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https://www.readbyqxmd.com/read/29768064/a-look-at-treatment-strategies-for-relapsed-multiple-myeloma
#1
Giusy Cetani, Mario Boccadoro, Stefania Oliva
Multiple myeloma treatment considerably improved during the past decade, thanks to novel effective drugs, a better understanding of myeloma biology and clonal heterogeneity, and an improved management of toxicities. The choice of regimen at relapse is usually based on prior response, toxicities, age and comorbidities of relapsed patients. Areas covered: A review was performed of the most recent and effective therapeutic strategies for the relapsed myeloma setting, by documenting the latest clinical evidence from phase II and III clinical trials...
May 16, 2018: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29765356/soluble-and-cell-cell-mediated-drivers-of-proteasome-inhibitor-resistance-in-multiple-myeloma
#2
REVIEW
Mariah L Farrell, Michaela R Reagan
It is becoming clear that myeloma cell-induced disruption of the highly organized bone marrow components (both cellular and extracellular) results in destruction of the marrow and support for multiple myeloma (MM) cell proliferation, survival, migration, and drug resistance. Since the first phase I clinical trial on bortezomib was published 15 years ago, proteasome inhibitors (PIs) have become increasingly common for treatment of MM and are currently an essential part of any anti-myeloma combination therapy...
2018: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29755650/preclinical-comparison-of-proteasome-and-ubiquitin-e1-enzyme-inhibitors-in-cutaneous-squamous-cell-carcinoma-the-identification-of-mechanisms-of-differential-sensitivity
#3
Angela McHugh, Kenneth Fernandes, Andrew P South, Jemima E Mellerio, Julio C Salas-Alanís, Charlotte M Proby, Irene M Leigh, Mark K Saville
Proteasome inhibitors have distinct properties and the biochemical consequences of suppressing ubiquitin E1 enzymes and the proteasome differ. We compared the effects of the proteasome inhibitors bortezomib, ixazomib and carfilzomib and the ubiquitin E1 enzyme inhibitor MLN7243/TAK-243 on cell viability and cell death in normal keratinocytes and cutaneous squamous cell carcinoma (cSCC) cell lines. The effects of both a pulse of treatment and more extended incubation were investigated. This is relevant to directly-delivered therapy (topical treatment/intratumoral injection) where the time of exposure can be controlled and a short exposure may better reflect systemically-delivered inhibitor pharmacokinetics...
April 17, 2018: Oncotarget
https://www.readbyqxmd.com/read/29748955/investigational-agents-in-immunotherapy-a-new-horizon-for-the-treatment-of-multiple-myeloma
#4
REVIEW
Cindy Varga, Jacob P Laubach, Kenneth C Anderson, Paul G Richardson
The treatment of multiple myeloma (MM) has gone through several major advances over the last 5 years with the introduction of next generation proteasome inhibitors (PI; carfilzomib, ixazomib) and immunomodulatory derivatives (IMiD; pomalidomide), with these new agents having a substantial impact on patient outcome. However, despite these advances, MM remains a highly resistant disease given its propensity for clonal heterogeneity and its complex interaction with the surrounding bone marrow microenvironment...
May 10, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29741409/healthcare-resource-utilization-with-ixazomib-or-placebo-plus-lenalidomide-dexamethasone-in-the-randomized-double-blind-phase-3-tourmaline-mm1-study-in-relapsed-refractory-multiple-myeloma
#5
Parameswaran Hari, Huamao Mark Lin, Yanyan Zhu, Deborah Berg, Paul G Richardson, Philippe Moreau
AIMS: The aim of this analysis was to assess healthcare resource utilization in the pivotal phase 3 TOURMALINE-MM1 study of the oral proteasome inhibitor ixazomib or placebo plus lenalidomide and dexamethasone (Rd) in relapsed and/or refractory multiple myeloma (RRMM). METHODS: In this double-blind, placebo-controlled, randomized study (NCT01564537), 722 patients with RRMM following 1-3 prior lines of therapy received Rd plus ixazomib (ixazomib-Rd; N = 360) or matching placebo (placebo-Rd; N = 362) until disease progression or unacceptable toxicity...
