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https://www.readbyqxmd.com/read/29098319/-multiple-myeloma-what-has-been-confirmed-in-therapy
#1
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
#2
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
#3
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
#4
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-Rd. This pre-planned analysis assessed the efficacy and safety of IRd versus 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...
October 20, 2017: Blood
https://www.readbyqxmd.com/read/28978849/therapeutic-approach-for-relapsed-refractory-multiple-myeloma-the-logic-and-practice
#5
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
#6
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, I(2) = 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, I(2) = 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
#7
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
#8
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
#9
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
#10
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...
July 14, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28901535/a-benefit-risk-analysis-approach-to-capture-regulatory-decision-making-multiple-myeloma
#11
G K Raju, Karthik Gurumurthi, Reuben Domike, Dickran Kazandjian, Ola Landgren, Gideon M Blumenthal, Ann Farrell, Richard Pazdur, Janet Woodcock
Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analysis. In this work, a quantitative benefit-risk analysis approach captures regulatory decision-making about new drugs to treat multiple myeloma (MM). MM assessments have been based on endpoints such as time to progression (TTP), progression-free survival (PFS), and objective response rate (ORR) which are different than benefit-risk analysis based on overall survival (OS) due to an increased focus on quality of life instead of quantity of life...
September 13, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28883286/proteasome-inhibitors-in-first-line-treatment-of-transplant-ineligible-multiple-myeloma-patients
#12
Junya Kuroda, Yuji Shimura
Since the turn of the century, many agents against multiple myeloma (MM) have been introduced into daily clinical practice. The development of further agents is ongoing and some of these will reach the point of use in clinical practice in the near future. As various treatment options become available, the selection of an appropriate treatment strategy for an individual patient becomes more important. Treatment selection and decision making are based on the following two apparently opposite factors: 1) generalized findings and evidence from clinical trials, and 2) disease risks and background of individuals, which are diverse among patients...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28883264/treatment-algorithms-for-multiple-myeloma-in-japan
#13
Shuji Ozaki
Recent progress in the development of novel therapeutic agents has remarkably improved the treatment outcome for multiple myeloma (MM). Proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib; immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide; the histone deacetylase (HDAC) inhibitor panobinostat; and the monoclonal antibody, elotuzumab, have all been approved in Japan, although only bortezomib and lenalidomide have been approved for initial therapy. Accordingly, the Japanese Society of Hematology has released updated treatment guidelines for MM...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28860887/new-developments-in-the-management-of-relapsed-refractory-multiple-myeloma-the-role-of-ixazomib
#14
REVIEW
Paul G Richardson, Shaji Kumar, Jacob P Laubach, Claudia Paba-Prada, Neeraj Gupta, Deborah Berg, Helgi van de Velde, Philippe Moreau
Ixazomib is the first oral proteasome inhibitor to be approved, in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was on the basis of results from the phase 3, double-blind, placebo-controlled TOURMALINE-MM1 study, which demonstrated a 35% improvement in progression-free survival with the all-oral combination of ixazomib plus lenalidomide-dexamethasone versus lenalidomide-dexamethasone alone (median: 20...
2017: Journal of Blood Medicine
https://www.readbyqxmd.com/read/28842936/a-single-center-phase-ii-study-of-ixazomib-in-patients-with-relapsed-or-refractory-cutaneous-or-peripheral-t-cell-lymphomas
#15
Philip S Boonstra, Avery Polk, Noah Brown, Alexandra C Hristov, Nathanael G Bailey, Mark S Kaminski, Tycel Phillips, Sumana Devata, Tera Mayer, Ryan A Wilcox
The transcription factor GATA-3, highly expressed in many cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphomas (PTCL), confers resistance to chemotherapy in a cell-autonomous manner. As GATA-3 is transcriptionally regulated by NF-κB, we sought to determine the extent to which proteasomal inhibition impairs NF-κB activation and GATA-3 expression and cell viability in malignant T cells. Proteasome inhibition, NF-κB activity, GATA-3 expression, and cell viability were examined in patient-derived cell lines and primary T-cell lymphoma specimens ex vivo treated with the oral proteasome inhibitor ixazomib...
