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Multiple Myeloma, Bortezomib

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https://www.readbyqxmd.com/read/28211054/real-world-use-of-pomalidomide-and-dexamethasone-in-double-refractory-multiple-myeloma-suggests-benefit-in-renal-impairment-and-adverse-genetics-a-multi-centre-uk-experience
#1
Nicola Maciocia, Andrew Melville, Simon Cheesman, Faye Sharpley, Karthik Ramasamy, Matthew Streetly, Matthew Jenner, Reuben Benjamin, Steve Schey, Paul Maciocia, Rakesh Popat, Shirley D'sa, Ali Rismani, Aviva Cerner, Kwee Yong, Neil Rabin
Myeloma patients who become refractory to immunomodulatory agents (IMiDs) and bortezomib have poor survival, with limited therapeutic options. Pomalidomide has shown improved survival and good tolerability in this patient cohort in clinical trials, but real world data are scarce. We retrospectively analysed all patients treated with pomalidomide at five UK centres between 2013 and 2016. Of 85 patients identified, 70 had sufficient information for response assessments. Median age was 66 years [40-89], 96·5% were refractory to IMiDs, 72·9% were refractory to both an IMiD and bortezomib and 92·9% were refractory to their last treatment...
February 17, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28205262/modern-multiple-myeloma-therapy-deep-sustained-treatment-response-and-good-clinical-outcomes
#2
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/28201976/immunomodulatory-drugs-imids-in-multiple-myeloma
#3
Shahzad Raza, Rachael A Safyan, Lentzsch Suzanne
Multiple myeloma (MM) is a plasma cell neoplasm that is incurable with conventional therapy. However, the treatment of MM has dramatically changed since the emergence of immunomodulatory drugs and proteasome inhibitors. The improvements in survival are linked to a deeper understanding of the molecular mechanisms of the disease. Thalidomide, although highly active in MM, is associated with considerable toxicity, particularly in older patients. Immunomodulatory drugs (IMiDs) are structural and functional analogues of thalidomide that represent a promising new class of immunomodulators for treatment of a variety of inflammatory, autoimmune, and neoplastic diseases...
February 13, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28194054/tumor-lysis-syndrome-in-multiple-myeloma-an-increasingly-recognized-risk-a-report-of-seven-cases
#4
Abhijai Singh, Shweta Gupta, Barbara Yim, Romy Thekkekara
Tumor lysis syndrome is a constellation of metabolic disturbances commonly seen during therapy of bulky, rapidly proliferative tumors. Multiple myeloma is a low proliferation tumor with rare incidence of tumor lysis syndrome in the pre-Bortezomib era. Post Bortezomib use, a rise in the incidence of tumor lysis has been noted. We present seven cases of tumor lysis syndrome with three patients in spontaneous tumor lysis and four developing the same after chemotherapy. In the previous studies, elevated LDH and deletion of chromosome 13 has been associated with risk of TLS...
March 2017: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/28194052/once-weekly-1-6%C3%A2-mg-m-2-bortezomib-bcd-regimen-in-elderly-patients-with-newly-diagnosed-multiple-myeloma-who-are-unfit-for-standard-dose-chemotherapy
#5
Yong Tang, Ye-Hua Yu, Yi-Yun Yao, Li-Fang Zou, Hong-Ju Dou, Lei Wang, Qi Zhu
Bortezomib has shown anti-myeloma effects in combination with alkylating agents, but clinical benefits can be limited by neurotoxicity. There is less information on the efficacy and tolerability of once-weekly 1.6 mg/m(2) bortezomib combined with cyclophosphamide and dexamethasone (BCD) regimen in elderly patients with newly diagnosed multiple myeloma who are unfit for standard dose chemotherapy. Here, we report our experience of weekly 1.6 mg/m(2) intravenous bortezomib in this group of patients. Between March 2010 and February 2015, we treated 34 newly diagnosed elderly patients with the combination of bortezomib 1...
March 2017: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/28186131/recq1-helicase-is-involved-in-replication-stress-survival-and-drug-resistance-in-multiple-myeloma
#6
E Viziteu, B Klein, J Basbous, Y-L Lin, C Hirtz, C Gourzones, L Tiers, A Bruyer, L Vincent, C Grandmougin, A Seckinger, H Goldschmidt, A Constantinou, P Pasero, D Hose, J Moreaux
Multiple myeloma (MM) is a plasma cell cancer with poor survival, characterized by the expansion of multiple myeloma cells (MMCs) in the bone marrow. Using a microarray-based genome-wide screen for genes responding to DNA methyltransferases (DNMT) inhibition in MM cells, we identified RECQ1 among the most downregulated genes. RecQ helicases are DNA unwinding enzymes involved in the maintenance of chromosome stability. Here, we show that RECQ1 is significantly overexpressed in MMCs compared to normal plasma cells and that increased RECQ1 expression is associated with poor prognosis in three independent cohorts of patients...
