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https://www.readbyqxmd.com/read/29768064/a-look-at-treatment-strategies-for-relapsed-multiple-myeloma
#1
Giusy Cetani, Mario Boccadoro, Stefania Oliva
Multiple myeloma treatment considerably improved during the past decade, thanks to novel effective drugs, a better understanding of myeloma biology and clonal heterogeneity, and an improved management of toxicities. The choice of regimen at relapse is usually based on prior response, toxicities, age and comorbidities of relapsed patients. Areas covered: A review was performed of the most recent and effective therapeutic strategies for the relapsed myeloma setting, by documenting the latest clinical evidence from phase II and III clinical trials...
May 16, 2018: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29765255/distribution-of-pomalidomide-into-semen-of-healthy-male-subjects-after-multiple-doses
#2
Yan Li, Xiaomin Wang, Liangang Liu, Josephine Reyes, Maria Palmisano, Simon Zhou
Objective: To assess whether pomalidomide can distribute into human semen and its duration in human semen. Method: A phase 1, randomized, double-blind, placebo-controlled study (CC-4047-CP-006) was conducted to evaluate the safety, tolerability, and pharmacokinetics of pomalidomide (CC-4047) following multiple daily doses in healthy male subjects. Semen samples were collected on Day -1 and 4 hours after dosing on Day 4 to quantify the pomalidomide concentrations in ejaculate after multiple oral doses of pomalidomide...
2018: Clinical Pharmacology: Advances and Applications
https://www.readbyqxmd.com/read/29762875/in-vivo-assessment-of-the-effect-of-cyp1a2-inhibition-and-induction-on-pomalidomide-pharmacokinetics-in-healthy-subjects
#3
Yan Li, Liangang Liu, Xiaomin Wang, Chengyue Zhang, Josephine Reyes, Matthew Hoffmann, Maria Palmisano, Simon Zhou
Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open-label, single-dose studies...
May 15, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29760948/the-diagnosis-and-treatment-of-primary-vitreoretinal-lymphoma-a-review
#4
REVIEW
Jose S Pulido, Patrick B Johnston, Grzegorz S Nowakowski, Allessia Castellino, Harish Raja
Background: To describe the recent diagnostic and treatment options for the most predominant form of primary vitreoretinal lymphoma (PVRL), namely diffuse large B cell lymphoma. This is mainly based on the experience at the Mayo Clinic as well as a partial review of the literature. MYD88 L265P mutation is seen in about 80% of cases; therefore, a polymerase chain reaction for this mutation helps in making the diagnosis that has been notoriously difficult to make. Local therapy using intravitreal methotrexate and rituximab has been very helpful in the treatment of the local disease...
2018: International Journal of Retina and Vitreous
https://www.readbyqxmd.com/read/29748955/investigational-agents-in-immunotherapy-a-new-horizon-for-the-treatment-of-multiple-myeloma
#5
REVIEW
Cindy Varga, Jacob P Laubach, Kenneth C Anderson, Paul G Richardson
The treatment of multiple myeloma (MM) has gone through several major advances over the last 5 years with the introduction of next generation proteasome inhibitors (PI; carfilzomib, ixazomib) and immunomodulatory derivatives (IMiD; pomalidomide), with these new agents having a substantial impact on patient outcome. However, despite these advances, MM remains a highly resistant disease given its propensity for clonal heterogeneity and its complex interaction with the surrounding bone marrow microenvironment...
May 10, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29746728/an-open-label-phase-1-study-to-assess-the-effects-of-hepatic-impairment-on-pomalidomide-pharmacokinetics
#6
Yan Li, Xiaomin Wang, Liangang Liu, Chengyue Zhang, Diana Gomez, Josephine Reyes, Maria Palmisano, Simon Zhou
Pomalidomide is an immunomodulatory drug and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and United States to treat patients with relapsed/refractory multiple myeloma. Because pomalidomide is extensively metabolized prior to excretion, a total of 32 subjects (8 healthy subjects in group 1; 8 subjects with severe hepatic impairment in group 2; 8 subjects with moderate hepatic impairment in group 3; and 8 subjects with mild hepatic impairment in group 4) were enrolled in a multicenter, open-label, single-dose study to assess the impact of hepatic impairment on pomalidomide exposure...
