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https://www.readbyqxmd.com/read/28434255/daratumumab-for-the-treatment-of-multiple-myeloma
#1
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...
April 24, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28425720/a-cereblon-modulator-cc-220-with-improved-degradation-of-ikaros-and-aiolos
#2
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
#3
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
#4
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
#5
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...
March 7, 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
#6
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
#7
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...
April 4, 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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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