Comparing Momelotinib and Ruxolitinib in People With Untreated Myelofibrosis and Low Blood Cell Counts

Registration Step 1: Randomization Inclusion Criteria: * Participants must have confirmed diagnosis of primary myelofibrosis (PMF), post-polycythemia vera (PV) MF or post-essential thrombocythemia (ET) MF as assessed by the treating physician per 2022 WHO classification, and confirmed by a bone marrow biopsy within four years. * Participants must have a spleen measuring ≥ 450 cm3 by MRI within 14 days prior to Step 1 registration. For participants with a medical contraindication to MRI or if MRI is unavailable, a CT scan may be performed. * Participants must have DIPSS risk category of Intermediate-1, Intermediate-2 or High per Dynamic International Prognostic Scoring System (DIPSS) for MF. * Participants must have blasts \<10% in peripheral blood within 28 days of Step 1 registration. If bone marrow biopsy performed within 28 days prior to Step 1 registration blasts must be \<10% as well. * Participants must have discontinued all drugs used to treat MF, including hydroxyurea, peginterferon alfa-2a, ropeginterferon alfa-2b, anagrelide or busulfan ≥ 14 days prior to Step 1 registration. * Participants must be ≥ 18 years old at the time of registration. * Participants must have Zubrod/ECOG Performance Status of 0-2. * Participants must have a complete medical history and physical exam within 28 days prior to Step 1 registration. * Participants must meet hematologic parameters within 28 days prior to Step 1 registration. * Participants must have a calculated creatinine clearance ≥ 30 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to Step 1 registration. For creatinine clearance formula see the tools on the CRA Workbench https://txwb.crab.org/TXWB/Tools.aspx. * Participants must be able to take orally administered medication and comply with the oral regimen. * Participants with a history of human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at Step 1 registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to Step 1 registration. * Participants with a history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load while on suppressive therapy on the most recent test results obtained within 6 months prior to Step 1 registration, if indicated. * Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to Step 1 registration, if indicated. * Participants must be offered the opportunity to participate in specimen banking. * Participants who can complete PRO and QOL questionnaires in English or Spanish languages must agree to participate in the patient-reported outcomes and quality of life questionnaires. * Participants or their legally authorized representative must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines. For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and WCG IRB regulations. Exclusion Criteria: * Participants must have discontinued all drugs used to treat MF, including hydroxyurea, peginterferon alfa-2a, ropeginterferon alfa-2b, anagrelide or busulfan ≥ 14 days prior to Step 1 registration. * Participants must not be considered eligible for hematopoietic stem cell transplantation (HSCT) or have prior HSCT for MF. * Participants must not have received prior JAK or ACVR1 inhibitor treatment. * Participants must not have received investigational therapy within 14 days prior to Step 1 registration. * Participants must not have had a prior splenectomy. * Participants must not have had splenic irradiation within 90 days prior to Step 1 registration. * Participants must not have received prior chemotherapy for their MF (e.g., hypomethylating agent, hypomethylating agent + venetoclax). * Participants must not have had major surgery within 21 days prior to Step 1 registration. * Participants must not have received a live vaccine within 14 days prior to Step 1 registration. * Participants must not have grade 2 or higher peripheral neuropathy. * Participants must not have clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; or unstable angina pectoris. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. * Participants must not have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). * Participants must not have history of stroke, reversible ischemic neurologic deficit, or transient ischemic attack within 90 days prior to Step 1 registration. * Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Participants with curatively treated basal or squamous cell skin cancer, superficial bladder cancer, in situ cervical cancer and/or in situ breast cancer may be enrolled. * Participants must not have uncontrolled systemic fungal, bacterial, viral or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) as determined by the local investigator. * Participants must not be pregnant or nursing (nursing includes breast milk fed to an infant by any means, including from the breast, milk expressed by hand, or pumped). Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen. Registration Step 2: Optional Crossover for All Participants after Week 24 Assessment Inclusion Criteria: * Participants must have met one or more of the following criteria on Registration Step 1: 1. Spleen volume decrease \<10% or spleen volume increase of any volume from baseline MRI (or CT) in response to initial treatment (momelotinib or ruxolitinib) from baseline MRI (or CT) at week 24. 2. ≥ 3 units of RBC transfusions during any rolling 8-week period starting at or after week 16 preceding Step 2 registration OR hemoglobin \< 8 g/dL on two consecutive measurements at least 1 week apart during any rolling 8-week period starting at or after week 16 preceding Step 2 registration. 3. Unacceptable toxicities attributed to initial treatment (momelotinib or ruxolitinib) of grade ≥ 3 (or grade \< 3 if determined clinically significant by treating physician) as determined by treating physician. 4. Unable to maintain total daily ruxolitinib dose ≥ 20 mg due to cytopenias or intolerance (crossover to momelotinib only). * Participants must be able to safely receive the crossover drug (either momelotinib or ruxolitinib) in the opinion of the treating investigator. * Participants must have adequate organ and marrow function within 14 days prior to Step 2 registration. * Participants must have a calculated creatinine clearance ≥ 30 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 14 days prior to Step 2 registration. For creatinine clearance formula see the tools on the CRA Workbench https://txwb.crab.org/TXWB/Tools.aspx.