May 9, 2018: Journal of Medical Economics
https://www.readbyqxmd.com/read/29726031/patient-reported-health-related-quality-of-life-from-the-phase-iii-tourmaline-mm1-study-of-ixazomib-lenalidomide-dexamethasone-versus-placebo-lenalidomide-dexamethasone-in-relapsed-refractory-multiple-myeloma
#6
Xavier Leleu, Tamas Masszi, Nizar J Bahlis, Luisa Viterbo, Bartrum Baker, Peter Gimsing, Vladimir Maisnar, Olga Samoilova, Laura Rosiñol, Christian Langer, Kevin Song, Tohru Izumi, Charles Cleeland, Deborah Berg, Huamao Mark Lin, Yanyan Zhu, Tomas Skacel, Philippe Moreau, Paul G Richardson
TOURMALINE-MM1 is a phase III, randomized, double-blind, placebo-controlled study of ixazomib plus lenalidomide and dexamethasone (IRd) versus placebo-Rd in patients with relapsed/refractory multiple myeloma following 1-3 prior lines of therapy. The study met its primary endpoint, demonstrating significantly longer progression-free survival (PFS) in the IRd arm versus placebo-Rd arm (median 20.6 vs 14.7 months, hazard ratio 0.74, P = 0.01), with limited additional toxicity. Patient-reported health-related quality of life (HRQoL) was a secondary endpoint of TOURMALINE-MM1...
May 4, 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29699990/trail-mediates-and-sustains-constitutive-nf-%C3%AE%C2%BAb-activation-in-lgl-leukemia
#7
Jun Yang, Francis R LeBlanc, Shubha A Dighe, Cait E Hamele, Thomas L Olson, David J Feith, Thomas P Loughran
Large granular lymphocyte (LGL) leukemia results from clonal expansion of CD3+ cytotoxic T-lymphocytes or CD3- natural killer (NK) cells. Chronic antigen stimulation is postulated to promote long-term survival of LGL leukemia cells through constitutive activation of multiple survival pathways, resulting in global dysregulation of apoptosis and resistance to activation-induced cell death. We reported previously that nuclear factor kappa B (NF-κB) is a central regulator of the survival network for leukemic LGL...
April 26, 2018: Blood
https://www.readbyqxmd.com/read/29695518/ixazomib-an-oral-proteasome-inhibitor-induces-rapid-mobilization-of-hematopoietic-progenitor-cells-in-mice
#8
Armin Ghobadi, Michael P Rettig, Matthew S Holt, Julie K Ritchey, Krista Kennerly, Ezhilarasi Chendamarai, Linda Eissenberg, John F DiPersio
No abstract text is available yet for this article.
April 25, 2018: Blood
https://www.readbyqxmd.com/read/29661775/prospective-clinical-trial-of-ixazomib-dexamethasone-and-rituximab-as-primary-therapy-in-waldenstr%C3%A3-m-macroglobulinemia
#9
Jorge J Castillo, Kirsten Meid, Joshua Gustine, Toni Dubeau, Patricia Severns, Zachary R Hunter, Guang Yang, Lian Xu, Steven P Treon
INTRODUCTION: Proteasome inhibition is of proven efficacy in patients with Waldenström macroglobulinemia (WM). However, WM remains incurable with standard treatments. Novel agents, safe and effective, are needed. METHODS: We designed a prospective phase II study evaluating the combination of ixazomib, dexamethasone and rituximab (IDR) as primary therapy in symptomatic patients with WM. Protocol therapy consisted of oral ixazomib, 4 mg, with intravenous or oral dexamethasone, 20 mg, on days 1, 8 and 15 every 4 weeks for induction cycles 1 and 2, and in combination with intravenous rituximab, 375 mg/m2, on day 1, every 4 weeks for cycles 3 to 6...
April 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29643240/the-proapoptotic-hiv-protease-generated-casp8p41-when-bound-and-inactivated-by-bcl2-is-degraded-by-the-proteasome
#10
Sekar Natesampillai, Nathan W Cummins, Zilin Nie, Rahul Sampath, Jason V Baker, Keith Henry, Marilia Pinzone, Una O'Doherty, Eric C Polley, Gary D Bren, David J Katzmann, Andrew D Badley
HIV protease is known to cause cell death which is dependent upon cleavage of procaspase 8. HIV protease cleavage of procaspase 8 generates Casp8p41 which directly binds Bak with nanomolar affinity causing Bak activation and consequent cell death. Casp8p41 can also bind Bcl2 with nanomolar affinity in which case cell death is averted. Central memory CD4 T cells express high levels of Bcl2 possibly explaining why these cells do not die when they reactivate HIV. Here we determine that the Casp8p41:Bcl2 complex is polyubiquitinated and degraded by the proteasome...
