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Pomalidomide

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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
#1
Konstantinos Dimopoulos, Alexandra Søgaard Helbo, Helga Fibiger Munch-Petersen, Lene Sjö, Jesper Christensen, Lasse Sommer Kristensen, Fazila Asmar, Emil 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- (-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
#2
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
#3
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
#4
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/m(2) ) 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
#5
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
https://www.readbyqxmd.com/read/29022836/-real-world-australian-experience-of-pomalidomide-for-relapsed-and-refractory-myeloma
#6
Ashleigh Scott, Nicholas Weber, Campbell Tiley, Kerry Taylor, John Taper, Simon Harrison, Kah-Lok Chan, Richard Stark, Cindy Lee, Kirk Morris, P Joy Ho, Anthony Dodds, Sundra Ramanathan, Raj Ramakrishna, Anne-Marie Watson, Bradley Auguston, Fiona Kwok, Hang Quach, Pauline Warburton, Philip Rowlings, Peter Mollee
No abstract text is available yet for this article.
October 12, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28978850/recent-topics-in-imids-and-cereblon
#7
Takumi Ito, Hiroshi Handa
Immunomodulatory drugs (IMiDs) are a new class of anticancer compounds that are derived from thalidomide. Lenalidomide and pomalidomide are well-known IMiDs, and they have already been approved by FDA for the treatment of several diseases, including multiple myeloma. Cereblon (CRBN) is a common primary target for IMiDs. It works as a substrate receptor of CRL4. Accumulating evidence has shown that the substrate specificity of CRL4(CRBN) is altered by ligands such as IMiDs. Recently, novel CRBN-binding compounds have been developed and are called "cereblon modulators"...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28977957/meta-analysis-of-the-efficacy-of-treatments-for-newly-diagnosed-and-relapsed-refractory-multiple-myeloma-with-del-17p
#8
Jinghua Liu, Hui Yang, Xiaochan Liang, Yuxin Wang, Jian Hou, Yanqin Liu, Jigang Wang, Fan Zhou
We analyzed the treatment of newly diagnosed and relapsed/refractory multiple myeloma (NDMM/RRMM) patients with del(17p). Thirteen prospective studies that evaluated 3,187 MM patients, including 685with del(17p), were included in our meta-analysis. The incidence of del(17p) in NDMM and RRMM patients was similar (13% vs. 14%, respectively, P = 0.64, I(2) = 94%). The overall response rate (ORR) to new agents was 40.5% and 67.1%, respectively, in RRMM patients with or without del(17p) (P = 0.1, I(2) = 63.9%). NDMM patients with del(17p) treated with PAD (bortezomib, adriamycin, and dexamethasone) induction therapy followed by bortezomib maintenance therapy had higher progression-free survival (PFS) (25...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28977921/docking-of-cdk1-with-antibiotic-drugs-revealed-novel-therapeutic-value-in-breast-ductal-cancer-in-situ
#9
Zhong-Hai Ding, Jia Qi, An-Quan Shang, Yu-Jie Zhang, Jun Wei, Li-Qing Hu, Wei-Wei Wang, Man Yang
The aim of our research is to identify potential genes associated with Ductal carcinoma in situ (DCIS) through microarrays. The microarray dataset GS54665 were downloaded from the GEO(Gene Expression Omnibus) database. Dysregulated genes were screened and their associations with DCIS was analyzed by comprehensive bioinformatics tools. A total of 649 differential expression genes were identified between normal and DCIS samples, including 224 up-regulated genes and 425 down-regulated genes. Biological process annotation and pathway enrichment analysis identified several DCIS-related signaling pathways...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28967482/cost-effectiveness-of-pomalidomide-carfilzomib-and-daratumumab-for-the-treatment-of-patients-with-heavily-pretreated-relapsed-refractory-multiple-myeloma-in-the-united-states
#10
Christopher G Pelligra, Kejal Parikh, Shien Guo, Conor Chandler, Jorge Mouro, Safiya Abouzaid, Sikander Ailawadhi
PURPOSE: Pomalidomide plus low-dose dexamethasone (POM-d), daratumumab monotherapy (DARA), and carfilzomib monotherapy (CAR) have been approved for use in the treatment of patients with heavily pretreated relapsed-refractory multiple myeloma (RRMM) in the US, based on findings from the MM-002, SIRIUS, and PX-171-003-A1 studies, respectively. The objective of this study was to assess the cost-effectiveness of POM-d, DARA, and CAR in this patient population from a US payer's perspective...
