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      Management of adverse events associated with ixazomib plus lenalidomide/dexamethasone in relapsed/refractory multiple myeloma

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          Summary

          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 TOURMALINEMM1 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. 14·7 months; hazard ratio 0·74). Common toxicities observed more commonly with IRd versus placebo‐Rd were thrombocytopenia, nausea, vomiting, diarrhoea, constipation, rash, peripheral neuropathy, peripheral oedema and back pain; these were generally grade 1/2 in severity except for thrombocytopenia (19% vs. 9% grade 3/4), which appeared manageable and reversible, with no differences between arms in significant bleeding or dose discontinuations. No cumulative toxicities were observed, indicating the potential feasibility of long‐term IRd treatment. Safety data from TOURMALINEMM1 are reviewed and guidance for managing clinically relevant adverse events associated with IRd is provided. Most toxicities were manageable with supportive care and dose delays or reductions as needed. Clinicians should be aware of and understand these potential side effects to optimise and prolong patient benefit.

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          Most cited references32

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          Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3.

          This updated Good Publication Practice (GPP) guideline, known as GPP3, builds on earlier versions and provides recommendations for individuals and organizations that contribute to the publication of research results sponsored or supported by pharmaceutical, medical device, diagnostics, and biotechnology companies. The recommendations are designed to help individuals and organizations maintain ethical and transparent publication practices and comply with legal and regulatory requirements. These recommendations cover publications in peer-reviewed journals and presentations (oral or poster) at scientific congresses. The International Society for Medical Publication Professionals invited more than 3000 professionals worldwide to apply for a position on the steering committee, or as a reviewer, for this guideline. The GPP2 authors reviewed all applications (n = 241) and assembled an 18-member steering committee that represented 7 countries and a diversity of publication professions and institutions. From the 174 selected reviewers, 94 sent comments on the second draft, which steering committee members incorporated after discussion and consensus. The resulting guideline includes new sections (Principles of Good Publication Practice for Company-Sponsored Medical Research, Data Sharing, Studies That Should Be Published, and Plagiarism), expands guidance on the International Committee of Medical Journal Editors' authorship criteria and common authorship issues, improves clarity on appropriate author payment and reimbursement, and expands information on the role of medical writers. By following good publication practices (including GPP3), individuals and organizations will show integrity; accountability; and responsibility for accurate, complete, and transparent reporting in their publications and presentations.
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            Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients.

            Ixazomib is the first investigational oral proteasome inhibitor to be studied clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) received single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day cycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) occurred at 2.23 mg/m(2). The maximum tolerated dose was 2.0 mg/m(2), which 40 patients received in 4 expansion cohorts. Patients received a median of 4 cycles (range, 1-39); 18% received ≥12 cycles. Eighty-eight percent had drug-related adverse events, including nausea (42%), thrombocytopenia (42%), fatigue (40%), and rash (40%); drug-related grade ≥3 events included thrombocytopenia (37%) and neutropenia (17%). Grade 1/2 drug-related peripheral neuropathy occurred in 12% (no grade ≥3). Two patients died on the study (both considered unrelated to treatment). The terminal half-life of ixazomib was 3.3 to 7.4 days; plasma exposure increased proportionally with dose (0.48-2.23 mg/m(2)). Among 55 response-evaluable patients, 15% achieved partial response or better (76% stable disease or better). These findings have informed the subsequent clinical development of ixazomib in multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00932698.
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              Management of treatment-emergent peripheral neuropathy in multiple myeloma.

              Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions.
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                Author and article information

                Contributors
                kumar.shaji@mayo.edu
                Journal
                Br J Haematol
                Br. J. Haematol
                10.1111/(ISSN)1365-2141
                BJH
                British Journal of Haematology
                John Wiley and Sons Inc. (Hoboken )
                0007-1048
                1365-2141
                09 May 2017
                August 2017
                : 178
                : 4 ( doiID: 10.1111/bjh.2017.178.issue-4 )
                : 571-582
                Affiliations
                [ 1 ] Division of Hematology Mayo Clinic Rochester MN USA
                [ 2 ] University Hospital Hôtel Dieu Nantes France
                [ 3 ] Division of Hematology and Oncology Froedtert Hospital and the Medical College of Wisconsin Milwaukee WI USA
                [ 4 ] Servicio de Hematología Hospital Universitario de Salamanca Salamanca Spain
                [ 5 ] Wilhelminenspital der Stadt Wien Vienna Austria
                [ 6 ] McGill University Health Center Royal Victoria Hospital Montreal Canada
                [ 7 ] Department of Haematology and Stem Cell Transplantation St István and St László Hospital Semmelweis University Budapest Hungary
                [ 8 ] Alfred Health‐Monash University Melbourne Australia
                [ 9 ] Department of Haematooncology University Hospital Ostrava Ostrava Czech Republic
                [ 10 ] Wellington Blood and Cancer Centre Wellington Regional Hospital Wellington New Zealand
                [ 11 ] Department of Haematology and Bone Marrow Transplantation Tel Aviv Medical Centre Tel Aviv Israel
                [ 12 ] University of Perugia SC Oncoematologia AO S. Maria di Terni Terni Italy
                [ 13 ] Department of Haematology UMC Utrecht Cancer Centre Utrecht The Netherlands
                [ 14 ] Universitätsklinik Würzburg Medizinische Klinik und Poliklinik II Würzburg Germany
                [ 15 ] Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta GA USA
                [ 16 ] Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Cambridge MA USA
                [ 17 ] Dana‐Farber Cancer Institute Boston MA USA
                Author notes
                [*] [* ] Correspondence: Shaji K. Kumar, Division of Hematology, Mayo Clinic, Rochester, MN 55906, USA.

                E‐mail: kumar.shaji@ 123456mayo.edu

                Author information
                http://orcid.org/0000-0001-5392-9284
                http://orcid.org/0000-0003-1780-8746
                http://orcid.org/0000-0002-7680-0819
                http://orcid.org/0000-0002-5500-5218
                Article
                BJH14733
                10.1111/bjh.14733
                5574012
                28485007
                9c21d375-d439-4c8e-bd9f-1765cf4ed78e
                © 2017 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 21 December 2016
                : 06 March 2017
                Page count
                Figures: 1, Tables: 4, Pages: 12, Words: 9618
                Funding
                Funded by: Takeda Pharmaceutical Company Limited
                Categories
                Research Paper
                Haematological Malignancy
                Custom metadata
                2.0
                bjh14733
                August 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.8 mode:remove_FC converted:29.08.2017

                Hematology
                multiple myeloma,ixazomib,toxicity,proteasome inhibitor,dosing
                Hematology
                multiple myeloma, ixazomib, toxicity, proteasome inhibitor, dosing

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