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Carfilzomib

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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
#1
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
#2
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...
February 17, 2017: Acta Haematologica
https://www.readbyqxmd.com/read/28205262/modern-multiple-myeloma-therapy-deep-sustained-treatment-response-and-good-clinical-outcomes
#3
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
#4
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
#5
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
#6
Christopher R Ensor, Samuel A Yousem, Marilyn Marrari, Matthew R Morrell, Massimo Mangiola, Joseph M Pilewski, Jonathan D'Cunha, Stephen R Wisniewski, Raman Venkataramanan, Adriana Zeevi, John 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 C1q-fixing ability of their immunodominant (ID) 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. DSA IgG MFI fell from 7664 (IQR 3230-11874) to 1878 (653-7791) after therapy (p=0...
February 7, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28151709/progress-and-paradigms-in-multiple-myeloma
#7
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
#8
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...
January 25, 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
#9
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
https://www.readbyqxmd.com/read/28122920/combined-traf6-targeting-and-proteasome-blockade-has-anti-tumor-and-anti-bone-resorptive-effects
#10
Haiming Chen, Mingjie Li, Eric Sanchez, Cathy S Wang, Tiffany Lee, Camilia M Soof, Christian E Casas, Jasmin Cao, Colin Xie, Kyle A Udd, Kevin DeCorso, George Y Tang, Tanya M Spektor, James R Berenson
: Tumor necrosis factor receptor-associated factor 6 (TRAF6) has been implicated in polyubiquitin-mediated IL-1R/TLR signaling through activation of IκB kinase (IKK) to regulate the NF-κB and JNK signaling pathways. Here, TRAF6 protein was determined to be overexpressed in bone marrow mononuclear cells (BMMCs) from multiple myeloma (MM) patients. TRAF6 expression in BMMCs from patients with progressive disease is significantly elevated as compared to individuals in complete remission, with monoclonal gammopathy of undetermined significance, or healthy subjects...
January 25, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28116920/safety-issues-and-management-of-toxicities-associated-with-new-treatments-for-multiple-myeloma
#11
Annamaria Brioli, Lars-Olof Mügge, Andreas Hochhaus, Marie Von Lilienfeld-Toal
In the last decade, the availability of new drugs for the treatment of Multiple Myeloma (MM) significantly improved patients' outcomes, but also raised attention towards a new spectrum of adverse events. Recently, four novel agents with different mechanisms of action (carfilzomib, elotuzumab, daratumumab and panobinostat) have been approved for the treatment of MM. This review aims at providing physicians with the tools to recognize and handle toxicity issues related with these new treatments. Areas covered: This review focuses on the management of drug related adverse events of the latest approved drug combinations...
January 27, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28110581/triplet-combinations-in-relapsed-refractory-myeloma-update-on-recent-phase-3-trials
#12
Jean-Samuel Boudreault, Cyrille Touzeau, Philippe Moreau
Multiple myeloma (MM) is a rare hematologic disease of antibody-secreting plasma cells. Our understanding of the pathogenesis of this malignancy has improved greatly, and at the same time, we have access to new and more effective treatments options. Over the last 5 years, a spectrum of novel therapies with different mechanisms of action, including third-generation immunomodulatory drugs (pomalidomide), second generation proteasome inhibitors (carfilzomib and ixazomib), a histone deacetylase inhibitor (panobinostat) and monoclonal antibodies (mAbs) (elotuzumab and daratumumab) has transformed our approach to the treatment of patients with relapsed/refractory MM (RRMM)...
January 21, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28094456/waldenstr%C3%A3-m-macroglobulinemia-2017-update-on-diagnosis-risk-stratification-and-management
#13
Morie A Gertz
: Disease Overview: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. DIAGNOSIS: Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients. Risk Stratification: Age, hemoglobin level, platelet count, β2 microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis...
February 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28092421/carfilzomib-lenalidomide-and-dexamethasone-in-patients-with-heavily-pretreated-multiple-myeloma-a-phase-1-study-in-japan
#14
Kenshi Suzuki, Masaki Ri, Takaaki Chou, Isamu Sugiura, Naoki Takezako, Kazutaka Sunami, Tadao Ishida, Tohru Izumi, Shuji Ozaki, Yoshihisa Shumiya, Kenji Ota, Shinsuke Iida
This is the first study in which the carfilzomib, lenalidomide, and dexamethasone (KRd) regimen was evaluated in heavily pretreated multiple myeloma. This study is a multicenter, open-label phase 1 study of KRd in Japanese patients with relapsed or refractory multiple myeloma (RRMM). The objectives were to evaluate the safety, tolerability, efficacy and pharmacokinetics. Carfilzomib was administrated intravenously over 10 min on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. In cycle 1, the dosage for days 1 and 2 was 20 mg/m(2) , followed by 27 mg/m(2) ...
