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.

High intratumoral FOXP3⁺ T regulatory cell (Tregs) density is an independent good prognosticator in nodal negative colorectal cancer.

Immunologic profiling of colorectal cancer (CRC) may help to predict the tumors metastatic potential and patients with an aggressive tumor, although not yet metastasized at time of surgery might benefit from adjuvant therapy. In this study we evaluated the prognostic significance of FOXP3(+) T regulatory cells (Tregs), CD3(+) and CD8(+) lymphocyte densities and conventional histopathologic features in nodal negative (n = 820, UICC stage II) CRC. Immunohistochemical studies showed that high expression of FOXP3(+) Tregs is significantly linked to a better clinical outcome (P = 0.0001). In multivariate analysis including tumor stage, tumor grade, type of tumor invasion margin (pushing vs. infiltrating type), lymphovascular invasion (absent vs. present), CD3(+), CD8(+) and FOXP3(+) Tregs expression, only low tumor stage, absence of lymphovascular invasion and high Foxp3 Tregs density showed prognostic significance (P = 0.0132, P = 0.0022 AND P = 0.0234, respectively). Our findings argue towards a clinical utility of FOXP3(+) Tregs immunostaining as an independent good prognostic biomarker in stage II colorectal cancers. FOXP3(+) Tregs immunoscoring, assessment of tumor stage and lymphovascular invasion may help to define stage II cancers with a potentially aggressive behavior and CRC patients who might benefit from adjuvant therapy. A two-scale immunosore related to the median count of FOXP3(+) Tregs proved to be easy and quick to perform.