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Multiple Myeloma, Bortezomib

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https://www.readbyqxmd.com/read/29034113/low-neurotoxicity-of-onx-0914-supports-the-idea-of-specific-immunoproteasome-inhibition-as-a-side-effect-limiting-therapeutic-strategy
#1
Laura von Brzezinski, Paula Säring, Peter Landgraf, Clemens Cammann, Ulrike Seifert, Daniela C Dieterich
Application of the proteasome inhibitor Bortezomib for the treatment of haematopoietic malignancies such as multiple myeloma significantly improves the average overall survival of patients. However, one of the most severe side effects is the development of peripheral neuropathies caused by neurotoxic effects of Bortezomib limiting its therapeutic efficacy. With ONX-0914 a specific inhibitor of the β5i (LMP7)-immunosubunit containing proteasomes was developed that targets exclusively the proteasome subtypes mainly expressed in immune cells including B lymphocytes as the origin of multiple myeloma...
September 2017: European Journal of Microbiology & Immunology
https://www.readbyqxmd.com/read/29032267/long-term-follow-up-of-a-donor-versus-no-donor-comparison-in-multiple-myeloma-patients-at-first-relapse-after-failing-autologous-transplantation
#2
Francesca Patriarca, Benedetto Bruno, Hermann Einsele, Francesco Spina, Luisa Giaccone, Vittorio Montefusco, Miriam Isola, Chiara Nozzoli, Andrea Nozza, Fortunato Morabito, Paolo Corradini, Renato Fanin
We report the long-term clinical outcomes of a retrospective multicentre study that enrolled 169 multiple myeloma (MM) patients at first relapse after failing autologous stem cell transplantation (SCT). After HLA-typing at relapse, 79 patients with a suitable donor, 72 (91%) of whom eventually underwent salvage allogeneic SCT, were compared with 90 patients without a donor who were treated with multiple lines of salvage treatment with bortezomib and/or immune-modulating agents. At a median follow-up of 30 months (range 2-180) for all patients and 110 months (range 38-180) for surviving patients, 7-year progression free survival (PFS) was 18% in the donor group and 0% in the no-donor group (hazard ratio [HR] 2...
October 12, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29030084/characterization-and-use-of-the-novel-human-multiple-myeloma-cell-line-mc-b11-14-to-study-biological-consequences-of-crispr-mediated-loss-of-immunoglobulin-a-heavy-chain
#3
Denise K Walters, Bonnie K Arendt, Renee C Tschumper, Xiaosheng Wu, Diane F Jelinek
The genetic abnormalities underlying multiple myeloma (MM) are notoriously complex and intraclonal heterogeneity is a common disease feature. In the current study, we describe the establishment of a monoclonal IgA kappa (κ) MM cell line, designated MC-B11/14. Cytogenetic and FISH analyses of the original and relapse patient samples revealed the MM clone was non-hyperdiploid and possessed an 11;14 chromosomal translocation. The MC-B11/14 cell line, established from the relapse sample, is tetraploid and houses the t(11;14) abnormality...
October 10, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/29027825/cost-effectiveness-of-carfilzomib-plus-dexamethasone-compared-with-bortezomib-plus-dexamethasone-for-patients-with-relapsed-or-refractory-multiple-myeloma-in-the-united-states
#4
Andrzej J Jakubowiak, Ivan Houisse, István Májer, Ágnes Benedict, Marco Campioni, Sumeet Panjabi, Sikander Ailawadhi
BACKGROUND: We assessed the economic value of carfilzomib 56 mg/m(2) and dexamethasone (Kd56) vs bortezomib and dexamethasone (Vd) for relapsed/refractory multiple myeloma (R/RMM) using ENDEAVOR trial results. RESEARCH DESIGN AND METHODS: Cost-effectiveness of Kd56 vs Vd was assessed using a partitioned survival model by estimating progression-free survival, overall survival, and direct costs over a lifetime horizon. Surveillance Epidemiology and End Results (SEER) survival data were extrapolated after matching registry and ENDEAVOR patients...
