Targeting Nuclear Export Proteins in Multiple Myeloma Therapy
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REVIEW ARTICLE
Targeting Nuclear Export Proteins in Multiple Myeloma Therapy Nicholas Theodoropoulos1 · Guido Lancman2 · Ajai Chari2
© Springer Nature Switzerland AG 2020
Abstract Multiple myeloma (MM) is an incurable malignancy of plasma cells with a clinical course characterized by multiple relapses and treatment refractoriness. While recent treatment advancements have extended overall survival (OS), refractory MM has a poor prognosis, with a median OS of between 4 and 6 months. Nuclear export inhibition, specifically inhibition of CRM1/ XPO1, is an emerging novel treatment modality that has shown promise in treatment-refractory MM. Initially discovered in yeast in 1983, early clinical applications were met with significant toxicities that limited their utility. The creation of small molecule inhibitors of nuclear export (SINE) has improved on toxicity limitations and has led to investigation in a number of malignancies at the preclinical and clinical stages. Preclinical studies of SINEs in MM have shown that these molecules are cytotoxic to myeloma cells, play a role in therapy resensitization, and suggest a role in limiting bone disease progression. In July 2019, selinexor became the first nuclear export inhibitor approved for use in relapsed/refractory MM based on the STORM trial. As of May 2020, there were eight ongoing trials combining selinexor with standard treatment regimens in relapsed/refractory MM. Eltanexor, a second-generation SINE, is also under investigation and has shown preliminary signs of efficacy in an early clinical trial while potentially having an improved toxicity profile compared with selinexor. Results in ongoing trials will help further define the role of SINEs in MM.
Key Points Multiple myeloma (MM) cells have been shown to have increased nuclear export protein expression that has been associated with increased lytic lesions as well as shorter progression-free survival and overall survival. Selinexor, an inhibitor of nuclear export, has shown benefit in treatment-refractory MM when used alone or in combination with dexamethasone or other conventional MM therapies. Results from numerous clinical trials evaluating selinexor in MM are eagerly anticipated to help define the role of nuclear export inhibition in MM.
* Ajai Chari [email protected] 1
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, Box 1185, New York, NY 10029, USA
2
1 Introduction Multiple myeloma (MM) is a plasma cell malignancy treated with combinations of drugs from a variety of drug classes, including immunomodulatory drugs (IMiDs; thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (PIs; bortezomib, carflizomib, ixazomib), anti-CD38 monoclonal antibodies (daratumumab, isatuximab), pan-deacetylase inhibitor (panobinostat), or immunostimulatory antiSLAMF7 antibody (elotuzumab), in addition to cytotoxic chemotherapy, corticosteroids, and autologous stem cell transplan
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