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https://www.readbyqxmd.com/read/28325256/how-have-evolutions-in-strategies-for-the-treatment-of-relapsed-refractory-multiple-myeloma-translated-into-improved-outcomes-for-patients
#1
REVIEW
Pieter Sonneveld, Edwin De Wit, Philippe Moreau
Although multiple myeloma (MM) remains incurable, the introduction of novel agents has improved clinical outcomes dramatically over the past 15 years. Response rates have risen from ∼30% with single agents to up to 90% with combination therapies. The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, and the proteasome inhibitor bortezomib, form the foundations for treatment of relapsed and/or refractory MM (RRMM). Newer agents, such as the IMiD pomalidomide, the histone deacetylase inhibitor panobinostat and the proteasome inhibitors carfilzomib and ixazomib, as well as the monoclonal antibodies daratumumab and elotuzumab, have further improved overall response rates in these patients...
April 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28318679/treatment-with-carfilzomib-should-these-patients-be-admitted-in-the-intensive-care-unit
#2
R Rodríguez-García, M J Espina, L Viña, I Astola, L López-Amor, D Escudero
No abstract text is available yet for this article.
March 16, 2017: Medicina Intensiva
https://www.readbyqxmd.com/read/28314790/selinexor-kpt-330-induces-tumor-suppression-through-nuclear-sequestration-of-i%C3%AE%C2%BAb-and-down-regulation-of-survivin
#3
Jayasree S Nair, Elgilda Musi, Gary K Schwartz
PURPOSE: Selinexor, a small molecule that inhibits nuclear export protein XPO1 has demonstrated efficacy in solid tumors and hematologic malignancies with the evidence of clinical activity in sarcoma as a single agent. Treatment options available are very few and hence the need to identify novel targets and strategic therapies is of utmost importance. EXPERIMENTAL DESIGN: The mechanistic effects of selinexor in sarcomas as a monotherapy and in combination with proteasome inhibitor, carfilzomib, across a panel of cell lines in vitro and few in xenograft mouse models were investigated...
March 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28306371/carfilzomib-and-dexamethasone-vs-bortezomib-and-dexamethasone-in-patients-with-relapsed-multiple-myeloma-results-of-the-phase-3-study-endeavor-nct01568866-according-to-age-subgroup
#4
Heinz Ludwig, Meletios A Dimopoulos, Philippe Moreau, Wee-Joo Chng, Hartmut Goldschmidt, Roman Hájek, Thierry Facon, Ludek Pour, Ruben Niesvizky, Albert Oriol, Laura Rosiñol, Aleksandr Suvorov, Gianluca Gaidano, Tomas Pika, Katja Weisel, Vesselina Goranova-Marinova, Antonio Palumbo, Heidi H Gillenwater, Nehal Mohamed, Sanjay Aggarwal, Shibao Feng, Douglas Joshua
No abstract text is available yet for this article.
March 17, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28295593/carfilzomib-containing-combinations-as-frontline-therapy-for-multiple-myeloma-a-meta-analysis-of-13-trials
#5
Zhixin Sheng, Guifang Li, Bin Li, Yanju Liu, Lida Wang
OBJECTIVE: To investigate the activity and safety of carfilzomib-containing combinations as frontline therapy for multiple myeloma. METHODS: We searched published carfilzomib reports for newly diagnosed multiple myeloma. RESULTS: Thirteen trials were identified, covering 704 subjects. Pooled analysis showed that carfilzomib combinations as frontline therapy for multiple myeloma attained an impressive at least complete response (≥CR) rate of 21%, at least very good partial response (≥VGPR) rate of 68%, overall response rate (ORR) of 94%...
March 12, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28288323/anti-angiogenic-and-anti-multiple-myeloma-effects-of-oprozomib-opz-alone-and-in-combination-with-pomalidomide-pom-and-or-dexamethasone-dex
#6
REVIEW
Eric Sanchez, Mingjie Li, Cathy S Wang, George Tang, Abigail Gillespie, Haiming Chen, James R Berenson
Oprozomib (OPZ or ONYX 0912) is an irreversible, orally administered proteasome inhibitor (PI) and an analog of carfilzomib. We set out to determine the anti-angiogenic effect of OPZ using the choriollantoic membrane/feather bud (CAM/FB) model and its anti-MM effects using MM xenograft models (LAGκ-1A, LAGλ-1). OPZ significantly reduced blood vessel formation, endothelial gene and protein expression using the CAM/FB assay. In vivo, we determined the anti-MM effects of OPZ, dexamethasone (Dex) and pomalidomide (Pom) and showed that the combinations of two drugs (OPZ+Dex or OPZ+Pom) showed marked anti-MM effects when compared to monotherapy...