October 13, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/29026167/the-proteasome-inhibitor-bortezomib-attenuates-renal-fibrosis-in-mice-via-the-suppression-of-tgf-%C3%AE-1
#5
Moko Zeniya, Takayasu Mori, Naofumi Yui, Naohiro Nomura, Shintaro Mandai, Kiyoshi Isobe, Motoko Chiga, Eisei Sohara, Tatemitsu Rai, Shinichi Uchida
Kidney fibrosis and fibrogenesis significantly exacerbate chronic kidney disease (CKD) progression and are essential therapeutic targets. Bortezomib (BZM) is a proteasome inhibitor used for the treatment of multiple myeloma (MM). Several studies have demonstrated that BZM attenuates renal impairment in patients with MM, although this effect is generally considered to be the result of MM remission. Recently, several studies on BZM reported anti-fibrotic effects on liver and skin in experimental animal models...
October 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29018077/efficacy-of-venetoclax-as-targeted-therapy-for-relapsed-refractory-t-11-14-multiple-myeloma
#6
Shaji Kumar, Jonathan L Kaufman, Cristina Gasparetto, Joseph Mikhael, Ravi Vij, Brigitte Pegourie, Lofti Benboubker, Thierry Facon, Martine Amiot, Philippe Moreau, Elizabeth A Punnoose, Stefanie Alzate, Martin Dunbar, Tu Xu, Suresh K Agarwal, Sari Heitner Enschede, Joel D Leverson, Jeremy A Ross, Paulo C Maciag, Maria Verdugo, Cyrille Touzeau
Venetoclax is a selective, orally bioavailable BCL-2 inhibitor that induces cell death in MM cells, particularly in those harboring t(11;14), which express high levels of BCL-2 relative to BCL-XL and MCL-1. In this phase I study, patients with relapsed/refractory MM received venetoclax monotherapy. After a 2-week lead-in with weekly dose escalation, daily venetoclax was given at 300, 600, 900, or 1200 mg in dose-escalation cohorts and 1200 mg in the safety expansion. Dexamethasone could be added upon progression during treatment...
October 10, 2017: Blood
https://www.readbyqxmd.com/read/29018054/the-induction-of-myeloma-cell-death-and-dna-damage-by-tetrac-a-thyroid-hormone-derivative
#7
Keren Cohen, Uri Abadi, Aleck Hercbergs, Paul J Davis, Martin Ellis, Osnat Ashur-Fabian
Multiple myeloma (MM) is a plasma cell malignancy in which involvement of the thyroid hormone-integrin αvβ3 pathway was shown and pharmacologic inhibition of this pathway is a rational approach to disease management. A thyroid hormone derivative, tetraiodothyroacetic acid (tetrac), which inhibits L-thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3) binding to αvβ3 integrin, was studied in five MM cell lines and primary bone marrow (BM) MM cells. Tetrac inhibited MM cell proliferation (absolute cell number/viability) and induced caspase-dependent apoptosis (annexin-V/PI and cell cycle)...
October 10, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28978848/initial-treatment-strategy-for-patients-newly-diagnosed-with-multiple-myeloma
#8
Hideo Yagi
In Japan, the latest trends in induction therapy for patients newly diagnosed with multiple myeloma are multi-drug combinations, including bortezomib, lenalidomide, and thalidomide. Patients <65 years old and those <70 years old who have normal cardiac and lung functions without any serious complications are good candidates for high-dose L-PAM with autologous stem cell transplantation. For successful stem cell collection, anti-cancer drugs that have a negative impact on stem cell mobilization are usually excluded from induction therapies...
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
#9
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/28972783/multiple-myeloma-cell-drug-responses-differ-in-thermoplastic-vs-pdms-microfluidic-devices
#10
Thomas A Moore, Peter Brodersen, Edmond W K Young
Poly(dimethylsiloxane) (PDMS) is a commonly used elastomer for fabricating microfluidic devices, but it has previously been shown to absorb hydrophobic molecules. Although this has been demonstrated for molecules such as estrogen and Nile Red, the absorption of small hydrophobic molecules in PDMS specifically used to treat cancer and its subsequent impact on cytotoxicity measurements and assays have not been investigated. This is critical for the development of microfluidic chemosensitivity and resistance assay (CSRA) platforms that have shown potential to help guide clinical therapy selection and which rely on the accuracy of the readout involving interactions between patient-derived cells and cancer drugs...
