Background: Myelofibrosis (MF) is a myeloproliferative neoplasm with common somatic gene driver mutations in JAK2, CALR, and MPL. Selinexor, an investigational oral XPO1 inhibitor, may inhibit MF-relevant JAK/STAT and non-JAK/STAT pathways. Preclinical studies have shown potential synergy with ruxolitinib treatment. In the phase 1 portion of XPORT-MF-034 evaluating selinexor plus ruxolitinib in JAKi-naïve patients with MF, the most common AEs in the 60 mg cohort were nausea (79%), anemia (64%), thrombocytopenia (64%), and fatigue (57%). Nausea was predominantly Grade 1 and transient in nature. Treatment-related AEs leading to treatment discontinuation were thrombocytopenia (n=1) and neuropathy (n=1). SVR35 and TSS50 was achieved by 79% and 58% of the 60 mg cohort intent-to-treat population at Week 24, respectively. Response rates were consistent across subgroups, including sex and regardless of ruxolitinib starting dose. These data provide strong support to further evaluate selinexor (60 mg) and ruxolitinib in patients with JAKi-naïve MF. Methods: The XPORT-MF-034 (NCT04562389) trial includes a global, Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate selinexor and ruxolitinib. JAKi-naïve patients with MF will be randomized 2:1 to receive oral selinexor 60 mg or placebo once weekly (28-day cycle) and twice daily ruxolitinib. Randomization will be stratified by DIPSS risk category (int-1 vs int-2 or high-risk), spleen volume (<1800 cm³ vs >1800 cm³ by MRI/CT scan), and baseline platelet counts (100-200x10⁹/L vs >200x10⁹/L). Dual anti-emetics for nausea prophylaxis will be required for the first two cycles. Select eligibility criteria include ≥18 years of age, spleen volume ≥450 cm³ by MRI or CT, DIPSS intermediate-1, intermediate-2, or high-risk, active symptoms of MF (MFSAF v4.0), currently not eligible for stem cell transplantation, ECOG≤2, and platelet count ≥100 x 10⁹/L. Select exclusion criteria include >10% blasts in peripheral blood or bone marrow; previous treatment with JAKi for MF, or previous treatment with selinexor or other XPO1 inhibitors. The co-primary study endpoints are SVR35 and TSS50 at Week 24 and will be tested hierarchically. The key secondary endpoint is anemia response at Week 24 per the IWG-MRT and ELN criteria. The XPORT-MF-034 Phase 3 trial is currently open for enrollment; a total of 306 JAKi-naïve MF patients will be enrolled and the study was initiated on June 28, 2023. Clinical trial information: NCT04562389.