Arterial Hypertension and Multiple Myeloma: Physiopathology and Cardiovascular Risk and ‘Practical’ Indications in Patients Receiving Carfilzomib

The introduction of carfilzomib in the treatment of relapsing and refractory multiple myeloma has allowed a significant increase in survival. The most frequent adverse effect of Carfilzomib treatment is arterial hypertension, even though the exact physiopathological mechanism are still unclear. MM patients, on the other hand, often present significant cardiovascular risk factors and comorbidities. Uncontrolled hypertension is frequently the cause of cardiovascular complications. It has been estimated that up to 50% of subjects in the general population are unaware of their hypertensive condition and only half of those who are aware of this risk factor present good control of blood pressure. Although the management of arterial hypertension is clearly important in reducing the risk of cardiovascular events, and is well described by the current guidelines, no clear indications are provided on how to approach and treat specifically MM patients undergoing treatment with proteasome inhibitors. The aim of our work is to summarize a practical approach to the stratification of cardiovascular risk of hypertensive in patients who are candidates for or actively treated with carfilzomib for refractory multiple myeloma (MMR). MM patients eligible for carfilzomib treatment should preliminary undergo a careful cardiovascular risk stratification. Perspective studies will help to better identify the specific risk factors that should be considered and treated in these patients.

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Risk factors of disturbances in carbohydrate and lipid metabolism and some pleiotropic effects of antihypertensive therapy in pregnant women

Obesity and metabolism ◽

10.14341/2071-8713-5064 ◽

2013 ◽

Vol 10 (1) ◽

pp. 9-13

Author(s):

A V Padyganova

Keyword(s):

Risk Factors ◽

Cardiovascular Risk ◽

Lipid Metabolism ◽

Arterial Hypertension ◽

Cardiovascular Complications ◽

Mechanisms Of Action ◽

High Cardiovascular Risk ◽

Carbohydrate And Lipid Metabolism ◽

Exchange Processes ◽

Modern Population

The any kind of hypertension developing during the pregnancy, associated with high cardiovascular risk in the future. At the pregnancy complicated by development by arterial hypertension, there are more expressed changes of a carbohydrate and lipide metabolism, than it is peculiar to normally proceeding pregnancy, were by important pathogenetic links of obesity, diabetes, cardiovascular complications. Identification of new mechanisms of action of antihypertensive means associated with positive influences on exchange processes, is represented very demanded, considering pandemic nature of prevalence of metabolic violations in modern population.

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Real-world treatment patterns in relapsed/refractory multiple myeloma: Clinical and economic outcomes in patients treated with pomalidomide or daratumumab

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155221995532 ◽

2021 ◽

pp. 107815522199553

Author(s):

Joshua Richter ◽

Vamshi Ruthwik Anupindi ◽

Jason Yeaw ◽

Suneel Kudaravalli ◽

Stojan Zavisic ◽

...

Keyword(s):

Multiple Myeloma ◽

Real World ◽

Treatment Options ◽

Proteasome Inhibitors ◽

Economic Outcomes ◽

Office Visits ◽

Refractory Multiple Myeloma ◽

Kaplan Meier ◽

Real World Evidence ◽

New Treatment

Introduction Real-world evidence on later line treatment of relapsed/refractory multiple myeloma (RRMM) is sparse. We evaluated clinical outcomes among RRMM patients in the 1-year following treatment with pomalidomide or daratumumab and compared economic outcomes between RRMM patients and non-MM patients. Patient and Methods Adult patients with ≥1 claim of pomalidomide or daratumumab were identified between January 2012 and February 2018 using IQVIA PharMetrics® Plus US claims database. Patients were required to have a diagnosis or treatment for MM and a claim of any immunomodulatory drugs and proteasome inhibitors before the index date. Mean time to new therapy, overall survival (OS) using Kaplan-Meier curve and adverse events (AEs) were reported over the 1-year post-index period. RRMM patients were also matched to a non-MM comparator cohort and economic outcomes were compared between the two cohorts. Results 289 RRMM patients were matched to 1,445 patients without MM. Most prevalent hematological AE was anemia (72.0%) and non-hematological AE was infections (75.4%). Mean (SD) time to a new treatment was 4.7 (5.3) months and median OS was 14.6 months. RRMM patients had significantly higher hospitalizations and physician office visits (Both P < .0001) compared to non-MM patients. Adjusting for baseline characteristics, patients with RRMM had 4.9 times (95% CI 3.8-6.4, P < .0001) the total healthcare costs compared with patients without MM. The major driver of total costs among RRMM patients was pharmacy costs (67.3%). Conclusion RRMM patients showed a high frequency of AEs, low OS, and a substantial economic burden suggesting need for effective treatment options.

