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Multiple Myeloma, Bortezomib

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https://www.readbyqxmd.com/read/27913521/sequencing-of-nontransplant-treatments-in-multiple-myeloma-patients-with-active-disease
#1
Andrew J Yee, Noopur S Raje
The approval of several different classes of drugs in recent years has resulted in a dramatic expansion of treatment options for multiple myeloma patients, improving both survival and quality of life. Lenalidomide and bortezomib are now core components of treatment both at time of diagnosis and at relapse. Next-generation immunomodulatory drugs, like pomalidomide, and newer proteasome inhibitors like carfilzomib and ixazomib are available for use at relapse. Drugs with novel mechanisms of action such as the histone deacetylase inhibitor panobinostat and the monoclonal antibodies targeting SLAMF7 (elotuzumab) and CD38 (daratumumab) are significant steps forward...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913520/myeloma-management-of-the-newly-diagnosed-high-risk-patient
#2
Angela Dispenzieri
Although there have been many definitions for high-risk (HR) myeloma, most recent consensus for classifying risk in patients with newly diagnosed multiple myeloma (NMM) comes from the International Myeloma Working Group. This recently published revised International Staging System includes del(17p) or t(4;14) by fluorescence in situ hybridization, β-2 microglobulin, albumin, and lactate dehydrogenase. These elements should be captured in all NMM patients. The optimal treatments for HR myeloma have not been fully worked out; therefore, these patients should be considered for clinical trials...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27911437/the-role-of-the-proteasome-in-aml
#3
REVIEW
C M Csizmar, D-H Kim, Z Sachs
Acute myeloid leukemia (AML) is deadly hematologic malignancy. Despite a well-characterized genetic and molecular landscape, targeted therapies for AML have failed to significantly improve clinical outcomes. Over the past decade, proteasome inhibition has been demonstrated to be an effective therapeutic strategy in several hematologic malignancies. Proteasome inhibitors, such as bortezomib and carfilzomib, have become mainstays of treatment for multiple myeloma and mantle cell lymphoma. In light of this success, there has been a surge of literature exploring both the role of the proteasome and the effects of proteasome inhibition in AML...
December 2, 2016: Blood Cancer Journal
https://www.readbyqxmd.com/read/27910963/daratumumab-monoclonal-antibody-therapy-to-treat-multiple-myeloma
#4
C Xia, M Ribeiro, S Scott, S Lonial
Daratumumab (Darzalex[TM]) is a human monoclonal antibody (MAb) that targets CD38; a surface protein highly expressed across multiple myeloma (MM) cells. Preclinical studies have shown daratumumab induces MM cell death through several mechanisms, including complement-dependent cytotoxicity (CDC) antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), apoptosis upon secondary crosslinking and immunomodulatory effects via a decrease in immune suppressive cells. Daratumumab has a favorable toxicity profile and encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) and stem cell transplant have already failed...
October 2016: Drugs of Today
https://www.readbyqxmd.com/read/27909306/rpl5-on-1p22-1-is-recurrently-deleted-in-multiple-myeloma-and-its-expression-is-linked-to-bortezomib-response
#5
I J F Hofman, M Van Duin, E De Bruyne, L Fancello, G Mulligan, E Geerdens, E Garelli, C Mancini, H Lemmens, M Delforge, P Vandenberghe, I Wlodarska, A Aspesi, L Michaux, K Vanderkerken, P Sonneveld, K De Keersmaecker
Chromosomal region 1p22 is deleted in ⩾20% of multiple myeloma (MM) patients, suggesting the presence of an unidentified tumor suppressor. Using high-resolution genomic profiling, we delimit a 58 kb minimal deleted region (MDR) on 1p22.1 encompassing two genes: ectopic viral integration site 5 (EVI5) and ribosomal protein L5 (RPL5). Low mRNA expression of EVI5 and RPL5 was associated with worse survival in diagnostic cases. Patients with 1p22 deletion had lower mRNA expression of EVI5 and RPL5, however, 1p22 deletion status is a bad predictor of RPL5 expression in some cases, suggesting that other mechanisms downregulate RPL5 expression...
