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Multiple Myeloma, Bortezomib

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...
January 5, 2018: Clinical Lymphoma, Myeloma & Leukemia
Nobuo Takemori, Goro Imai, Kazuo Hoshino, Akishi Ooi, Masaru Kojima
BACKGROUND: In general, dexamethasone is a required component drug in various combination chemotherapies for treating multiple myeloma, and its efficacy has been widely recognized. However, administration of dexamethasone is known to cause various adverse effects including hyperglycemia which requires insulin therapy. During the course of treatment, we developed a novel effective dexamethasone-free combination regimen and evaluated it for its effect in multiple myeloma. CASE PRESENTATION: We report a case of 68-year-old Japanese woman with refractory advanced Bence-Jones-λ type multiple myeloma associated with diabetes mellitus...
February 18, 2018: Journal of Medical Case Reports
Jie Ying, Miaomiao Zhang, Xiaoyan Qiu, Yu Lu
The ubiquitin-proteasome system (UPS) is an important system that regulates the balance of intracellular proteins, and it is involved in the regulation of multiple vital biological processes. The approval of bortezomib for relapsed and refractory multiple myeloma has proven that agents targeting the UPS have the potential to be effective treatment strategies for diseases. Among of all of the components of the UPS, cullin-RING ligases (CRLs) are the focus of research. CRLs are the largest family of ubiquitin E3 ligases and they play a critical role in substrate binding...
February 15, 2018: Cancer Chemotherapy and Pharmacology
Maria-Victoria Mateos, Hartmut Goldschmidt, Jesus San-Miguel, Joseph Mikhael, Lucy DeCosta, Lifen Zhou, Mihaela Obreja, Julie Blaedel, Zsolt Szabo, Xavier Leleu
We performed analyses of the randomized phase 3 ASPIRE and ENDEAVOR trials to investigate the efficacy of carfilzomib among subgroups of relapsed or refractory multiple myeloma patients who had early or late disease relapse following initiation of the immediately prior therapy. In ASPIRE and ENDEAVOR, patients had received 1 to 3 prior lines of therapy. Patients in ASPIRE received carfilzomib, lenalidomide, and dexamethasone (KRd) or lenalidomide and dexamethasone (Rd), and patients in ENDEAVOR received carfilzomib and dexamethasone (Kd) or bortezomib and dexamethasone (Vd)...
February 15, 2018: Hematological Oncology
Li Yang, Jing Chen, Xiaoyan Han, Enfan Zhang, Xi Huang, Xing Guo, Qingxiao Chen, Wenjun Wu, Gaofeng Zheng, Donghua He, Yi Zhao, Yang Yang, Jingsong He, Zhen Cai
Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma (MM). While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 (Pirh2) in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM...
February 13, 2018: Protein & Cell
Lu Gao, Bo Li, Guang Yang, Peng Liu, Xiucai Lan, Shuaikang Chang, Yi Tao, Zhijian Xu, Bingqian Xie, Xi Sun, Yingcong Wang, Liangning Hu, Dandan Yu, Yongsheng Xie, Wenxuan Bu, Xiaosong Wu, Weiliang Zhu, Jumei Shi
Interaction of multiple myeloma (MM) cells with the bone marrow (BM) microenvironment promotes the proliferation, survival and chemoresistance of MM. The mTOR pathway plays a key role in these undesirable BM microenvironment-mediated events. We synthesized a novel alkaloid compound, DCZ0358, that effectively inhibits mTOR signaling via dual mTORC1/2 inhibition and exhibits potent anti-MM activity in cultured and primary MM cells, as well as a MM xenograft model but has little effect on normal cells. Importantly, we show that this compound can block the BM stromal cell-mediated activation of mTOR/Akt signaling and antagonizes the protective effect of the BM microenvironment...
