Predictive biomarkers and practical considerations in the management of carfilzomib-associated cardiotoxicity

Lendvai, Nikoletta; Tsakos, Ioanna; Devlin, Sean M.; Schaffer, Wendy; Hassoun, Hani; Lesokhin, Alexander M.; Landau, Heather; Korde, Neha; Mailankody, Sham; Smith, Eric L.; Chung, David J.; Koehne, Guenther; Shah, Gunjan L.; Alexander, A.; Patel, Minal; Ballagi, Andrea; Grundberg, Ida; Giralt, Sergío; Landgren, Ola

doi:10.1080/10428194.2017.1403020

Cited by 16 publications

(9 citation statements)

References 14 publications

(14 reference statements)

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“…Importantly, grade ≥3 heart failure rates are relatively low considering carfilzomib efficacy. Clinical experience with carfilzomib has aided development of strategies for managing and mitigating cardiovascular events [56, 57]; clinical guidelines have been developed in collaboration with cardiologists to minimize cardiotoxicity with carfilzomib treatment [59].…”

Section: Resultsmentioning

confidence: 99%

Carfilzomib with immunomodulatory drugs for the treatment of newly diagnosed multiple myeloma

et al. 2019

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Carfilzomib, a selective proteasome inhibitor (PI), is approved for the treatment of patients with relapsed or refractory multiple myeloma (MM). Combination regimens incorporating a PI and immunomodulatory drug (IMiD) have been associated with deep responses and extended survival in patients with newly diagnosed MM (NDMM). Carfilzomib-based combinations with immunomodulators are being extensively studied in the frontline setting. The objective of this review was to describe efficacy and safety data for carfilzomib-based, PI/immunomodulatory combinations in NDMM. Information sources were articles indexed in PubMed and abstracts from key hematology/oncology congresses published between January 2012 and December 2018. PubMed and congresses were searched for prospective clinical studies assessing the combination of carfilzomib with an IMiD for NDMM treatment. Retrospective and preclinical reports, case reports/series, reviews, and clinical studies not evaluating carfilzomib–immunomodulator combinations in NDMM were excluded based on review of titles and abstracts. A total of nine articles and 72 abstracts were deemed relevant and included in the review. A total of six distinct carfilzomib-based, PI/immunomodulator combination regimens have been evaluated in 12 clinical trials. Overall, treatment with these regimens has resulted in deep responses, including high rates of negativity for minimal residual disease. These deep responses have translated to long progression-free survival and overall survival rates. Efficacy results for these regimens have generally been consistent across subgroups defined by age, transplant eligibility, and cytogenetic risk. The safety profile of carfilzomib in NDMM is consistent with that observed in the relapsed-refractory MM setting. Clinical studies have found that carfilzomib-based combinations with immunomodulators are highly active with a favorable safety profile in NDMM. The carfilzomib, lenalidomide, and dexamethasone (KRd) drug backbone is a promising foundation for treatment strategies aimed at achieving long-term, deep responses (functional cures) in the frontline setting. Several ongoing studies are evaluating KRd, with or without anti-CD38 monoclonal antibodies.

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Section: Resultsmentioning

confidence: 99%

Carfilzomib with immunomodulatory drugs for the treatment of newly diagnosed multiple myeloma

et al. 2019

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“…40,41 A single-institution study to identify potential biomarkers in MM patients at high risk for cardiac AEs when treated with carfilzomib indicated a trend toward differential baseline expression of 8 proteins (tumor necrosis factor-related apoptosis-inducing ligand, myoglobin, matrix metalloproteinase-1, heparin-binding EGF-like growth factor, CD40 ligand, platelet-derived growth factor, heat shock protein 27, and epidermal growth factor). 42 Multivariate analysis did not reveal any association between these proteins and cardiac AEs. Furthermore, a single-institution prospective observational study of patients receiving carfilzomib-or bortezomib-based therapy to assess CV risk factors and outcomes showed that elevated baseline levels of brain natriuretic peptide (.100 pg/mL) were associated with a higher risk for cardiac AEs in patients treated with a carfilzomib-based regimen (odds ratio, 35.1; 95% CI, 4.3-289.5; P , .001).…”

Section: Discussionmentioning

confidence: 99%

Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials

et al. 2018

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“…These complications can be managed by a combination of basic risk assessments, hydration, cardiovascular monitoring, intervention (such as reducing the carfilzomib dose), and patient education to notice cardiovascular symptoms and regularly monitor blood pressure [121]. Clinical guidelines were developed in collaboration with cardiologists to minimize the risk of cardiovascular events in patients treated with carfilzomib [122]. Despite the improvements of carfilzomib over first-generation proteasome inhibitors, it still has to be administered intravenously, and has demonstrated limited efficacy in patients with solid tumors [123].…”

Section: Carfilzomib (Kyprolis)mentioning

confidence: 99%

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

Sherman

Li²

2020

Molecules

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The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular “machine.” As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases.

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Predictive biomarkers and practical considerations in the management of carfilzomib-associated cardiotoxicity

Cited by 16 publications

References 14 publications

Carfilzomib with immunomodulatory drugs for the treatment of newly diagnosed multiple myeloma

Carfilzomib with immunomodulatory drugs for the treatment of newly diagnosed multiple myeloma

Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

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