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https://www.readbyqxmd.com/read/29305052/progress-curve-analysis-of-the-kinetics-of-slow-binding-anticancer-drug-inhibitors-of-the-20s-proteasome
#1
Brian B Hasinoff
Bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib are anticancer drugs that target the proteasomal system. Carfilzomib and oprozomib are epoxyketones that form an irreversible covalent bond with the 20S proteasome, whereas bortezomib, ixazomib, and delanzomib are boronic acids that form slowly reversible adducts. The binding kinetics of some of these drugs have either not been well characterized, or have been studied under a variety of different conditions. Utilizing a fluorogenic substrate the kinetics of the slow-binding inhibition of the chymotrypsin-like proteasomal activity of human 20S proteasome was determined under a standard set of conditions in order to compare the kinetic and equilibrium properties of these drugs...
January 2, 2018: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/29290170/cost-effectiveness-of-drugs-to-treat-relapsed-refractory-multiple-myeloma-in-the-united-states
#2
Josh J Carlson, Gregory F Guzauskas, Richard H Chapman, Patricia G Synnott, Shanshan Liu, Elizabeth T Russo, Steven D Pearson, Elizabeth D Brouwer, Daniel A Ollendorf
BACKGROUND: New 3-drug regimens have been developed and approved to treat multiple myeloma (MM). The absence of direct comparative data and the high cost of treatment support the need to assess the relative clinical and economic outcomes across all approved regimens. OBJECTIVE: To evaluate the cost-effectiveness of treatments for relapsed and/or refractory MM from a U.S. health system perspective. METHODS: We developed a partition survival model with 3 health states (progression-free, progression, and death) to evaluate the following regimens: carfilzomib (CFZ), elotuzumab (ELO), ixazomib (IX), daratumumab (DAR), and panobinostat (PAN) in combination with lenalidomide (LEN) or bortezomib (BOR) plus dexamethasone (DEX) in the second and/or third line of therapy...
January 2018: Journal of Managed Care & Specialty Pharmacy
https://www.readbyqxmd.com/read/29290169/evaluating-oncology-value-based-frameworks-in-the-u-s-marketplace-and-challenges-in-real-world-application-a-multiple-myeloma-test-case
#3
Laurence M Djatche, Joseph A Goble, Grace Chun, Stefan Varga
BACKGROUND: With the continuous rise in costs for oncology drugs, the American Society of Clinical Oncology (ASCO), the Institute for Clinical and Economic Review (ICER), the Memorial Sloan Kettering Cancer Center's Drug Abacus (DrugAbacus), and the National Comprehensive Cancer Network (NCCN) have developed value-based frameworks (VBFs) to assist stakeholders in formulary and treatment decision-making processes. Since emerging VBFs have the potential to affect available treatment options for patients, it is important to understand the differences associated with these VBFs within various therapeutic areas...
January 2018: Journal of Managed Care & Specialty Pharmacy
https://www.readbyqxmd.com/read/29249822/phase-i-ii-trial-of-the-oral-regimen-ixazomib-pomalidomide-and-dexamethasone-in-relapsed-refractory-multiple-myeloma
#4
A Krishnan, P Kapoor, J M Palmer, N-C Tsai, S Kumar, S Lonial, M Htut, C Karanes, N Nathwani, M Rosenzweig, F Sahebi, G Somlo, L Duarte, J F Sanchez, D Auclair, S J Forman, J G Berdeja
In this phase I/II trial, a triplet regimen of ixazomib (Ixa: 3 or 4 mg), pomalidomide (Pom: 4 mg), and dexamethasone (Dex: 40 mg) was administered to 32 lenalidomide-refractory multiple myeloma (MM) patients; 31 were evaluable for response and toxicity. At dose level 1 (DL1, 3 mg Ixa), 1/3 patients experienced grade 3 fatigue, grade 3 lung infection, grade 4 neutropenia, and grade 4 thrombocytopenia; all were considered dose limiting. Per 3+3 phase I design, an additional 3 patients were enrolled to DL1, with no further dose limiting toxicity (DLT)...
