Inclusion Criteria:

• - Diagnosis of primary myelofibrosis (PMF) according to the revised World Health Organization (WHO) criteria or post-essential thrombocythemia-MF or post-polycythemia vera according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria.

• - Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, intermediate-2 or high-risk MF.

• - Candidate for ruxolitinib treatment: 1.

Part 1 participants only: On ruxolitinib treatment for at least 12 weeks with at least 4 consecutive weeks immediately prior to enrollment at a stable dose. 2. Part 2 participants only: Candidate for ruxolitinib treatment as assessed by the investigator and has not previously been treated with a JAK inhibitor.

• - Clinical signs/symptoms of MF demonstrated by one of the following: 1.

Measurable splenomegaly demonstrated by either a palpable spleen measuring ≥5 cm below the left costal margin or a spleen volume ≥450 cm^3 by MRI or CT, 2. active symptoms of MF on the MFSAF v4.0.

• - Ineligible for or unwilling to undergo hematopoietic stem cell transplant at time of study entry.

• - Hematology laboratory test values within protocol defined limits.

• - Biochemical laboratory test values within protocol defined limits.

• - Eastern Cooperative Oncology Group Performance Status score of 0, 1, or 2.

• - Participants should follow protocol defined contraceptives procedures.

• - A woman of childbearing potential must have a negative serum or urine pregnancy test at screening.

Exclusion Criteria:

• - Peripheral blood blast count of ≥10% or bone marrow blast count of ≥10%.

• - Prior treatment with JAK inhibitor.

• - Known allergies, hypersensitivity, or intolerance to imetelstat or ruxolitinib or excipients.

• - Prior treatment with imetelstat.

• - Major surgery within 28 days prior to enrollment.

• - Any investigational drug regardless of class or mechanism of action, hydroxyurea, chemotherapy, immunomodulatory or immunosuppressive therapy, corticosteroids >30 mg/day prednisone or equivalent ≤14 days prior to enrollment.

• - Prior history of hematopoietic stem cell transplant.

• - Prior history of partial or complete splenectomy.

• - Diagnosis or treatment for malignancy other than MF, except: - Malignancy treated with curative intent and with no known active disease present for ≥3 years before enrollment.

• - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.

• - Adequately treated cervical carcinoma in situ without evidence of disease.

• - Clinically significant cardiovascular disease.

• - Known history of human immunodeficiency virus (HIV) or any uncontrolled active systemic infection requiring IV antibiotics.

• - Active systemic hepatitis infection requiring treatment or any known acute or chronic liver disease unless related to MF.

Carriers of hepatitis virus are permitted to enter the study.

Arms

Experimental: Imetelstat + Ruxolitinib

Part 1: Participants who have received ruxolitinib orally (PO) as part of standard of care (SOC) for at least 12 weeks prior to Screening will be enrolled. After enrollment, participants will initiate imetelstat therapy. Dose levels of imetelstat may include 4.7, 6, 7.5, 9.4mg, until a RP2D is established. Part 2: Janus kinase (JAK) inhibitor naïve participants will receive initial treatment with ruxolitinib for at least 12 weeks, including 4 weeks at a stable dose, followed by imetelstat treatment at the RP2D in combination with ruxolitinib.

Interventions

Drug: - Imetelstat

Imetelstat sodium will be administered as intravenous (IV) every 28 days.

Drug: - Ruxolitinib

Ruxolitinib will be administered, orally (PO), twice daily (BID) as the standard of care per local prescribing guidelines.