May 10, 2018: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/29743398/-achievement-of-a-stringent-complete-response-with-low-dose-pomalidomide-monotherapy-in-a-multiple-myeloma-patient
#7
Toshihide Endo, Takashi Hamada, Shimon Otake, Masaru Nakagawa, Yshihito Uchino, Hiromichi Takahashi, Katsuhiro Miura, Noriyoshi Iriyama, Takashi Koike, Kazuya Kurihara, Hiroko Sato, Yoshihiro Hatta, Msamai Takei
An 80-year-old man presented to our hospital with a thoracic vertebrae compression fracture. He was diagnosed with IgG-λ myeloma (International Staging System stage II, Durie-Salmon stage IIIA). Since melphalan-prednisolone (MP) was not effective, we treated him with lenalidomide and low-dose dexamethasone (DEX) (Ld), achieving a partial response. As DEX provoked edema and psychiatric symptoms, the patient disagreed with its use, and pomalidomide (POM) monotherapy was initiated. Although the POM dosage was reduced to 1-2 mg/day due to somnolence, which was reported as an adverse event, stringent complete response (sCR) was achieved and sustained for 10 months following 11 cycles of low-dose POM monotherapy...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/29718735/expression-of-crbn-ikzf1-and-ikzf3-does-not-predict-lenalidomide-sensitivity-and-mutations-in-the-cereblon-pathway-are-infrequent-in-multiple-myeloma
#8
Konstantinos Dimopoulos, Helga Fibiger Munch-Petersen, Christian Winther Eskelund, Lene Dissing Sjö, Elisabeth Ralfkiaer, Peter Gimsing, Kirsten Grønbaek
The immunomodulatory drug thalidomide, and its analogs, lenalidomide, and pomalidomide (IMiDs), have become essential components of the standard treatment for multiple myeloma (MM), and have led to significant improvement of survival in patients with this devastating disease. Cereblon (CRBN), the direct target of IMiDs, has been proposed as a predictive biomarker of response to IMiDs. Using standard immunohistochemistry in formalin-fixed paraffin embedded (FFPE) bone marrow samples of 23 patients treated with a lenalidomide-containing regimen, we found that the malignant plasma cells of all the patients stained positive for CRBN, IKZF1, and IKZF3, regardless of sensitivity to IMiDs...
May 2, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29702148/immunomodulatory-effects-of-cd38-targeting-antibodies
#9
REVIEW
Niels W C J van de Donk
The fist in class CD38-targeting antibody, daratumumab, is currently approved as single agent and in combination with standards of care for the treatment of relapsed and refractory multiple myeloma. Based on the high activity and favorable toxicity profile of daratumumab, other CD38 antibodies, such as isatuximab, MOR202, and TAK-079, are being evaluated in MM and other malignancies. The CD38-targeting antibodies have classic Fc-dependent immune effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC)...
April 24, 2018: Immunology Letters
https://www.readbyqxmd.com/read/29660984/chemically-induced-degradation-of-anaplastic-lymphoma-kinase-alk
#10
Chelsea E Powell, Yang Gao, Li Tan, Katherine A Donovan, Radosław P Nowak, Amanda Loehr, Magda Bahcall, Eric S Fischer, Pasi A Janne, Rani E George, Nathanael S Gray
We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1)...
April 16, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29644009/pomalidomide-enhanced-gemcitabine-and-nab-paclitaxel-on-pancreatic-cancer-both-in-vitro-and-in-vivo
#11
Nobuhiro Saito, Yoshihiro Shirai, Tadashi Uwagawa, Takashi Horiuchi, Hiroshi Sugano, Koichiro Haruki, Hiroaki Shiba, Toya Ohashi, Katsuhiko Yanaga
Background: Chemotherapy with gemcitabine and nab-paclitaxel (gemcitabine/nab-paclitaxel) is recommended for unresectable pancreatic cancer. However, the therapeutic efficacy is attenuated by the antitumor agent-induced activation of nuclear factor-κB (NF-κB). Thalidomide inhibits NF-κB activation, therefore, we hypothesized that pomalidomide, a third-generation IMiD, would also inhibit NF-κB activation and enhance the antitumor effects of gemcitabine/nab-paclitaxel. Methods: In vitro , we assessed NF-κB activity and apoptosis in response to pomalidomide alone, gemcitabine/nab-paclitaxel, or combination of pomalidomide and gemcitabine/nab-paclitaxel in human pancreatic cancer cell lines (PANC-1 and MIA PaCa-2)...