October 17, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28972650/characterisation-of-a-rat-model-of-bortezomib-induced-painful-neuropathy
#11
Natalie A Duggett, Sarah J L Flatters
BACKGROUND: Bortezomib (Velcade®) is a breakthrough treatment for multiple myeloma, significantly improving patient survival. However, its use is limited by painful neuropathy often resulting in dose reduction/cessation of first-line treatment due to lack of treatment. The aim of this study was to characterise a clinically-relevant rat model of bortezomib-induced painful neuropathy, using established evoked measures and novel ethological techniques, to aid drug discovery. EXPERIMENTAL APPROACH: Adult male Sprague-Dawley rats were injected intraperitoneally (i...
October 3, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28966941/increased-expression-of-the-tight-junction-protein-tjp1-zo-1-is-associated-with-upregulation-of-taz-tead-activity-and-an-adult-tissue-stem-cell-signature-in-carfilzomib-resistant-multiple-myeloma-cells-and-high-risk-multiple-myeloma-patients
#12
Irene Riz, Robert G Hawley
Tight junction protein 1 (TJP1) has recently been proposed as a biomarker to identify multiple myeloma (MM) patients most likely to respond to bortezomib- and carfilzomib-based proteasome inhibitor regimens. Herein we report increased expression of TJP1 during the adaptive response mediating carfilzomib resistance in the LP-1/Cfz MM cell line. Moreover, increased TJP1 expression delineated a subset of relapsed/refractory MM patients on bortezomib-based therapy sharing an LP-1/Cfz-like phenotype characterized by activation of interacting transcriptional effectors of the Hippo signaling cascade (TAZ and TEAD1) and an adult tissue stem cell signature...
July 2017: Oncoscience
https://www.readbyqxmd.com/read/28963446/clinical-features-of-multiple-myeloma-patients-with-isolated-extramedullary-relapse
#13
Xiao-Yan Qu, Li-Juan Chen, Tian Tian, Li-Min Duan, Rui-Nan Lu, Hua Lu, Han-Xin Wu, Jian-Yong Li
This study sought to analyze the clinical features and prognosis of multiple myeloma with isolated extramedullary relapse and with the absence of systemic progression. The clinical features and outcome were retrospectively analyzed in six multiple myeloma patients. These patients had secretory multiple myeloma at diagnosis. When relapsed, the dissociation between medullary and extramedullary response was detected. The serum or urine monoclonal component was extremely low or absent. The plasma cells in bone marrow were<5%...
September 30, 2017: Journal of Biomedical Research
https://www.readbyqxmd.com/read/28961309/phase-ii-study-of-bortezomib-cyclophosphamide-and-dexamethasone-as-induction-therapy-in-multiple-myeloma-dsmm-xi-trial
#14
Hermann Einsele, Monika Engelhardt, Christoph Tapprich, Jürgen Müller, Peter Liebisch, Christian Langer, Martin Kropff, Lars O Mügge, Wolfram Jung, Hans-Heinrich Wolf, Bernd Metzner, Christina Hart, Martin Gramatzki, Bernd Hertenstein, Michael Pfreundschuh, Wolf Rösler, Thomas Fischer, Georg Maschmeyer, Lothar Kanz, Georg Hess, Elke Jäger, Martin Bentz, Heinz A Dürk, Hans Salwender, Holger Hebart, Christian Straka, Stefan Knop
We assessed the safety and efficacy of bortezomib, cyclophosphamide and dexamethasone (VCD) induction therapy in previously untreated multiple myeloma patients. A total of 414 patients received three 21-day cycles of VCD prior to autologous stem-cell transplantation (ASCT). Most common grade ≥3 adverse events were leucopenia (31·4%) and thrombocytopenia (6·8%). The overall response rate (ORR) by investigator-based assessment was 85·4%. Most patients (74%) underwent successful central laboratory-based molecular cytogenetic analysis...