August 26, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28828905/the-activity-and-safety-of-novel-proteasome-inhibitors-strategies-single-doublet-and-triplet-for-relapsed-refractory-multiple-myeloma
#16
Huanwen Ma, Zheng Su, Fengqiang Sun, Ningning Zhao
PURPOSE: We sought to evaluate the activity and safety of these novel proteasome inhibitors (PIs) (carfilzomib, ixazomib, oprozomib and marizomib) containing regimens (single, doublet and triplet) for relapsed/refractory multiple myeloma (R/RMM). METHODS: We searched published reports including these novel PIs containing regimens for R/RMM. RESULTS: Finally, we identified 28 prospective studies that evaluated 4123 patients. Pooled analysis showed that novel PIs doublet combinations attained an impressive overall response rate (ORR) of 67%, which was higher than that of 22% from novel PIs single-agent (p < ...
August 22, 2017: Acta Oncologica
https://www.readbyqxmd.com/read/28803351/dose-and-schedule-selection-of-the-oral-proteasome-inhibitor-ixazomib-in-relapsed-refractory-multiple-myeloma-clinical-and-model-based-analyses
#17
Neeraj Gupta, Huyuan Yang, Michael J Hanley, Steven Zhang, Rachael Liu, Shaji Kumar, Paul G Richardson, Tomas Skacel, Karthik Venkatakrishnan
BACKGROUND: The oral proteasome inhibitor ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study. OBJECTIVE: The objective of this study was to quantitatively characterize the benefit-risk profile of ixazomib in relapsed/refractory MM in support of the approved dose and schedule...
October 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28800141/effects-of-strong-cyp3a-inhibition-and-induction-on-the-pharmacokinetics-of-ixazomib-an-oral-proteasome-inhibitor-results-of-drug-drug-interaction-studies-in-patients-with-advanced-solid-tumors-or-lymphoma-and-a-physiologically-based-pharmacokinetic-analysis
#18
Neeraj Gupta, Michael J Hanley, Karthik Venkatakrishnan, Alberto Bessudo, Drew W Rasco, Sunil Sharma, Bert H O'Neil, Bingxia Wang, Guohui Liu, Alice Ke, Chirag Patel, Karen Rowland Yeo, Cindy Xia, Xiaoquan Zhang, Dixie-Lee Esseltine, John Nemunaitis
At clinically relevant ixazomib concentrations, in vitro studies demonstrated that no specific cytochrome P450 (CYP) enzyme predominantly contributes to ixazomib metabolism. However, at higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms, with the estimated relative contribution being highest for CYP3A at 42%. This multiarm phase 1 study (Clinicaltrials.gov identifier: NCT01454076) investigated the effect of the strong CYP3A inhibitors ketoconazole and clarithromycin and the strong CYP3A inducer rifampin on the pharmacokinetics of ixazomib...
August 11, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28790851/identification-of-the-anticancer-effects-of-a-novel-proteasome-inhibitor-ixazomib-on-colorectal-cancer-using-a-combined-method-of-microarray-and-bioinformatics-analysis
#19
Qiaowei Fan, Bingrong Liu
PURPOSE: The study aimed to explore the anticancer effects of a novel proteasome inhibitor, ixazomib, on colorectal cancer (CRC) using a combined method of microarray and bioinformatics analysis. MATERIALS AND METHODS: Cell proliferation was tested by Cell Counting Kit-8 (CCK-8) assay for SW620 cells treated with different concentrations of ixazomib and different treatment times. The microarray analysis was conducted for six samples, including three samples of SW620 cells untreated with ixazomib and three samples of SW620 cells treated with ixazomib...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28783865/a-phase-1-study-to-assess-the-relative-bioavailability-of-two-capsule-formulations-of-ixazomib-an-oral-proteasome-inhibitor-in-patients-with-advanced-solid-tumors-or-lymphoma
#20
Michael J Hanley, Neeraj Gupta, Karthik Venkatakrishnan, Alberto Bessudo, Sunil Sharma, Bert H O'Neil, Bingxia Wang, Helgi van de Velde, John Nemunaitis
The oral proteasome inhibitor ixazomib is approved in multiple countries in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. Two oral capsule formulations of ixazomib have been used during clinical development. This randomized, 2-period, 2-sequence crossover study (Clinicaltrials.gov identifier NCT01454076) assessed the relative bioavailability of capsule B in reference to capsule A in adult patients with advanced solid tumors or lymphoma...
August 7, 2017: Journal of Clinical Pharmacology
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