December 18, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29235380/pharmacokinetic-drug-evaluation-of-ixazomib-citrate-for-the-treatment-of-multiple-myeloma
#5
REVIEW
Marco Salvini, Rossella Troia, Davide Giudice, Chiara Pautasso, Mario Boccadoro, Alessandra Larocca
multiple myeloma (MM) is a plasma cell disorder that represents the second most frequent hematologic cancer. Although MM is still an incurable disease, prognosis has improved in the last decades thanks to the introduction of novel agents such as proteasome inhibitors (PIs), immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors. Areas covered: ixazomib is the first oral PI recently approved by Food and Drug Administration (FDA) and European Medicine Agency (EMA) in combination with lenalidomide and dexamethasone as salvage therapy in MM patients...
January 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29200420/the-effect-of-novel-therapies-in-high-molecular-risk-multiple-myeloma
#6
Guido Lancman, Douglas Tremblay, Kevin Barley, Bart Barlogie, Hearn Jay Cho, Sundar Jagannath, Deepu Madduri, Erin Moshier, Samir Parekh, Ajai Chari
Multiple myeloma is a heterogeneous disease with a prognosis that varies with patient factors, disease burden, tumor biology, and treatments. Certain molecular abnormalities confer a worse prognosis and thus are considered high-risk. These include t(4;14), del(17p), t(14;16), t(14;20), hypodiploidy, and gain(1q)/del(1p). In our previous review in 2013, we discussed the effect of available therapies on prognosis in these high-risk patients. Since then, seven phase 3 clinical trials in relapsed myeloma with 1 to 3 lines of therapy have been conducted, resulting in the approval of panobinostat, ixazomib, daratumumab, and elotuzumab, as well as additional data on carfilzomib...
November 2017: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/29196868/the-proteasome-and-proteasome-inhibitors-in-multiple-myeloma
#7
Sara Gandolfi, Jacob P Laubach, Teru Hideshima, Dharminder Chauhan, Kenneth C Anderson, Paul G Richardson
Proteasome inhibitors are one of the most important classes of agents to have emerged for the treatment of multiple myeloma in the past two decades, and now form one of the backbones of treatment. Three agents in this class have been approved by the United States Food and Drug Administration-the first-in-class compound bortezomib, the second-generation agent carfilzomib, and the first oral proteasome inhibitor, ixazomib. The success of this class of agents is due to the exquisite sensitivity of myeloma cells to the inhibition of the 26S proteasome, which plays a critical role in the pathogenesis and proliferation of the disease...
December 2, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29188449/current-and-new-therapeutic-strategies-for-relapsed-and-refractory-multiple-myeloma-an-update
#8
REVIEW
Inger S Nijhof, Niels W C J van de Donk, Sonja Zweegman, Henk M Lokhorst
Although survival of multiple myeloma patients has at least doubled during recent years, most patients eventually relapse, and treatment at this stage may be particularly complex. At the time of relapse, the use of alternative drugs to those given upfront is current practice. However, many new options are currently available for the treatment of relapsed multiple myeloma, including recently approved drugs, such as the second- and third-generation proteasome inhibitors carfilzomib and ixazomib, the immunomodulatory agent pomalidomide, the monoclonal antibodies daratumumab and elotuzumab and the histone deacetylase inhibitor panobinostat, but also new targeted agents are under active investigation (e...
November 29, 2017: Drugs
https://www.readbyqxmd.com/read/29159498/pooled-analysis-of-the-reports-of-carfilzomib-ixazomib-combinations-for-relapsed-refractory-multiple-myeloma
#9
Wenjun Xu, Xuedong Sun, Baohong Wang, Hui Guo
We sought to evaluate the activity and safety of carfilzomib-/ixazomib-containing combinations for patients with relapsed/refractory multiple myeloma (RRMM). We searched published reports including carfilzomib-/ixazomib-containing combinations for RRMM. Finally, we identified 11 prospective studies covering 2845 relapsed/refractory patients. Carfilzomib- and ixazomib-containing combinations respectively resulted in an impressive overall response rate (ORR 77 vs. 64%, P = 0.14), very good partial response or better (≥ VGPR 48 vs...