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The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

Therapeutic Advances in Hematology ◽

10.1177/20406207211019622 ◽

2021 ◽

Vol 12 ◽

pp. 204062072110196

Author(s):

Albert Oriol ◽

Laura Abril ◽

Anna Torrent ◽

Gladys Ibarra ◽

Josep-Maria Ribera

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Safety Profile ◽

Proteasome Inhibitors ◽

Clinical Development ◽

Phase Iii ◽

Acceptable Safety Profile ◽

Refractory Multiple Myeloma ◽

High Risk Patients ◽

Risk Patients

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody–drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.

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[PP.10.16] RHEUMATOID ARTHRITIS PATIENTS WITH ARTERIAL HYPERTENSION HAVE HIGH PREVALENCE OF CARDIOVASCULAR RISK FACTORS

Journal of Hypertension ◽

10.1097/01.hjh.0000523437.04277.13 ◽

2017 ◽

Vol 35 ◽

pp. e161-e162

Author(s):

L. Krougly ◽

O. Fomicheva ◽

Yu Karpov ◽

T. Popkova ◽

E. Nasonov

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factors ◽

Cardiovascular Risk ◽

Arterial Hypertension ◽

Cardiovascular Risk Factors ◽

High Prevalence

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Retrospective Study on the Safety of Daratumumab in Japanese Relapsed or Refractory Multiple Myeloma and Search for Risk Factors for Infusion Related Reaction

Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) ◽

10.5649/jjphcs.45.706 ◽

2019 ◽

Vol 45 (12) ◽

pp. 706-713

Author(s):

Yusuke Nakagawa ◽

Hiroyuki Ogura ◽

Tatsuya Isezaki ◽

Osamu Yasumuro ◽

Hiroki Kobayashi ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Retrospective Study ◽

Refractory Multiple Myeloma ◽

Related Reaction

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Obesity in Humans Is Characterized by Gut Inflammation as Shown by Pro-Inflammatory Intestinal Macrophage Accumulation

Frontiers in Immunology ◽

10.3389/fimmu.2021.668654 ◽

2021 ◽

Vol 12 ◽

Author(s):

Theresa V. Rohm ◽

Regula Fuchs ◽

Rahel L. Müller ◽

Lena Keller ◽

Zora Baumann ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Risk ◽

Cardiovascular Risk Factors ◽

Vegetable Intake ◽

Cardiovascular Complications ◽

Processed Meat ◽

Low Grade ◽

Blood Monocytes ◽

Unhealthy Lifestyle ◽

Gut Inflammation

Chronic low-grade inflammation is a hallmark of obesity and associated with cardiovascular complications. However, it remains unclear where this inflammation starts. As the gut is constantly exposed to food, gut microbiota, and metabolites, we hypothesized that mucosal immunity triggers an innate inflammatory response in obesity. We characterized five distinct macrophage subpopulations (P1-P5) along the gastrointestinal tract and blood monocyte subpopulations (classical, non-classical, intermediate), which replenish intestinal macrophages, in non-obese (BMI<27kg/m2) and obese individuals (BMI>32kg/m2). To elucidate factors that potentially trigger gut inflammation, we correlated these subpopulations with cardiovascular risk factors and lifestyle behaviors. In obese individuals, we found higher pro-inflammatory macrophages in the stomach, duodenum, and colon. Intermediate blood monocytes were also increased in obesity, suggesting enhanced recruitment to the gut. We identified unhealthy lifestyle habits as potential triggers of gut and systemic inflammation (i.e., low vegetable intake, high processed meat consumption, sedentary lifestyle). Cardiovascular risk factors other than body weight did not affect the innate immune response. Thus, obesity in humans is characterized by gut inflammation as shown by accumulation of pro-inflammatory intestinal macrophages, potentially via recruited blood monocytes. Understanding gut innate immunity in human obesity might open up new targets for immune-modulatory treatments in metabolic disease.

