Selinexor in Combination with Pomalidomide and Low Dose Dexamethasone in a Relapsed / Refractory Multiple Myeloma Patient Population with Prior Proteasome Inhibitor and Lenalidomide Exposure

Introduction - The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of cell cycle regulators such as p53, IkB, and Rb. Pomalidomide/dexamethasone (Pd) is approved in relapsed/refractory MM (RRMM) with an overall response rate (ORR) of 30% and progression-free survival (PFS) rate of 3.6 months in patients (pts) having received a prior proteasome inhibitor (PI) and IMiD. Strategies to improve the ORR and PFS are needed. In murine MM models, the combination of selinexor with IMiDs shows synergistic anti-MM activity and good tolerability. We present the results of a phase I dose escalation study of selinexor in combination with pom and dex (SPd) in RRMM.

Methods - The primary objective of this phase 1b/2 study (NCT02343042) is to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of SPd. Patients (pts) with RRMM who received ≥ 2 prior therapies including lenalidomide (len) and a PI were enrolled. Selinexor was evaluated in 2 different dosing schedules of once-weekly (QW, 60; 80 mg) or twice-weekly (BIW, 60; 80 mg), with pomalidomide (pom) 4 mg PO daily, and dexamethasone (dex) 20 mg BIW or 40 mg QW.

Results - As of 15-Jul-2017, 29 pts (14 male / 15 female) have been enrolled. The median age is 61 years, with a median of 4 (range, 2 - 9) prior treatment regimens. Twenty-five patients were IMiD refractory (15 len, 2 pom, 8 pom/len). Three dose limiting toxicities (DLTs) were observed: G3 fatigue (60 mg BIW, pom 4 mg), G3 febrile neutropenia (60 mg BIW, pom 3 mg) and 4 missed doses in Cycle 1 (100 mg QW, pom 4 mg). Common treatment related Grade 1/2 adverse events (AEs) include: nausea (55%), fatigue (48%), anorexia (48%) and diarrhea (24%). Grade 3/4 AEs include: neutropenia (48%), thrombocytopenia (31%), and anemia (28%). Doses of 60 mg QW and 80 mg QW are being evaluted to determine RP2D. Twenty-four pts were evaluable for response. Responses rates can be seen in Table 1. Median PFS is 11.6 months with a median follow up of 7.7 months. Eight pts are still on study, (range 1 - 16+ months).

Conclusions - Once weekly selinexor can be safely combined with Pd. This all oral combination of selinexor, pom and dex (SPd) has significant clinical activity with an ORR 54% in pts with heavily pretreated MM compared to previously published data of 30% ORR. No additional toxicities over monotherapy with selinexor or the Pd combination were observed. The novel all oral combination of SPd is a well-tolerated regimen and supports further clinical development in RRMM.

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