September 26, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28948001/emerging-drugs-and-combinations-to-treat-multiple-myeloma
#11
REVIEW
Alessandra Larocca, Roberto Mina, Francesca Gay, Sara Bringhen, Mario Boccadoro
In the past few years, multiple targeted therapies and immunotherapies including second generation immunomodulatory drugs (pomalidomide) and proteasome inhibitors (carfilzomib, ixazomib), monoclonal antibodies and checkpoint inhibitors were approved for the treatment of myeloma or entered advanced phases of clinical testing. These agents showed significant activity in advanced myeloma and increased the available treatment strategies. Pomalidomide is well-tolerated and effective in patients with relapsed/refractory multiple myeloma who have exhausted any possible treatment with lenalidomide and bortezomib...
September 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28892086/allogeneic-stem-cell-transplantation-and-subsequent-treatments-as-a-comprehensive-strategy-for-long-term-survival-of-multiple-myeloma-patients
#12
V Montefusco, A Mussetti, F Rezzonico, F Maura, M Pennisi, C de Philippis, M Capecchi, P Corradini
We evaluated 71 patients treated with allogeneic hematopoietic cell transplantation (allo-HCT) for multiple myeloma (MM). Forty-three patients (61%) received allo-HCT after the first line of therapy. Fifty-eight patients (82%) had chemosensitive disease at the time of allo-HCT. A HLA-matched related or unrelated donor was available for 68 patients (96%). Non-myeloablative or reduced-intensity conditioning regimen and peripheral blood hematopoietic cells as a graft source were used in most patients. The cumulative incidence of grade II-IV acute GVHD at day +100 and chronic GVHD at 5 years was 13% (95% CI 7-23%) and 35% (95% CI 24-46), respectively...
September 11, 2017: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/28883264/treatment-algorithms-for-multiple-myeloma-in-japan
#13
Shuji Ozaki
Recent progress in the development of novel therapeutic agents has remarkably improved the treatment outcome for multiple myeloma (MM). Proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib; immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide; the histone deacetylase (HDAC) inhibitor panobinostat; and the monoclonal antibody, elotuzumab, have all been approved in Japan, although only bortezomib and lenalidomide have been approved for initial therapy. Accordingly, the Japanese Society of Hematology has released updated treatment guidelines for MM...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28881567/restoration-of-immune-surface-molecules-in-kaposi-sarcoma-associated-herpes-virus-infected-cells-by-lenalidomide-and-pomalidomide
#14
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...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28874903/pomalidomide-desensitization-in-a-patient-hypersensitive-to-immunomodulating-agents
#15
J T Seki, N Sakurai, W Lam, D E Reece
Despite progressive treatments with tandem stem-cell transplantation, patients with incurable myeloma eventually succumb to relapsed or refractory disease if left untreated. Promising agents such as proteasome inhibitors and immunomodulating imide drugs (imids), including the newer-generation agent pomalidomide, in combination with lower-dose dexamethasone, have been shown to be effective and to significantly improve and prolong survival in pretreated patients. Although the incidence of pomalidomide hypersensitivity reaction (hsr) in this class of drugs is not as well known, we have documented cutaneous toxicity (grade 3 by the Common Terminology Criteria for Adverse Events, version 4) in 2 separate cases (not yet published)...
August 2017: Current Oncology
https://www.readbyqxmd.com/read/28863804/investigation-of-a-gene-signature-to-predict-response-to-immunomodulatory-derivatives-for-patients-with-multiple-myeloma-an-exploratory-retrospective-study-using-microarray-datasets-from-prospective-clinical-trials
#16
Manisha Bhutani, Qing Zhang, Reed Friend, Peter M Voorhees, Lawrence J Druhan, Bart Barlogie, Pieter Sonneveld, Gareth J Morgan, James T Symanowski, Belinda R Avalos, Edward A Copelan, Saad Z Usmani
BACKGROUND: Immunomodulatory derivatives (IMiDs), along with proteasome inhibitors, are key components of treatment regimens for multiple myeloma. Nonetheless, outcomes vary among treated individuals. Drug-specific gene-expression profile (GEP) signatures that aid the prediction of favourable and unfavourable outcomes can provide patients with the most effective therapy for their individual disease. We aimed to develop and validate a gene expression signature to suggest which patients would benefit most from IMiD-based therapies...