February 10, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28185460/-daratumumab-hope-for-myeloma-patients-a-challenge-for-clinical-laboratories
#7
T Jelínek, M Kořístka, Z Čermáková, R Hájek
Monoclonal antibodies represent a standard part in the treatment of oncologic patients, but their efficacy in multiple myeloma used to be unsatisfactory. Daratumumab monotherapy was approved by the American FDA in 2015, after unprecedented results were obtained in a heavily pre-treated group of patients. In 2016 daratumumab was approved in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of myeloma patients who have received at least one prior therapy.The toxicity of the drug is low, and is dominated by infusion-related reactions in more or less half of patients...
2017: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/28179738/lenalidomide-bortezomib-and-dexamethasone-rvd-regimen-for-multiple-myeloma
#8
Alexandra P Punke, J Aubrey Waddell, Dominic A Solimando
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast...
January 2017: Hospital Pharmacy
https://www.readbyqxmd.com/read/28169430/phase-ii-study-of-bendamustine-bortezomib-and-dexamethasone-bbd-in-the-first-line-treatment-of-patients-with-multiple-myeloma-who-are-not-candidates-for-high-dose-chemotherapy
#9
Jesus G Berdeja, Todd Bauer, Edward Arrowsmith, James Essell, Patrick Murphy, James A Reeves, Ralph V Boccia, William Donnellan, Ian Flinn
The combination of bendamustine, bortezomib and dexamethasone (BBD) was evaluated as a first-line therapy for multiple myeloma. The original treatment regimen of bendamustine 80 mg/m(2) , days 1, 4; bortezomib 1·3 mg/m(2) , days 1, 4, 8, 11; dexamethasone 40 mg, days 1, 2, 3, 4 on a 28-day cycle (up to 8 cycles) was efficacious but determined relatively toxic in an interim analysis. The regimen was amended to bendamustine 80 mg/m(2) , days 1, 2; bortezomib 1·3 mg/m(2) , days 1, 8, 15; dexamethasone 20 mg, days 1, 2, 8, 9, 15, 16 every 28 days (up to 8 cycles), then maintenance 1·3 mg/m(2) IV bortezomib every 2 weeks...
February 7, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28162031/successful-treatment-of-refractory-systemic-lupus-erythematosus-using-proteasome-inhibitor-bortezomib-followed-by-belimumab-description-of-two-cases
#10
C Sjöwall, M Hjorth, P Eriksson
Although the putative therapeutic options for patients with systemic lupus erythematosus (SLE) are steadily increasing, refractory disease is indeed a major challenge to many clinicians and patients. The proteasome inhibitor bortezomib - approved for the treatment of multiple myeloma since the beginning of this century - was recently reported successful in twelve cases of refractory SLE by German colleagues. Herein, we describe two Swedish SLE cases with refractory renal and pulmonary manifestations that were rescued by bortezomib as induction of remission followed by monthly doses of belimumab...
January 1, 2017: Lupus
https://www.readbyqxmd.com/read/28152765/evaluation-of-relative-thrombocytopenia-identification-of-neuropathy-and-bleeding-risk-secondary-to-utilization-of-neuromodulating-agents-in-multiple-myeloma-patients-receiving-autologous-stem-cell-transplant-treated-with-melphalan-bortezomib-and-lenalidomide
#11
Joel Marcus, Robyn Jackson, Marco A Ruiz, Ryan Patrick Griffin, Rubina Hafeez Khan
: 212 Background: Chemotherapy-induced polyneuropathy (CIPN) is a crippling manifestation in multiple myeloma (MM) patients that requires attentiveness to safety and quality of life.(2) Bortezomib, lenalidomide, and melphalan are commonly utilized chemotherapy agents that can cause both CIPN(3,4) and significant myelosuppression. Within this subset of patients we wish to insure efficacy and minimization of neuropathic pain while being mindful of bleeding risks. METHODS: IRB approval was obtained for a retrospective study of patients with MM who received a bone marrow transplant (BMT)...
March 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28151709/progress-and-paradigms-in-multiple-myeloma
#12
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
#13
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/28130214/the-amyloidogenic-light-chain-is-a-stressor-that-sensitizes-plasma-cells-to-proteasome-inhibitor-toxicity
#14
Laura Oliva, Ugo Orfanelli, Massimo Resnati, Andrea Raimondi, Andrea Orsi, Enrico Milan, Giovanni Palladini, Paolo Milani, Fulvia Cerruti, Paolo Cascio, Simona Casarini, Paola Rognoni, Thierry Touvier, Magda Marcatti, Fabio Ciceri, Silvia Mangiacavalli, Alessandro Corso, Giampaolo Merlini, Simone Cenci
Systemic light chain (AL) amyloidosis is caused by the clonal production of an unstable immunoglobulin light chain (LC), which affects organ function systemically. While pathogenic LCs have been characterized biochemically, little is known about the biology of amyloidogenic PCs. Intrigued by the unique response rates of AL amyloidosis patients to the first-in-class proteasome inhibitor (PI) bortezomib, we purified and investigated patient-derived AL PCs, in comparison with primary multiple myeloma (MM) PCs, the prototypical PI-responsive cells...
