma have increased significantly over the last years with
      the approval of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). These
      therapies have markedly improved overall survival for these patients to a median of 5-7
      years, many continue to live for more than 10 years. Due to the advanced age, the myeloma
      patient collective has a high prevalence of pre-existing cardiovascular comorbidities. In
      addition, the primary disease process contributes to cardiovascular complications. With the
      beginning of anti-tumor therapy, an increased incidence of cardiovascular complications in
      myeloma patients can be determined. This includes hypertension, left ventricular dysfunction,
      heart failure and both arterial and venous thromboembolic events.

      Proteasome inhibitors including bortezomib and carfilzomib, and immunomodulatory agents, e.g.
      lenalidomide, represent cornerstone therapies for multiple myeloma. The most common therapy
      choices are Bortezomib-based therapy (VCD, VC) and Carfilzomib-based therapy (KRD, KD).
      Induction therapy is given 4-6 cycles followed by autologous hematopoietic cell
      transplantation. Thereafter, many patients receive consolidation therapy. In patients not
      eligible for autologous hematopoietic cell transplantation, a prolonged course of initial
      chemotherapy is typically administered. The proteasome inhibitor Bortezomib is used
      predominately in the front line setting, while second-generation carfilzomib is used in
      relapsed/refractory disease.

      Despite their efficacy, increased rates of cardiovascular complications occur in patients
      exposed to these particular therapies. Higher incidences of cardiac adverse events including
      hypertension, arrhythmia, heart failure, ischemic heart disease and cardiomyopathy has been
      reported in patients receiving carfilzomib and bortezomib. Immunomodulatory agents are known
      to increase the risk of venous thromboembolic disease particularly when combined with
      dexamethasone or other chemotherapy. Furthermore, increased incidence of myocardial
      infarction (MI) and cerebrovascular events has been demonstrated in patients treated with
      lenalidomide. The mechanism of PI- and IMiD-associated cardiotoxicity is not fully
      elucidated. PIs inhibit proteasome activity, leading to the accumulation of abnormal proteins
      which in turn activates apoptotic pathways in myeloma cells. IMiDs bind cereblon, a component
      of the E3 ubiquitin ligase which promotes proteasome-mediated degradation of the
      transcription factors, IKZF1 and IKZF. It is unclear if the protein degradation properties of
      these drugs contribute to cardiotoxicity, although clinical features of the toxicity suggest
      endothelial cell injury and dysfunction. It is possible that CV events may be augmented when
      these two classes of medications are co-administered and further enhanced by the additional
      endothelial stress conferred by steroids. The detailed mechanism by which proteasome
      inhibitors and immunomodulatory agents lead to increased cardiovascular events is not
      established at this time.

      Endothelial dysfunction, as a possible mechanism of cardiovascular toxicity, is difficult to
      assess. Flow-mediated dilation (FMD) is an noninvasive method to measure endothelial function
      by assessing the change in the vasodilatative reserve of the brachial artery. Several
      independent recent investigations implicate that vascular (endothelial) dysfunction precedes
      hypertension and heart failure. This has been related to a reduced level of metabolites of
      the l-arginine-nitric oxide (NO) signaling pathway.

      Hypothesis:

        1. Anti-myeloma therapy exert vascular toxicity by limiting endothelial function.
           Endothelial function, assessed by the change in the vasodilatative reserve of the
           brachial artery (flow-mediated dilation = FMD) decreases after myeloma therapy.

        2. Patients with multiple myeloma have a limited endothelial function compared to a healthy
           control group.

      Study design:

      A total of 40 myeloma patients will be examined. Measurements will be taken at baseline, 1
      month 6 month after myeloma therapy. Patients should not have received chemotherapy for at
      least 3 months. Furthermore a healthy sex- and age-matched control group will be examined.

      Primary endpoint:

      • Endothelial function, assessed by the change in the vasodilatative reserve of the brachial
      artery (flow-mediated dilation = FMD), between baseline and 1 month data

      Secondary endpoints:

        -  Endothelial function, assessed by the vasodilatative reserve of the brachial artery
           (flow-mediated dilation = FMD) between baseline data in myeloma patients and control
           group

        -  Change of left ventricular pump function (3D-EF, global longitudinal strain)

        -  Alteration of echocardiographic parameters of diastolic dysfunction

        -  Change in dyspnea symptoms (NYHA Classification)

        -  Modification of cardiac biomarkers (NT-pro BNP, Troponin)

        -  Change of circulating NO-Pool

        -  Change in metabolomics (Biobank)

