Eltanexor (KPT-8602) With Inqovi (Decitabine-Cedazuridine) in High-Risk Myelodysplastic Syndromes

-INCLUSION CRITERIA:

1. Participants must have histologically or cytologically confirmed Myelodysplastic Syndromes (MDS) by the Laboratory of Pathology, NCI- according to 2016 World Health Organization (WHO) criteria AND:

   -Cohort 1 (Phase 1) \& 2 (Phase 2): have high-risk Myelodysplastic Syndromes (HR-MDS) Revised International Prognostic Scoring System (IPSS-R \> 3.5) with inadequate response to hypomethylating agent (HMA) therapy \[(received \>= 4 cycles of the standard dose (35 mg decitabine and 100 mg cedazuridine) without prior dose reductions, with failure to achieve at least a partial remission (PR) or experienced disease progression prior to completing 4 cycles)
2. Age \>=18 years
3. Eastern Cooperative Oncology Group (ECOG) performance status \<= 2 (Karnofsky \>= 60%,)
4. Participants must have adequate organ and marrow function as defined below:

   -total bilirubin \<= 1.5 X institutional upper limit of normal

   OR

   \<= 3 X institutional upper limit of normal in participants with Gilbert's syndrome (except for participants with increased bilirubin levels attributed to intramedullary hemolysis, which will be allowable)

   -Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine transaminase (ALT) serum glutamic pyruvic transaminase (SGPT) \<= 3 X institutional upper limit of normal

   OR

   \<= 5 X institutional upper limit of normal if related to MDS-specific cause
   * creatinine clearance (by Cockcroft-Gault) \>= 60 mL/min/1.73m\^2
   * corrected QT interval using the Fridericia formula (QTc(F) \<= 470 ms
5. Individuals of child-bearing potential (IOCBP) must have a negative serum test at screening. IOCBP is defined as the following:

   * Has not undergone a hysterectomy, tubal ligation, or bilateral oophorectomy
   * Has not been naturally postmenopausal for at least 24 consecutive months (i.e.,has had menses at any time in the preceding 24 consecutive months).
6. Individuals of childbearing potential (IOCBP) as well as those able to father a child with an individual able to become pregnant potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) unless they have had a prior vasectomy, hysterectomy, or bilateral oophorectomy, prior to study entry, for the duration of study participation, and for at least 6 months after last dose of HMA.
7. Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 30 days after the last administration of study drug
8. Any prior therapy must have been completed \>4 weeks or, if known, \>= 5 half-lives of the prior agent (whichever is shorter) prior to treatment (with a minimum of 1 week between prior therapy and study treatment). Note: This does not apply to prior HMA therapy if that therapy is Inqovi.
9. Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

1. Participants with platelet transfusion-refractory thrombocytopenia, with inability to keep platelet threshold above 10K/mcL with transfusions or those with ongoing or uncontrolled hemorrhagic complications.
2. Participants with clinically significant neutropenia, defined as absolute neutrophil count (ANC) \<100 cells/mcL with frequent hospitalizations for infection (average \> 1 hospitalization per month in the past 6 months).
3. Participants on treatment with a myeloid growth factor (e.g., granulocyte colony-stimulating factor (G-CSF) within 14 days prior to initiation of study treatment.
4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to HMAs, or other agents used in study.
5. Uncontrolled intercurrent illness evaluated by history, physical exam, and chemistries or situations that would limit compliance with study requirements, interpretation of results or that could increase risk to the participant
6. Participants with the following cardiac conditions: symptomatic congestive heart failure, unstable angina pectoris, or uncontrolled cardiac arrhythmia as assessed by electrocardiogram (ECG).
7. Pregnancy (confirmed with Beta-human chorionic gonadatropin (HCG) serum or urine pregnancy test performed in individuals of childbearing potential at screening)
8. Presence of any other malignancy (except basal and squamous cell carcinoma of the skin, or stable chronic cancers on hormone or targeted therapy) for which participant received systemic anticancer treatment (except maintenance therapy) within 24 months prior to treatment.
9. Participants with active/uncontrolled Hepatitis B
10. Participants with active/uncontrolled Hepatitis C
11. Participants with active/uncontrolled human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
12. Participants currently taking contraindicated medications for HIV, Hepatitis B, or Hepatitis C disease control