Inclusion Criteria:  Confirmed diagnosis of PMF, post-PV MF or post-ET MF (WHO) High-risk, or intermediate-1 and 2 risk, defined by Dynamic International Prognostic System (DIPSS) ECOG of 0 or 1  Exclusion Criteria:  Subjects who are positive for p53 mutation (Arm 1) Prior MDM2 inhibitor therapy or p53-directed therapy (Arm 1) Prior treatment with any JAK inhibitor Prior splenectomy Splenic irradiation within 24 weeks prior to randomization Prior allogeneic stem-cell transplantation or plans for allogeneic stem-cell transplant History of major organ transplant Grade 2 or higher QTc prolongation Major hemorrhage or intracranial hemorrhage within 24 weeks prior to randomization