December 2, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27905203/efficacy-and-toxicity-of-the-combination-chemotherapy-of-thalidomide-alkylating-agent-and-steroid-for-relapsed-refractory-myeloma-patients-a-report-from-the-korean-multiple-myeloma-working-party-kmmwp-retrospective-study
#6
Jihyun Kwon, Chang-Ki Min, Kihyun Kim, Jae-Joon Han, Joon Ho Moon, Hye Jin Kang, Hyeon-Seok Eom, Min Kyoung Kim, Hyo Jung Kim, Dok Hyun Yoon, Jeong-Ok Lee, Won Sik Lee, Jae Hoon Lee, Je-Jung Lee, Yoon-Seok Choi, Sung Hyun Kim, Sung-Soo Yoon
We analyzed the treatment responses, toxicities, and survival outcomes of patients with relapsed or refractory multiple myeloma who received daily thalidomide, cyclophosphamide, and dexamethasone (CTD) or daily thalidomide, melphalan, and prednisolone (MTP) at 17 medical centers in Korea. Three-hundred and seventy-six patients were enrolled. The combined chemotherapy of thalidomide, corticosteroid, and an alkylating agent (TAS) was second-line chemotherapy in 142 (37.8%) patients, and third-line chemotherapy in 135 (35...
December 1, 2016: Cancer Medicine
https://www.readbyqxmd.com/read/27904737/a-clinical-update-on-the-role-of-carfilzomib-in-the-treatment-of-relapsed-or-refractory-multiple-myeloma
#7
REVIEW
B Franken, N W C J van de Donk, J C Cloos, S Zweegman, H M Lokhorst
Even though the prognosis of patients with multiple myeloma is continuing to improve, all patients eventually develop relapsed refractory disease. Several novel therapeutics have been developed in the last few years including the second-generation proteasome inhibitor carfilzomib which has been approved for patients with relapsed and refractory multiple myeloma in the United States since 2012. Recently data from several phase III studies have become available showing the promising efficacy of carfilzomib in combination with lenalidomide, which led to the renewed approval of carfilzomib in combination with lenalidomide and dexamethasone for relapsed myeloma in 2015...
December 2016: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/27903750/nuclear-export-of-ubiquitinated-proteins-determines-the-sensitivity-of-colorectal-cancer-to-proteasome-inhibitor
#8
Tingyu Wu, Wei Chen, Yongwang Zhong, Xiaodan Hou, Shengyun Fang, Chen-Ying Liu, Guanghui Wang, Tong Yu, Yu-Yang Huang, Xuesong Ouyang, Henry Q X Li, Long Cui, Yili Yang
Although proteasome inhibitors such as Bortezomib had significant therapeutic effects in multiple myeloma and mantel cell lymphoma, they exhibited minimal clinical activity as a mono-therapy for solid tumors, including colorectal cancer. We found in the present study that proteasome inhibition induced a remarkable nuclear exportation of ubiquitinated proteins. Inhibition of CRM1, the nuclear export carrier protein, hampered protein export and synergistically enhanced the cytotoxic action of Bortezomib on colon cancer cells containing wild type p53, which underwent G2/M cell cycle block and apoptosis...
November 30, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27900079/solitary-pleural-myeloma-diagnosed-by-semi-rigid-thoracoscopy-a-case-report-and-literature-review
#9
Jin-Sheng Ouyang, Yu-Ping Li, Peng Li, Min Ye, Jun-Ru Ye, Bei-Bei Wang, Ying Zhou, Cheng-Shui Chen
Multiple myeloma (MM) is characterized by abnormal proliferation of neoplastic plasma cells. Pleural effusion as an initial presentation of this disease is rare, as is true pleural myeloma. We herein present a case of solitary pleural myelomatous lesion in a 70-year-old male patient diagnosed by pleural biopsy via semi-rigid thoracoscopy followed by histopathological examination. Furthermore, a review of the related English literature identified 22 cases of pleural myeloma, only 3 of which were diagnosed by video-assisted thoracoscopy...
November 2016: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/27893836/prognostic-value-of-serum-free-light-chains-measurements-in-multiple-myeloma-patients
#10
José Luis García de Veas Silva, Carmen Bermudo Guitarte, Paloma Menéndez Valladares, Johanna Carolina Rojas Noboa, Krysta Kestler, Rafael Duro Millán
BACKGROUND: The outcome for patients with Multiple Myeloma (MM) is highly variable, therefore, the existence of robust and easy to determine prognostic markers is extremely important for an efficient management of these patients. Presently, there is a debate about the role of the serum free light chains (sFLC) in the prognosis of MM patients both at diagnosis and after treatment. The aim of this study is to evaluate in a cohort of newly diagnosed MM patients from the Southern area of Spain, the prognostic value of sFLC both at baseline and after treatment...
