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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
#1
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
https://www.readbyqxmd.com/read/28320958/p97-vcp-promotes-degradation-of-crbn-substrate-glutamine-synthetase-and-neosubstrates
#2
Thang Van Nguyen, Jing Li, Chin-Chun Jean Lu, Jennifer L Mamrosh, Gang Lu, Brian E Cathers, Raymond J Deshaies
Glutamine synthetase (GS) plays an essential role in metabolism by catalyzing the synthesis of glutamine from glutamate and ammonia. Our recent study showed that CRBN, a direct protein target for the teratogenic and antitumor activities of immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide, recognizes an acetyl degron of GS, resulting in ubiquitylation and degradation of GS in response to glutamine. Here, we report that valosin-containing protein (VCP)/p97 promotes the degradation of ubiquitylated GS, resulting in its accumulation in cells with compromised p97 function...
March 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28288323/anti-angiogenic-and-anti-multiple-myeloma-effects-of-oprozomib-opz-alone-and-in-combination-with-pomalidomide-pom-and-or-dexamethasone-dex
#3
REVIEW
Eric Sanchez, Mingjie Li, Cathy S Wang, George Tang, Abigail Gillespie, Haiming Chen, James R Berenson
Oprozomib (OPZ or ONYX 0912) is an irreversible, orally administered proteasome inhibitor (PI) and an analog of carfilzomib. We set out to determine the anti-angiogenic effect of OPZ using the choriollantoic membrane/feather bud (CAM/FB) model and its anti-MM effects using MM xenograft models (LAGκ-1A, LAGλ-1). OPZ significantly reduced blood vessel formation, endothelial gene and protein expression using the CAM/FB assay. In vivo, we determined the anti-MM effects of OPZ, dexamethasone (Dex) and pomalidomide (Pom) and showed that the combinations of two drugs (OPZ+Dex or OPZ+Pom) showed marked anti-MM effects when compared to monotherapy...
March 6, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28286633/successful-intrathecal-chemotherapy-combined-with-radiotherapy-followed-by-pomalidomide-and-low-dose-dexamethasone-maintenance-therapy-for-a-primary-plasma-cell-leukemia-patient
#4
Yusuke Yamashita, Shinobu Tamura, Takehiro Oiwa, Hiroshi Kobata, Kodai Kuriyama, Toshiki Mushino, Shogo Murata, Hiroki Hosoi, Akinori Nishikawa, Nobuyoshi Hanaoka, Takashi Sonoki
Primary plasma cell leukemia (PPCL) is a rare aggressive variant of plasma cell disorder and frequently presents with extramedullary disease. Central nervous system (CNS) involvement with PPCL has an extremely poor prognosis. We describe a 46-year-old man with PPCL treated with a combination of lenalidomide, bortezomib, and dexamethasone as induction therapy following upfront allogeneic stem cell transplantation (allo-SCT). Despite achieving a very good partial response, the patient suffered from an isolated CNS relapse 12 months after allo-SCT...
February 23, 2017: Hematology Reports
https://www.readbyqxmd.com/read/28270494/blockade-of-deubiquitylating-enzyme-usp1-inhibits-dna-repair-and-triggers-apoptosis-in-multiple-myeloma-cells
#5
Deepika Sharma Das, Abhishek Das, Arghya Ray, Yan Song, Mehmet K Samur, Nikhil C Munshi, Dharminder Chauhan, Kenneth C Anderson
PURPOSE: The ubiquitin proteasome pathway is a validated therapeutic target in multiple myeloma (MM). Deubiquitylating enzyme USP1 participates in DNA damage response and cellular differentiation pathways. To date, the role of USP1 in MM biology is not defined. In the present study, we investigated the functional significance of USP1 in MM using genetic and biochemical approaches. EXPERIMENTAL DESIGN: To investigate the role of USP1 in myeloma, we utilized USP1 inhibitor SJB3-019A (SJB) for studies in myeloma cell lines and patient MM cells...