April 11, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29628465/-pharmacological-characteristics-and-clinical-study-results-of-the-oral-proteasome-inhibitor-ixazomib-ninlaro-%C3%A2-capsules-2-3-mg-3-mg-and-4-mg
#11
Michiko Machida, Shinichi Fukunaga, Takahito Hara
Ixazomib (Ninlaro® capsule) is an oral small molecule 20S proteasome inhibitor created by Millennium Pharmaceuticals, Inc (Takeda Oncology Company). Ubiquitin proteasome system is a major regulatory system for maintaining protein homeostasis, and an important mechanism for degrading proteins, such as those involved in proliferation regulation, cell cycle regulation and apoptosis, in cells. Ixazomib selectively and reversibly binds to the β5 subunit of the 20S proteasome, inhibits its chymotrypsin-like activity, and thereby accumulates ubiquitinated proteins...
2018: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
https://www.readbyqxmd.com/read/29603798/the-start-of-a-new-wave-developments-in-proteasome-inhibition-in-multiple-myeloma
#12
REVIEW
Kwee Yong, Sebastian Gonzalez-McQuire, Zsolt Szabo, Paul Schoen, Roman Hajek
Multiple myeloma (MM) accounts for 10% of hematological cancers. Stem cell transplantation remains the cornerstone of first-line treatment for eligible patients but, historically, pharmaceutical treatment options for MM have been limited. The proteasome was identified as a target for MM therapy in the early 2000s and, in 2004, the boronic acid proteasome inhibitor bortezomib gained European approval. Bortezomib now plays a major role in MM treatment, but the duration of its use can be limited by toxicities such as peripheral neuropathy, and the development of resistance...
March 30, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29582405/ixazomib-for-relapsed-or-refractory-multiple-myeloma-review-from-an-evidence-review-group-on-a-nice-single-technology-appraisal
#13
REVIEW
Xavier Armoiry, Martin Connock, Alexander Tsertsvadze, Ewen Cummins, G J Melendez-Torres, Pam Royle, Aileen Clarke
Ixazomib is an oral proteasome inhibitor used in combination with lenalidomide plus dexamethasone (IXA-LEN-DEX) and licensed for relapsed or refractory multiple myeloma. As part of a single technology appraisal (ID807) undertaken by the National Institute of Health and Care Excellence, the Evidence Review Group, Warwick Evidence was invited to independently review the evidence submitted by the manufacturer of ixazomib, Takeda UK Ltd. The main source of clinical effectiveness data about IXA-LEN-DEX came from the Tourmaline-MM1 randomized controlled trial in which 771 patients with relapsed or refractory multiple myeloma received either IXA-LEN-DEX or placebo-LEN-DEX as their second-, third-, or fourth-line treatment...
March 26, 2018: PharmacoEconomics
https://www.readbyqxmd.com/read/29514706/the-role-of-ixazomib-as-an-augmented-conditioning-therapy-in-salvage-autologous-stem-cell-transplant-asct-and-as-a-post-asct-consolidation-and-maintenance-strategy-in-patients-with-relapsed-multiple-myeloma-accord-uk-mra-myeloma-xii-trial-study-protocol-for
#14
Alina Striha, A John Ashcroft, Anna Hockaday, David A Cairns, Karen Boardman, Gwen Jacques, Cathy Williams, John A Snowden, Mamta Garg, Jamie Cavenagh, Kwee Yong, Mark T Drayson, Roger Owen, Mark Cook, Gordon Cook
BACKGROUND: Multiple myeloma (MM) is a plasma cell tumour with an approximate annual incidence of 4500 in the UK. Therapeutic options for patients with MM have changed in the last decade with the arrival of proteasome inhibitors and immunomodulatory drugs. Despite these options, almost all patients will relapse post first-line autologous stem cell transplantation (ASCT). First relapse management (second-line treatment) has evolved in recent years with an expanding portfolio of novel agents, driving response rates influencing the durability of response...
March 7, 2018: Trials
https://www.readbyqxmd.com/read/29508087/cardiovascular-complications-of-multiple-myeloma-treatment-evaluation-management-and-prevention
#15
REVIEW
Dae Hyun Lee, Michael G Fradley
PURPOSE OF REVIEW: Multiple myeloma treatment regimens consist of proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide), and steroids. In this paper, we will review the pathophysiology and associated cardiotoxicities of the different multiple myeloma therapeutic modalities and present methods to mitigate the development of cardiovascular complications. RECENT FINDINGS: Although proteasome inhibitors and immunomodulatory drugs have led to significant improvements in oncologic outcomes, there is increasing evidence of serious cardiovascular side effects which may be exacerbated in the setting of underlying cardiovascular risk factors or disease...
