Inclusion Criteria:  Documented morphologically confirmed diagnosis of HR MDS according to the 2016 World Health Organisation (WHO) classification. All participants must also have one of the following Prognostic Risk Categories based on the Revised International Prognostic Staging System (IPSS-R): Very high >6 points, high (4.5 to 6 points), or intermediate >3 to 4.5 points. Participants in the intermediate category must have >5% bone marrow myeloblasts. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of ≤2. Able to undergo the study-required bone marrow sample collection procedures. Suitable venous access for the study-required blood sampling (i.e., including pharmacokinetic (PK) sampling).  Known Human Immunodeficiency Virus (HIV)-positive participants who meet the following criteria will be considered eligible:  Cluster of differentiation 4 (CD4) count >350 cells per cubic millimeter (cells/mm^3). Undetectable viral load. Maintained on modern therapeutic regimens. No history of Acquired Immune Deficiency Syndrome (AIDS)-defining opportunistic infections.  Exclusion Criteria:  Histologically or cytologically documented diagnosis of Acute Myelogenous Leukemia (AML) or Chronic Myelomonocytic Leukemia (CMML). Previous treatment for HR MDS with chemotherapy or other antineoplastic agents, including hypomethylating agents (HMAs), such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first dose of study drug(s). Have known hypersensitivity to pevonedistat or its excipients. Have known hypersensitivity to oral decitabine and cedazuridine or its excipients. Diagnosed or treated for another malignancy within 2 years before enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection. Participants with either clinical evidence of or history of central nervous system (CNS) involvement. Are known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. (Note: Participants who have isolated positive hepatitis B core antibody [i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody] must have an undetectable hepatitis B viral load. Participants with history of hepatitis C virus [HCV] infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.) Have known hepatic cirrhosis or severe pre-existing hepatic impairment. Have known cardiopulmonary disease, defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or myocardial infarction within 6 months before first dose, or severe pulmonary hypertension. As an example, well-controlled atrial fibrillation (AF) would not be an exclusion, whereas uncontrolled AF would be an exclusion. Have positive test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that is laboratory confirmed by a reverse transcription polymerase chain reaction (RT-PCR) test at screening. Testing related to coronavirus disease 2019 (COVID-19) must be performed according to institutional policy and/or per local regulatory guidelines. Participants who have had a known infection of SARS-CoV-2 or COVID-19 are permitted if COVID-19 RT-PCR test is negative prior to the screening visit and they present with no symptoms. Participants with documented vaccination history for COVID-19 do not need to be tested, unless they are symptomatic, according to institutional policy and/or local regulatory guidelines.