November 20, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/29157092/single-agent-and-synergistic-combinatorial-efficacy-of-first-in-class-small-molecule-imipridone-onc201-in-hematological-malignancies
#10
Varun V Prabhu, Mala K Talekar, Amriti R Lulla, C Leah B Kline, Lanlan Zhou, Junior Hall, A Pieter J Van den Heuvel, David T Dicker, Jawad Babar, Stephan A Grupp, Mathew J Garnett, Ultan McDermott, Cyril H Benes, Jeffrey J Pu, David F Claxton, Nadia Khan, Wolfgang Oster, Joshua E Allen, Wafik S El-Deiry
ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples...
November 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29098319/-multiple-myeloma-what-has-been-confirmed-in-therapy
#11
REVIEW
M-A Baertsch, H Goldschmidt
Multiple myeloma (MM) is a malignancy of terminally differentiated B cells/plasma cells and is primarily located in the bone marrow. Symptomatic multiple myeloma typically presents with osteolyses, anemia, reduced renal function, and/or hypercalcemia. In the case of such MM-related end organ damage, urgent systemic treatment is indicated. In order to prevent end organ damage, current guidelines now recommend treatment initiation already when certain biomarkers are met. Current first-line treatment is based on proteasome inhibition and immunomodulation...
November 2, 2017: Der Internist
https://www.readbyqxmd.com/read/29077585/cardiovascular-complications-of-proteasome-inhibitors-used-in-multiple-myeloma
#12
Daniel C Cole, William H Frishman
The use of proteasome inhibitors (PI) as targeted chemotherapeutics have significantly improved survival in patients with multiple myeloma (MM). However, rare and serious cardiovascular complications have occurred as a result of their use, most commonly congestive heart failure, hypertension, and arrhythmias. MM occurs in an aged population with many concurrent cardiovascular risk factors. The primary disease process also contributes to cardiovascular complications. Furthermore, many MM patients have prior exposure to cardiotoxic chemotherapy such as anthracyclines...
October 25, 2017: Cardiology in Review
https://www.readbyqxmd.com/read/29071526/the-ubiquitin-proteasome-pathway-in-adult-and-pediatric-brain-tumors-biological-insights-and-therapeutic-opportunities
#13
Wafik Zaky, Christa Manton, Claudia P Miller, Soumen Khatua, Vidya Gopalakrishnan, Joya Chandra
Nearly 20 years ago, the concept of targeting the proteasome for cancer therapy began gaining momentum. This concept was driven by increased understanding of the biology/structure and function of the 26S proteasome, insight into the role of the proteasome in transformed cells, and the synthesis of pharmacological inhibitors with clinically favorable features. Subsequent in vitro, in vivo, and clinical testing culminated in the FDA approval of three proteasome inhibitors-bortezomib, carfilzomib, and ixazomib -for specific hematological malignancies...
October 25, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29054911/ixazomib-significantly-prolongs-progression-free-survival-in-high-risk-relapsed-refractory-myeloma-patients
#14
Hervé Avet-Loiseau, Nizar J Bahlis, Wee-Joo Chng, Tamas Masszi, Luisa Viterbo, Ludek Pour, Peter Ganly, Antonio Palumbo, Michele Cavo, Christian Langer, Andrzej Pluta, Arnon Nagler, Shaji Kumar, Dina Ben-Yehuda, S Vincent Rajkumar, Jesus San-Miguel, Deborah Berg, Jianchang Lin, Helgi van de Velde, Dixie-Lee Esseltine, Alessandra di Bacco, Philippe Moreau, Paul G Richardson
Certain cytogenetic abnormalities are known to adversely impact outcomes in patients with multiple myeloma (MM). The phase 3 TOURMALINE-MM1 study demonstrated a significant improvement in progression-free survival (PFS) with ixazomib-lenalidomide-dexamethasone (IRd) compared with placebo-lenalidomide-dexamethasone (placebo-Rd). This preplanned analysis assessed the efficacy and safety of IRd vs placebo-Rd according to cytogenetic risk, as assessed using fluorescence in situ hybridization. High-risk cytogenetic abnormalities were defined as del(17p), t(4;14), and/or t(14;16); additionally, patients were assessed for 1q21 amplification...
