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https://www.readbyqxmd.com/read/28747580/emerging-drugs-and-combinations-to-treat-multiple-myeloma
#1
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...
July 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28747306/how-i-treat-new-agents-in-myeloma
#2
Philippe Moreau
At present, multiple classes of agents with distinct mechanisms of action are available for the treatment of patients with multiple myeloma (MM), including alkylators, steroids, immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), histone deacetylase inhibitors (DACIs) and monoclonal antibodies (mAbs). Over the last 5 years, several new agents, such as the third-generation IMiD pomalidomide, the second generation PIs carfilzomib and ixazomib, the DACI panobinostat and two monoclonal antibodies, elotuzumab and daratumumab, have been approved, incorporated into clinical guidelines and have transformed our approach to the treatment of patients...
July 26, 2017: Blood
https://www.readbyqxmd.com/read/28723635/meta-analysis-of-the-efficacy-of-treatments-for-newly-diagnosed-and-relapsed-refractory-multiple-myeloma-with-del-17p
#3
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, I2 = 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, I2 = 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...
June 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28683766/randomized-double-blind-placebo-controlled-phase-iii-study-of-ixazomib-plus-lenalidomide-dexamethasone-in-patients-with-relapsed-refractory-multiple-myeloma-china-continuation-study
#4
Jian Hou, Jie Jin, Yan Xu, Depei Wu, Xiaoyan Ke, Daobin Zhou, Jin Lu, Xin Du, Xiequn Chen, Junmin Li, Jing Liu, Neeraj Gupta, Michael J Hanley, Hongmei Li, Zhaowei Hua, Bingxia Wang, Xiaoquan Zhang, Hui Wang, Helgi van de Velde, Paul G Richardson, Philippe Moreau
BACKGROUND: The China Continuation study was a separate regional expansion of the global, double-blind, placebo-controlled, randomized phase III TOURMALINE-MM1 study of ixazomib plus lenalidomide-dexamethasone (Rd) in patients with relapsed/refractory multiple myeloma (RRMM) following one to three prior therapies. METHODS: Patients were randomized (1:1) to receive ixazomib 4.0 mg or placebo on days 1, 8, and 15, plus lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22, in 28-day cycles...
July 6, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28679737/how-i-treat-first-relapse-of-myeloma
#5
Jean Luc Harousseau, Michel Attal
The standard treatment of relapsed multiple myeloma (MM) was either lenalidomide-dexamethasone (RD) or bortezomib-dexamethasone (VD) but it is changing rapidly for two reasons. Firstly lenalidomide and bortezomib are currently used in frontline treatment and many patients become resistant to these agents early in the course of their disease. Secondly six second-line new agents have been recently developed and offer new possibilities (pomalidomide, carfilzomib and ixazomib, panobinostat, elotuzumab and daratumumab)...
July 5, 2017: Blood
https://www.readbyqxmd.com/read/28665416/a-gene-expression-signature-distinguishes-innate-response-and-resistance-to-proteasome-inhibitors-in-multiple-myeloma
#6
A K Mitra, T Harding, U K Mukherjee, J S Jang, Y Li, R HongZheng, J Jen, P Sonneveld, S Kumar, W M Kuehl, V Rajkumar, B Van Ness
Extensive interindividual variation in response to chemotherapy is a major stumbling block in achieving desirable efficacy in the treatment of cancers, including multiple myeloma (MM). In this study, our goal was to develop a gene expression signature that predicts response specific to proteasome inhibitor (PI) treatment in MM. Using a well-characterized panel of human myeloma cell lines (HMCLs) representing the biological and genetic heterogeneity of MM, we created an in vitro chemosensitivity profile in response to treatment with the four PIs bortezomib, carfilzomib, ixazomib and oprozomib as single agents...
June 30, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28661711/safety-of-ixazomib-for-the-treatment-of-multiple-myeloma
#7
Antoine Bonnet, Philippe Moreau
Despite a major positive impact of proteasome inhibitors (PI), such as bortezomib and carfilzomib, on the survival of patients with multiple myeloma (MM) over the last few years, their use in clinical practice is limited by the development of drug resistance, significant side-effects or constraining administration schedules. Ixazomib is the first, and for now the only, oral PI, which was approved by the US Food and Drug Administration in 2015 and by the European Medicines Agency in 2016. Areas covered: In this review, we provide an overview of the preclinical and early-phase studies of ixazomib used as single-agent and in combination...