March 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28264055/enhancement-of-pomalidomide-anti-tumor-response-with-acy-241-a-selective-hdac6-inhibitor
#6
Brian J North, Ingrid Almeciga-Pinto, David Tamang, Min Yang, Simon S Jones, Steven N Quayle
Thalidomide-based Immunomodulatory Drugs (IMiDs®), including lenalidomide and pomalidomide, are effective therapeutics for multiple myeloma. These agents have been approved with, or are under clinical development with, other targeted therapies including proteasome inhibitors, αCD38 monoclonal antibodies, as well as histone deacetylase (HDAC) inhibitors for combination therapy. HDAC inhibitors broadly targeting Class I and IIb HDACs have shown potent preclinical efficacy but have frequently demonstrated an undesirable safety profile in combination therapy approaches in clinical studies...
2017: PloS One
https://www.readbyqxmd.com/read/28249894/targeting-cd38-suppresses-induction-and-function-of-t-regulatory-cells-to-mitigate-immunosuppression-in-multiple-myeloma
#7
Xiaoyan Feng, Li Zhang, Chirag Acharya, Gang An, Kenneth Wen, Luqui Qiu, Nikhil C Munshi, Yu-Tzu Tai, Kenneth C Anderson
PURPOSE: We study CD38 levels in immunosuppressive CD4+CD25highFoxp3+ Tregs and further define immune modulating effects of a therapeutic CD38 monoclonal antibody (mAb) Isatuximab (Isa)/SAR650984 in multiple myeloma (MM). EXPERIMENTAL DESIGN: We evaluated percentages of CD38-expressing subsets in Tregs from normal donors and MM patients. PBMCs were then treated with Isa with or without Lenalidomide (Len) or Pomalidomide (Pom) to identify their impact on percentage and immunosuppressive activity of Tregs on CD4+CD25- T cells (Tcons)...
March 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28211054/real-world-use-of-pomalidomide-and-dexamethasone-in-double-refractory-multiple-myeloma-suggests-benefit-in-renal-impairment-and-adverse-genetics-a-multi-centre-uk-experience
#8
Nicola Maciocia, Andrew Melville, Simon Cheesman, Faye Sharpley, Karthik Ramasamy, Matthew Streetly, Matthew Jenner, Reuben Benjamin, Steve Schey, Paul Maciocia, Rakesh Popat, Shirley D'sa, Ali Rismani, Aviva Cerner, Kwee Yong, Neil Rabin
Myeloma patients who become refractory to immunomodulatory agents (IMiDs) and bortezomib have poor survival, with limited therapeutic options. Pomalidomide has shown improved survival and good tolerability in this patient cohort in clinical trials, but real world data are scarce. We retrospectively analysed all patients treated with pomalidomide at five UK centres between 2013 and 2016. Of 85 patients identified, 70 had sufficient information for response assessments. Median age was 66 years [40-89], 96·5% were refractory to IMiDs, 72·9% were refractory to both an IMiD and bortezomib and 92·9% were refractory to their last treatment...
March 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28205024/immunomodulatory-drugs-in-multiple-myeloma-mechanisms-of-action-and-clinical-experience
#9
REVIEW
Sarah A Holstein, Philip L McCarthy
Over the last two decades, the outcomes for patients with multiple myeloma, a plasma cell malignancy, have dramatically improved. The development of the immunomodulatory drugs (IMiDs), which include thalidomide, lenalidomide, and pomalidomide, has contributed significantly to these improved outcomes. While thalidomide is now less commonly prescribed, lenalidomide is widely used in the treatment of newly diagnosed transplant-eligible and transplant-ineligible patients, in the maintenance setting post-transplant and in the relapsed/refractory setting, while pomalidomide is currently utilized in the relapsed/refractory setting...
February 16, 2017: Drugs
https://www.readbyqxmd.com/read/28203342/optimizing-current-and-emerging-therapies-in-multiple-myeloma-a-guide-for-the-hematologist
#10
REVIEW
Shahzad Raza, Rachael A Safyan, Evan Rosenbaum, Alex S Bowman, Suzanne Lentzsch
Multiple myeloma (MM) is the second most common hematologic malignancy. The diagnosis of MM requires ⩾10% clonal plasma cells in the bone marrow or biopsy-proven plasmacytoma, plus evidence of end-organ damage (hypercalcemia, renal failure, anemia, and lytic bone lesions). The definition of MM has recently been expanded to include a ⩾60% clonal plasma cell burden in the bone marrow, serum involved/uninvolved light chain ratio of ⩾100, or more than one focal lesion on magnetic resonance imaging ⩾5 mm in the absence of end-organ damage...