March 6, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28280367/clarifying-the-molecular-mechanism-associated-with-carfilzomib-resistance-in-human-multiple-myeloma-using-microarray-gene-expression-profile-and-genetic-interaction-network
#7
Zhihong Zheng, Tingbo Liu, Jing Zheng, Jianda Hu
Carfilzomib is a Food and Drug Administration-approved selective proteasome inhibitor for patients with multiple myeloma (MM). However, recent studies indicate that MM cells still develop resistance to carfilzomib, and the molecular mechanisms associated with carfilzomib resistance have not been studied in detail. In this study, to better understand its potential resistant effect and its underlying mechanisms in MM, microarray gene expression profile associated with carfilzomib-resistant KMS-11 and its parental cell line was downloaded from Gene Expression Omnibus database...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28273193/-drug-therapy-of-lymphomas
#8
Lajos Gergely
The therapy of lymphomas has undergone a major expansion during the last decade. Novel therapeutic targets have appeared beyond classical chemotherapeutic combinations. These novel drugs have very pronounced action across lymphoma types, and their toxicity profile is usually better tolerable compared to standard chemotherapies. These new therapies are enabling us to offer treatment to those patients who have refractory disease, and we had no option to treat them before these drugs. The author describes several new therapeutic options...
March 8, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28273121/polymer-micelle-formulation-for-the-proteasome-inhibitor-drug-carfilzomib-anticancer-efficacy-and-pharmacokinetic-studies-in-mice
#9
Ji Eun Park, Se-Eun Chun, Derek Reichel, Jee Sun Min, Su-Chan Lee, Songhee Han, Gongmi Ryoo, Yunseok Oh, Shin-Hyung Park, Heon-Min Ryu, Kyung Bo Kim, Ho-Young Lee, Soo Kyung Bae, Younsoo Bae, Wooin Lee
Carfilzomib (CFZ) is a peptide epoxyketone proteasome inhibitor approved for the treatment of multiple myeloma (MM). Despite the remarkable efficacy of CFZ against MM, the clinical trials in patients with solid cancers yielded rather disappointing results with minimal clinical benefits. Rapid degradation of CFZ in vivo and its poor penetration to tumor sites are considered to be major factors limiting its efficacy against solid cancers. We previously reported that polymer micelles (PMs) composed of biodegradable block copolymers poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) can improve the metabolic stability of CFZ in vitro...
2017: PloS One
https://www.readbyqxmd.com/read/28244987/capzimin-is-a-potent-and-specific-inhibitor-of-proteasome-isopeptidase-rpn11
#10
Jing Li, Tanya Yakushi, Francesco Parlati, Andrew L Mackinnon, Christian Perez, Yuyong Ma, Kyle P Carter, Sharon Colayco, Gavin Magnuson, Brock Brown, Kevin Nguyen, Stefan Vasile, Eigo Suyama, Layton H Smith, Eduard Sergienko, Anthony B Pinkerton, Thomas D Y Chung, Amy E Palmer, Ian Pass, Sonja Hess, Seth M Cohen, Raymond J Deshaies
The proteasome is a vital cellular machine that maintains protein homeostasis, which is of particular importance in multiple myeloma and possibly other cancers. Targeting of proteasome 20S peptidase activity with bortezomib and carfilzomib has been widely used to treat myeloma. However, not all patients respond to these compounds, and those who do eventually suffer relapse. Therefore, there is an urgent and unmet need to develop new drugs that target proteostasis through different mechanisms. We identified quinoline-8-thiol (8TQ) as a first-in-class inhibitor of the proteasome 19S subunit Rpn11...
