A Study of Tazemetostat in Combination With Various Treatments in Participants With Blood Cancer.

This trial will study how safely the tazemetostat works with other therapies in various hematological malignancies. Hematologic malignancies are cancers that most often begin in the bone marrow or lymph nodes where blood precursors are produced.

They are often called blood cancers and fall into three categories: leukemia, lymphoma and myeloma.

Tazemetostat has been found to be a safe and effective drug that works in patients with follicular lymphoma where the disease has come back after treatment (known as relapsed) and when other treatment no longer works (known as refractory).

Combining tazemetostat with other treatments may work better in treating patients with hematological malignancies and may improve disease response and durability of response.

This phase 1b/2 trial studies how safely the EZH2 inhibitor tazemetostat works with other therapies in various hematological malignancies. Tazemetostat has been found to be a safe and effective drug that works in patients with relapsed refractory (R/R) follicular lymphoma. Giving tazemetostat in combination with other treatments may work better in treating patients with hematological malignancies and may improve disease response and durability of response.

Eligibility Criteria:
Inclusion Criteria:

1. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 for Phase 1b and status 0 to 2 for Phase 2
2. Must have documented relapsed, refractory, or progressive disease after 2 lines of treatment with systemic therapy
3. Measurable disease
4. Demonstrate adequate organ function
5. Negative test results for acute or chronic hepatitis B virus (HBV) infection, hepatitis C virus (HCV) and human immunodeficiency virus
6. No ongoing clinically significant reactions to prior anticancer treatments
7. Willingness to follow pregnancy precautions and register into the mandatory REMS program in lenalidomide and pomalizdomide arms

Exclusion Criteria:

1. Presence or history of central nervous system involvement by lymphoma
2. Less than minimum washout period of prior anticancer therapy as specified by the protocol
3. Prior allogeneic haematopoietic stem cell transplantation
4. History of solid organ transplant
5. Major surgery within 4 weeks of the start of study drug.
6. Significant cardiac or cardiovascular impairment as specified by protocol
7. Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat
8. History of any bleeding disorder, peptic ulcer disease, or significant bleeding within the last 1 month prior to enrollment
9. Are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition
10. Patients with known active infection, or reactivation of a latent infection, as specified by the protocol
11. Known sensitivity or allergy to the study medications
12. Unwilling to refrain from eating or drinking grapefruit juice, Seville oranges, and grapefruits while on study
13. Prior exposure to tazemetostat
14. Any condition that places the subject at unacceptable risk if he/she were to participate in the study or that confounds the ability to interpret data from the study.
15. Prior history of myeloid malignancies or T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL)
16. For patients with DLBCL in Arm 1 (tazemetostat plus tafasitamab plus lenalidomide) or Arm 2 (tazemetostat plus lenalidomide):

    - Prior exposure to lenalidomide
17. For patients with MCL in Arm 3 (tazemetostat plus acalabrutinib):

    * Prior exposure to a BTKi
    * Medical condition that would make treatment with a BTKi not reasonable (e.g. allergy to BTKi or mutations known not to respond to BTKi treatment or subjects unable to be transitioned off of proton pump inhibitors)
18. For patients with MM in Arm 4:

    * Prior exposure to pomalidomide
    * Untreated or impending spinal cord compression in subjects
19. For patients with FL in Arm 5:

    * Grade 3b, mixed histology, or FL that has histologically transformed to DLBCL.
    * History of significant neurological disorders, hemophagocytic lymphohistiocytosis (HLH), chronic active Epstein-Barr virus (EBV) infection, progressive multifocal leukoencephalopathy (PML), lung disease (ILD), drug-induced pneumonitis, autoimmune pneumonitis, and/or history of severe autoimmune disease