Inclusion Criteria:
* Adults ≥ 18 years of age capable of providing informed consent
* Pathologically confirmed diagnosis of PMF, post-ET MF, or post-PV MF as per the World Health Organization (WHO) diagnostic criteria - Intermediate-1, Intermediate-2, or High-Risk disease by the Dynamic International Prognostic Scoring System (DIPSS)
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
* Baseline splenomegaly ≥ 5cm palpable below the left costal margin and in the midclavicular line OR ≥ 450cc by imaging (i.e. ultrasound, CT, MRI)
* Baseline anemia, defined by hemoglobin \< 10 g/dL within 28 days prior to Cycle 1 Day 1
* Baseline thrombocytopenia, defined by platelet count 50-150 x 109/L without platelet transfusions within 28 days prior to Cycle 1 Day 1
* Adequate organ function as demonstrated by the following within 28 days prior to Cycle 1 Day 1:
* ALT (SGPT) and/or AST (SGOT) ≤ 3x the upper limit of normal (ULN), or ≤ 4 x ULN if, upon judgment of the treating physician, it is believed to be due to MF-related extramedullary hematopoiesis (EMH);
* Direct bilirubin ≤ 1.5 x ULN; or ≤ 2x ULN if, upon judgment of the treating physician, it is believed to be due to MF-related extramedullary hematopoiesis (EMH) or documented Gilbert's syndrome;
* Creatinine clearance ≥ 30 mL/min;
* Prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (Exceptions to coagulation parameters may be considered for patients who are taking concomitant anticoagulation medications or have a documented anti-phospholipid antibody, after discussion with Study Chair approval)
* Bone marrow and/or peripheral blood blast count \< 5%; and
* Absolute neutrophil count (ANC) ≥ 1500 mm3 without need for growth factors within 7 days prior to Cycle 1 Day 1.
* Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia
* Life expectancy of at least six months
* Patients with active hepatitis B virus are eligible if antiviral therapy for hepatitis B has been given for \>8 weeks and the viral load is \<100 IU/mL.
* Patients with history of hepatitis C virus (HCV) are eligible if they have received adequate curative anti-HCV treatment and HCV viral load is below the limit of quantification.
* Patients with history of human immunodeficiency virus are eligible if they have cluster of differentiation (CD)4+ T-cell counts ≥350 cells/μL, negative viral load, and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last year and should be on established antiretroviral therapy for at least 4 weeks.
* Women of childbearing potential (WOCBP) and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Men must agree to use a condom and not father a child or donate sperm for the duration of the study and for 90 days after the last dose of study therapy
* Able to adhere to the study visit schedule and all protocol requirements
Exclusion Criteria:
* Prior treatment with Janus kinase (JAK) inhibitors
* Prior treatment with selinexor or other Exportin 1 (XPO1) inhibitors
* Treatment with any MF-directed therapy (including investigational therapies and excluding hydroxyurea) within 2 weeks or 5.5 half-lives, whichever is shorter, of Cycle 1 Day 1
* Completed hematopoietic cell transplant (HCT)
* Prior splenectomy, splenic irradiation, or splenic artery embolization within 6 months of Cycle 1 Day 1
* Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of pacritinib or selinexor, including any unresolved nausea, vomiting, or diarrhea \> National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v6.0 Grade 1
* Uncontrolled or currently progressing ocular toxicities
* Moderate or severe cardiovascular disease meeting one or both of the below criteria:
* Presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, or uncontrolled hypertension
* Documented major electrocardiogram (ECG) abnormalities (not responding to medical treatments)
* Grade 2 or greater bleeding event within the past 6 months
* QT corrected by the Fridericia method (QTcF) prolongation \> 480 ms or other factors that increase the risk for QT interval prolongation (eg, hypokalemia \[defined as serum potassium \< 3.0 mEq/L that is persistent and refractory to correction\], or history of long QT interval syndrome)
* Recipient of organ transplant
* History of major surgery or any planned surgical procedures within 28 days prior to Cycle 1 Day 1
* Other malignancy within the last three years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated non-metastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial/non-invasive transitional cell bladder carcinoma.
* Presence of active serious infection
* Use of any prohibited medications (5.8) within two weeks or five half-lives, whichever is longer, prior to Cycle 1 Day 1
* Women who are pregnant or lactating
* Any serious, unstable medical or psychiatric condition that would prevent (as judged by the Investigator) the subject from signing the informed consent form (ICF) or any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if they were to participate in the study or confounds the ability to interpret data from the study
* Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is investigational site or sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject
