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https://www.readbyqxmd.com/read/29348877/role-of-irf4-in-resistance-to-immunomodulatory-imid-compounds%C3%A2-in-waldenstr%C3%A3-m-s-macroglobulinemia
#1
Elisabeth Bertrand, Nathalie Jouy, Salomon Manier, Guillemette Fouquet, Stéphanie Guidez, Eileen Boyle, Stéphanie Noel, Cécile Tomowiak, Charles Herbaux, Susanna Schraen, Claude Preudhomme, Bruno Quesnel, Stéphanie Poulain, Xavier Leleu
Background: Immunomodulatory drugs, IMid compounds, are active in Waldenström's macroglobulinemia (WM), although in a lesser extent than multiple myeloma, where it was initially developed. We hypothesized WM tumour cells might develop mechanisms of resistance, and sought to identify and describe these mechanisms. Material and Method: MM and WM-derived cell lines, and Waldenström's CD19+ cells were treated using both lenalidomide and pomalidomide. Stable CRBN expressing cells were generated...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29330561/salvage-therapy-post-pomalidomide-based-regimen-in-relapsed-refractory-myeloma
#2
Guillemette Fouquet, Lionel Karlin, Margaret Macro, Denis Caillot, Murielle Roussel, Bertrand Arnulf, Brigitte Pegourie, Marie Odile Petillon, Claire Mathiot, Cyrille Hulin, Brigitte Kolb, Anne-Marie Stoppa, Sabine Brechiniac, Philippe Rodon, Mamoun Dib, Mourad Tiab, Valentine Richez, Carla Araujo, Marc Wetterwald, Laurent Garderet, Bruno Royer, Aurore Perrot, Lotfi Benboubker, Olivier Decaux, Martine Escoffre-Barbe, Jean Paul Fermand, Philippe Moreau, Hervé Avet-Loiseau, Michel Attal, Thierry Facon, Xavier Leleu
The combination of pomalidomide and low-dose dexamethasone (Pom-Dex) has proved effective and safe in patients with end-stage relapsed/refractory multiple myeloma (RRMM), otherwise characterized by a very poor outcome. MM remains an incurable disease with unavoidable relapses, and the outcome after pomalidomide is still dismal. However, some patients demonstrate prolonged survival even beyond pomalidomide therapy.We sought to analyze the treatment of RRMM patients following Pom-Dex therapy and the response and survival after this next treatment line...
January 12, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29296944/recent-trends-in-multiple-myeloma-incidence-and-survival-by-age-race-and-ethnicity-in-the-united-states
#3
Luciano J Costa, Ilene K Brill, James Omel, Kelly Godby, Shaji K Kumar, Elizabeth E Brown
Prior improvements in multiple myeloma (MM) survival were not fully observed in racial and ethnic minorities and older individuals. We hypothesized that improvements in MM management in recent years have reduced these disparities. We used the Surveillance, Epidemiology, and End Results registries to calculate the incidence and relative survival rates (RSRs) of MM in the United States for patients diagnosed from 1993 to 1997 (prethalidomide), 1998 to 2002 (introduction of thalidomide), 2003 to 2007 (bortezomib and lenalidomide), and 2008 to 2012 (upfront bortezomib and lenalidomide, early availability of carfilzomib and pomalidomide)...
January 10, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296884/changes-in-bone-marrow-innate-lymphoid-cell-subsets-in-monoclonal-gammopathy-target-for-imid-therapy
#4
Jithendra Kini Bailur, Sameet Mehta, Lin Zhang, Natalia Neparidze, Terri Parker, Noffar Bar, Tara Anderson, Mina L Xu, Kavita M Dhodapkar, Madhav V Dhodapkar
Altered number, subset composition, and function of bone marrow innate lymphoid cells are early events in monoclonal gammopathies.Pomalidomide therapy leads to reduction in Ikzf1 and Ikzf3 and enhanced human innate lymphoid cell function in vivo.
November 28, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296798/a-phase-2-study-of-panobinostat-with-lenalidomide-and-weekly-dexamethasone-in-myeloma
#5
Ajai Chari, Hearn J Cho, Amishi Dhadwal, Gillian Morgan, Lisa La, Katarzyna Zarychta, Donna Catamero, Erika Florendo, Nadege Stevens, Daniel Verina, Elaine Chan, Violetta Leshchenko, Alessandro Laganà, Deepak Perumal, Anna Huo-Chang Mei, Kaity Tung, Jami Fukui, Sundar Jagannath, Samir Parekh
Phase 3 studies combining histone deacetylase inhibitors with bortezomib were hampered by gastrointestinal (GI) intolerance, which was not observed when combined with immunomodulatory drugs. This study is a single-center phase 2 study of panobinostat with lenalidomide and dexamethasone (FRD). Twenty-seven relapsed multiple myeloma patients were enrolled. Twenty-two patients (81%) were lenalidomide refractory and 9 (33%), 14 (52%), and 7 (26%) were refractory to pomalidomide, bortezomib, and carfilzomib, respectively...
August 22, 2017: Blood Advances
https://www.readbyqxmd.com/read/29278014/healthcare-resource-utilization-among-patients-with-relapsed-multiple-myeloma-in-the-uk-france-and-italy
#6
Sebastian Gonzalez-McQuire, Kwee Yong, Henri Leleu, Francesco S Mennini, Alain Flinois, Carlotta Gazzola, Paul Schoen, Marco Campioni, Lucy DeCosta, Leah Fink
AIMS: To assess the real-world healthcare resource utilization (HRU) and costs associated with different treatment regimens used in the management of patients with relapsed multiple myeloma in the UK, France, and Italy. METHODS: Retrospective medical chart review of characteristics, time to progression, level of response, HRU during treatment, and adverse events (AEs). Data collection started on 1 June 2015 and was completed on 15 July 2015. In the 3 months before record abstraction, eligible patients had either disease progression after receiving one of their country's most commonly prescribed regimens or had received best supportive care and died...
December 26, 2017: Journal of Medical Economics
https://www.readbyqxmd.com/read/29249822/phase-i-ii-trial-of-the-oral-regimen-ixazomib-pomalidomide-and-dexamethasone-in-relapsed-refractory-multiple-myeloma
#7
A Krishnan, P Kapoor, J M Palmer, N-C Tsai, S Kumar, S Lonial, M Htut, C Karanes, N Nathwani, M Rosenzweig, F Sahebi, G Somlo, L Duarte, J F Sanchez, D Auclair, S J Forman, J 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 3 patients were enrolled to DL1, with no further dose limiting toxicity (DLT)...
December 18, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29228683/lenalidomide-overcomes-the-immunosuppression-of-regulatory-cd8-cd28-t-cells
#8
Brigitte Neuber, Jingying Dai, Wjahat A Waraich, Mohamed H S Awwad, Melanie Engelhardt, Michael Schmitt, Sergej Medenhoff, Mathias Witzens-Harig, Anthony D Ho, Hartmut Goldschmidt, Michael Hundemer
Although lenalidomide and pomalidomide are well-established treatment options in patients with multiple myeloma, their immune-modulating effects are not fully understood. While CD8+CD28- regulatory T-cells in patients with hematologic disorders display a known immune-escape mechanism, we show that lenalidomide can overcome the immunosuppressive impact of CD8+CD28- T-cells. We analyzed in vitro the antigen-specific T-cell responses of healthy donors and patients with multiple myeloma with or without the addition of autologous CD8+CD28- T-cells in the absence and presence of lenalidomide...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29222299/management-of-multiple-myeloma-in-the-relapsed-refractory-patient
#9
REVIEW
Pieter Sonneveld
The approach to the patient with relapsed or relapsed/refractory multiple myeloma requires a careful evaluation of the results of previous treatments, the toxicities associated with it, and an assessment of prognostic factors. The majority of patients will have received prior therapy with drug combinations, including a proteasome inhibitor and an immune-modulatory agent. It is the physician's task to choose the right moment for the start of therapy and decide with the patient which goals need to be achieved...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29212974/-ige-%C3%AE%C2%BA-type-multiple-myeloma-achieving-complete-response-with-novel-agents
#10
Tomomi Takei, Tadao Ishida, Masahiro Ikeda, Sumito Shingaki, Kanji Miyazaki, Yumiko Yoshiki, Yu Abe, Kiyoshi Okazuka, Seiko Iki, Nobuhiro Tsukada, Kenshi Suzuki
IgE multiple myeloma (MM) is a rare subtype of MM characterized by an aggressive and poor prognosis. Although novel agents have improved the prognosis of MM, there are few case reports of IgE MM treated with these agents. A 53-year-old male patient presented with pain in the right rib and was diagnosed with IgE-κ MM. He was treated with multidrug chemotherapy, including bortezomib and lenalidomide, and underwent autologous stem-cell transplantation (ASCT). Finally, he achieved a complete response after the initiation of pomalidomide...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/29192016/comparative-efficacy-of-daratumumab-monotherapy-and-pomalidomide-plus-low-dose-dexamethasone-in-the-treatment-of-multiple-myeloma-a-matching-adjusted-indirect-comparison
#11
Suzy Van Sanden, Tetsuro Ito, Joris Diels, Martin Vogel, Andrew Belch, Albert Oriol
BACKGROUND: Daratumumab (a human CD38-directed monoclonal antibody) and pomalidomide (an immunomodulatory drug) plus dexamethasone are both relatively new treatment options for patients with heavily pretreated multiple myeloma. A matching adjusted indirect comparison (MAIC) was used to compare absolute treatment effects of daratumumab versus pomalidomide + low-dose dexamethasone (LoDex; 40 mg) on overall survival (OS), while adjusting for differences between the trial populations...
