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      Twice‐weekly ixazomib in combination with lenalidomide‐dexamethasone in patients with newly diagnosed multiple myeloma

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          Weekly ixazomib with lenalidomide‐dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma ( NDMM) patients. This phase 1/2 study ( NCT01383928) evaluated the recommended phase 2 dose ( RP2D), pharmacokinetics, safety and efficacy of twice‐weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice‐weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9–16) for up to sixteen 21‐day cycles, followed by maintenance with twice‐weekly ixazomib alone. No dose‐limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression‐free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug‐related adverse events ( AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug‐related AEs. Thirteen patients discontinued due to AEs. Twice‐weekly ixazomib‐Rd offers substantial activity with promising long‐term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib‐Rd in this setting.

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          Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma.

          Paul Richardson, Edie Weller, Sagar Lonial … (2010)
          This phase 1/2 study is the first prospective evaluation of lenalidomide-bortezomib-dexamethasone in front-line myeloma. Patients (N = 66) received 3-week cycles (n = 8) of bortezomib 1.0 or 1.3 mg/m(2) (days 1, 4, 8, 11), lenalidomide 15 to 25 mg (days 1-14), and dexamethasone 40 or 20 mg (days 1, 2, 4, 5, 8, 9, 11, 12). Responding patients proceeded to maintenance or transplantation. Phase 2 dosing was determined to be bortezomib 1.3 mg/m(2), lenalidomide 25 mg, and dexamethasone 20 mg. Most common toxicities included sensory neuropathy (80%) and fatigue (64%), with only 27%/2% and 32%/3% grade 2/3, respectively. In addition, 32% reported neuropathic pain (11%/3%, grade 2/3). Grade 3/4 hematologic toxicities included lymphopenia (14%), neutropenia (9%), and thrombocytopenia (6%). Thrombosis was rare (6% overall), and no treatment-related mortality was observed. Rate of partial response was 100% in both the phase 2 population and overall, with 74% and 67% each achieving very good partial response or better. Twenty-eight patients (42%) proceeded to undergo transplantation. With median follow-up of 21 months, estimated 18-month progression-free and overall survival for the combination treatment with/without transplantation were 75% and 97%, respectively. Lenalidomide-bortezomib-dexamethasone demonstrates favorable tolerability and is highly effective in the treatment of newly diagnosed myeloma. This study is registered at http://clinicaltrials.gov as NCT00378105.
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            Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study.

            Michele Cavo, Paola Tacchetti, Francesca Patriarca … (2010)
            Thalidomide plus dexamethasone (TD) is a standard induction therapy for myeloma. We aimed to assess the efficacy and safety of addition of bortezomib to TD (VTD) versus TD alone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma. Patients (aged 18-65 years) with previously untreated symptomatic myeloma were enrolled from 73 sites in Italy between May, 2006, and April, 2008, and data collection continued until June 30, 2010. Patients were randomly allocated (1:1 ratio) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily for the first 14 days and 200 mg daily thereafter) plus dexamethasone (40 mg daily on 8 of the first 12 days, but not consecutively; total of 320 mg per cycle), either alone or with bortezomib (1·3 mg/m(2) on days 1, 4, 8, and 11). The randomisation sequence was computer generated by the study coordinating team and was stratified by disease stage. After double autologous stem-cell transplantation, patients received two 35-day cycles of their assigned drug regimen, VTD or TD, as consolidation therapy. The primary endpoint was the rate of complete or near complete response to induction therapy. Analysis was by intention to treat. Patients and treating physicians were not masked to treatment allocation. This study is still underway but is not recruiting participants, and is registered with ClinicalTrials.gov, number NCT01134484, and with EudraCT, number 2005-003723-39. 480 patients were enrolled and randomly assigned to receive VTD (n=241 patients) or TD (n=239). Six patients withdrew consent before start of treatment, and 236 on VTD and 238 on TD were included in the intention-to-treat analysis. After induction therapy, complete or near complete response was achieved in 73 patients (31%, 95% CI 25·0-36·8) receiving VTD, and 27 (11%, 7·3-15·4) on TD (p<0·0001). Grade 3 or 4 adverse events were recorded in a significantly higher number of patients on VTD (n=132, 56%) than in those on TD (n=79, 33%; p<0·0001), with a higher occurrence of peripheral neuropathy in patients on VTD (n=23, 10%) than in those on TD (n=5, 2%; p=0·0004). Resolution or improvement of severe peripheral neuropathy was recorded in 18 of 23 patients on VTD, and in three of five patients on TD. VTD induction therapy before double autologous stem-cell transplantation significantly improves rate of complete or near complete response, and represents a new standard of care for patients with multiple myeloma who are eligible for transplant. Seràgnoli Institute of Haematology at the University of Bologna, Bologna, Italy. Copyright © 2010 Elsevier Ltd. All rights reserved.
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              Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3.