March 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29618692/-transfusion-independence-achieved-with-pomalidomide-therapy-in-a-patient-with-primary-myelofibrosis
#12
Yoko Edahiro, Akihiko Gotoh, Tadaaki Inano, Miyuki Tsutsui, Yutaka Tsukune, Hajime Yasuda, Norio Komatsu
Primary myelofibrosis (PMF) is commonly associated with anemia. IMiD® immunomodulatory drugs including thalidomide and lenalidomide have been shown to be effective in improving anemia associated with PMF. However, because of adverse events, their use has been restricted. Herein we report the case of a 67-year-old male patient with transfusion-dependent PMF treated with the immunomodulatory drug pomalidomide in a clinical trial. Significant improvements in anemia and thrombocytopenia were observed with pomalidomide, and the patient recovered from transfusion dependence for 8 months...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/29618684/-successful-treatment-with-thalidomide-combined-therapy-in-an-amyloidosis-complicated-multiple-myeloma-patient-refractory-to-bortezomib-lenalidomide-and-pomalidomide
#13
Yuka Aoki, Toshiaki Hayashi, Hiroshi Ikeda, Tadao Ishida
A 77-year-old man suffering from back and arm pain was referred for anemia to the hospital by an orthopedic clinic. Serum examination of the patient revealed monoclonal IgA, and he consulted the Sapporo Medical University Hospital, where he was diagnosed with multiple myeloma complicated with AL amyloidosis. He was then enrolled for a randomized double-blind study aimed to compare between melphalan-prednisone (MP) and thalidomide-melphalan-prednisone (MPT) treatments, which revealed the patient to be in the MP arm...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/29581547/protein-targeting-chimeric-molecules-specific-for-bromodomain-and-extra-terminal-motif-family-proteins-are-active-against-pre-clinical-models-of-multiple-myeloma
#14
Xiaohui Zhang, Hans C Lee, Fazal Shirazi, Veerabhadran Baladandayuthapani, Heather Lin, Isere Kuiatse, Hua Wang, Richard J Jones, Zuzana Berkova, Ram Kumar Singh, Jing Lu, Yimin Qian, Kanak Raina, Kevin G Coleman, Craig M Crews, Bingzong Li, Huihan Wang, Yared Hailemichael, Sheeba K Thomas, Zhiqiang Wang, R Eric Davis, Robert Z Orlowski
Bromodomain and extraterminal (BET) domain containing protein (BRD)-4 modulates the expression of oncogenes such as c-myc, and is a promising therapeutic target in diverse cancer types. We performed pre-clinical studies in myeloma models with bi-functional protein-targeting chimeric molecules (PROTACs) which target BRD4 and other BET family members for ubiquitination and proteasomal degradation. PROTACs potently reduced the viability of myeloma cell lines in a time-dependent and concentration-dependent manner associated with G0 /G1 arrest, reduced levels of CDKs 4 and 6, increased p21 levels, and induction of apoptosis...
March 27, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29550629/steroid-refractory-chronic-graft-versus-host-disease-cost-effectiveness-analysis
#15
Fevzi F Yalniz, Mohammad H Murad, Stephanie J Lee, Steven Z Pavletic, Nandita Khera, Nilay D Shah, Shahrukh K Hashmi
Given the increasing incidence of chronic graft-versus-host disease (cGVHD) and its rapidly escalating costs due to many lines of drug treatments, we aimed to perform a meta-analysis to assess the comparative effectiveness of various treatment options. Using these results, we then conducted a cost-effectiveness analysis for the frequently utilized agents in steroid-refractory cGVHD. We searched for studies examining tacrolimus, sirolimus, rituximab, ruxolitinib, hydroxychloroquine, imatinib, bortezomib, ibrutinib, extracorporeal photopheresis, pomalidomide, and methotrexate...
