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https://www.readbyqxmd.com/read/28620163/natural-history-of-relapsed-myeloma-refractory-to-immunomodulatory-drugs-and-proteasome-inhibitors-a-multicenter-imwg-study
#1
S K Kumar, M A Dimopoulos, E Kastritis, E Terpos, H Nahi, H Goldschmidt, J Hillengass, X Leleu, M Beksac, M Alsina, A Oriol, M Cavo, E M Ocio, M V Mateos, E K O'Donnell, R Vij, H M Lokhorst, N W C J van de Donk, C Min, T Mark, I Turesson, M Hansson, H Ludwig, S Jagannath, M Delforge, C Kyriakou, P Hari, U Mellqvist, S Z Usmani, D Dytfeld, A Z Badros, P Moreau, K Kim, P R Otero, J H Lee, C Shustik, D Waller, W J Chng, S Ozaki, J-J Lee, J de la Rubia, H S Eom, L Rosinol, J J Lahuerta, A Sureda, J S Kim, B G M Durie
Introduction of new myeloma therapies offers new options for patients refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). In this multicenter study, patients with relapsed multiple myeloma, who have received at least three prior lines of therapy, are refractory to both an IMiD (lenalidomide or pomalidomide) and a PI (bortezomib or carfilzomib), and have been exposed to an alkylating agent were identified. The time patients met the above criteria was defined as time zero (T0). Five hundred and forty-three patients diagnosed between 2006 and 2014 were enrolled in this study...
May 12, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28601492/new-agents-in-multiple-myeloma-an%C3%A2-examination-of-safety-profiles
#2
REVIEW
Sara Bringhen, Edwin De Wit, Meletios-Athanassios Dimopoulos
Numerous treatments are available for relapsed and/or refractory multiple myeloma (MM), with safety profiles varying across drug classes and across agents within the same class. Thus, it is important to understand the toxicities of each antimyeloma agent when making treatment decisions. Neutropenia is commonly associated with lenalidomide and pomalidomide, and may be common with histone deacetylase (HDAC) inhibitors, but is relatively unusual with thalidomide, bortezomib, and carfilzomib. Infection was common in trials of lenalidomide and pomalidomide, and upper respiratory tract infection and pneumonia have been seen with carfilzomib...
May 10, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28591700/restoration-of-immune-surface-molecules-in-kaposi-sarcoma-associated-herpesvirus-infected-cells-by-lenalidomide-and-pomalidomide
#3
David A Davis, Suraj Mishra, Holda A Anagho, Ashley I Aisabor, Prabha Shrestha, Victoria Wang, Yuki Takamatsu, Kenji Maeda, Hiroaki Mitsuya, Jerome B Zeldis, Robert Yarchoan
Kaposi sarcoma-associated herpesvirus (KSHV) is the cause of several tumors, including Kaposi sarcoma and primary effusion lymphoma (PEL). Most viruses have evolved means of escaping immune recognition. KSHV downregulates MHC-I expression during lytic infection, and expression of ICAM-1 and B7-2 (CD86) during latent infection, allowing evasion of T cell and natural killer immunity respectively. These effects are largely mediated by two KSHV-encoded proteins, K3 and K5. We show here that lenalidomide (Len) and pomalidomide (Pom) prevent down-regulation of MHC-I during lytic activation, and restore ICAM-1 and B7-2 surface expression in latently infected PEL cells...
May 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28583668/-pomalidomide-for-multiple-myeloma
#4
Aurore Dougé, Richard Lemal, Carine Chaleteix
Pomalidomide is a second-generation immunomodulatory drug (IMID). Its efficiency overtakes its predecessors' (thalidomide, lenalidomide), with less toxicity. It is indicated in the treatment of refractory or relapsed multiple myeloma, associated to dexamethasone. It is available in France since 2013, following the results of different studies.
June 2, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/28581522/blockade-of-deubiquitylating-enzyme-rpn11-triggers-apoptosis-in-multiple-myeloma-cells-and-overcomes-bortezomib-resistance
#5
Y Song, S Li, A Ray, D S Das, J Qi, M K Samur, Y-T Tai, N Munshi, R D Carrasco, D Chauhan, K C Anderson
Proteasome inhibition is an effective therapy for multiple myeloma (MM) patients; however, the emergence of drug resistance is common. Novel therapeutic strategies to overcome proteasome inhibitor resistance are needed. In this study, we examined whether targeting deubiquitylating (DUB) enzymes upstream of 20S proteasome overcomes proteasome inhibitor resistance. Gene expression analysis, immunohistochemical studies of MM patient bone marrow, reverse transcription-PCR and protein analysis show that Rpn11/POH1, a DUB enzyme upstream of 20S proteasome, is more highly expressed in patient MM cells than in normal plasma cells...
