A Study Comparing Imetelstat Versus Best Available Therapy for the Treatment of Intermediate-2 or High-risk Myelofibrosis (MF) Who Have Not Responded to Janus Kinase (JAK)-Inhibitor Treatment

Inclusion Criteria:

• Diagnosis of primary myelofibrosis according to the revised World HealthOrganization criteria or post-essential thrombocythemia-MF or post-polycythemiavera-MF according to the IWG-MRT criteria

• Dynamic International Prognostic Scoring System intermediate-2 or high-risk MF

• Relapsed/refractory to JAK-inhibitor treatment as defined in either inclusion (i), (ii) or (iii) and not eligible for allogeneic stem cell transplantation (ASCT) atscreening:

• (i) Treatment with JAK-inhibitor for >= 6 months duration, including at least 2months at an optimal dose as assessed by the investigator for that participantand at least one of the following:

1. no decrease in spleen volume (< 10% by MRI or CT) from the start oftreatment with JAK-inhibitor
2. no decrease in spleen size (< 30% by palpation or length by imaging) fromthe start of treatment with JAK-inhibitor
3. no decrease in symptoms (< 20% by Myelofibrosis Symptom Assessment Form [MFSAF] or myeloproliferative neoplasm SAF) from the start of treatmentwith JAK-inhibitor
4. a score of at least 15 on TSS assessed using the MFSAF v4.0 duringscreening.

• (ii) Treatment with JAK-inhibitor treatment for>= 3 months duration withmaximal doses (e.g., 20-25 mg twice daily ruxolitinib) for that participant andno decrease in spleen volume/size or symptoms as defined in inclusion criterion (i [a, b, or c]).

• (iii) Following maximum tolerated doses of JAK inhibitor therapy for ≥3 monthsduration, having documented relapsed disease defined as either

1. Increase in spleen volume from time of best response by 25% measured byMRI or CT, or
2. Increase in spleen size by palpation, CT, or ultrasound

• (b.i) For splenomegaly of 5-10 cm at the start of JAK inhibitortreatment, at least 100% increase in palpable spleen size from timeof best response;
• (b.ii) For splenomegaly of > 10 cm at the start of JAK inhibitortreatment, at least 50% increase in palpable spleen size from time ofbest response;

AND not a candidate for further JAK inhibitor at screening per investigator.

• Measurable splenomegaly demonstrated by a palpable spleen measuring >= 5 cm belowthe left costal margin or a spleen volume >= 450 cm^3 by MRI or CT

• Active symptoms of MF on the MFSAF v4.0 demonstrated by a symptom score of at least 5 points (on a 0 to 10 scale)

• Hematology laboratory test values within the protocol defined limits

• Biochemical laboratory test values must be 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 testat screening

Exclusion Criteria:

• Peripheral blood blast count of >= 10% or bone marrow blast count of >=10%

• Known allergies, hypersensitivity, or intolerance to imetelstat or its excipients

• Prior treatment with imetelstat

• Any chemotherapy or MF directed therapy, including investigational drug regardlessof class or mechanism of action, immunomodulatory or immunosuppressive therapy,corticosteroids greater than 30 mg/day prednisone or equivalent, and JAK-inhibitortreatment less than equal to 14 days prior to randomization

• Diagnosis or treatment for malignancy other than MF except:

• Malignancy treated with curative intent and with no known active diseasepresent for >= 3 years before randomization

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease

• Adequately treated cervical carcinoma in situ without evidence of disease

• Known history of human immunodeficiency virus or any uncontrolled active systemicinfection requiring IV antibiotics

• Active systemic hepatitis infection requiring treatment (carriers of hepatitis virusare permitted to enter the study), or any known acute or chronic liver diseaserequiring treatment unless related to underlying hepatosplenomegaly due to MF

• Major surgery within 28 days prior to randomization

• Any life-threatening illness (e.g., coronavirus disease-2019), medical condition, ororgan system dysfunction which, in the investigator's opinion, could compromise theparticipant's safety, interfere with the imetelstat metabolism, or put the studyoutcomes at undue risk