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      Lenalidomide, bortezomib and dexamethasone induction therapy for the treatment of newly diagnosed multiple myeloma: a practical review

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          Summary

          For patients with newly diagnosed multiple myeloma, survival outcomes continue to improve significantly: however, nearly all patients will relapse following induction treatment. Optimisation of induction therapy is essential to provide longer term disease control and the current standard of care for most patients incorporates an immunomodulatory agent and proteasome inhibitor, most commonly lenalidomide and bortezomib in combination with dexamethasone (RVD), with maintenance until progression. Historically there has been limited access to RVD as an induction strategy outside of the United States; fortunately, there is now increasing access worldwide. This review discusses the rationale for use of RVD as induction therapy and aims to provide guidance in prescribing this regimen in order to optimise efficacy while minimising the toxicities of treatment. We also highlight the increasing evidence for the utility of addition of a monoclonal antibody to the RVD backbone to deepen responses and potentially provide longer disease control.

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          Most cited references99

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          Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells.

          Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, we found that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3. These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.
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            Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma.

            Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma.
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              The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins.

              Thalidomide-like drugs such as lenalidomide are clinically important treatments for multiple myeloma and show promise for other B cell malignancies. The biochemical mechanisms underlying their antitumor activity are unknown. Thalidomide was recently shown to bind to, and inhibit, the cereblon ubiquitin ligase. Cereblon loss in zebrafish causes fin defects reminiscent of the limb defects seen in children exposed to thalidomide in utero. Here we show that lenalidomide-bound cereblon acquires the ability to target for proteasomal degradation two specific B cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). Analysis of myeloma cell lines revealed that loss of IKZF1 and IKZF3 is both necessary and sufficient for lenalidomide's therapeutic effect, suggesting that the antitumor and teratogenic activities of thalidomide-like drugs are dissociable.
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                Author and article information

                Contributors
                georgia.mccaughan@svha.org.au
                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
                07 July 2022
                October 2022
                : 199
                : 2 ( doiID: 10.1111/bjh.v199.2 )
                : 190-204
                Affiliations
                [ 1 ] Department of Haematology St Vincent's Hospital Sydney Australia
                [ 2 ] University of New South Wales, Medicine and Health Sydney Australia
                [ 3 ] Translational Research Program University of Helsinki Helsinki Finland
                [ 4 ] Haematology Research Unit University of Helsinki and Helsinki University Hospital Helsinki Finland
                [ 5 ] Dana‐Farber Cancer Institute, Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology Boston Massachusetts USA
                Author notes
                [*] [* ] Correspondence

                Georgia McCaughan, Department of Haematology, Kinghorn Cancer Centre, St Vincent's Hospital, 370 Victoria Street, Darlinghurst 2010, Australia.

                Email: georgia.mccaughan@ 123456svha.org.au

                Author information
                https://orcid.org/0000-0002-4838-9022
                Article
                BJH18295 BJH-2022-00202.R1
                10.1111/bjh.18295
                9796722
                35796524
                9b09debb-ff3a-452c-a0c6-8992109ab999
                © 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

                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
                : 10 May 2022
                : 02 February 2022
                : 20 May 2022
                Page count
                Figures: 2, Tables: 4, Pages: 15, Words: 10004
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                October 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.3 mode:remove_FC converted:28.12.2022

                Hematology
                Hematology

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