July 12, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28660423/ixazomib-a-review-in-relapsed-and-or-refractory-multiple-myeloma
#8
REVIEW
Zaina T Al-Salama, Karly P Garnock-Jones, Lesley J Scott
The oral proteasome inhibitor ixazomib (Ninlaro(®)) is approved in the USA, EU and Japan in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. In adults with relapsed and/or refractory MM who had received one to three prior therapies, progression-free survival (PFS) was significantly prolonged in patients who received the ixazomib- versus placebo-based triple therapy in the pivotal, global TOURMALINE-MM1 trial and its regional expansion (China continuation study)...
August 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28601492/new-agents-in-multiple-myeloma-an%C3%A2-examination-of-safety-profiles
#9
REVIEW
Sara Bringhen, Edwin De Wit, Meletios-Athanassios Dimopoulos
Numerous treatments are available for relapsed and/or refractory multiple myeloma (MM), with safety profiles varying across drug classes and across agents within the same class. Thus, it is important to understand the toxicities of each antimyeloma agent when making treatment decisions. Neutropenia is commonly associated with lenalidomide and pomalidomide, and may be common with histone deacetylase (HDAC) inhibitors, but is relatively unusual with thalidomide, bortezomib, and carfilzomib. Infection was common in trials of lenalidomide and pomalidomide, and upper respiratory tract infection and pneumonia have been seen with carfilzomib...
May 10, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28596644/highlights-of-multiple-myeloma-at-the-annual-meeting-of-american-society-of-hematology-2016
#10
REVIEW
Nidhi Tandon, Shaji K Kumar
This review discusses the landmark studies in the field of multiple myeloma (MM) which were presented at American society of hematology annual meeting, 2016. There were contrary results from two large phase III trials (one from US and one from Europe) that evaluated the role of additional interventions like tandem autologous transplant (ASCT) and consolidation after induction therapy followed by ASCT in newly diagnosed MM (NDMM) patients, but there were critical differences between the two studies. Novel agents like carfilzomib and ixazomib proved to be of benefit when used as induction and post ASCT consolidation and maintenance in NDMM...
June 2017: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/28556890/recent-progress-in-relapsed-multiple-myeloma-therapy-implications-for-treatment-decisions
#11
REVIEW
Philippe Moreau, Edwin de Wit
The availability of novel therapies for the treatment of multiple myeloma has had a dramatic impact on the depth of response that can be expected on initial treatment. Despite these advances, disease relapse remains inevitable in most patients and brings with it a different set of priorities for therapy. The most recent wave of novel agents may have a particular impact in the relapsed setting. In this review, we examine the evidence currently available from clinical trials for the use of novel agents, particularly in the formation of triplet therapy...
May 30, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28550039/a-phase-1-2-study-of-the-oral-proteasome-inhibitor-ixazomib-in-relapsed-or-refractory-light-chain-al-amyloidosis
#12
Vaishali Sanchorawala, Giovanni Palladini, Vishal Kukreti, Jeffrey A Zonder, Adam D Cohen, David C Seldin, Angela Dispenzieri, Arnaud Jaccard, Stefan O Schönland, Deborah Berg, Huyuan Yang, Neeraj Gupta, Ai-Min Hui, Raymond L Comenzo, Giampaolo Merlini
This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory AL amyloidosis (RRAL). Ixazomib was administered to adult patients with RRAL after ≥1 prior line of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naïve and PI-exposed patients) at the maximum tolerated dose (MTD)...
May 26, 2017: Blood
https://www.readbyqxmd.com/read/28504554/how-is-patient-care-for-multiple-myeloma-advancing
#13
REVIEW
Sonja Genadieva Stavric, Francesca Bonello, Sara Bringhen, Mario Boccadoro, Alessandra Larocca
Treatment of multiple myeloma has undergone profound changes in the past years thanks to the increased understanding of the biology of the disease and the new treatment options. New drugs and effective approaches are currently available for the treatment of multiple myeloma, including immunomodulatory agents, proteasome inhibitors and autologous stem cell transplantation. Areas covered: We have described the recent updated criteria to start treatment in multiple myeloma and summarized clinical data from major studies including most recent agents...
June 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28495797/ixazomib-enhances-parathyroid-hormone-induced-%C3%AE-catenin-t-cell-factor-signaling-by-dissociating-%C3%AE-catenin-from-the-parathyroid-hormone-receptor
#14
Yanmei Yang, Hong Lei, Ya-Wei Qiang, Bin Wang
The anabolic action of PTH in bone is mostly mediated by cAMP/PKA and Wnt-independent activation of β-catenin/T-cell factor (TCF) signaling. β-Catenin switches the PTH receptor (PTHR) signaling from cAMP/PKA to PLC/PKC activation by binding to the PTHR. Ixazomib (Izb) was recently approved as the first orally administered proteasome inhibitor for the treatment of multiple myeloma; it acts in part by inhibition of pathological bone destruction. Proteasome inhibitors were reported to stabilize β-catenin by the ubiquitin-proteasome pathway...