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Quantitative PK/PD Prediction of the Efficacious and Safe Dose Ranges of the LMP7 Inhibitor M3258 for Phase I Application in Relapsed/Refractory Multiple Myeloma Patients

Blood ◽

10.1182/blood-2019-126972 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5582-5582

Author(s):

Florian Lignet ◽

Christina Esdar ◽

Manja Friese-Hamim ◽

Andreas Becker ◽

Elise Drouin ◽

...

Keyword(s):

Multiple Myeloma ◽

Research And Development ◽

Phase I ◽

Dose Escalation ◽

Single Agent ◽

Proteasome Inhibitors ◽

Refractory Multiple Myeloma ◽

Oral Application ◽

Development Institute ◽

Safe Dose

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, β5i, PSMB8) proteolytic subunit of the immunoproteasome; a crucial component of the cellular protein degradation machinery, which is highly expressed in malignant hematopoietic cells including multiple myeloma. M3258 was previously shown to deliver strong in vivo preclinical efficacy in multiple myeloma xenograft models, as well as a more benign non-clinical safety profile compared to approved pan-proteasome inhibitors, exemplified by a lack of effects on the central and peripheral nervous systems and cardiac and respiratory organs. Here we describe preclinical PK/PD and PK/efficacy modelling which led to a prediction of the PK profile, and the efficacious and safe dose ranges of M3258 in human which were used to guide the design of the phase I dose-escalation trial of M3258 in >3 line relapsed/refractory multiple myeloma (RRMM) patients. Mouse, rat, dog and monkey PK, plasma protein binding and intrinsic clearance data were used to estimate a half-life of approximately 6 hours for M3258 in human. The human total clearance and volume of distribution for M3258 were predicted to be 0.033 L/h/kg and 0.28 L/kg, respectively, whilst oral bioavailability was estimated to be above 80%. LMP7 proteolytic activity was assessed as a PD readout in human multiple myeloma tumor cells xenografted to mice as well as in dog peripheral blood mononuclear cells (PBMCs). A strong PK/PD relationship was observed for M3258 across both species. LMP7 inhibition by M3258 also correlated strongly with anti-tumor efficacy in multiple myeloma xenografts, with maximal efficacy observed at M3258 exposure delivering sustained inhibition of tumor LMP7 activity. Quantitative PK/PD/efficacy modeling predicted the biologically efficacious dose (BED) of M3258 upon oral application to be between 10 - 90 mg daily in human. By incorporating data from nonclinical safety studies, these data suggest an attractive human PK profile of M3258, enabling oral application, as well as an improved human therapeutic index compared to approved pan-proteasome inhibitors. M3258 is being investigated in a phase I, first-in-man, 2-part, open label clinical study designed to determine the safety, tolerability, PK, PD and early signs of efficacy of M3258 as a single agent (dose-escalation) and co-administered with dexamethasone (dose-expansion) in participants with RRMM whose disease has progressed following > 3 prior lines of therapy and for whom no effective standard therapy exists. Integration of these data will guide the selection of the BED for potential further clinical development of M3258. Disclosures Lignet: Merck Healthcare KGaA: Employment. Esdar:Merck Healthcare KGaA: Employment. Friese-Hamim:Merck Healthcare KGaA: Employment. Becker:Merck Healthcare KGaA: Employment, Other: Holding shares with a value below 1000-USD. Drouin:EMD Serono Research and Development Institute: Employment. El Bawab:Merck Healthcare KGaA: Employment. Goodstal:EMD Serono Research and Development Institute: Employment. Gimmi:Merck Healthcare KGaA: Employment. Haselmayer:Merck Healthcare KGaA: Employment. Jährling:Merck Healthcare KGaA: Employment. Sanderson:Merck Healthcare KGaA: Employment. Sloot:Merck Healthcare KGaA: Employment. Stinchi:Merck Healthcare KGaA: Employment. Victor:Merck Healthcare KGaA: Employment. Walter:Merck Healthcare KGaA: Employment. Rohdich:Merck Healthcare KGaA: Employment.

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