Selinexor for the treatment of multiple myeloma

ABSTRACT

Introduction: Despite unprecedented advances in the treatment of multiple myeloma (MM), almost all patients develop a disease that is resistant to the five most commonly used and active anti-MM agents. The prognosis for this patient population is particularly poor resulting in an unmet need for additional therapeutic options. Exportin-1 (XPO-1) is a major nuclear export protein of macromolecular cargo frequently overexpressed in MM. Selinexor is a first-in-class, oral Selective-Inhibitor-of-Nuclear-Export (SINE) compound that impedes XPO-1. Based on results of the STORM-trial, selinexor in combination with dexamethasone was granted accelerated FDA approval for patients with penta-refractory MM in July 2019.

Areas covered: This article summarizes our up-to-date knowledge on the pathophysiologic role of XPO-1 in MM. Furthermore, it reviews the most recent clinical data on selinexor in combination with dexamethasone and other anti-MM agents; and discusses its safety profile, management strategies; and potential future developments.

Expert opinion: Selinexor represents a next-generation-novel agent with an innovative mechanism of action that marks a significant advance in the treatment of heavily pretreated MM patients. Ongoing studies investigate its therapeutic potential also in earlier lines of therapy. Additional data is needed to confirm that selinexor and other SINE compounds are a valuable addition to our current therapeutic armamentarium.

KEYWORDS:

• Multiple myeloma
• exportin-1
• selective inhibitor of nuclear export (sine) compounds
• penta-refractoriness

Article Highlights

• With the increasing and earlier use of novel agents, a growing number of multiple myeloma (MM) patients are refractory to proteasome inhibitors (PIs), IMiDs, and the CD38 monoclonal antibody daratumumab (triple class refractory).

• Exportin-1 (XPO-1) is a major nuclear export protein of macromolecular cargo overexpressed in nearly all malignancies, including MM.

• Cargo molecules include almost all tumor suppressor proteins [TSPs], cell-cycle regulators, glucocorticoid receptor [GR], and translation initiation factor 4E-bound oncoprotein mRNAs.

• XPO-1 inhibition results in nuclear retention and accumulation of TSPs, the GR and oncogenic mRNAs thereby amplifying their apoptotic function and reducing oncoprotein synthesis in cells with damaged DNA/cancer cells.

• Selinexor is a first-in-class oral Selective Inhibitor of Nuclear Export (SINE) compound targeting XPO-1.

• Based on results of the STORM trial selinexor in combination with dexamethasone is the first FDA-approved SINE-containing therapy with clear activity in patients with penta-refractory MM.

• Selinexor crosses the blood-brain barrier and may therefore be a promising candidate for the treatment of central nervous and meningeal mmanifestation of MM.

• Ongoing studies investigate the efficiency and tolerability of other selinexor-containing combinations in heavily pretreated MM patients.

• Positive, preliminary results are likely to propel selinexor also into earlier lines of therapy.

Box 1. Drug summary box

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Declaration of interest

K Podar has received speaker’s honoraria from Celgene, Amgen Inc. and Janssen Pharmaceuticals as well as consultancy fees from Celgene, Takeda and Janssen Pharmaceuticals. He has also received research support from Roche Pharmaceuticals. A. Chari received grant support and consulting fees from Millennium/Takeda, grant support, advisory board fees, and consulting fees from Celgene, Novartis Pharmaceuticals, Amgen, and Janssen, and consulting fees from Bristol-Myers Squibb. A Chari has received advisory board fees from Sanofi and Oncopeptides, grant support from Pharmacyclics, and grant support and advisory board fees from Seattle Genetics. P Richardson has received grant support and honoraria from Oncopeptides, Celgene, and Takeda, grant support from Bristol-Myers Squibb, and honoraria from Amgen, Janssen, and Karyopharm Therapeutics. S Jagannath has received advisory board fees and consulting fees from Celgene, Bristol-Myers Squibb, Janssen Pharmaceuticals and Merck & Co. Finally, J Shah is employed by Karyopharm Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This manuscript has not been funded.