July 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28485007/management-of-adverse-events-associated-with-ixazomib-plus-lenalidomide-dexamethasone-in-relapsed-refractory-multiple-myeloma
#15
Shaji Kumar, Philippe Moreau, Parameswaran Hari, Maria-Victoria Mateos, Heinz Ludwig, Chaim Shustik, Tamas Masszi, Andrew Spencer, Roman Hájek, Kenneth Romeril, Irit Avivi, Anna M Liberati, Monique C Minnema, Hermann Einsele, Sagar Lonial, Deborah Berg, Jianchang Lin, Neeraj Gupta, Dixie-Lee Esseltine, Paul G Richardson
The oral proteasome inhibitor ixazomib is approved in the United States, European Union and other countries, in combination with oral lenalidomide and dexamethasone (Rd), for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on the global, randomised, double-blind, placebo-controlled Phase III TOURMALINE-MM1 study of ixazomib-Rd (IRd) versus placebo-Rd in patients with relapsed/refractory multiple myeloma. IRd resulted in a significant improvement in progression-free survival versus placebo-Rd (median: 20·6 vs...
May 9, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28388244/which-therapies-will-move-to-the-front-line-for-multiple-myeloma
#16
REVIEW
María J Cejalvo, Javier de la Rubia
Despite substantial progress, multiple myeloma (MM) remains an incurable disease. Recently the availability of several novel drugs with different and innovative mechanisms of action (daratumumab, elotuzumab, carfilzomib, ixazomib, and panobinostat) has increased the therapeutic options but has also increased complexity in the management of patients with MM. Areas covered: The outstanding results observed in the relapsed setting with regimens including these new drugs has provided the investigators with several treatment options that are being tested also in patients with newly diagnosed MM...
May 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28347676/treating-multiple-myeloma-patients-with-oral-therapies
#17
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...
May 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28342223/ritonavir-and-ixazomib-kill-bladder-cancer-cells-by-causing-ubiquitinated-protein-accumulation
#18
Akinori Sato, Takako Asano, Kazuki Okubo, Makoto Isono, Tomohiko Asano
There is no curative treatment for advanced bladder cancer. Causing ubiquitinated protein accumulation and endoplasmic reticulum stress is a novel approach to cancer treatment. The HIV protease inhibitor ritonavir has been reported to suppress heat shock protein 90 and increase the amount of unfolded proteins in the cell. If the proteasome functions normally, however, they are rapidly degraded. We postulated that the novel proteasome inhibitor ixazomib combined with ritonavir would kill bladder cancer cells effectively by inhibiting degradation of these unfolded proteins and thereby causing ubiquitinated proteins to accumulate...
June 2017: Cancer Science
https://www.readbyqxmd.com/read/28333868/proteasome-inhibitor-induced-gastrointestinal-toxicity
#19
Romany L Stansborough, Rachel J Gibson
PURPOSE OF REVIEW: Gastrointestinal toxicities are commonly reported following treatment with proteasome inhibitors. The first-generation proteasome inhibitor, bortezomib, induces significant gastrointestinal side effects including nausea, vomiting, diarrhoea, and constipation, occurring in up to 84% of patients. Despite the development of safer proteasome inhibitors, such as carfilzomib, gastrointestinal toxicities remain some of the most common side effects. This review aims to summarize the previous literature on proteasome inhibitor-induced gastrointestinal toxicities, report on recent updates in the field, and investigate possible mechanisms of this toxicity...
June 2017: Current Opinion in Supportive and Palliative Care
https://www.readbyqxmd.com/read/28327055/the-evaluation-of-the-anti-cancer-activity-of-ixazomib-on-caco2-colon-solid-tumor-cells-comparison-with-bortezomib
#20
Selin Engür, Miriş Dikmen
Proteasome inhibition has recently emerged as a clinically effective anticancer therapeutic approach. The first proteasome inhibitor, bortezomib (Velcade, PS-341), and new proteasome inhibitors including ixazomib have become more important in the development of targeted cancer therapies. Under physiological conditions, MLN9708 (ixazomib citrate), the stable citrate ester drug substance, hydrolyzes rapidly to MLN2238 (ixazomib), the biologically active boronic acid. It is a second-generation proteasome inhibitor, similar to the well-known proteasome inhibitor bortezomib, which is currently being investigated in phase 3 trials as a treatment for multiple Myeloma...
March 22, 2017: Acta Clinica Belgica
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