February 8, 2018: Cancer Letters
Yingying Wang, Yong Tang, Haifang Hang, Mingming Wang, Yuyang Pang, Yehua Yu, Yingli Wu, Qi Zhu
The acquired resistance to bortezomib represents a major obstacle for multiple myeloma (MM) treatment. Studies revealed that the treatment with cyclic adenosine monophosphate (cAMP) may be a promising strategy for MM therapy. Therefore, the present study aimed to explore the mechanism of action of cAMP in MM cells. Our results showed that 8-CPT-cAMP and bortezomib synergistically induced growth inhibition and apoptosis in MM bortezomib-resistant cell lines and primary MM cells, in which protein kinase A (PKA) activation was involved...
2018: American Journal of Cancer Research
Shosaku Nomura, Tomoki Ito, Hideaki Yoshimura, Masaaki Hotta, Takahisa Nakanishi, Shinya Fujita, Aya Nakaya, Atsushi Satake, Kazuyoshi Ishii
Background: Thrombosis is one of the complications in the clinical course of multiple myeloma (MM). Vascular endothelial cells and/or the hemostatic-coagulatory system are thought to play an important role in thrombosis of MM. In addition to melphalan-prednisone (Mel-P) therapy, several new therapeutic drugs such as lenalidomide or bortezomib have been developed and show effectiveness against MM. However, these new drugs also have risk of therapy-related thrombosis. Methods: We assessed 103 MM patients and 30 healthy controls, using enzyme-linked immunosorbent assays to evaluate five biomarkers: platelet-derived microparticles (PDMP), plasminogen activator inhibitor-1 (PAI-1), high mobility group box protein-1 (HMGB1), endothelial protein C receptor (EPCR), and soluble vascular cell adhesion molecule-1 (sVCAM-1)...
2018: Journal of Blood Medicine
Henry Chan, Madeline Phillips, Manjula Maganti, Sophia Farooki, Giovanni Piza Rodriguez, Esther Masih-Khan, Christine Chen, Anca Prica, Donna Reece, Rodger Tiedemann, Suzanne Trudel, Vishal Kukreti
BACKGROUND: Translocation t(4;14) has traditionally been classified as a high-risk cytogenetic feature in patients with multiple myeloma with shortened progression-free (PFS) and overall survival (OS) despite initial response to treatment. Recent data have shown an improved long-term survival in these patients treated with novel agents, such as bortezomib. PATIENTS AND METHODS: We conducted a retrospective study on our patients with t(4;14) multiple myeloma treated with bortezomib-based induction between July 1, 2006 and June 30, 2014 to assess the real-world outcomes of these patients in a tertiary center...
January 5, 2018: Clinical Lymphoma, Myeloma & Leukemia
Akira Mima, Dai Nagahara, Kosuke Tansho
BACKGROUND: Light chain deposition disease (LCDD) is a monoclonal immunoglobulin deposition disease (MIDD) that is characterized by the deposition of monoclonal light chains in multiple organs, including the kidney. It is a rare disorder caused by an underlying monoclonal plasma cell dyscrasia. LCDD with renal involvement causes proteinuria, which sometimes can lead to nephrotic syndrome. The monoclonal light chains are mostly in the κ form. Treatment of LCDD is the same as that for multiple myeloma (MM); however, some conventional anticancer drugs show substantial toxicity and therefore cannot be administered to older patients or those with renal impairment...
February 2, 2018: Clinical Nephrology
Angela Isabel Pereira Eugênio, Veruska Lia Fook-Alves, Mariana Bleker de Oliveira, Rodrigo Carlini Fernando, Daniela B Zanatta, Bryan Eric Strauss, Maria Regina Regis Silva, Marimélia Aparecida Porcionatto, Gisele Wally Braga Colleoni
HSP70 connects multiple signaling pathways that work synergistically to protect tumor cells from death by proteotoxic stress and represents a possible target to establish a new approach for multiple myeloma treatment. Therefore, bioluminescent cell lines RPMI8226-LUC-PURO and U266-LUC-PURO were treated with HSP70 (VER155008) and/or proteasome (bortezomib) inhibitors and immunodeficient mice were used for subcutaneous xenograft models to evaluate tumor growth reduction and tumor growth inhibition after treatment...