February 28, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28243125/carfilzomib-boosted-combination-therapy-for-relapsed-multiple-myeloma
#11
REVIEW
Raphael E Steiner, Elisabet E Manasanch
Carfilzomib is a proteasome inhibitor that binds selectively and irreversibly to the 20S proteasome, the proteolytic core particle within the 26S proteasome, resulting in the accumulation of proteasome substrates and ultimately growth arrest and apoptosis of tumor cells. The development and ultimate approval of this medication by regulatory agencies has been an important step toward improving clinical outcomes in multiple myeloma. Although initially approved as a single agent for the treatment of multiply relapsed and/or refractory myeloma, in the USA, it is now widely used in the early relapse setting in combination with lenalidomide and dexamethasone...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28211560/carfilzomib-lenalidomide-and-dexamethasone-in-patients-with-relapsed-multiple-myeloma-categorised-by-age-secondary-analysis-from-the-phase-3-aspire-study
#12
Meletios A Dimopoulos, A Keith Stewart, Tamás Masszi, Ivan Špička, Albert Oriol, Roman Hájek, Laura Rosiñol, David Siegel, Georgi G Mihaylov, Vesselina Goranova-Marinova, Péter Rajnics, Aleksandr Suvorov, Ruben Niesvizky, Andrzej Jakubowiak, Jesus San-Miguel, Heinz Ludwig, Antonio Palumbo, Mihaela Obreja, Sanjay Aggarwal, Philippe Moreau
A primary analysis of the ASPIRE study found that the addition of carfilzomib to lenalidomide and dexamethasone (carfilzomib group) significantly improved progression-free survival (PFS) compared with lenalidomide and dexamethasone alone (control group) in patients with relapsed multiple myeloma (RMM). This post hoc analysis examined outcomes from ASPIRE in patients categorised by age. In the carfilzomib group, 103/396 patients were ≥70 years old, and in the control group, 115/396 patients were ≥70 years old...
February 17, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28208145/carfilzomib-inhibits-constitutive-nf-%C3%AE%C2%BAb-activation-in-mantle-cell-lymphoma-b-cells-and-leads-to-the-induction-of-apoptosis
#13
Yong-Li Zhang, Matthew Ho Zhi Guang, Hui-Qin Zhuo, Xiang-Hui Min, Qin Yao, Ai-Qi Gu, Sheng-Hua Wu, Dai-Bo Zhang, Jing-Yuan Lu, Yan Chen, Yu-Han Chen, Ke-Jie Zhang
Mantle cell lymphoma (MCL) remains incurable and new treatments are needed, especially in the relapsed/refractory setting. We therefore investigated the effects of carfilzomib, a novel, long-acting, second-generation proteasome inhibitor, in MCL cells. Eight established MCL cell lines and freshly isolated primary MCL cells were treated with carfilzomib. Cell proliferation was assessed by a 3H-thymidine incorporation assay. Cell apoptosis was evaluated by flow cytometry with annexin V and propidium iodide. Electrophoresis mobility shift (EMSA), Western blot, and luciferase assays were used to analyze NF-κB activation and related signaling proteins...
2017: Acta Haematologica
https://www.readbyqxmd.com/read/28205262/modern-multiple-myeloma-therapy-deep-sustained-treatment-response-and-good-clinical-outcomes
#14
REVIEW
O Landgren, K Iskander
In the USA at the beginning of this century, the average overall survival in patients with multiple myeloma was about 3 years. Around that time, three drugs (bortezomib, lenalidomide and thalidomide) were introduced for the treatment of multiple myeloma and, in 2012, carfilzomib received accelerated approval by the US Food and Drug Administration (FDA). Driven by access to better drugs, median overall survival in younger patients (aged <50 years) was >10 years by 2014. The FDA approved 14 new drugs for the treatment of cancer in 2015; four of these were approved for the treatment of myeloma (panobinostat, daratumumab, elotuzumab and ixazomib)...
February 16, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/28204981/phase-1b-trial-of-proteasome-inhibitor-carfilzomib-with-irinotecan-in-lung-cancer-and-other-irinotecan-sensitive-malignancies-that-have-progressed-on-prior-therapy-onyx-ist-reference-number-car-ist-553
#15
Susanne M Arnold, Kari Chansky, Markos Leggas, Michael A Thompson, John L Villano, John Hamm, Rachel E Sanborn, Glen J Weiss, Gurkamal Chatta, Maria Q Baggstrom
Introduction Proteasome inhibition is an established therapy for many malignancies. Carfilzomib, a novel proteasome inhibitor, was combined with irinotecan to provide a synergistic approach in relapsed, irinotecan-sensitive cancers. Materials and Methods Patients with relapsed irinotecan-sensitive cancers received carfilzomib (Day 1, 2, 8, 9, 15, and 16) at three dose levels (20/27 mg/m2, 20/36 mg/m2 and 20/45 mg/m2/day) in combination with irinotecan (Days 1, 8 and 15) at 125 mg/m2/day. Key eligibility criteria included measurable disease, a Zubrod PS of 0 or 1, and acceptable organ function...