2016: PloS One
https://www.readbyqxmd.com/read/27893171/salvage-therapy-in-first-relapse-a-retrospective-study-in-a-large-patient-population-with-multiple-myeloma
#11
Massimo Offidani, Laura Corvatta, Sara Bringhen, Silvia Gentili, Rossella Troia, Laura Maracci, Alessandra Larocca, Pietro Leoni, Mario Boccadoro
OBJECTIVE: there is no strong evidence to guide therapeutic approach to multiple myeloma (MM) patients who experience first relapse. The treatment choice can be difficult since currently all patients are exposed to novel agents as thalidomide, bortezomib and lenalidomide. METHODS: in this retrospective analysis we evaluated the best therapeutic sequence, the role of re-treatment and the most beneficial cut-off of first remission in order to choose re-treatment, analyzing 476 patients relapsed after first-line therapy...
November 28, 2016: European Journal of Haematology
https://www.readbyqxmd.com/read/27890930/histone-deacetylase-inhibitors-interrupt-hsp90-rasgrp1-and-hsp90-craf-interactions-to-upregulate-bim-and-circumvent-drug-resistance-in-lymphoma-cells
#12
H Ding, K L Peterson, C Correia, B Koh, P A Schneider, G S Nowakowski, S H Kaufmann
Histone deacetylase (HDAC) inhibitors, which are approved for the treatment of cutaneous T cell lymphoma and multiple myeloma, are undergoing evaluation in other lymphoid neoplasms. How they kill susceptible cells is incompletely understood. Here we show that trichostatin A, romidepsin, and panobinostat induce apoptosis across a panel of malignant B cell lines, including lines that are intrinsically resistant to bortezomib, etoposide, cytarabine, and BH3 mimetics. Further analysis traces the pro-apoptotic effects of HDAC inhibitors to increased acetylation of the chaperone heat shock protein 90 (HSP90), causing release and degradation of the HSP90 client proteins RASGRP1 and CRAF, which in turn leads to downregulation of mitogen activated protein kinase pathway signaling and upregulation of the pro-apoptotic BCL2 family member BIM in vitro and in vivo...
November 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27890927/the-ap-1-transcription-factor-junb-is-essential-for-multiple-myeloma-cell-proliferation-and-drug-resistance-in-the-bone-marrow-microenvironment
#13
F Fan, M H Bashari, E Morelli, G Tonon, S Malvestiti, S Vallet, M Jarahian, A Seckinger, D Hose, L Bakiri, C Sun, Y Hu, C R Ball, H Glimm, M Sattler, H Goldschmidt, E F Wagner, P Tassone, D Jaeger, K Podar
Despite therapeutic advances, multiple myeloma (MM) remains an incurable disease, predominantly due to the development of drug resistance. The activator protein-1 (AP-1) transcription factor family has been implicated in a multitude of physiologic processes and tumorigenesis; however, its role in MM is largely unknown. Here we demonstrate specific and rapid induction of the AP-1 family member JunB in MM cells when co-cultured with bone marrow stromal cells. Supporting a functional key role of JunB in MM pathogenesis, knockdown of JUNB significantly inhibited in vitro MM cell proliferation and survival...
November 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27884726/deacetylase-inhibitors-as-a-novel-modality-in-the-treatment-of-multiple-myeloma
#14
REVIEW
Paul G Richardson, Philippe Moreau, Jacob P Laubach, Michelle E Maglio, Sagar Lonial, Jesus San-Miguel
Deacetylase enzymes remove acetyl groups from histone and nonhistone proteins. Dysregulation of deacetylase activity is a hallmark of malignancy, including multiple myeloma (MM). Deacetylase inhibitors (DACi) cause epigenetic modification and inhibition of the aggresome pathway, resulting in death of MM cells. Panobinostat, a pan-DACi, has shown significant clinical benefit and is the first DACi approved for the treatment of MM. It is approved for use in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or relapsed and refractory MM who have received ≥2 prior regimens including bortezomib and an immunomodulatory drug...
November 21, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/27882113/peripheral-neuropathy-outcomes-and-efficacy-of-subcutaneous-bortezomib-when-combined-with-thalidomide-and-dexamethasone-in-the-treatment-of-multiple-myeloma
#15
Hong Liu, Ruirong Xu, Hongming Huang
Due to the safety, convenience and efficacy of subcutaneous administration of bortezomib (scBor), it is becoming increasingly common to treat multiple myeloma (MM) using this treatment method. The current retrospective study suggested a lower incidence of peripheral neuropathy (PN) outcomes and superior efficacy following treatment with scBor combined with thalidomide and dexamethasone (VTD) in MM when compared with intravenous Bor (ivBor) treatment. The data of 81 patients from the Affiliated Hospital of Nantong University between September 2011 and February 2014 were analyzed, including 37 scBor and 44 ivBor patients administered a median (range) of 5...
