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Alina Striha, A John Ashcroft, Anna Hockaday, David A Cairns, Karen Boardman, Gwen Jacques, Cathy Williams, John A Snowden, Mamta Garg, Jamie Cavenagh, Kwee Yong, Mark T Drayson, Roger Owen, Mark Cook, Gordon Cook
BACKGROUND: Multiple myeloma (MM) is a plasma cell tumour with an approximate annual incidence of 4500 in the UK. Therapeutic options for patients with MM have changed in the last decade with the arrival of proteasome inhibitors and immunomodulatory drugs. Despite these options, almost all patients will relapse post first-line autologous stem cell transplantation (ASCT). First relapse management (second-line treatment) has evolved in recent years with an expanding portfolio of novel agents, driving response rates influencing the durability of response...
March 7, 2018: Trials
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
C P Sawicki, S A Climans, C C Hsia, J A Fraser
Progressive multifocal leukoencephalopathy (pml) is a rare demyelinating disease of the central nervous system that most often affects immunocompromised individuals. It is caused by the reactivation of the John Cunningham virus (jcv), which is found in latent form in the majority of adults. We describe a 59-year-old man with multiple myeloma who developed severe neurological deficits during treatment with ixazomib-based chemotherapy. A diagnosis of pml was established with gadolinium-enhanced magnetic resonance imaging (mri) and by detection of jcv in the cerebrospinal fluid...
February 2018: Current Oncology
Emilia Scalzulli, Sara Grammatico, Federico Vozella, Maria Teresa Petrucci
Multiple Myeloma (MM) management is rapidly evolving, with a spectrum of novel treatments that have changed our approach to the therapy. Proteasome inhibitors (PIs) have revolutionized the scenario of both relapsed/refractory and newly diagnosed patients. The efficacy of bortezomib, the first PI approved, followed by carfilzomib and, the oral ixazomib, have been tested in several trials as single agents or in combination. Areas covered: In this review, the authors summarize mechanism of action, efficacy and safety of proteasome inhibitors in MM and focus on data derived from clinical trials, analyzing adverse events and their relative management...
February 26, 2018: Expert Opinion on Pharmacotherapy
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
Cyrille Touzeau, Philippe Moreau
The development of proteasome inhibitors contributed to the dramatic life expectancy improvement observed in myeloma patients over the past decades. Ixazomib is a boron-containing selective and reversible proteasome inhibitor that demonstrated antimyeloma activity with excellent safety profile. Ixazomib is the first orally available proteasome inhibitor approved in combination with lenalidomide and dexamethasone for the treatment of myeloma patients who received at least one prior therapy. The present review addresses the current knowledge regarding the clinical use of ixazomib in relapsed myeloma patients...
February 22, 2018: Future Oncology
Meletios Athanasios Dimopoulos, Jonathan L Kaufman, Darrell White, Gordon Cook, Maria Rizzo, Yingxin Xu, Kyle Fahrbach, Maren Gaudig, Mary Slavcev, Lindsay Dearden, Annette Lam
BACKGROUND: Previous network meta-analyses combined studies of immunomodulatory drug (IMiD)-containing and IMiD-free regimens, despite a lack of head-to-head randomized controlled trials to robustly link them. However, patients with relapsed or refractory multiple myeloma (RRMM) treated with IMiD-containing regimens differ from those treated with IMiD-free regimens, especially relating to treatment history, which is an important treatment-effect modifier requiring clinical consideration when evaluating the most appropriate subsequent treatment options...
January 5, 2018: Clinical Lymphoma, Myeloma & Leukemia
Neeraj Gupta, Michael J Hanley, Paul M Diderichsen, Huyuan Yang, Alice Ke, Zhaoyang Teng, Richard Labotka, Deborah Berg, Chirag Patel, Guohui Liu, Helgi van de Velde, Karthik Venkatakrishnan
No abstract text is available yet for this article.