February 2017: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/28201976/immunomodulatory-drugs-imids-in-multiple-myeloma
#11
Shahzad Raza, Rachael A Safyan, Suzanne Lentzsch
Multiple myeloma (MM) is a plasma cell neoplasm that is incurable with conventional therapy. However, the treatment of MM has dramatically changed since the emergence of immunomodulatory drugs and proteasome inhibitors. The improvements in survival are linked to a deeper understanding of the molecular mechanisms of the disease. Thalidomide, although highly active in MM, is associated with considerable toxicity, particularly in older patients. Immunomodulatory drugs (IMiDs) are structural and functional analogues of thalidomide that represent a promising new class of immunomodulators for treatment of a variety of inflammatory, autoimmune, and neoplastic diseases...
February 13, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28198064/real-life-practices-for-preventing-venous-thromboembolism-in-multiple-myeloma-patients-a-cohort-study-from-the-french-health-insurance-database
#12
Aurore Palmaro, Marie-Eve Rougé-Bugat, Martin Gauthier, Fabien Despas, Guillaume Moulis, Maryse Lapeyre-Mestre
PURPOSE: The risk of venous thromboembolic event (VTE) in multiple myeloma is particularly increased. Current guidelines recommend systematic VTE prophylaxis with vitamin K antagonists (VKA) or low weight molecular heparin (LWMH) or unfractionated heparin (UFH) in high-risk patients, based on treatment received [e.g. use of IMiDs (thalidomide, lenalidomide and pomalidomide), alkylating agents or erythropoietin] and individual risk factors (e.g. history of VTE). The aim of this study was to describe strategy of VTE prophylaxis and prescribing of other antithrombotic agents during the first 6 months of multiple myeloma therapy, with stratification on IMiD-based regimens and drug and disease-related risk factors...
February 15, 2017: Pharmacoepidemiology and Drug Safety
https://www.readbyqxmd.com/read/28154372/therapeutic-effect-of-the-immunomodulatory-drug-lenalidomide-but-not-pomalidomide-in-experimental-models-of-rheumatoid-arthritis-and-inflammatory-bowel-disease
#13
Belen Lopez-Millan, Rafael Diaz de la Guardia, Heleia Roca-Ho, Carmen M García-Herrero, Jessie R Lavoie, Michael Rosu-Myles, Elena Gonzalez-Rey, Francisco O'Valle, Gabriel Criado, Mario Delgado, Pablo Menendez
Thalidomide is an immunomodulatory drug (IMiD) with proven therapeutic action in several autoimmune/inflammatory diseases; however, its inherent high toxicity has led to the development of more powerful and safer thalidomide analogs, including lenalidomide and pomalidomide. These are new generation IMiDs that exhibit direct antitumor activity as well as anti-inflammatory/immunomodulatory properties, and are FDA-approved for the treatment of several hematological malignances. Here we investigated the potential therapeutic effects of lenalidomide and pomalidomide in several experimental murine models of autoimmune/inflammatory diseases: 2,4,6-trinitrobenzene sulfonic acid- and dextran sulfate sodium-induced inflammatory bowel disease and type II collagen-induced arthritis...
February 3, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28151713/immune-therapies-in-multiple-myeloma
#14
EDITORIAL
Shaji K Kumar, Kenneth C Anderson
Treatment paradigms have changed rapidly for multiple myeloma, and immune therapies have taken center stage. Advances in therapies for myeloma have led to a dramatic improvement in the survival of patients with this incurable malignancy. The immune system is significantly impaired in patients with myeloma as a result of the disease leading to suppression of normal plasma cells as well the negative effects on cellular immunity. Given this scenario, immune approaches have not been successful until recently. Monoclonal antibodies directed against CD38 (daratumumab) and SLAMF7 (elotuzumab) are already in the clinic, and several other antibodies directed against different plasma cell antigens are under evaluation...