June 5, 2017: Oncogene
https://www.readbyqxmd.com/read/28530236/psilac-mass-spectrometry-reveals-zfp91-as-imid-dependent-substrate-of-the-crl4-crbn-ubiquitin-ligase
#6
Jian An, Charles M Ponthier, Ragna Sack, Jan Seebacher, Michael B Stadler, Katherine A Donovan, Eric S Fischer
Thalidomide and its derivatives lenalidomide and pomalidomide (IMiDs) are effective treatments of haematologic malignancies. It was shown that IMiDs impart gain-of-function properties to the CUL4-RBX1-DDB1-CRBN (CRL4(CRBN)) ubiquitin ligase that enable binding, ubiquitination and degradation of key therapeutic targets such as IKZF1, IKZF3 and CSNK1A1. While these substrates have been implicated as efficacy targets in multiple myeloma (MM) and 5q deletion associated myelodysplastic syndrome (del(5q)-MDS), other targets likely exist...
May 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/28529311/spotlight-on-pomalidomide-could-less-be-more
#7
T J Zander, S Aebi, T Pabst, C Renner, C Driessen
Leukemia accepted article preview online, 22 May 2017. doi:10.1038/leu.2017.156.
May 22, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28504846/adverse-event-management-in-patients-with-relapsed-and-refractory-multiple-myeloma-taking-pomalidomide-plus-low-dose-dexamethasone-a-pooled-analysis
#8
Philippe Moreau, Meletios A Dimopoulos, Paul G Richardson, David S Siegel, Michele Cavo, Paolo Corradini, Katja Weisel, Michel Delforge, Peter O'Gorman, Kevin Song, Christine Chen, Nizar Bahlis, Albert Oriol, Markus Hansson, Martin Kaiser, Pekka Anttila, Reinier Raymakers, Cristina Joao, Gordon Cook, Lars Sternas, Tsvetan Biyukov, Ana Slaughter, Kevin Hong, Jennifer Herring, Xin Yu, Mohamed Zaki, Jesus San-Miguel
OBJECTIVES: Heavily pretreated patients with relapsed and refractory multiple myeloma are susceptible to treatment-related adverse events (AEs). Managing AEs is important to ensure patients continue therapy long enough to receive the best clinical benefit. Data from the MM-002, MM-003, and MM-010 trials were pooled to further characterize the safety profile of pomalidomide plus low-dose dexamethasone and AE management. METHODS: This analysis included 1088 patients who received ≥ 2 prior therapies, including lenalidomide and bortezomib, and progressed ≤ 60 days of last therapy...
May 15, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28504554/how-is-patient-care-for-multiple-myeloma-advancing
#9
REVIEW
Sonja Genadieva Stavric, Francesca Bonello, Sara Bringhen, Mario Boccadoro, Alessandra Larocca
Treatment of multiple myeloma has undergone profound changes in the past years thanks to the increased understanding of the biology of the disease and the new treatment options. New drugs and effective approaches are currently available for the treatment of multiple myeloma, including immunomodulatory agents, proteasome inhibitors and autologous stem cell transplantation. Areas covered: We have described the recent updated criteria to start treatment in multiple myeloma and summarized clinical data from major studies including most recent agents...
June 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28479592/a-novel-agent-sl-401-induces-anti-myeloma-activity-by-targeting-plasmacytoid-dendritic-cells-osteoclastogenesis-and-cancer-stem-like-cells
#10
A Ray, D S Das, Y Song, V Macri, P Richardson, C L Brooks, D Chauhan, K C Anderson
Novel therapies for multiple myeloma (MM) can target mechanism(s) in the host-MM bone marrow (BM) microenvironment mediating MM progression and chemoresistance. Our studies showed increased numbers of tumor-promoting, immunosuppressive, and drug-resistant plasmacytoid dendritic cells (pDCs) in the MM BM microenvironment. pDC-MM cell interactions upregulate interleukin-3 (IL-3), which stimulates both pDC survival and MM cell growth. Since IL-3R is highly expressed on pDCs in the MM BM milieu, we here targeted pDCs using a novel IL-3R-targeted therapeutic SL-401...