December 29, 2017: Oncotarget
Dan T Vogl, David Dingli, Robert Frank Cornell, Carol Ann Huff, Sundar Jagannath, Divaya Bhutani, Jeffrey Zonder, Rachid Baz, Ajay Nooka, Joshua Richter, Craig Cole, Ravi Vij, Andrzej Jakubowiak, Rafat Abonour, Gary Schiller, Terri L Parker, Luciano J Costa, David Kaminetzky, James E Hoffman, Andrew J Yee, Ajai Chari, David Siegel, Rafael Fonseca, Scott Van Wier, Gregory Ahmann, Ilsel Lopez, Michael Kauffman, Sharon Shacham, Jean-Richard Saint-Martin, Carla D Picklesimer, Cassandra Choe-Juliak, A Keith Stewart
Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease)...
January 30, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Ja Min Byun, Dong-Yeop Shin, Junshik Hong, Inho Kim, Hyun Kyung Kim, Dong Soon Lee, Youngil Koh, Sung-Soo Yoon
For risk-adaptive therapeutic approaches in multiple myeloma (MM) treatment, we analyzed treatment outcome according to in situ hybridization (FISH) profiles to investigate the prognostic and predictive values of structural variations in a large series of Asian population. A total of 565 newly diagnosed patients with multiple myeloma between January 2005 and June 2015 were evaluated. FISH results showed del(17p13) in 8.8% (29/331), del(13q14) in 35.5% (184/519), t(14;16) in 2.5% (8/326), t(4;14) in 27.9% (109/390), IgH rearrangement in 47...
January 29, 2018: Cancer Medicine
Yayoi Matsumura-Kimoto, Junya Kuroda, Hitomi Kaneko, Yuri Kamitsuji, Shin-Ichi Fuchida, Aya Nakaya, Hirohiko Shibayama, Nobuhiko Uoshima, Isao Yokota, Hitoji Uchiyama, Hideo Yagi, Satoru Kosugi, Toshimitsu Matsui, Jun Ishikawa, Mitsuhiro Matsuda, Kensuke Ohta, Masato Iida, Hirokazu Tanaka, Masayuki Kobayashi, Katsuya Wada, Chihiro Shimazaki, Shosaku Nomura, Kazunori Imada, Masayuki Hino, Itaru Matsumura, Yuzuru Kanakura, Akifumi Takaori-Kondo
Determinants of the efficacy and safety of pomalidomide (POM) monotherapy or POM plus dexamethasone (DEX) (POM/DEX) for relapsed and refractory multiple myeloma (RRMM) were examined retrospectively in a real-world clinical practice setting in Japan. The subjects were 108 patients registered with the Kansai Myeloma Forum, who were treated with either POM or POM/DEX. Of these, 79 (73%), 73 (68%), and 58 (54%) were resistant to bortezomib (BTZ), lenalidomide (LEN), and both BTZ and LEN, respectively. The median overall survival (OS) was not reached...
January 29, 2018: International Journal of Hematology
Andrew C Tiu, Vivian Arguello-Guerra, Gabor Varadi
Introduction: Multiple myeloma is caused by abnormal proliferation of plasma cells that affects more commonly African Americans. It classically presents with hypercalcemia, renal failure, anemia, and lytic bone lesions. The aim of this article is to present an unusual case of a 63-year-old African-American female with multiple myeloma who presented with worsening right-sided eye swelling for the past 3 weeks and to briefly review ophthalmologic manifestations of multiple myeloma. Case description: Our patient's presentation was associated with a throbbing frontal headache, nasal congestion, malaise, and weight loss...
2018: SAGE Open Medical Case Reports
Hua Wang, Veerabhadran Baladandayuthapani, Zhiqiang Wang, Heather Lin, Zuzana Berkova, Richard E Davis, Lin Yang, Robert Z Orlowski
Proteasome inhibitors are an important part of our chemotherapeutic armamentarium against multiple myeloma, but the vast majority of patients eventually develop drug-resistant disease through incompletely understood mechanisms. Comparison of gene expression profiles (GEPs) of bortezomib-resistant (BR) myeloma cell lines with their drug-naïve counterparts revealed decreased expression of truncated Protein tyrosine phosphatase receptor-type O (PTPROt) in BR cells. Over-expression of wild-type PTPROt in drug-naïve and BR cells reduced myeloma cell proliferation, induced apoptosis, and sensitized cells to bortezomib and to alkylating agents...