November 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28151709/progress-and-paradigms-in-multiple-myeloma
#15
EDITORIAL
Kenneth C Anderson
Remarkable progress has been achieved in multiple myeloma, and patient median survival has been extended 3- to 4-fold. Specifically, there have been 18 newly approved treatments for multiple myeloma in the past 12 years, including seven in 2015, and the treatment paradigm and patient outcome have been transformed. The definition of patients benefitting from these therapies has been broadened. Response criteria now include minimal residual disease (MRD), assessed in bone marrow by multicolor flow cytometry or sequencing, and by imaging for extramedullary disease...
November 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28138259/advances-in-antiangiogenic-treatment-of-small-cell-lung-cancer
#16
REVIEW
Hongyang Lu, Zhiming Jiang
Small-cell lung cancer (SCLC), a poorly differentiated neuroendocrine malignancy, has a rapid growth rate, strong aggressiveness, early metastases, and poor prognosis. Angiogenesis greatly contributes to the metastatic process of SCLC, which has a higher vascularization compared with non-small-cell lung cancer (NSCLC). SCLC might constitute an ideal malignancy for assessing new antiangiogenic drugs and therapeutic strategies. Combining bevacizumab with paclitaxel has therapeutic benefits in chemoresistant, relapsed SCLC...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28130212/a-phase-ii-trial-of-pomalidomide-and-dexamethasone-rescue-treatment-in-patients-with-al-amyloidosis
#17
Giovanni Palladini, Paolo Milani, Andrea Foli, Marco Basset, Francesca Russo, Stefano Perlini, Giampaolo Merlini
Immunomodulatory drugs are active agents in AL amyloidosis. However, previous studies could not show a survival advantage for patients with AL amyloidosis responding to salvage treatment with pomalidomide. In this phase II trial, we assessed safety and efficacy of pomalidomide and dexamethasone in patients with AL amyloidosis previously exposed to bortezomib, alkylators, and other immunomodulatory drugs. Twenty-eight patients were enrolled. Three patients received pomalidomide 2 mg/day with no dose-limiting toxicity...
January 27, 2017: Blood
https://www.readbyqxmd.com/read/28125372/real-world-treatment-patterns-time-to-next-treatment-and-economic-outcomes-in-relapsed-or-refractory-multiple-myeloma-patients-treated-with-pomalidomide-or-carfilzomib
#18
Chi-Chang Chen, Kejal Parikh, Safiya Abouzaid, Lea Purnomo, Catherine B McGuiness, Mohamed Hussein, Rolin L Wade
BACKGROUND: Negligible real-world evidence exists for later line treatment of multiple myeloma (MM) to assist treatment decisions or reimbursement models, such as episode-based payments. OBJECTIVE: To describe the treatment patterns and clinical/economic outcomes when pomalidomide or carfilzomib is used for relapsed/refractory MM. METHODS: A U.S. claims database was used to identify MM patients with an initial pomalidomide or carfilzomib claim (index date) between February 1, 2013, and February 28, 2015, which was assumed to be relapse therapy...
February 2017: Journal of Managed Care & Specialty Pharmacy
https://www.readbyqxmd.com/read/28116941/pomalidomide-experience-an-effective-therapeutic-approach-with-immunomodulatory-drugs-in-a-patient-with-relapsed-refractory-multiple-myeloma
#19
Concetta Conticello, Marina Parisi, Alessandra Romano, Valeria Calafiore, Flavia Ancora, Alessia La Fauci, Maria Letizia Consoli, Francesco Di Raimondo
Here we discuss the case of a heavily pretreated male patient with relapsed-refractory multiple myeloma and previous monoclonal gammopathy of undetermined significance who initiated a fifth-line treatment with pomalidomide (4 mg orally, days 1-21 of a 28-day cycle) and low-dose dexamethasone (40 mg weekly orally). A total of 3 months later, very good partial response was achieved and complete response was maintained for 7 months. This case illustrates the field-practice experience on the benefits of pomalidomide in a relapsed-refractory multiple myeloma patient with a previous history of monoclonal gammopathy of undetermined significance...
February 2017: Future Oncology
https://www.readbyqxmd.com/read/28116940/pomalidomide-when-expectations-are-understated
#20
EDITORIAL
Francesco Di Raimondo, Concetta Conticello
No abstract text is available yet for this article.
February 2017: Future Oncology
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