November 30, 2017: Oncologist
https://www.readbyqxmd.com/read/29188449/current-and-new-therapeutic-strategies-for-relapsed-and-refractory-multiple-myeloma-an-update
#12
REVIEW
Inger S Nijhof, Niels W C J van de Donk, Sonja Zweegman, Henk M Lokhorst
Although survival of multiple myeloma patients has at least doubled during recent years, most patients eventually relapse, and treatment at this stage may be particularly complex. At the time of relapse, the use of alternative drugs to those given upfront is current practice. However, many new options are currently available for the treatment of relapsed multiple myeloma, including recently approved drugs, such as the second- and third-generation proteasome inhibitors carfilzomib and ixazomib, the immunomodulatory agent pomalidomide, the monoclonal antibodies daratumumab and elotuzumab and the histone deacetylase inhibitor panobinostat, but also new targeted agents are under active investigation (e...
November 29, 2017: Drugs
https://www.readbyqxmd.com/read/29184451/population-pharmacokinetics-of-pomalidomide-in-patients-with-relapsed-or-refractory-multiple-myeloma-with-various-degrees-of-impaired-renal-function
#13
Yan Li, Xiaomin Wang, Edward O'Mara, Meletios A Dimopoulos, Pieter Sonneveld, Katja C Weisel, Jeffrey Matous, David S Siegel, Jatin J Shah, Elisabeth Kueenburg, Lars Sternas, Chloe Cavanaugh, Mohamed Zaki, Maria Palmisano, Simon Zhou
Pomalidomide is an immunomodulatory drug for treatment of relapsed or refractory multiple myeloma (rrMM) in patients who often have comorbid renal conditions. To assess the impact of renal impairment on pomalidomide exposure, a population pharmacokinetics (PPK) model of pomalidomide in rrMM patients with various degrees of impaired renal function was developed. Intensive and sparse pomalidomide concentration data collected from two clinical studies in rrMM patients with normal renal function, moderately impaired renal function, severely impaired renal function not requiring dialysis, and with severely impaired renal function requiring dialysis were pooled over the dose range of 2 to 4 mg, to assess specifically the influence of the impaired renal function as a categorical variable and a continuous variable on pomalidomide clearance and plasma exposure...
2017: Clinical Pharmacology: Advances and Applications
https://www.readbyqxmd.com/read/29172760/adjusted-comparison-of-daratumumab-monotherapy-versus-real-world-historical-control-data-from-the-czech-republic-in-heavily-pretreated-and-highly-refractory-multiple-myeloma-patients
#14
Tomáš Jelínek, Vladimír Maisnar, Luděk Pour, Ivan Špička, Jiří Minařík, Evžen Gregora, Petr Kessler, Michal Sýkora, Hana Fraňková, Dagmar Adamová, Marek Wróbel, Peter Mikula, Jiří Jarkovský, Joris Diels, Xenia Gatopoulou, Šárka Veselá, Hervé Besson, Lucie Brožová, Tetsuro Ito, Roman Hájek
OBJECTIVES: We conducted an adjusted comparison of progression-free survival (PFS) and overall survival (OS) for daratumumab monotherapy versus standard of care, as observed in a real-world historical cohort of heavily pretreated multiple myeloma patients from Czech Republic. METHODS: Using longitudinal chart data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group, patient-level data from the RMG were pooled with pivotal daratumumab monotherapy studies (GEN501 and SIRIUS; 16 mg/kg)...
November 25, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/29164606/safety-and-efficacy-of-pomalidomide-dexamethasone-and-pegylated-liposomal-doxorubicin-for-patients-with-relapsed-or-refractory-multiple-myeloma
#15
Alexa Cohen, Tanya M Spektor, Laura Stampleman, Alberto Bessudo, Peter J Rosen, Leonard M Klein, Thomas Woliver, Marshall Flam, Shahrooz Eshaghian, Youram Nassir, Tina Maluso, Regina A Swift, Robert Vescio, James R Berenson
Immunomodulatory drugs including thalidomide, lenalidomide (LEN) and pomalidomide (POM), are effective for treating multiple myeloma (MM). POM has shown enhanced efficacy with dexamethasone (DEX). Pegylated liposomal doxorubicin (PLD) with bortezomib is US Food and Drug Administration-approved for treating MM. PLD with LEN or thalidomide has shown efficacy for MM patients. LEN with DEX, PLD and bortezomib achieves high response rates. We evaluated the combination of POM with DEX 40 mg and PLD 5 mg/m2 with the latter two drugs administered on days 1, 4, 8 and 11 on a 28-day cycle for the treatment of relapsed/refractory MM patients...