May 8, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28474745/daratumumab-monotherapy-compared-with-historical-control-data-in-heavily-pretreated-and-highly-refractory-patients-with-multiple-myeloma-an-adjusted-treatment-comparison
#11
Saad Z Usmani, Joris Diels, Tetsuro Ito, Maneesha Mehra, Imran Khan, Annette Lam
Daratumumab is a human CD38-directed monoclonal antibody approved in the United States as monotherapy for patients with multiple myeloma (MM) who have received ≥3 prior lines of therapy (LOTs), including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double refractory to a PI and an IMiD, and in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone for patients with MM who have received ≥1 prior LOT. This study compared the efficacy of daratumumab monotherapy versus historical controls through adjusted treatment comparison...
May 5, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28465517/a-randomized-study-of-pomalidomide-vs-placebo-in-persons-with-myeloproliferative-neoplasm-associated-myelofibrosis-and-rbc-transfusion-dependence
#12
A Tefferi, H K Al-Ali, G Barosi, T Devos, H Gisslinger, Q Jiang, J-J Kiladjian, R Mesa, F Passamonti, M F McMullin, V Ribrag, G Schiller, A M Vannucchi, D Zhou, D Reiser, J Zhong, R P Gale
No abstract text is available yet for this article.
May 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28461396/pembrolizumab-pomalidomide-and-low-dose-dexamethasone-for-relapsed-refractory-multiple-myeloma
#13
Ashraf Badros, Elizabeth Hyjek, Ning Ma, Alexander Lesokhin, Ahmet Dogan, Aaron P Rapoport, Mehmet Kocoglu, Emily Lederer, Sunita Philip, Todd Milliron, Cameron Dell, Olga Goloubeva, Zeba Singh
Programmed death 1 (PD-1) receptor and its ligand (PD-L1) facilitate immune evasion in multiple myeloma (MM). We hypothesized that pembrolizumab, PD-1-antibody, can enhance anti-myeloma cellular immunity generated by pomalidomide leading to improved clinical responses. In this single-center, phase II study, 48 patients with relapsed/refractory MM (RRMM) received 28-days cycles of pembrolizumab, 200 mg intravenously every 2 weeks, pomalidomide 4 mg daily for 21 days and dexamethasone 40 mg weekly. Patients had a median of 3 (range: 2-5) lines of therapy, median age 64 (range: 35-83) years and had received both immune modulatory agent and proteasome inhibitor; (35 [73%] of 48) were refractory to both; (31 [70%]) had received an autologous transplant and (30 [62%]) had high-risk cytogenetics...
May 1, 2017: Blood
https://www.readbyqxmd.com/read/28452243/evaluation-of-us-2016-0115161-a1-isoindoline-compounds-and-methods-of-their-use
#14
Rok Frlan, Stanislav Gobec
Immunomodulatory drugs (IMIDs®) are small orally available molecules that modulate the immune system and other biological targets through multiple mechanisms of action and have been successfully used in the treatment of myelodysplastic syndrome and multiple myeloma. However, recent studies of their complex mechanism of action revealed their potential in autoimmune diseases and solid tumors, which intensified scientific interest in these compounds. Areas covered: This patent application claims new IMIDs for the treatment of cancer and disorders associated with angiogenesis and inflammation...
June 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28434255/daratumumab-for-the-treatment-of-multiple-myeloma
#15
Cyrille Touzeau, Philippe Moreau
Proteasome inhibitors and immunomodulatory drugs have contributed to the dramatic improvement in survival for patients with myeloma over the past decades. However, the disease typically relapses and new classes of drugs are needed. In 2015, two monoclonal antibodies were approved for the treatment of patients with relapsed multiple myeloma, and immunotherapy has rapidly become indispensable in the management of myeloma patients. Areas covered: Here, the authors discuss the published data regarding the mechanism of action, safety and clinical efficacy of the CD38-targeted monoclonal antibody daratumumab for the treatment of patients with multiple myeloma...