February 16, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28203342/optimizing-current-and-emerging-therapies-in-multiple-myeloma-a-guide-for-the-hematologist
#16
REVIEW
Shahzad Raza, Rachael A Safyan, Evan Rosenbaum, Alex S Bowman, Suzanne Lentzsch
Multiple myeloma (MM) is the second most common hematologic malignancy. The diagnosis of MM requires ⩾10% clonal plasma cells in the bone marrow or biopsy-proven plasmacytoma, plus evidence of end-organ damage (hypercalcemia, renal failure, anemia, and lytic bone lesions). The definition of MM has recently been expanded to include a ⩾60% clonal plasma cell burden in the bone marrow, serum involved/uninvolved light chain ratio of ⩾100, or more than one focal lesion on magnetic resonance imaging ⩾5 mm in the absence of end-organ damage...
February 2017: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/28173620/proteasome-inhibitor-carfilzomib-based-therapy-for-antibody-mediated-rejection-of-the-pulmonary-allograft-use-and-short-term-findings
#17
C R Ensor, S A Yousem, M Marrari, M R Morrell, M Mangiola, J M Pilewski, J D'Cunha, S R Wisniewski, R Venkataramanan, A Zeevi, J F McDyer
We present this observational study of lung transplant recipients (LTR) treated with carfilzomib (CFZ)-based therapy for antibody-mediated rejection (AMR) of the lung. Patients were considered responders to CFZ if complement-1q (C1q)-fixing ability of their immunodominant (ID) donor-specific anti-human leukocyte antibody (DSA) was suppressed after treatment. Treatment consisted of CFZ plus plasma exchange and immunoglobulins. Fourteen LTRs underwent CFZ for 20 ID DSA AMR. Ten (71.4%) of LTRs responded to CFZ...
February 7, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28151709/progress-and-paradigms-in-multiple-myeloma
#18
EDITORIAL
Kenneth C Anderson
Remarkable progress has been achieved in multiple myeloma, and patient median survival has been extended 3- to 4-fold. Specifically, there have been 18 newly approved treatments for multiple myeloma in the past 12 years, including seven in 2015, and the treatment paradigm and patient outcome have been transformed. The definition of patients benefitting from these therapies has been broadened. Response criteria now include minimal residual disease (MRD), assessed in bone marrow by multicolor flow cytometry or sequencing, and by imaging for extramedullary disease...
November 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28132893/inhibition-of-the-proteasome-%C3%AE-2-site-sensitizes-triple-negative-breast-cancer-cells-to-%C3%AE-5-inhibitors-and-suppresses-nrf1-activation
#19
Emily S Weyburne, Owen M Wilkins, Zhe Sha, David A Williams, Alexandre A Pletnev, Gerjan de Bruin, Hermann S Overkleeft, Alfred L Goldberg, Michael D Cole, Alexei F Kisselev
The proteasome inhibitors carfilzomib (Cfz) and bortezomib (Btz) are used successfully to treat multiple myeloma, but have not shown clinical efficacy in solid tumors. Here we show that clinically achievable inhibition of the β5 site of the proteasome by Cfz and Btz does not result in loss of viability of triple-negative breast cancer cell lines. We use site-specific inhibitors and CRISPR-mediated genetic inactivation of β1 and β2 to demonstrate that inhibiting a second site of the proteasome, particularly the β2 site, sensitizes cell lines to Btz and Cfz in vitro and in vivo...
February 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28125372/real-world-treatment-patterns-time-to-next-treatment-and-economic-outcomes-in-relapsed-or-refractory-multiple-myeloma-patients-treated-with-pomalidomide-or-carfilzomib
#20
Chi-Chang Chen, Kejal Parikh, Safiya Abouzaid, Lea Purnomo, Catherine B McGuiness, Mohamed Hussein, Rolin L Wade
BACKGROUND: Negligible real-world evidence exists for later line treatment of multiple myeloma (MM) to assist treatment decisions or reimbursement models, such as episode-based payments. OBJECTIVE: To describe the treatment patterns and clinical/economic outcomes when pomalidomide or carfilzomib is used for relapsed/refractory MM. METHODS: A U.S. claims database was used to identify MM patients with an initial pomalidomide or carfilzomib claim (index date) between February 1, 2013, and February 28, 2015, which was assumed to be relapse therapy...
February 2017: Journal of Managed Care & Specialty Pharmacy
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