November 21, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/29130642/dual-inhibition-of-dnmts-and-ezh2-can-overcome-both-intrinsic-and-acquired-resistance-of-myeloma-cells-to-imids-in-a-cereblon-independent-manner
#16
Konstantinos Dimopoulos, Alexandra Søgaard Helbo, Helga Fibiger Munch-Petersen, Lene Sjö, Jesper Christensen, Lasse Sommer Kristensen, Fazila Asmar, Niels Emil Ulrich Hermansen, Casey O'Connel, Peter Gimsing, Gangning Liang, Kirsten Grønbaek
Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism of action. In an effort to comprehend the precise mechanisms behind the development of IMiD resistance and examine whether it is potentially reversible, we established lenalidomide-resistant (-LR) and pomalidomide-resistant (-PR) human myeloma cell lines from two IMiD-sensitive cell lines, OPM2 and NCI-H929, by continuous culture in the presence of lenalidomide or pomalidomide for 4-6 months, until acquirement of stable resistance...
November 11, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29110190/pomalidomide-a-review-in-relapsed-and-refractory-multiple-myeloma
#17
Sheridan M Hoy
Pomalidomide (Imnovid®; Pomalyst®), an analogue of thalidomide, is an immunomodulatory agent, with several mechanisms of action (both direct and indirect) thought to be involved in its anti-myeloma activity. Oral pomalidomide is available in several countries for use in combination with low-dose dexamethasone in adults with relapsed and refractory multiple myeloma. In multinational, phase II or III studies in patients with refractory, or relapsed and refractory multiple myeloma who had received ≥ 2 prior treatment regimens (including ≥ 2 cycles of both lenalidomide and bortezomib), pomalidomide plus low-dose dexamethasone was associated with prolonged progression-free survival (PFS) and overall survival and an improved overall response rate...
November 2017: Drugs
https://www.readbyqxmd.com/read/29093152/pomalidomide-in-patients-with-interstitial-lung-disease-due-to-systemic-sclerosis-a-phase-ii-multicenter-randomized-double-blind-placebo-controlled-parallel-group-study
#18
Vivien M Hsu, Christopher P Denton, Robyn T Domsic, Daniel E Furst, Maureen Rischmueller, Marina Stanislav, Virginia D Steen, Jörg H W Distler, Shimon Korish, Alyse Cooper, Suktae Choi, Peter H Schafer, Gerald Horan, Douglas R Hough
OBJECTIVE: To evaluate the safety and efficacy of pomalidomide (POM) on forced vital capacity (FVC), modified Rodnan skin score (mRSS), and gastrointestinal (GI) symptomatology over 52 weeks of treatment in patients with interstitial lung disease due to systemic sclerosis (SSc). METHODS: Twenty-three adult patients diagnosed with SSc were randomized 1:1 POM:placebo (PBO). RESULTS: Mean change at Week 52 from baseline in predicted FVC% -5.2 and -2...
November 1, 2017: Journal of Rheumatology
https://www.readbyqxmd.com/read/29076150/a-phase-1-clinical-trial-evaluating-marizomib-pomalidomide-and-low-dose-dexamethasone-in-relapsed-and-refractory-multiple-myeloma-npi-0052-107-final-study-results
#19
Andrew Spencer, Simon Harrison, Jeffrey Zonder, Ashraf Badros, Jacob Laubach, Krystal Bergin, Amit Khot, Todd Zimmerman, Dharminder Chauhan, Nancy Levin, Ann MacLaren, Steven D Reich, Mohit Trikha, Paul Richardson
Marizomib (MRZ) is an irreversible, pan-subunit proteasome inhibitor (PI) in clinical development for relapsed/refractory multiple myeloma (RRMM) and glioma. This study analysed MRZ, pomalidomide (POM) and low-dose dexamethasone (Lo-DEX) [PMD] in RRMM to evaluate safety and determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Intravenous MRZ (0·3-0·5 mg/m2 ) was administered over 2 h on days 1, 4, 8, 11; POM (3-4 mg) on days 1-21; and Lo-DEX (5 or 10 mg) on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22 and 23 of every 28-day cycle...
October 26, 2017: British Journal of Haematology
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
#20
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
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