February 15, 2018: Clinical Pharmacology and Therapeutics
Wei Liu, Juan Chen, Archito T Tamayo, Changgeng Ruan, Li Li, Shouhao Zhou, Chan Shen, Ken H Young, Jason Westin, Richard E Davis, Shimin Hu, Leonard J Medeiros, Richard J Ford, Lan V Pham
Despite advances in deciphering the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL), patients with relapsed/refractory disease, particularly those with adverse genetic features (e.g., mutated p53 or double hit lymphoma (DHL)) have very poor prognoses, and effective therapies are lacking. In this study we examined the preclinical efficacy and associated biological effects of the first oral proteasome inhibitor, ixazomib, in DLBCL in vitro and in vivo models. We demonstrated that ixazomib exhibited anti-tumor activities in 28 representative DLBCL cell lines, 10 primary DLBCL samples, and a DHL xenotransplant mouse model, at clinically achievable drug concentrations...
January 2, 2018: Oncotarget
Raphael E Steiner, Robert Z Orlowski, Hans C Lee
BACKGROUND: Acute pancreatitis is an uncommon complication of anti-myeloma agents. Ixazomib is a first-in-class oral proteasome inhibitor to receive regulatory approval for the treatment of multiple myeloma. This case report describes the first case of ixazomib-associated pancreatitis. CASE PRESENTATION: An 80-year-old female with relapsed multiple myeloma presented with severe diarrhea, nausea, vomiting, abdominal pain, and acute renal failure 3 weeks after starting ixazomib and dexamethasone for disease progression...
February 2, 2018: Acta Haematologica
A Alloo, H Khosravi, S R Granter, S M Jadeja, P G Richardson, J J Castillo, N R LeBoeuf
Ixazomib is a second-generation proteasome inhibitor that has been approved in the combination treatment of multiple myeloma and is currently under clinical investigation for the management of Waldenstrom's macroglobulinemia. While cutaneous adverse events secondary to proteasome inhibitors have been reported, the side effect profile of ixazomib remains to be documented. We report two patients, one with multiple myeloma and one with Waldenstrom's macroglobulinemia, who developed cutaneous necrotizing vasculitis after the initiation of ixazomib...
February 1, 2018: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
Giuseppa Augello, Martina Modica, Antonina Azzolina, Roberto Puleio, Giovanni Cassata, Maria Rita Emma, Caterina Di Sano, Antonella Cusimano, Giuseppe Montalto, Melchiorre Cervello
Hepatocellular carcinoma (HCC) is one of the common malignancies and is an increasingly important cause of cancer death worldwide. Surgery, chemotherapy, and radiation therapy extend the 5-year survival limit in HCC patients by only 6%. Therefore, there is a need to develop new therapeutic approaches for the treatment of this disease. The orally bioavailable proteasome inhibitor MLN2238 (ixazomib) has been demonstrated to have anticancer activity. In the present study, we investigated the preclinical therapeutic efficacy of MLN2238 in HCC cells through in vitro and in vivo models, and examined its molecular mechanisms of action...
January 18, 2018: Cell Death & Disease
Brian B Hasinoff
Bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib are anticancer drugs that target the proteasomal system. Carfilzomib and oprozomib are epoxyketones that form an irreversible covalent bond with the 20S proteasome, whereas bortezomib, ixazomib, and delanzomib are boronic acids that form slowly reversible adducts. The binding kinetics of some of these drugs have either not been well characterized, or have been studied under a variety of different conditions. Utilizing a fluorogenic substrate the kinetics of the slow-binding inhibition of the chymotrypsin-like proteasomal activity of human 20S proteasome was determined under a standard set of conditions in order to compare the kinetic and equilibrium properties of these drugs...
January 2, 2018: Archives of Biochemistry and Biophysics
Josh J Carlson, Gregory F Guzauskas, Richard H Chapman, Patricia G Synnott, Shanshan Liu, Elizabeth T Russo, Steven D Pearson, Elizabeth D Brouwer, Daniel A Ollendorf
BACKGROUND: New 3-drug regimens have been developed and approved to treat multiple myeloma (MM). The absence of direct comparative data and the high cost of treatment support the need to assess the relative clinical and economic outcomes across all approved regimens. OBJECTIVE: To evaluate the cost-effectiveness of treatments for relapsed and/or refractory MM from a U.S. health system perspective. METHODS: We developed a partition survival model with 3 health states (progression-free, progression, and death) to evaluate the following regimens: carfilzomib (CFZ), elotuzumab (ELO), ixazomib (IX), daratumumab (DAR), and panobinostat (PAN) in combination with lenalidomide (LEN) or bortezomib (BOR) plus dexamethasone (DEX) in the second and/or third line of therapy...