September 2017: Lancet Haematology
https://www.readbyqxmd.com/read/28860711/pomalidomide-in-the-treatment-of-multiple-myeloma-design-development-and-place-in-therapy
#17
REVIEW
Rafael Ríos-Tamayo, Agustín Martín-García, Carolina Alarcón-Payer, Dolores Sánchez-Rodríguez, Ana María Del Valle Díaz de la Guardia, Carlos Gustavo García Collado, Alberto Jiménez Morales, Manuel Jurado Chacón, José Cabeza Barrera
Multiple myeloma is a very heterogeneous disease with variable survival. Despite recent progress and the widespread use of new agents, patients with relapsed and refractory disease have a poor outcome. Immunomodulatory drugs play a key role in both the front-line and the relapsed/refractory setting. The combination of pomalidomide (POM) and dexamethasone is safe and effective in relapsed and refractory patients, even in those with high-risk cytogenetic features. Furthermore, it can be used in most patients without the need to adjust according to the degree of renal failure...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28860655/pomalidomide-dexamethasone-in-refractory-multiple-myeloma-long-term-follow-up-of-a-multi-cohort-phase-ii-clinical-trial
#18
S Ailawadhi, J R Mikhael, B R LaPlant, K M Laumann, S Kumar, V Roy, D Dingli, P L Bergsagel, F K Buadi, S V Rajkumar, R Fonseca, M A Gertz, P Kapoor, T Sher, S R Hayman, A K Stewart, A Dispenzieri, R A Kyle, W I Gonsalves, C B Reeder, Y Lin, R S Go, N Leung, T Kourelis, J A Lust, S J Russell, A A Chanan-Khan, M Q Lacy
Despite therapeutic advances, multiple myeloma remains incurable, with limited options for patients with refractory disease. We conducted a large, multi-cohort clinical trial testing various doses and treatment schedules of pomalidomide and dexamethasone (Pom/dex) in patients with refractory multiple myeloma. Overall, 345 patients were enrolled to six cohorts based on number and type of prior lines of therapy, pomalidomide dose and schedule. Median prior lines of therapy were three with near universal prior exposure to proteasome inhibitors and/or immunomodulatory drugs...
September 1, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28860344/the-kinesin-spindle-protein-inhibitor-filanesib-enhances-the-activity-of-pomalidomide-and-dexamethasone-in-multiple-myeloma
#19
Susana Hernández-García, Laura San-Segundo, Lorena González-Méndez, Luis A Corchete, Irena Misiewicz-Krzeminska, Montserrat Martín-Sánchez, Ana-Alicia López-Iglesias, Esperanza-Macarena Algarín, Pedro Mogollón, Andrea Díaz-Tejedor, Teresa Paíno, Brian Tunquist, María-Victoria Mateos, Norma C Gutiérrez, Elena Díaz-Rodriguez, Mercedes Garayoa, Enrique M Ocio
Kinesin spindle protein inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (ARRY-520), an inhibitor if this proteins, has demonstrated activity in heavily pretreated multiple myeloma patients. The aim of this work was to investigate the activity of filanesib in combination with pomalidomide plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect.The ability of filanesib to enhance the activity of pomalidomide plus dexamethasone was studied in several in vitro and in vivo models...
August 31, 2017: Haematologica
https://www.readbyqxmd.com/read/28844714/up-regulation-of-olr1-expression-by-tbc1d3-through-activation-of-tnf%C3%AE-nf-%C3%AE%C2%BAb-pathway-promotes-the-migration-of-human-breast-cancer-cells
#20
Bei Wang, Huzi Zhao, Lei Zhao, Yongchen Zhang, Qing Wan, Yong Shen, Xiaodong Bu, Meiling Wan, Chuanlu Shen
Metastatic spread of cancer cells is the most life-threatening aspect of breast cancer and involves multiple steps including cell migration. We recently found that the TBC1D3 oncogene promotes the migration of breast cancer cells, and its interaction with CaM enhances the effects of TBC1D3. However, little is known regarding the mechanism by which TBC1D3 induces the migration of cancer cells. Here, we demonstrated that TBC1D3 stimulated the expression of oxidized low density lipoprotein receptor 1 (OLR1), a stimulator of cell migration, in breast cancer cells at the transcriptional level...
November 1, 2017: Cancer Letters
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