January 27, 2017: Blood
https://www.readbyqxmd.com/read/28123303/vtd-melphalan-is-well-tolerated-and-results-in-very-high-rates-of-stringent-cr-and-mrd-negative-status-in-multiple-myeloma
#15
Kalyan Nadiminti, Kamal Kant Singh Abbi, Sarah L Mott, Lindsay Dozeman, Annick Tricot, Allyson Schultz, Sonya Behrends, Fenghuang Zhan, Guido Tricot
The addition of cytotoxic drugs to high-dose melphalan as a preparative regimen for autologous stem cell transplantation in multiple myeloma has not resulted in superior activity. Although novel agents have significantly improved outcome in multiple myeloma, their role in preparative regimens remains largely unknown. We have evaluated the toxicity and efficacy of combining bortezomib, thalidomide, and dexamethasone with high-dose melphalan. An institutional review board-approved retrospective analysis was performed on 100 consecutive patients receiving 153 transplants; 53 had tandem transplants; 64 patients received early transplants; and 36 had salvage transplantation...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28122920/combined-traf6-targeting-and-proteasome-blockade-has-anti-tumor-and-anti-bone-resorptive-effects
#16
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/28111466/bortezomib-and-thalidomide-maintenance-after-stem-cell-transplantation-for-multiple-myeloma-a-pethema-gem-trial
#17
L Rosiñol, A Oriol, A I Teruel, A L de la Guía, MaJ Blanchard, J de la Rubia, M Granell, MaA Sampol, L Palomera, Y González, MaA Etxebeste, R Martínez-Martínez, M T Hernández, F de Arriba, A Alegre, MaT Cibeira, MaV Mateos, J Martínez-López, J J Lahuerta, J San Miguel, J Bladé
The phase III trial GEM05MENOS65 randomized 390 patients 65 years old or younger with newly diagnosed symptomatic multiple myeloma (MM) to receive induction with thalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone and Vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone bortezomib (VBMCP/VBAD/B) followed by autologous stem cell transplantation (ASCT) with MEL-200. After ASCT, a second randomization was performed to compare thalidomide/bortezomib (TV), thalidomide (T) and alfa-2b interferon (alfa2-IFN)...
February 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28107546/bone-marrow-stroma-protects-myeloma-cells-from-cytotoxic-damage-via-induction-of-the-oncoprotein-muc1
#18
Michal Bar-Natan, Dina Stroopinsky, Katarina Luptakova, Maxwell D Coll, Arie Apel, Hasan Rajabi, Athalia R Pyzer, Kristen Palmer, Michaela R Reagan, Myrna R Nahas, Rebecca Karp Leaf, Salvia Jain, Jon Arnason, Irene M Ghobrial, Kenneth C Anderson, Donald Kufe, Jacalyn Rosenblatt, David Avigan
Multiple myeloma (MM) is a lethal haematological malignancy that arises in the context of a tumour microenvironment that promotes resistance to apoptosis and immune escape. In the present study, we demonstrate that co-culture of MM cells with stromal cells results in increased resistance to cytotoxic and biological agents as manifested by decreased rates of cell death following exposure to alkylating agents and the proteosome inhibitor, bortezomib. To identify the mechanism of increased resistance, we examined the effect of the co-culture of MM cells with stroma cells, on expression of the MUC1 oncogene, known to confer tumour cells with resistance to apoptosis and necrosis...
January 20, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28105211/diagnostic-and-therapeutic-approaches-to-multiple-myeloma-patients-real-world-data-from-representative-multicentre-treatment-surveys-in-germany-between-2008-and-2011
#19
Thomas M Moehler, Maximilian Merz, Lenka Kellermann, Hartmut Goldschmidt, Wolfgang Knauf
A survey was conducted to investigate the standard of care for multiple myeloma in Germany, in order to clarify the status of implementation of international and national treatment guidelines. In addition, the changes in disease management over time were investigated by comparison with surveys conducted in 2008 and 2009. The survey captured a representative sample of 478 myeloma patients with a mean age of 67.9 years across various stages of the disease. Diagnostic approaches, prognostic aspects and treatment decisions were evaluated based on a survey conducted in 2011 in 58 representative centres in Germany, including university and non-university hospitals and office-based haematologists...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28101809/sequential-exposure-of-bortezomib-and-vorinostat-is-synergistic-in-multiple-myeloma-cells
#20
Charvi Nanavati, Donald E Mager
PURPOSE: To examine the combination of bortezomib and vorinostat in multiple myeloma cells (U266) and xenografts, and to assess the nature of their potential interactions with semi-mechanistic pharmacodynamic models and biomarkers. METHODS: U266 proliferation was examined for a range of bortezomib and vorinostat exposure times and concentrations (alone and in combination). A non-competitive interaction model was used with interaction parameters that reflect the nature of drug interactions after simultaneous and sequential exposures...
January 18, 2017: Pharmaceutical Research
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