January 2018: Journal of Managed Care & Specialty Pharmacy
Laurence M Djatche, Joseph A Goble, Grace Chun, Stefan Varga
BACKGROUND: With the continuous rise in costs for oncology drugs, the American Society of Clinical Oncology (ASCO), the Institute for Clinical and Economic Review (ICER), the Memorial Sloan Kettering Cancer Center's Drug Abacus (DrugAbacus), and the National Comprehensive Cancer Network (NCCN) have developed value-based frameworks (VBFs) to assist stakeholders in formulary and treatment decision-making processes. Since emerging VBFs have the potential to affect available treatment options for patients, it is important to understand the differences associated with these VBFs within various therapeutic areas...
January 2018: Journal of Managed Care & Specialty Pharmacy
A Krishnan, P Kapoor, J M Palmer, N-C Tsai, S Kumar, S Lonial, M Htut, C Karanes, N Nathwani, M Rosenzweig, F Sahebi, G Somlo, L Duarte, J F Sanchez, D Auclair, S J Forman, J 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 3 patients were enrolled to DL1, with no further dose limiting toxicity (DLT)...
December 18, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Marco Salvini, Rossella Troia, Davide Giudice, Chiara Pautasso, Mario Boccadoro, Alessandra Larocca
multiple myeloma (MM) is a plasma cell disorder that represents the second most frequent hematologic cancer. Although MM is still an incurable disease, prognosis has improved in the last decades thanks to the introduction of novel agents such as proteasome inhibitors (PIs), immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors. Areas covered: ixazomib is the first oral PI recently approved by Food and Drug Administration (FDA) and European Medicine Agency (EMA) in combination with lenalidomide and dexamethasone as salvage therapy in MM patients...
January 2018: Expert Opinion on Drug Metabolism & Toxicology
Guido Lancman, Douglas Tremblay, Kevin Barley, Bart Barlogie, Hearn Jay Cho, Sundar Jagannath, Deepu Madduri, Erin Moshier, Samir Parekh, Ajai Chari
Multiple myeloma is a heterogeneous disease with a prognosis that varies with patient factors, disease burden, tumor biology, and treatments. Certain molecular abnormalities confer a worse prognosis and thus are considered high-risk. These include t(4;14), del(17p), t(14;16), t(14;20), hypodiploidy, and gain(1q)/del(1p). In our previous review in 2013, we discussed the effect of available therapies on prognosis in these high-risk patients. Since then, seven phase 3 clinical trials in relapsed myeloma with 1 to 3 lines of therapy have been conducted, resulting in the approval of panobinostat, ixazomib, daratumumab, and elotuzumab, as well as additional data on carfilzomib...
November 2017: Clinical Advances in Hematology & Oncology: H&O
Sara Gandolfi, Jacob P Laubach, Teru Hideshima, Dharminder Chauhan, Kenneth C Anderson, Paul G Richardson
Proteasome inhibitors are one of the most important classes of agents to have emerged for the treatment of multiple myeloma in the past two decades, and now form one of the backbones of treatment. Three agents in this class have been approved by the United States Food and Drug Administration-the first-in-class compound bortezomib, the second-generation agent carfilzomib, and the first oral proteasome inhibitor, ixazomib. The success of this class of agents is due to the exquisite sensitivity of myeloma cells to the inhibition of the 26S proteasome, which plays a critical role in the pathogenesis and proliferation of the disease...
December 2017: Cancer Metastasis Reviews
Inger S Nijhof, Niels W C J van de Donk, Sonja Zweegman, Henk M Lokhorst
Although survival of multiple myeloma patients has at least doubled during recent years, most patients eventually relapse, and treatment at this stage may be particularly complex. At the time of relapse, the use of alternative drugs to those given upfront is current practice. However, many new options are currently available for the treatment of relapsed multiple myeloma, including recently approved drugs, such as the second- and third-generation proteasome inhibitors carfilzomib and ixazomib, the immunomodulatory agent pomalidomide, the monoclonal antibodies daratumumab and elotuzumab and the histone deacetylase inhibitor panobinostat, but also new targeted agents are under active investigation (e...
January 2018: Drugs
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