Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom's macroglobulinemia

Novel therapies are needed for patients with relapsed or refractory multiple myeloma (MM). We conducted a multicenter, phase 1 study in advanced hematological malignancies to assess the safety, efficacy and recommended phase 2 dose (RP2D) of oral selinexor, a selective inhibitor of the nuclear export protein XPO1. In the dose-escalation phase, 25 patients with heavily pretreated MM (22) or Waldenstrom's macroglobulinemia (3) were administered selinexor (3-60 mg/m2) in 8 or 10 doses per 28-day cycle. In the dose-expansion phase, 59 patients with MM received selinexor at 45 or 60 mg/m2 with 20 mg dexamethasone, twice-weekly in 28-day cycles, or selinexor (40 or 60mg flat dose) without corticosteroids in 21 day cycles. The most common non-hematologic adverse events (AEs) were nausea (75%), fatigue (70%), anorexia (64%), vomiting (43%), weight loss (32%) and diarrhea (32%), which were primarily grade 1 or 2. The most common grade 3 or 4 AEs were hematologic, particularly thrombocytopenia (45%). Single agent selinexor showed modest efficacy with an objective response rate (ORR) of 4% and clinical benefit rate (CBR) of 21%. In contrast, the addition of dexamethasone increased the ORR with all responses of ≥PR occurring in the 45 mg/m2 selinexor plus 20mg dexamethasone twice weekly cohort (ORR=50%). Furthermore, 46% of all patients showed a reduction in MM markers from baseline. Based on these findings, we conclude that selinexor in combination with dexamethasone is active in heavily pretreated MM and propose a RP2D of 45 mg/m2 (80mg) plus 20mg dexamethasone given twice-weekly.