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Review
. 2023 May 15;4(3):792-810.
doi: 10.1002/jha2.709. eCollection 2023 Aug.

Selinexor: Targeting a novel pathway in multiple myeloma

Clifton C Mo  1 , Andrew J Yee  2 , Shonali Midha  1   3 , Monique A Hartley-Brown  1   3 , Omar Nadeem  1 , Elizabeth K O'Donnell  1   3 , Giada Bianchi  1   3 , Adam S Sperling  1   3 , Jacob P Laubach  1 , Paul G Richardson  1
Affiliations
Review

Selinexor: Targeting a novel pathway in multiple myeloma

Clifton C Mo et al. EJHaem. .

Abstract

Selinexor is an orally bioavailable selective inhibitor of nuclear export compound that inhibits exportin-1 (XPO1), a novel therapeutic target that is overexpressed in multiple myeloma (MM) and is responsible for the transport of ∼220 nuclear proteins to the cytoplasm, including tumour suppressor proteins. Inhibition of this process has demonstrated substantial antimyeloma activity in preclinical studies, both alone and in combination with established MM therapeutics. Based on a clinical trial programme encompassing multiple combination regimens, selinexor-based therapy has been approved for the treatment of relapsed/refractory MM (RRMM), with selinexor-dexamethasone approved in the later-relapse setting for penta-refractory patients and selinexor-bortezomib-dexamethasone approved for patients who have received ≥1 prior therapy. Here, we provide a comprehensive review of the clinical data on selinexor-based regimens, including recent updates from the 2022 American Society of Hematology annual meeting, and summarise ongoing studies of this novel targeted agent in newly diagnosed MM and RRMM.

Keywords: XPO1; multiple myeloma; nuclear export; refractory; relapsed; selective inhibitor of nuclear export; targeted therapy.

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Conflict of interest statement

Clifton C. Mo: Advisory Boards for AbbVie, BMS, GSK, Janssen, Karyopharm, Sanofi, Takeda. Consulting for AbbVie, Janssen, Karyopharm, Sanofi. Andrew J. Yee: Consulting for AbbVie, Adaptive Biotechnologies, Amgen, BMS, Celgene, GSK, Janssen, Karyopharm, Oncopeptides, Regeneron, Sanofi, Takeda. Research funding from Amgen, BMS, Janssen. Shonali Midha: No conflict of interest to declare. Monique A. Hartley‐Brown: Advisory board participation for Abbvie, BMS, Celgene, GSK, Janssen, Karyopharm, Sanofi. Research funding from BMS /Celgene, GSK, Sanofi. Omar Nadeem: Advisory board participation for BMS, Janssen, Takeda, Sanofi, GPCR Therapeutics. Research funding from Takeda, Janssen. Elizabeth K. O'Donnell: No conflict of interests to declare. Giada Bianchi: No conflict of interests to declare. Adam S. Sperling: Consulting for Novartis, Adaptive Biotechnologies, Roche. Jacob P. Laubach: No conflict of interest to declare. Paul G. Richardson: Grants to institution for clinical trials from Bristol Myers Squibb/Celgene, Karyopharm, Oncopeptides, and Takeda. Service on advisory committees for AstraZeneca, Bristol Myers Squibb/Celgene, GSK, Karyopharm, Oncopeptides, Regeneron, Sanofi and Takeda.

Figures

FIGURE 1
FIGURE 1
Schematic of the role of XPO1 in transporting various cargoes from the nucleus to the cytoplasm and the effects of XPO1 inhibition with selinexor [27, 29]. CDK, cyclin‐dependent kinase; cIAP, cellular inhibitor of apoptosis protein; NF‐κB, nuclear factor‐κB; GR, glucocorticoid receptor; IL, interleukin; MCL1, myeloid cell leukaemia sequence 1; PUMA, P53 up‐regulated modulator of apoptosis; Rb, retinoblastoma; TSP, tumour suppressor protein; VEGF, vascular endothelial growth factor; XPO1, exportin‐1.
FIGURE 2
FIGURE 2
US FDA and EMA approvals of selinexor in relapsed/refractory multiple myeloma. dex, dexamethasone; EMA, European Medicines Agency; FDA, Food and Drug Administration; US, United States; Vd, bortezomib‐dexamethasone.
See this image and copyright information in PMC

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