        -  Change in arterial stiffness and augmentation index

        -  Change of quality of life rated according to Medical Outcomes Short-Form Survey, SF-36,
           Minnesota Living With Heart Failure Questionnaire

        -  Change in blood pressure
observational model: Cohort
time perspective: Prospective
measure: Change of endothelial function, assessed by the change in the vasodilatative reserve of the brachial artery (flow-mediated dilation = FMD)
time frame: between baseline and 1 month data
measure: Change of endothelial function, assessed by the change in the vasodilatative reserve of the brachial artery (flow-mediated dilation = FMD)
time frame: between baseline and 6 month data
measure: Change of endothelial function, assessed by the change in the vasodilatative reserve of the brachial artery (flow-mediated dilation = FMD)
time frame: between 1 and 6 month data
measure: Change of endothelial function, assessed by the vasodilatative reserve of the brachial artery (flow-mediated dilation = FMD) between baseline data in myeloma patients and control group
time frame: baseline data
measure: Change of left ventricular pump function (3D-EF)
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
measure: Change of left ventricular pump function (global longitudinal strain)
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
measure: Alteration of grade of diastolic dysfunction
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
description: Assesed by E, E/A, E/e', IVRT, DT, e', e'/a', TEI index, sPAP, according to ASE/EACVI GUIDELINES AND STANDARDS, Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging, Sherif et al, 2016, J Am Soc Echocardiogr, 2016
measure: Change in dyspnea symptoms (NYHA Classification)
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
measure: Change in concentration of Troponin
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
measure: Change in concentration of NT-pro BNP
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
measure: Change in circulating arginine-nitric oxide (NO) metabolites
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
description: Levels of arginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-monomethylarginine (MMA)
measure: Change in levels of circulating arginine
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
measure: Change in leves of circulating citrulline
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
measure: Change in levels of circulating ornithine
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
measure: Change in levels of circulating asymmetric dimethylarginine (ADMA)
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
measure: Change in levels of circulating symmetric dimethylarginine (SDMA)
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
measure: Change in levels of circulating N-monomethylarginine (MMA)
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
measure: Change in pulse wave velocity as a parameter of arterial stiffness
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
measure: Change in augmentation index
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
description: Augmentation index (AIx), the pressure difference between the shoulder on the pressure wave and systolic pressure expressed as a ratio of pulse pressure is widely used as a proxy of wave reflection
measure: Change of quality of life rated according to Minnesota Living With Heart Failure Questionnaire
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
description: The questionnaire is comprised of 21 important physical, emotional and socioeconomic ways heart failure can adversely affect a patient's life. After receiving brief standardized instructions, the patient marks a 0 (zero) to 5 scale to indicate how much each itemized adverse of heart failure has prevented the patient from living as he or she wanted to live during the past 4 weeks. The questionnaire is simply scored by summation of all 21 responses.
measure: Change of quality of life rated according to Medical Outcomes Short-Form Survey
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
description: The SF-36 consists of 36 questions and is a general health questionnaire that provides information about the health status of the patient through 8 different dimensions. He makes statements about:
General Health Perception, Physical Health, Restricted physical role function, Physical pain, Vitality, Mental Healt, Restricted emotional role function, Social functioning. For the evaluation of the SF-36 questionnaire v1.0 you first recode all answers in predefined points using a recoding table. Then you calculate the average score of all questions of the respective health dimension, e.g. physical health, so you have 8 average points for the 8 dimensions. These 8 scores now describe the health status of the patient in their respective dimensions, which can then be assessed using comparison charts.
The possible score ranges from 0 to 100 points. 0 points represent the greatest possible restriction of health, while 100 points represent the absence of health restrictions.
measure: Change in blood pressure (systolic, diastolic and MAD)
time frame: between baseline and 1 month data/baseline and 6 month data/1 and 6 month data
arm group label: Myeloma Patients
arm group label: Controll group
intervention type: Diagnostic Test
intervention name: Flow mediated dilation
description: Measurement of the change in the vasodilatative reserve of the brachial artery
arm group label: Controll group
arm group label: Myeloma Patients
Blood tissue
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Matthias Totzeck
role: Principal Investigator
affiliation: Universitätsklinikum Essen AOeR
last name: Matthias Totzeck
phone: 004920172384805
email: matthias.totzeck@uk-essen.de
last name: Lena Hinrichs
phone: 015144531284
email: lena.hinrichs@uk-essen.de
responsible party type: Principal Investigator
investigator affiliation: University Hospital, Essen
investigator full name: Fadi Al-Rashid
investigator title: Principal Investigator
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
sharing ipd: Yes
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Clinical Study Report (CSR)