March 14, 2018: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29515123/enumeration-functional-responses-and-cytotoxic-capacity-of-mait-cells-in-newly-diagnosed-and-relapsed-multiple-myeloma
#16
Nicholas A Gherardin, Liyen Loh, Lorenztino Admojo, Alexander J Davenport, Kelden Richardson, Amy Rogers, Phillip K Darcy, Misty R Jenkins, H Miles Prince, Simon J Harrison, Hang Quach, David P Fairlie, Katherine Kedzierska, James McCluskey, Adam P Uldrich, Paul J Neeson, David S Ritchie, Dale I Godfrey
Mucosal-associated invariant T (MAIT) cells are T cells that recognise vitamin-B derivative Ag presented by the MHC-related-protein 1 (MR1) antigen-presenting molecule. While MAIT cells are highly abundant in humans, their role in tumour immunity remains unknown. Here we have analysed the frequency and function of MAIT cells in multiple myeloma (MM) patients. We show that MAIT cell frequency in blood is reduced compared to healthy adult donors, but comparable to elderly healthy control donors. Furthermore, there was no evidence that MAIT cells accumulated at the disease site (bone marrow) of these patients...
March 7, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29508087/cardiovascular-complications-of-multiple-myeloma-treatment-evaluation-management-and-prevention
#17
REVIEW
Dae Hyun Lee, Michael G Fradley
PURPOSE OF REVIEW: Multiple myeloma treatment regimens consist of proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide), and steroids. In this paper, we will review the pathophysiology and associated cardiotoxicities of the different multiple myeloma therapeutic modalities and present methods to mitigate the development of cardiovascular complications. RECENT FINDINGS: Although proteasome inhibitors and immunomodulatory drugs have led to significant improvements in oncologic outcomes, there is increasing evidence of serious cardiovascular side effects which may be exacerbated in the setting of underlying cardiovascular risk factors or disease...
March 6, 2018: Current Treatment Options in Cardiovascular Medicine
https://www.readbyqxmd.com/read/29486638/evaluating-the-use-of-appropriate-anticoagulation-with-lenalidomide-and-pomalidomide-in-patients-with-multiple-myeloma
#18
Sarah M Anderson, Bradley Beck, Susan Sterud, Robin Lockhorst, Surachat Ngorsuraches
Background Lenalidomide and pomalidomide are two immunomodulatory medications with the potential to improve outcomes for patients with multiple myeloma; however, a black box warning for venous thromboembolism exists. Purpose The purpose of this study was to assess overall adherence to guideline recommendations for anticoagulation therapy with lenalidomide and pomalidomide in multiple myeloma patients. Methods This retrospective study at an ambulatory oncology clinic utilized chart reviews from the calendar years 2013-2016...
January 1, 2018: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/29479061/once-weekly-carfilzomib-pomalidomide-and-low-dose-dexamethasone-for-relapsed-refractory-myeloma-a-phase-i-ii-study
#19
Sara Bringhen, Roberto Mina, Anna Maria Cafro, Anna Marina Liberati, Stefano Spada, Angelo Belotti, Gianluca Gaidano, Francesca Patriarca, Rossella Troia, Renato Fanin, Lorenzo De Paoli, Giuseppe Rossi, Alessandra Lombardo, Paola Bertazzoni, Antonio Palumbo, Pieter Sonneveld, Mario Boccadoro
No abstract text is available yet for this article.
January 30, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29472721/phase-i-ii-trial-of-the-oral-regimen-ixazomib-pomalidomide-and-dexamethasone-in-relapsed-refractory-multiple-myeloma
#20
Amrita Krishnan, Prashant Kapoor, Joycelynne M Palmer, Ni-Chun Tsai, Shaji Kumar, Sagar Lonial, Myo Htut, Chatchada Karanes, Nitya Nathwani, Michael Rosenzweig, Firoozeh Sahebi, George Somlo, Lupe Duarte, James F Sanchez, Daniel Auclair, Stephen J Forman, Jesus 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 three patients were enrolled to DL1, with no further dose-limiting toxicity (DLT)...
February 23, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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