July 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28425720/a-cereblon-modulator-cc-220-with-improved-degradation-of-ikaros-and-aiolos
#16
Mary E Matyskiela, Weihong Zhang, Hon-Wah Man, George Muller, Godrej Khambatta, Frans Baculi, Matthew Hickman, Laurie LeBrun, Barbra Pagarigan, Gilles Carmel, Chin-Chun Lu, Gang Lu, Mariko Riley, Yoshitaka Satoh, Peter Schafer, Thomas O Daniel, James Carmichael, Brian E Cathers, Philip P Chamberlain
The drugs lenalidomide and pomalidomide bind to the protein cereblon, directing the CRL4-CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation. Here we describe CC-220 (compound 6), a cereblon modulator in clinical development for systemic lupus erythematosis and relapsed/refractory multiple myeloma. Compound 6 binds cereblon with a higher affinity than lenalidomide or pomalidomide. Consistent with this, the cellular degradation of Ikaros and Aiolos is more potent and the extent of substrate depletion is greater...
April 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28409228/diagnosis-and-treatment-of-multiple-myeloma-in-germany-analysis-of-a-nationwide-multi-institutional-survey
#17
Maximilian Merz, Lenka Kellermann, Wolfram Poenisch, Hans-Joachim Tischler, Joern Kohnke, Wolfgang Knauf, Hartmut Goldschmidt
A nationwide, multi-institutional survey was performed in 2011 and 2015 to analyze routine practice for myeloma patients outside clinical trials in Germany. We contacted university hospitals, community hospitals, and office-based hematologists in order to enter clinical data from newly diagnosed and relapsed patients into an online platform. Complete datasets were available for 478 (2011) and 515 (2015) patients. While median age at diagnosis increased from 70 to 72 years, patients had fewer concomitant diseases (2011 61%; 2015 51%) and presented with equal performance status (ECOG 0-1, 2011 66%; 2015 68%)...
April 13, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28396778/a-case-of-efficacy-of-bendamustine-in-heavily-pretreated-multiple-myeloma-refractory-to-pomalidomide
#18
Claudio Cerchione, Davide Nappi, Maria Di Perna, Irene Zacheo, Ilaria Migliaccio, Dalila Salvatore, Marco Picardi, Fabrizio Pane, Lucio Catalano
In this report, we would like to highlight the efficacy of bendamustine in a heavily pretreated patient, also refractory to pomalidomide. It is conceivable that different therapy combinations in heavily treated Multiple myeloma (MM) have to be explored, without "a priori" exclusion of ancient drugs, even after failure of the ultimate pharmacological options.
April 2017: Clinical Case Reports
https://www.readbyqxmd.com/read/28347676/treating-multiple-myeloma-patients-with-oral-therapies
#19
REVIEW
Shaji K Kumar, Ravi Vij, Stephen J Noga, Deborah Berg, Lonnie Brent, Lawrence Dollar, Ajai Chari
Recent advances have highlighted the importance of long-term, continuous treatment in multiple myeloma (MM) to improve survival. However, treatment burden continues to negatively impact the real-world duration of MM therapy, and strategies to limit the adverse impact of treatment on patient quality of life are therefore particularly important. Oral MM therapies include the immunomodulatory drugs lenalidomide, thalidomide, and pomalidomide; the alkylating agents melphalan and cyclophosphamide; the histone deacetylase inhibitor panobinostat; the corticosteroids prednisone and dexamethasone; and the proteasome inhibitor ixazomib...
May 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28325256/how-have-evolutions-in-strategies-for-the-treatment-of-relapsed-refractory-multiple-myeloma-translated-into-improved-outcomes-for-patients
#20
REVIEW
Pieter Sonneveld, Edwin De Wit, Philippe Moreau
Although multiple myeloma (MM) remains incurable, the introduction of novel agents has improved clinical outcomes dramatically over the past 15 years. Response rates have risen from ∼30% with single agents to up to 90% with combination therapies. The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, and the proteasome inhibitor bortezomib, form the foundations for treatment of relapsed and/or refractory MM (RRMM). Newer agents, such as the IMiD pomalidomide, the histone deacetylase inhibitor panobinostat and the proteasome inhibitors carfilzomib and ixazomib, as well as the monoclonal antibodies daratumumab and elotuzumab, have further improved overall response rates in these patients...
April 2017: Critical Reviews in Oncology/hematology
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