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Multiple Myeloma

Neoplasms, Plasma Cell

Dilatation, Pathologic

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Proteasome Inhibitors

Measurement of the change in the vasodilatative reserve of the brachial artery

Flow mediated dilation

Matthias Totzeck

Lena Hinrichs

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

Vascular Functions in Myeloma Patients During Anti-tumor Therapy

Characterization of Vascular Functions in Myeloma Patients Before and During Anti-tumor Therapy

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

Levels of arginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-monomethylarginine (MMA)

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

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.

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.

University Hospital, Essen

Principal Investigator

Neuroendocrine Tumors

Carcinoma, Neuroendocrine

Sarcoma, Ewing

Neuroectodermal Tumors, Primitive, Peripheral

Carcinoid Tumor

Carcinoma

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Pancreatic Neuroendocrine Tumor

Neuroepithelioma

Carfilzomib will be administered as intravenous (IV) infusion over 30 minutes on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle.

Cycle 1: First two doses of Carfilzomib 20 mg/m2 IV; subsequent doses at 56 mg/m2 IV

Cycle 2 onwards: Carfilzomib 56 mg/m2 IV

Carfilzomib

David Spigel, M.D.

The purpose of this study is to determine if carfilzomib is safe and effective in the treatment of patients with advanced neuroendocrine tumors.

Neuroendocrine malignancies such as pancreatic neuroendocrine tumors (PNETs) and gastrointestinal (GI) carcinoids, are generally rare but their incidences are increasing. In vitro and in vivo studies have shown that proteasome inhibitors have activity against a variety of tumor types. Carfilzomib (Kyprolis®) is an irreversible proteasome inhibitor with a favorable safety profile that has been studied in a variety of hematologic and solid tumors. Carfilzomib received accelerated approval from the U.S. FDA in 2012, based on a favorable response rate, for the treatment of patients with multiple myeloma who received at least two prior therapies, and demonstrated disease progression within 60 days of completing the last therapy. In this multi-center study, the investigators propose to evaluate carfilzomib for the treatment of patients with advanced neuroendocrine cancers.

Carfilzomib for the Treatment of Patients With Advanced Neuroendocrine Cancers

Phase II Study of Carfilzomib for the Treatment of Patients With Advanced Neuroendocrine Cancers

Percentage of participants with confirmed complete response (CR) or partial response (PR) (i.e. 2 CRs or PRs at least 4 weeks apart) to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) CR=disappearance of all target lesions. PR=at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Percentage of participants with complete response (CR), partial response (PR), or stable disease (SD) (≥ 6 cycles) according to RECIST v1.1 criteria. Complete Response is defined per RECIST as the disappearance of all target/non-target lesions and normalization of tumor markers. Partial Response is defined per RECIST as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable disease is defined per RECIST as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest (nadir) sum LD since the treatment started.

Measured from Day 1 of study drug administration to disease progression as defined by RECIST v1.1, or death on the study. Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or unequivocal progression of non-target lesions or the appearance of one or more new lesions. Patients who did not have disease progression or death documented were censored on the date of the last visit with adequate assessment.

The number of treatment-emergent adverse events will be graded utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03

Amgen

SCRI Development Innovations, LLC

All patients who received at least one dose of protocol treatment were followed for safety. Adverse events and serious adverse events were collected from the day of the first dose to 30 days after the last dose of the study medication and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Carfilzomib - administered as an intravenous (IV) infusion over 30 minutes on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle.

Cycle 1: First two doses of Carfilzomib 20 mg/m\^2 IV; subsequent doses at 56 mg/m2 IV

Cycle 2 onwards: Carfilzomib 56 mg/m\^2 IV

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Full analysis set - all enrolled patients who receive at least one full or partial dose of the study group and who have measurable disease at baseline

Sarah Cannon Development Innovations, LLC

All enrolled patients who received at least one full or partial dose of the study drug and who had measurable disease at baseline were included in the analysis.

Overall Response Rate (ORR)

Disease Control Rate (DCR)

Progression Free Survival (PFS)

All enrolled patients who received at least one full or partial dose of the study drug.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Vascular Functions in Myeloma Patients During Anti-tumor Therapy	NCT03776331	Cardiooncology Myeloma Endothelial Dys...	Flow mediated d...	18 Years -	University Hospital, Essen
Carfilzomib for the Treatment of Patients With Advanced Neuroendocrine Cancers	NCT02318784	Neuroendocrine ...	Carfilzomib	18 Years -	SCRI Development Innovations, LLC

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