December 14, 2017: Blood
https://www.readbyqxmd.com/read/28978849/therapeutic-approach-for-relapsed-refractory-multiple-myeloma-the-logic-and-practice
#15
Junya Kuroda
The long-term outcome of multiple myeloma (MM) has been greatly improved by the advent of new agents such as proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), despite the disease remaining mostly incurable. Treatment design is the critical determinant for the survival period and for the quality and way of life in patients with relapsed/refractory MM (RRMM). Recently, the choice of therapeutic options for RRMM has been expanded by the introduction of second generation PIs such as carfilzomib and ixazomib, and therapeutic monoclonal antibodies such as elotuzumab and daratumumab...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28977957/meta-analysis-of-the-efficacy-of-treatments-for-newly-diagnosed-and-relapsed-refractory-multiple-myeloma-with-del-17p
#16
Jinghua Liu, Hui Yang, Xiaochan Liang, Yuxin Wang, Jian Hou, Yanqin Liu, Jigang Wang, Fan Zhou
We analyzed the treatment of newly diagnosed and relapsed/refractory multiple myeloma (NDMM/RRMM) patients with del(17p). Thirteen prospective studies that evaluated 3,187 MM patients, including 685with del(17p), were included in our meta-analysis. The incidence of del(17p) in NDMM and RRMM patients was similar (13% vs. 14%, respectively, P = 0.64, I2 = 94%). The overall response rate (ORR) to new agents was 40.5% and 67.1%, respectively, in RRMM patients with or without del(17p) (P = 0.1, I2 = 63.9%). NDMM patients with del(17p) treated with PAD (bortezomib, adriamycin, and dexamethasone) induction therapy followed by bortezomib maintenance therapy had higher progression-free survival (PFS) (25...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28948001/emerging-drugs-and-combinations-to-treat-multiple-myeloma
#17
REVIEW
Alessandra Larocca, Roberto Mina, Francesca Gay, Sara Bringhen, Mario Boccadoro
In the past few years, multiple targeted therapies and immunotherapies including second generation immunomodulatory drugs (pomalidomide) and proteasome inhibitors (carfilzomib, ixazomib), monoclonal antibodies and checkpoint inhibitors were approved for the treatment of myeloma or entered advanced phases of clinical testing. These agents showed significant activity in advanced myeloma and increased the available treatment strategies. Pomalidomide is well-tolerated and effective in patients with relapsed/refractory multiple myeloma who have exhausted any possible treatment with lenalidomide and bortezomib...
September 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28932928/a-phase-i-study-to-assess-the-mass-balance-excretion-and-pharmacokinetics-of-14-c-ixazomib-an-oral-proteasome-inhibitor-in-patients-with-advanced-solid-tumors
#18
Neeraj Gupta, Steven Zhang, Sandeepraj Pusalkar, Mihaela Plesescu, Swapan Chowdhury, Michael J Hanley, Bingxia Wang, Cindy Xia, Xiaoquan Zhang, Karthik Venkatakrishnan, Dale R Shepard
This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [(14)C]-ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35...
September 21, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28927064/bortezomib-carfilzomib-and-ixazomib-do-not-mediate-relevant-transporter-based-drug-drug-interactions
#19
Jannick Clemens, Lukas Welti, Julia Schäfer, Anja Seckinger, Jürgen Burhenne, Dirk Theile, Johanna Weiss
In order to optimize the clinical application of an increasing number of proteasome inhibitors, investigations into the differences between their respective pharmacodynamic and pharmacokinetic profiles, including their ability to act as a perpetrator in drug-drug interactions, are warranted. Therefore, in the present in vitro study, it was investigated whether bortezomib, carfilzomib and ixazomib are able to alter the expression, and/or the activity, of specific drug transporters generally relevant for pharmacokinetic drug-drug interactions...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28918995/cutaneous-adverse-events-of-targeted-therapies-for-hematolymphoid-malignancies
#20
REVIEW
Julia D Ransohoff, Bernice Y Kwong
The identification of oncogenic drivers of liquid tumors has led to the rapid development of targeted agents with distinct cutaneous adverse event (AE) profiles. The diagnosis and management of these skin toxicities has motivated a novel partnership between dermatologists and oncologists in developing supportive oncodermatology clinics. In this article we review the current state of knowledge of clinical presentation, mechanisms, and management of the most common and significant cutaneous AEs observed during treatment with targeted therapies for hematologic and lymphoid malignancies...
December 2017: Clinical Lymphoma, Myeloma & Leukemia
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