Skip to main content
Erschienen in: International Journal of Hematology 3/2016

09.06.2016 | Progress in Hematology

Mechanisms of action and resistance for multiple myeloma novel drug treatments

verfasst von: Shinsuke Iida

Erschienen in: International Journal of Hematology | Ausgabe 3/2016

Einloggen, um Zugang zu erhalten

Excerpt

Multiple myeloma (MM) is an incurable plasma cell malignancy that develops as a result of multistep tumorigenic events [1]. The median overall survival of patients with newly diagnosed MM was approximately 2.5–3 years when melphalan and prednisone (MP) therapy was the standard of care. However, since the end of the 20th century, genetic and epigenetic alterations associated with the pathogenesis of MM and tumor cell biology of the bone marrow microenvironment have been gradually unraveled [2, 3]. In parallel, the discovery of thalidomide as an active agent for MM in 1999 ushered in a new era in the treatment of this intractable disease [4]. This was followed by the clinical application of bortezomib, a first-generation proteasome inhibitor (PI), based on the results of pre-clinical translational studies [3, 5]. Novel thalidomide derivatives called immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, were also developed [6, 7]. Second-generation PIs, such as carfilzomib and ixazomib, have recently been approved by the FDA [8]. Currently, PIs and IMiDs, as well as corticosteroid and alkylating agents, are the key novel drugs for MM treatment which have resulted in the achievement of a median survival of approximately 5–6 years [9]. Moreover, additional agents with different mechanisms of action have been incorporated into the treatment of MM, including the deacetylase inhibitor panobinostat and monoclonal antibodies, targeting SLAMF7, CD38, and PD-1 represented by elotuzumab, daratumumab/isatuximab, and pembrolizumab/nivolumab, respectively [10, 11]. Thus, the prognosis of patients with MM is expected to continue to improve. …
Literatur
1.
Zurück zum Zitat Iida S, Ueda R. Multistep tumorigenesis of multiple myeloma: Its molecular delineation. Int J Hematol. 2003;77:207–12.CrossRefPubMed Iida S, Ueda R. Multistep tumorigenesis of multiple myeloma: Its molecular delineation. Int J Hematol. 2003;77:207–12.CrossRefPubMed
2.
Zurück zum Zitat Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471:467–72.CrossRefPubMedPubMedCentral Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471:467–72.CrossRefPubMedPubMedCentral
3.
Zurück zum Zitat Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7:585–98.CrossRefPubMed Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7:585–98.CrossRefPubMed
4.
Zurück zum Zitat Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341:1565–71.CrossRefPubMed Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341:1565–71.CrossRefPubMed
5.
Zurück zum Zitat Richardson PG, Barlogie A, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609–17.CrossRefPubMed Richardson PG, Barlogie A, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609–17.CrossRefPubMed
6.
Zurück zum Zitat Dimopoulos MA, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123–32.CrossRefPubMed Dimopoulos MA, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123–32.CrossRefPubMed
7.
Zurück zum Zitat San-Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomized, open-label, phase 3 trial. Lancet Oncol. 2013;14:1055–66.CrossRefPubMed San-Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomized, open-label, phase 3 trial. Lancet Oncol. 2013;14:1055–66.CrossRefPubMed
8.
Zurück zum Zitat Dimoloulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hajek R, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomized, phase 3, open-label, multicenter study. Lancet Oncol. 2016;17:27–38.CrossRef Dimoloulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hajek R, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomized, phase 3, open-label, multicenter study. Lancet Oncol. 2016;17:27–38.CrossRef
9.
Zurück zum Zitat Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28:1122–8.CrossRefPubMed Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28:1122–8.CrossRefPubMed
10.
Zurück zum Zitat San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimoloulos MA, Elghandour A, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicenter, randomized, double-blind phase 3 trial. Lancet Oncol. 2014;15:1195–206.CrossRefPubMed San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimoloulos MA, Elghandour A, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicenter, randomized, double-blind phase 3 trial. Lancet Oncol. 2014;15:1195–206.CrossRefPubMed
11.
Zurück zum Zitat Lonial S, Durie B, Palumbo A, San-Miguel J. Monoclonal antibodies in the treatment of multiple myeloma: current status and future perspectives. Leukemia. 2016;30:526–35.CrossRefPubMed Lonial S, Durie B, Palumbo A, San-Miguel J. Monoclonal antibodies in the treatment of multiple myeloma: current status and future perspectives. Leukemia. 2016;30:526–35.CrossRefPubMed
12.
13.
Zurück zum Zitat Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, et al. Identification of a primary target of thalidomide tetragenicity. Science. 2010;327:1345–50.CrossRefPubMed Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, et al. Identification of a primary target of thalidomide tetragenicity. Science. 2010;327:1345–50.CrossRefPubMed
15.
Zurück zum Zitat Fisher ES, Böhm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature. 2014;512:49–53. Fisher ES, Böhm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature. 2014;512:49–53.
16.
Zurück zum Zitat Chamberlain PP, Miller K, Carmel G, Pagarigan B, Chie-Leon B, Rychak E, et al. Structure of the human cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat Struct Mol Biol. 2014;21:803–9.CrossRefPubMed Chamberlain PP, Miller K, Carmel G, Pagarigan B, Chie-Leon B, Rychak E, et al. Structure of the human cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat Struct Mol Biol. 2014;21:803–9.CrossRefPubMed
17.
Zurück zum Zitat Leung-Hagesteijn C, Erdmann N, Cheung G, Keats JJ, Stewart AK, Reece DE, et al. Xbp1 s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome resistance in multiple myeloma. Cancer Cell. 2013;24:289–304.CrossRefPubMedPubMedCentral Leung-Hagesteijn C, Erdmann N, Cheung G, Keats JJ, Stewart AK, Reece DE, et al. Xbp1 s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome resistance in multiple myeloma. Cancer Cell. 2013;24:289–304.CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Ri M, Iida S, Nakashima T, Miyazaki H, Mori F, Ito A, et al. Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fetal ER stress. Leukemia. 2010;24:1506–12.CrossRefPubMed Ri M, Iida S, Nakashima T, Miyazaki H, Mori F, Ito A, et al. Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fetal ER stress. Leukemia. 2010;24:1506–12.CrossRefPubMed
19.
Zurück zum Zitat Hideshima T, Bradner JE, Wong J, Chauhan D, Richardson P, Schreiber SL, et al. Small-molecule inhibition of proteasome and aggresome function induces synergic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA. 2005;102:8567–72.CrossRefPubMedPubMedCentral Hideshima T, Bradner JE, Wong J, Chauhan D, Richardson P, Schreiber SL, et al. Small-molecule inhibition of proteasome and aggresome function induces synergic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA. 2005;102:8567–72.CrossRefPubMedPubMedCentral
Metadaten
Titel
Mechanisms of action and resistance for multiple myeloma novel drug treatments
verfasst von
Shinsuke Iida
Publikationsdatum
09.06.2016
Verlag
Springer Japan
Erschienen in
International Journal of Hematology / Ausgabe 3/2016
Print ISSN: 0925-5710
Elektronische ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-016-2040-0

Weitere Artikel der Ausgabe 3/2016

International Journal of Hematology 3/2016 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.