December 26, 2017: Oncotarget
Kyriaki Tzogani, Elisabeth Penninga, Marie Louise Schougaard Christiansen, Doris Hovgaard, Sinan B Sarac, Jorge Camarero Jimenez, Isabel Garcia, Marta Lafuente, Arantxa Sancho-López, Tomas Salmonson, Christian Gisselbrecht, Francesco Pignatti
On May 20, 2016, a conditional marketing authorization valid through the European Union (EU) was issued for daratumumab as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) and who had demonstrated disease progression on the last therapy. The review of daratumumab was conducted under the EMA's accelerated assessment program for drugs that are of major interest for public health, especially from the point of view of therapeutic innovation...
January 25, 2018: Oncologist
H M Mo, Q Y Wu, D Y Han, R Liu, X Ma, P Zhou, K L Xu
Objective: To investigate the effects of proteasome beta 5 subunit (PSMB5) on proliferation and bortezomib (BTZ) chemo-sensitivity of multiple myeloma (MM) and its related molecular mechanisms. Methods: We used two MM cell lines, RPMI 8226 and BTZ drug-resistant cell line RPMI 8226/BTZ100 (hereinafter referred to as BTZ100) , as the research object. PSMB5 was overexpressed or knocked down in two myeloma cell lines via lentivirus transfection. CCK8 assay was used to detect the impact of PSMB5 on cell viability and bortezomib sensitivity in human myeloma cells; Using flow cytometry to test the effects of PSMB5 on apoptosis rate of human myeloma cells under the treatment of bortezomib; Apoptosis-related gene expression of Bax, Bcl-2, p-Akt and cleaved caspase-3 were detected by Western blot...
December 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Sikander Ailawadhi, Ryan D Frank, Mayank Sharma, Richa Menghani, M'hamed Temkit, Shumail Paulus, Nandita Khera, Shahrukh Hashmi, Pooja Advani, Abhisek Swaika, Aneel Paulus, Nabeel Aslam, Taimur Sher, Vivek Roy, Gerardo Colon-Otero, Asher Chanan-Khan
BACKGROUND: Outcomes have improved significantly in multiple myeloma (MM), but racial disparities in health care access and survival exist. A comprehensive analysis exploring MM care and racial disparities is warranted. METHODS: Patients with MM from 1991 to 2010 in the Surveillance, Epidemiology, and End Results-Medicare database were evaluated for racial trends in clinical myeloma-defining events (MDEs), the receipt of treatment (drugs and stem cell transplantation; [SCT]), the cost of care, and overall survival (OS)...
January 23, 2018: Cancer
Maximilian Merz, Anna Jauch, Thomas Hielscher, Tilmann Bochtler, Stefan Olaf Schönland, Anja Seckinger, Dirk Hose, Uta Bertsch, Kai Neben, Marc Steffen Raab, Jens Hillengass, Hans Salwender, Igor Wolfgang Blau, Hans-Walter Lindemann, Ingo G H Schmidt-Wolf, Christof Scheid, Mathias Haenel, Katja C Weisel, Hartmut Goldschmidt
We investigated subclonal cytogenetic aberrations (CA) detected by interphase fluorescence in situ hybridization (iFISH) in patients with newly diagnosed multiple myeloma (MM) enrolled in the Haemato Oncology Foundation for Adults in the Netherlands (HOVON)-65/German-Speaking MM Group (GMMG)-HD4 phase 3 trial. Patients were either treated with 3 cycles of vincristine, Adriamycin, and dexamethasone or bortezomib, Adriamycin, and dexamethasone and then thalidomide or bortezomib maintenance after tandem autologous transplantation...
January 9, 2018: Blood Advances
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