January 16, 2017: Cancer Science
https://www.readbyqxmd.com/read/28075552/nanoparticles-coated-with-neutrophil-membranes-can-effectively-treat-cancer-metastasis
#15
Ting Kang, Qianqian Zhu, Dan Wei, Jingxian Feng, Jianhui Yao, Tianze Jiang, Qingxiang Song, Xunbin Wei, Hong-Zhuan Chen, Xiaoling Gao, Jun Chen
The dissemination, seeding and colonization of circulating tumor cells (CTC) serves as the root of distant metastasis. As a key step in the early stage of metastasis formation, colonization of CTC in the (pre-) metastatic niche appears to be a valuable target. Evidence showed that inflammatory neutrophils possess both CTC- and niche-targeting property by the intrinsic cell adhesion molecules on neutrophils. Inspired by this mechanism, we developed a nanosize neutrophil-mimicking drug delivery system (NM-NP) by coating neutrophils membranes on the surface of poly (latic-co-glycolic acid) nanoparticles (NP)...
January 11, 2017: ACS Nano
https://www.readbyqxmd.com/read/28061991/combination-therapy-for-fit-younger-and-older-newly-diagnosed-multiple-myeloma-patients-data-support-carfilzomib-lenalidomide-and-dexamethasone-independent-of-cytogenetic-risk-status
#16
REVIEW
Ola Landgren
In this invited paper, I was asked to critically review available literature and seek scientific and clinical evidence to argue in support of carfilzomib, lenalidomide, and dexamethasone (KRd) as the new default therapy for fit patients with a new diagnosis of multiple myeloma (MM). When performing the review of existing data and when writing this paper it became clear to me that both KRd and bortezomib, lenalidomide, and dexamethasone (RVd) are both recommended by established, well-respected expert guidelines...
December 2016: Seminars in Oncology
https://www.readbyqxmd.com/read/28061990/treatment-of-newly-diagnosed-myeloma-bortezomib-based-triplet
#17
REVIEW
Archana M Rajan, S Vincent Rajkumar
We review the options for the treatment of newly diagnosed myeloma in a patient who is a candidate for autologous stem cell transplantation (ASCT). Bortezomib, lenalidomide, dexamethasone (VRD) has been studied in two randomized trials as first-line therapy. In one of these trials, VRD demonstrated improved overall survival compared with lenalidomide plus dexamethasone (Rd). By contrast, phase III data with overall survival differences are not available for other bortezomib-containing regimens compared with modern lenalidomide-containing regimens...
December 2016: Seminars in Oncology
https://www.readbyqxmd.com/read/28061984/controversies-in-multiple-myeloma-evidence-based-update
#18
REVIEW
Inhye E Ahn, Sham Mailankody
The US Food and Drug Administration (FDA) approved 10 new drugs for the treatment of multiple myeloma (MM) over the last two decades. The influx of new anti-myeloma agents with high efficacy and acceptable tolerability add complexity to the clinical decision-making process. First, treatment of smoldering multiple myeloma (SMM) remains investigational to date, although a randomized trial showed a survival gain in high-risk patients receiving lenalidomide. Second, in newly diagnosed MM, the majority of contemporary induction regimens have been studied in single-arm trials or compared to an older regimen, which complicates evidence-based treatment selection...
December 2016: Seminars in Oncology
https://www.readbyqxmd.com/read/28043164/current-treatment-options-and-investigational-drugs-for-waldenstrom-s-macroglobulinemia
#19
Maria Gavriatopoulou, Evangelos Terpos, Efstathios Kastritis, Meletios A Dimopoulos
Waldenström's Macroglobulinemia (WM) is a rare, indolent, incurable, low-grade B-cell lymphoplasmacytic neoplasm. This review article provides a modern clinical perspective of the individualized management of patients with symptomatic WM, in the context of the updated treatment guidelines and the currently available trial data. Areas covered: Rituximab-based regimens (such as the dexamethasone, rituximab and cyclophosphamide combination, DRC) are the most widely used in the management of both newly diagnosed and relapsed/refractory patients with WM...
January 3, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28040131/carfilzomib-induces-g2-m-cell-cycle-arrest-in-human-endometrial-cancer-cells-via-upregulation-of-p21-waf1-cip1-and-p27-kip1
#20
Yuanyuan Zhou, Ke Wang, Shuai Zhen, Ruili Wang, Wenjuan Luo
OBJECTIVE: Carfilzomib is a second-generation tetrapeptide epoxyketone proteasome inhibitor used in current clinical therapy of hematologic malignancies. The mechanism of proteasome inhibition in endometrial cancer is not very clear. Carfilzomib inhibition of type I endometrial carcinoma cell proliferation by inducing cell cycle arrest at the G2/M phase was investigated in our study. MATERIALS AND METHODS: HEC-1-A and Ishikawa endometrial carcinoma cell lines and three tumor cell lines were treated by different concentrations of carfilzomib...
December 2016: Taiwanese Journal of Obstetrics & Gynecology
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