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Studies have shown a correlation between the expression of exportin 1 (XPO1) in the nuclear export system and with progression from Monoclonal Gammopathy of Undetermined Significance (MGUS) to Smoldering Multiple Myeloma (SMM), and finally to active MM. Data from a phase I study indicated efficacy of selinexor against a number of hematologic malignancies, including MM, both alone and in combination with low-dose dexamethasone. Most of the patients in phase I trial had heavily pretreated myeloma, Non-Hodgkin Lymphoma (NHL) and, Acute Myeloid Leukemia (AML).
Dan T. Vogl, from the Division of Hematology and Oncology, University of Pennsylvania, US, and colleagues, set out to expand these findings in a study in which selinexor and low-dose dexamethasone was used to treat patients refractory to all of the most effective and currently available anti-myeloma agents. This phase II trial was published in the Journal of Clinical Oncology in January 2018.
Patients with measurable disease based on International Myeloma Working Group (IMWG) guidelines and who had been treated with at least three prior anti-myeloma regimens, including an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, and pomalidomide were included in this study. Patients were disease-refractory to their most recent regimen, as well as refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide, either alone or in combination. This study also included a subset of patients who were disease refractory to an anti-CD38 monoclonal antibody. The primary endpoint was overall response rate (ORR).
This study indicated the beneficial use of combining selinexor with low-dose dexamethasone displaying an ORR of 21% in heavily pretreated MM patients who are refractory to many of the commonly used therapies. Higher response rates were associated with the use of low-dose dexamethasone, in comparison to selinexor alone. The overall survival rate was also improved when compared to historical controls. A future phase II trial is now planned, in which 122 patients with penta-refractory myeloma will be enrolled.
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