March 6, 2018: Current Treatment Options in Cardiovascular Medicine
https://www.readbyqxmd.com/read/29507502/progressive-multifocal-leukoencephalopathy-during-ixazomib-based-chemotherapy
#16
C P Sawicki, S A Climans, C C Hsia, J A Fraser
Progressive multifocal leukoencephalopathy (pml) is a rare demyelinating disease of the central nervous system that most often affects immunocompromised individuals. It is caused by the reactivation of the John Cunningham virus (jcv), which is found in latent form in the majority of adults. We describe a 59-year-old man with multiple myeloma who developed severe neurological deficits during treatment with ixazomib-based chemotherapy. A diagnosis of pml was established with gadolinium-enhanced magnetic resonance imaging (mri) and by detection of jcv in the cerebrospinal fluid...
February 2018: Current Oncology
https://www.readbyqxmd.com/read/29478351/proteasome-inhibitors-for-the-treatment-of-multiple-myeloma
#17
REVIEW
Emilia Scalzulli, Sara Grammatico, Federico Vozella, Maria Teresa Petrucci
Multiple Myeloma (MM) management is rapidly evolving, with a spectrum of novel treatments that have changed our approach to the therapy. Proteasome inhibitors (PIs) have revolutionized the scenario of both relapsed/refractory and newly diagnosed patients. The efficacy of bortezomib, the first PI approved, followed by carfilzomib and, the oral ixazomib, have been tested in several trials as single agents or in combination. Areas covered: In this review, the authors summarize mechanism of action, efficacy and safety of proteasome inhibitors in MM and focus on data derived from clinical trials, analyzing adverse events and their relative management...
March 2018: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/29472721/phase-i-ii-trial-of-the-oral-regimen-ixazomib-pomalidomide-and-dexamethasone-in-relapsed-refractory-multiple-myeloma
#18
Amrita Krishnan, Prashant Kapoor, Joycelynne M Palmer, Ni-Chun Tsai, Shaji Kumar, Sagar Lonial, Myo Htut, Chatchada Karanes, Nitya Nathwani, Michael Rosenzweig, Firoozeh Sahebi, George Somlo, Lupe Duarte, James F Sanchez, Daniel Auclair, Stephen J Forman, Jesus 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 three patients were enrolled to DL1, with no further dose-limiting toxicity (DLT)...
February 23, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29469592/ixazomib-in-the-management-of-relapsed-multiple-myeloma
#19
Cyrille Touzeau, Philippe Moreau
The development of proteasome inhibitors contributed to the dramatic life expectancy improvement observed in myeloma patients over the past decades. Ixazomib is a boron-containing selective and reversible proteasome inhibitor that demonstrated antimyeloma activity with excellent safety profile. Ixazomib is the first orally available proteasome inhibitor approved in combination with lenalidomide and dexamethasone for the treatment of myeloma patients who received at least one prior therapy. The present review addresses the current knowledge regarding the clinical use of ixazomib in relapsed myeloma patients...
February 22, 2018: Future Oncology
https://www.readbyqxmd.com/read/29456035/a-comparison-of-the-efficacy-of-immunomodulatory-containing-regimens-in-relapsed-refractory-multiple-myeloma-a-network-meta-analysis
#20
Meletios Athanasios Dimopoulos, Jonathan L Kaufman, Darrell White, Gordon Cook, Maria Rizzo, Yingxin Xu, Kyle Fahrbach, Maren Gaudig, Mary Slavcev, Lindsay Dearden, Annette Lam
BACKGROUND: Previous network meta-analyses combined studies of immunomodulatory drug (IMiD)-containing and IMiD-free regimens, despite a lack of head-to-head randomized controlled trials to robustly link them. However, patients with relapsed or refractory multiple myeloma (RRMM) treated with IMiD-containing regimens differ from those treated with IMiD-free regimens, especially relating to treatment history, which is an important treatment-effect modifier requiring clinical consideration when evaluating the most appropriate subsequent treatment options...
March 2018: Clinical Lymphoma, Myeloma & Leukemia
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