September 29, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28959638/bortezomib-alters-sour-taste-sensitivity-in-mice
#15
Akihiro Ohishi, Kentaro Nishida, Karin Miyamoto, Mizuka Imai, Ryoko Nakanishi, Kyoko Kobayashi, Akiko Hayashi, Kazuki Nagasawa
Chemotherapy-induced taste disorder is one of the critical issues in cancer therapy. Bortezomib, a proteasome inhibitor, is a key agent in multiple myeloma therapy, but it induces a taste disorder. In this study, we investigated the characteristics of bortezomib-induced taste disorder and the underlying mechanism in mice. Among the five basic tastes, the sour taste sensitivity of mice was significantly increased by bortezomib administration. In bortezomib-administered mice, protein expression of PKD2L1 was increased...
2017: Toxicology Reports
https://www.readbyqxmd.com/read/28958990/crispr-genome-wide-screening-identifies-dependence-on-the-proteasome-subunit-psmc6-for-bortezomib-sensitivity-in-multiple-myeloma
#16
Chang-Xin Shi, K Martin Kortüm, Yuan Xiao Zhu, Laura A Bruins, Patrick Jedlowski, Patrick G Votruba, Moulun Luo, Robert A Stewart, Jonathan Ahmann, Esteban Braggio, A Keith Stewart
Bortezomib (BTZ) is highly effective in the treatment of Multiple Myeloma (MM), however emergent drug resistance is common. Consequently, we employed CRISPR targeting 19,052 human genes to identify unbiased targets that contribute to BTZ resistance. Specifically, we engineered an RPMI8226 MM cell line to express Cas9 and a lentiviral-vector CRISPR library and cultured derived cells in doses of BTZ lethal to parental cells. Sequencing was performed on surviving cells to identify inactivated genes responsible for drug resistance...
September 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28954356/-comparison-of-the-efficacy-and-safety-of-bortezomib-between-the-twice-weekly-and-once-weekly-regimens-for-newly-diagnosed-multiple-myeloma
#17
J Shen, A J Liao, W Yang, Z G Liu
No abstract text is available yet for this article.
August 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28953414/prame-gene-copy-number-variation-is-related-to-its-expression-in-multiple-myeloma
#18
Lu Yang, Ya-Zhe Wang, Hong-Hu Zhu, Yan Chang, Ling-Di Li, Wen-Min Chen, Ling-Yu Long, Yan-Huan Zhang, Yan-Rong Liu, Jin Lu, Ya-Zhen Qin
Multiple myeloma (MM) patients commonly present abnormal expression of cancer-testis antigens, which may serve as immunotherapeutic targets and prognostic factors. We previously reported that preferentially expressed antigen of melanoma (PRAME) overexpression in bone marrow mononuclear cells is related to progression in MM patients treated with non-bortezomib-containing regimens. The mechanism underlying variations in PRAME expression remains unknown. To investigate the impact of gene copy number variation (CNV) on PRAME expression, plasma cells were sorted from 50 newly diagnosed patients and 8 healthy volunteers to measure PRAME transcript levels and gene copy numbers by real-time quantitative polymerase chain reaction...
September 27, 2017: DNA and Cell Biology
https://www.readbyqxmd.com/read/28948001/emerging-drugs-and-combinations-to-treat-multiple-myeloma
#19
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/28938651/positive-transcription-elongation-factor-b-p-tefb-is-a-therapeutic-target-in-human-multiple-myeloma
#20
Yu Zhang, Liang Zhou, Yun Leng, Yun Dai, Robert Z Orlowski, Steven Grant
The role of the positive RNA Pol II regulator, P-TEFb (positive transcription elongation factor b), in maintenance of the anti-apoptotic protein Mcl-1 and bortezomib (btz) resistance was investigated in human multiple myeloma (MM) cells. Mcl-1 was up-regulated in all MM lines tested, including bortezomib-resistant lines, human MM xenograft mouse models, and primary CD138(+) MM cells. Mcl-1 over-expression significantly reduced bortezomib lethality, indicating a functional role for Mcl-1 in bortezomib resistance...
August 29, 2017: Oncotarget
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