Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom 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 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 60 mg flat dose) without corticosteroids in 21-day cycles. The most common nonhematologic 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 of 21%. In contrast, the addition of dexamethasone increased the ORR with all responses of ≥partial response occurring in the 45 mg/m2 selinexor plus 20 mg 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 (80 mg) plus 20 mg dexamethasone given twice weekly. This trial was registered at clinicaltrials.gov as #NCT01607892.

The risk of secondary primary malignancies after therapy for multiple myeloma.

The development of a secondary primary malignancy (SPM) has become an important issue in myeloma management, given the remarkable improvement in survival afforded by the introduction of novel agents. Treatment with immunomodulatory derivatives, specifically lenalidomide, has recently been identified as a potential risk factor for SPM in several studies, especially in the maintenance setting. This study reviews potential mechanisms for development of SPM, incidence of SPM with different treatment regimens, risk factors associated with SPM and features of SPM after myeloma therapy. The incidence of SPM is discussed in the context of different settings in which lenalidomide is used during the course of the disease. No clear evidence indicates that lenalidomide alone is associated with SPM in the absence of other risk factors. Routine cancer surveillance, lifestyle modification to avoid cancer risk factors and prompt evaluation if new symptoms occur should be emphasized to patients who are on continuous myeloma therapy.