              Wendy P. Battisti, Elizabeth Wager, Lise Baltzer … (2015)
              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.
              Article 0 comments Cited 137 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Paul G. Richardson:
                ORCID: http://orcid.org/0000-0002-7426-8865
                Paul_Richardson@dfci.harvard.edu
                Journal
                Journal ID (nlm-ta): Br J Haematol
                Journal ID (iso-abbrev): Br. J. Haematol
                Journal ID (doi): 10.1111/(ISSN)1365-2141
                Journal ID (publisher-id): BJH
                Title: British Journal of Haematology
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 0007-1048
                ISSN (Electronic): 1365-2141
                Publication date (Electronic): 25 June 2018
                Publication date (Print): July 2018
                Volume: 182
                Issue: 2 ( doiID: 10.1111/bjh.2018.182.issue-2 )
                Pages: 231-244
                Affiliations
                [ 1 ] Dana‐Farber Cancer Institute Boston MA USA
                [ 2 ] Ohio State University Columbus OH USA
                [ 3 ] Hematology/Oncology University of Chicago Medicine Chicago IL USA
                [ 4 ] Hematology and Stem Cell Transplant City of Hope National Medical Center Duarte Duarte CA USA
                [ 5 ] John Theurer Cancer Center Hackensack University Medical Center Hackensack NJ USA
                [ 6 ] Sarah Cannon Research Institute Nashville TN USA
                [ 7 ] Stanford Comprehensive Cancer Center Stanford CA USA
                [ 8 ] Mount Sinai School of Medicine Ruttenberg Treatment Center New York NY USA
                [ 9 ] Fred Hutchinson Cancer Research Center University of Washington Seattle WA USA
                [ 10 ] University of Michigan Cancer Center Ann Arbor MI USA
                [ 11 ] Massachusetts General Hospital Boston MA USA
                [ 12 ] Millennium Pharmaceuticals Inc. Cambridge MA USA
                [ 13 ] Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute Tampa FL USA
                Author notes
                [*] [* ] Correspondence: Paul G. Richardson, Dana‐Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.

                E‐mail: Paul_Richardson@ 123456dfci.harvard.edu

                Author information
                http://orcid.org/0000-0002-7426-8865
                http://orcid.org/0000-0001-8945-5850
                http://orcid.org/0000-0002-5500-5218
                Article
                Publisher ID: BJH15394
                DOI: 10.1111/bjh.15394
                PMC ID: 6055619
                PubMed ID: 29938772
                SO-VID: 00ad0cf1-b646-42ee-9693-4a3cc185aa50
                Copyright © © 2018 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd and British Society for Haematology.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ 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
                Date received : 12 January 2018
                Date accepted : 19 March 2018
                Page count
                Figures: 3, Tables: 5, Pages: 14, Words: 11599
                Funding
                Funded by: Millennium Pharmaceuticals, Inc.
                Categories
                Subject: Research Paper
                Subject: Haematological Malignancy
                Custom metadata
                source-schema-version-number 2.0
                component-id bjh15394
                cover-date July 2018
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.3 mode:remove_FC converted:23.07.2018

                ScienceOpen disciplines: Hematology
                Keywords: ixazomib,oral,newly diagnosed,multiple myeloma,twice‐weekly
                Data availability:
                ScienceOpen disciplines: Hematology
                Keywords: ixazomib, oral, newly diagnosed, multiple myeloma, twice‐weekly

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