Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Adults ≥ 18 years of age at time of signing the informed consent

• Participants must voluntarily sign informed consent form (ICF) and be willing and able to adhere to the study visit schedule and all protocol requirements.

• Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• Participants must have a pathologically confirmed diagnosis of PMF, post-ET-MF or post-PV-MF as per the WHO diagnostic criteria, with intermediate-1 or higher risk disease by DIPSS (14.1).

• Criteria for COHORT-1 (Monotherapy): Treated with at least one prior line of JAK inhibitor therapy to which they were refractory/resistant, lost response, or intolerant, or is not a candidate for approved JAK inhibitor therapy per investigator judgement, and with one or more of the following features of active disease:

  • Spleen palpable ≥ 5 cm below the left costal margin or > 450cm3 by MRI/CT
  • MPN-SAF TSS ≥ 10
  • Transfusion dependence (requiring at least 6 units of PRBCs in the 12 weeks prior to study enrollment, for a hemoglobin < 8.5g/dL in the absence of bleeding or treatment-induced anemia)

• Criteria for COHORT-2 (Combination therapy): Currently receiving treatment with an approved JAK inhibitor (including ruxolitinib, fedratinib, or momelotinib) with stable dose for at least 12 weeks prior to study enrollment, and with one or more of the following features of active disease:

• Spleen palpable ≥ 5 cm below the left costal margin or > 450cm3 by MRI/CT

• MPN-SAF TSS ≥ 10

• Transfusion dependence (requiring at least 6 units of PRBCs in the 12 weeks prior to study enrollment, for a hemoglobin < 8.5g/dL in the absence of bleeding or treatment-induced anemia)

• Adequate organ function as demonstrated by the following within 28 days prior to Cycle 1 Day 1:

  • ALT (SGPT) and/or AST (SGOT) < 3 × the upper limit of normal (ULN), or < 5 × ULN if, upon judgment of the treating physician, it is believed to be due to MF-related extramedullary hematopoiesis (EMH);
  • Total bilirubin < 3 × ULN for age (< 4 x ULN for age if attributed to MF related EMH or Gilbert's syndrome)
  • Creatinine clearance ≥ 30 mL/min by Cockcroft Gault formula;
  • Prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 × upper limit of normal (ULN)
  • Adequate cardiac function defined as ejection fraction of ≥50% by echocardiogram or multigated acquisition (MUGA) scan
  • Bone marrow and/or peripheral blood blast count < 10%;
  • Absolute neutrophil count (ANC) ≥ 1000 mm3; and
  • Platelet count ≥ 75 x 109/L at time of enrollment

• QTcF ≤ 450msec at screening

• Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia

• Life expectancy of at least six months

• Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine or serum pregnancy test within 72 hours before the initiation of protocol therapy. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be obtained. Participants are considered to be not of childbearing potential if they are considered to be post-menopausal or surgically sterilized (eg, , hysterectomy, bilateral salpingectomy). Females who have been amenorrheic for at least 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression or any other reversible reason.

  • Females of childbearing potential must be willing to use a highly effective method of contraception from the time of first study intervention dose through the required contraceptive period (4 months following the last dose of study drug) and must be willing to refrain from in vitro fertilization and egg donation during the required contraceptive period.
  • Males must be surgically sterile or agree to use barrier contraception (male condoms) from the time of first study intervention dose through the required contraceptive period of 4 months after last dose of study drug. Males must be willing to refrain from sperm donation during the required contraceptive period.

• Able to adhere to the study visit schedule and all protocol requirements Exclusion Criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

• Treatment with any MF-directed therapy (including investigational therapies) within 2 weeks or 5 half-lives, whichever is shorter, of Cycle 1 Day 1

  • Participants in COHORT-1 should not have received a JAK inhibitor within 14 days prior to Cycle 1 Day 1. Participants who remain on JAK inhibitor at time of screening should be tapered off per investigator discretion.
  • Hydroxyurea is permitted until the day prior to C1D1, if needed for disease control.

• Undergone allogeneic hematopoietic stem cell transplant (allo-HSCT) within the last 6 months prior to enrollment, or with active GVHD and/or on immunosuppressive therapy.

• Not currently a candidate for allo-HSCT, per investigator discretion. Patients who are not willing to undergo transplantation or for whom a suitable donor is not available are considered as transplant ineligible.

• Prior splenectomy, splenic irradiation, or splenic artery embolization within 6 months of C1D1

• GI disease meeting any of the following criteria:

  • Impairment of GI function that could significantly alter the absorption of revumenib (eg. Gastric bypass, gastroparesis)
  • Cirrhosis with a Child-Pugh score of B or C, or National Cancer Institute (NCI) Organ Dysfunction Working Group category of Severe Dysfunction
  • Inability to swallow oral medications

• Any of the following cardiac abnormalities:

  • Any of the following within the 6 months before study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Class ≥II), life-threatening, uncontrolled arrhythmia, cerebrovascular accident or transient ischemic attack. Participants with controlled atrial fibrillation are allowed to enroll
  • QTcF (Fridericia's correction) > 450ms at screening
  • Diagnosis of suspicion of Long QT syndrome or family history of Long QT syndrome

• Recipient of organ transplant

• 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 uncontrolled active infection of any type. Mild to moderate localized infections under control with antibiotic treatment are acceptable for study entry. Patients with ongoing serious infection are not eligible regardless of antimicrobial therapy. Prophylactic antibiotics are acceptable per NCCN infection guidelines.

• If participant is known to be human immunodeficiency virus (HIV)-positive, they must have an undetectable HIV viral load within the previous 6 months. If viral load testing has not been performed within the previous 6 months, it much be performed during screening.

• Known active or chronic hepatitis B, or active hepatitis C infection. Participants with a history of HCV infection who have completed curative therapy for HCV at least 12 weeks before the Screening Visit and have a documented undetectable viral load at the Screening Visit are eligible for inclusion.

• The following exclusions apply related to concomitant use of CYP3A4 inhibitors and inducers:

  • Participants who will not receive revumenib with coadministration of a strong CYP3A4i (eg, itraconazole, ketoconazole, posaconazole, or voriconazole) must discontinue all strong CYP3A4 inhibitors at least 7 days or 5 half-lives, whichever is longer, before the first dose of revumenib. They will receive goal dose of revumenib 270 mg Q12h and they may continue to receive moderate or weak CYP3A4 inhibitors, including fluconazole and isavuconazole.
  • Participants who will receive revumenib with coadministration of a strong CYP3A4i (eg, itraconazole, ketoconazole, posaconazole, or voriconazole) must have started the treatment at least 24 hours before the first dose of revumenib. They will receive goal dose of revumenib 160 mg Q12h.
  • Concomitant use of a strong or moderate CYP3A4 inducer is prohibited while on study. Strong or moderate inducers of CYP3A4 should be discontinued at least five half-lives or 14 days (whichever is longer) prior to the first dose of revumenib.

• Participants requiring the concurrent use of medications known or suspected to prolong the QT/QTc interval, with the exception of drugs with low risk of QT/QTc prolongation that are used as standard supportive therapies (eg, diphenhydramine, famotidine, ondansetron, sulfamethoxazole and trimethoprim) and the azoles permitted. Females who are pregnant or lactating.

• Any serious, unstable medical or psychiatric condition that would prevent (as judged by the Investigator) the participant from signing the informed consent form or any condition, including the presence of laboratory abnormalities and inability to swallow pills, which places the participant 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 participant.