November 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/27881873/induction-of-iron-excess-restricts-malignant-plasma-cells-expansion-and-potentiates-bortezomib-effect-in-models-of-multiple-myeloma
#16
J Bordini, S Galvan, M Ponzoni, M T S Bertilaccio, M Chesi, P L Bergsagel, C Camaschella, A Campanella
Leukemia accepted article preview online, 24 November 2016. doi:10.1038/leu.2016.346.
November 24, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27877018/more-frequent-igd-and-reduced-cd200-expression-in-chinese-patients-younger-than-50-years-old-with-multiple-myeloma-a-multicenter-analysis
#17
Jin Lu, Jing Lu, Wenming Chen, Jing Wang, Yuliang Huo, Jian Hou, Xiaojun Huang
We retrospectively analyzed the presenting features and survival of 194 newly diagnosed patients with multiple myeloma in the People's Republic of China. Compared with older patients, younger patients had a higher percentage of IgD isotype, lower percentage of International Staging System Stage 3 disease, higher albumin level, and lower frequency of high β2-microglobulin and CD200 expression. There was no difference in sex, Durie-Salmon stage, bone lesion degree, creatinine, lactate dehydrogenase, fluorescence in situ hybridization, and expression of other antigens...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27873175/mobilization-of-human-immature-hematopoietic-progenitors-through-combinatory-use-of-bortezomib-and-immunomodulatory-drugs
#18
Taro Tochigi, Takatoshi Aoki, Yoshikane Kikushige, Tomohiko Kamimura, Yoshikiyo Ito, Takahiro Shima, Takuji Yamauchi, Yasuo Mori, Goichi Yoshimoto, Kenjiro Kamezaki, Koji Kato, Katsuto Takenaka, Hiromi Iwasaki, Koichi Akashi, Toshihiro Miyamoto
Combination use of the proteasome inhibitor bortezomib and the immunomodulatory drugs lenalidomide or thalidomide has provided superior outcomes in multiple myeloma over their single use; however, these combinations can produce significant toxicities. Unexpectedly, we found a small but significant increase in the population of immature granulocytes and erythrocytes/megakaryocytes in peripheral blood in 16 of 22 patients (73%) treated with dexamethasone in combination with bortezomib and immunomodulatory drugs (triplet), but not in any of 25 patients treated with either bortezomib or immunomodulatory drugs with dexamethasone (doublet)...
November 21, 2016: International Journal of Hematology
https://www.readbyqxmd.com/read/27867671/retreatment-with-bendamustine-bortezomib-dexamethasone-in-a-patient-with-relapsed-refractory-multiple-myeloma
#19
Claudio Cerchione, Davide Nappi, Maria Di Perna, Irene Zacheo, Anna Emanuele Pareto, Marco Picardi, Lucio Catalano, Fabrizio Pane
The clinical management of relapsed/refractory multiple myeloma and the correct choice of the most suitable therapy in heavily pretreated and fragile patients are tough clinical issues for clinicians. In advanced phases of disease, the choice of available therapies becomes very poor, and the retreatment with previously adopted and effective therapy, although unpredictable, could be an effective option. In this report, we describe the clinical history of a patient, previously treated with 9 lines of therapy, refractory to bortezomib and IMIDs, for whom the retreatment with bendamustine resulted in a stable disease with good quality of life...
2016: Case Reports in Hematology
https://www.readbyqxmd.com/read/27864218/second-primary-malignancies-in-multiple-myeloma-an-overview-and-imwg-consensus
#20
REVIEW
P Musto, K C Anderson, M Attal, P G Richardson, A Badros, J Hou, R Comenzo, J Du, B G M Durie, J San Miguel, H Einsele, W M Chen, L Garderet, G Pietrantuono, J Hillengass, R A Kyle, P Moreau, J J Lahuerta, O Landgren, H Ludwig, A Larocca, A Mahindra, M Cavo, A Mazumder, P L McCarthy, A Nouel, S V Rajkumar, A Reiman, E R Serra, O Sezer, E Terpos, I Turesson, S Usmani, B M Weiss, A Palumbo
BACKGROUND: Therapeutic advancements following the introduction of autologous stem cell transplantation and 'novel' agents have significantly improved clinical outcomes for patients with multiple myeloma (MM). Increased life expectancy, however, has led to renewed concerns about the long-term risk of second primary malignancies (SPMs). This review outlines the most up-to-date knowledge of possible host-, disease-, and treatment-related risk factors for the development of SPMs in patients with MM, and provides practical recommendations to assist physicians...
November 17, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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