Inclusion Criteria:  Subjects must meet ALL of the following inclusion criteria to be enrolled in this study:  Voluntarily agreed to provide written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol. Adults ≥18 years of age at the time of providing voluntary written informed consent. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 for Phase 1b and status 0-2 for Phase 2 (Appendix 4). Life expectancy (in the opinion of the Investigator) of ≥3 months before enrollment.  Measurable disease by Lugano Classification (Arms 1-3; see Appendix 1) or IMWG 2016 criteria modified for inclusion (Arm 4; see Appendix 2).  Note: Modification to measurable disease at screening. Study EZH-1501 will require serum M-protein ≥0.5 g/dL (IMWG 2016 criteria measurable disease requires of serum M-protein ≥1 g/dL).  Willingness to undergo lymph node or bone marrow biopsies/aspirates before and, if applicable, after treatment during the Phase 2 portion of this study (biopsies and aspirate optional during the escalation phase) For subjects who have experienced any clinically significant toxicity related to a prior anticancer treatment (i.e., chemotherapy, immunotherapy, and/or radiotherapy): At the time the subject provides voluntary written informed consent, all toxicities have either resolved to grade 1 per NCI CTCAE Version 5.0 OR are clinically stable and no longer clinically significant.  Demonstrate adequate organ function as defined below:  Absolute neutrophil count (ANC) ≥1,000 /μL (≥1.0 × 109/L), or ANC ≥ 750 /μL (≥0.75 × 109/L) with bone marrow infiltration without growth factor support for at least 14 days subjects in Arms 1-3 and without growth factor support for 7 days for Arm 4. Platelet Count ≥ 75,000 /μL (≥75 × 109/L), 7 days after last platelet transfusion, if applicable. Hemoglobin ≥ 8 g/dL, 7 days after last transfusion, if applicable. Activated partial thromboplastin time (aPTT) ≤ 1.5 x upper limit of normal (ULN) and international normalized ratio (INR) ≤1.5 × ULN (unless on warfarin, then INR ≤3.0). In subjects with thromboembolism risk, prophylactic anticoagulation or antiplatelet therapy at Investigator discretion is recommended (Section 9.2.1). Total bilirubin ≤ 1.5 × ULN unless evidence of Gilbert's disease in which case < 3 × ULN. Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 3 × ULN. Adequate renal function defined as creatinine clearance (CLcr) ≥ 40 mL/min as estimated by the Cockcroft-Gault formula  Negative serologic or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection (Appendix 7).  Note: Patients whose HBV infection status could not be determined by serologic test results have to be negative for HBV-DNA by PCR to be eligible for study participation  Negative test results for hepatitis C virus (HCV) and human immunodeficiency virus (Appendix 8).  Note: Patients who are positive for HCV antibody have to be negative for HCV-RNA by PCR to be eligible for study participation  Females of childbearing potential (FCBP) must have a negative serum pregnancy test (beta-human chorionic gonadotropin [β-hCG] test with a minimum sensitivity of 25 mIU/mL or equivalent units of β-hCG) at screening and within 24 hours prior to the first dose of study drug. All females will be considered to be of childbearing potential unless they are naturally postmenopausal (at least 24 months consecutively amenorrhoeic [amenorrhea following cancer therapy does not rule out childbearing potential] and without other known or suspected cause) or have been sterilized surgically (i.e., total hysterectomy and/or bilateral oophorectomy, with surgery completed at least 28 days prior to the first dose of study drug).  NOTE: Subjects receiving lenalidomide or pomalidomide must be registered into the mandatory Revlimid REMSTM or Pomalyst REMSTM program, respectively, as well as be willing and able to comply with the program requirements.  FCBP must either practice complete abstinence or agree to use a highly effective method of contraception (<1% failure rate) beginning at least 28 days prior to the first dose of study drug, during study treatment (including during dose interruptions), and for 6 months after study drug discontinuation (see Section 9.3 for contraception requirements). Subjects must not breastfeed or donate oocytes while on study treatment or for and for 6 months after study drug discontinuation.  Note: See arm-specific requirements in Inclusion 18.  Male subjects must either practice complete abstinence or agree to use a latex or synthetic condom, even with a successful vasectomy (medically confirmed azoospermia), during sexual contact with a pregnant female or FCBP from first dose of study drug, during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation.  NOTE: Male subjects must not donate semen or sperm from first dose of study drug, during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation.  Clinical Study Protocol EZH-1501 Tazemetostat Amendment 3.0 24 September 2021 Epizyme, Inc. Confidential Page 14 of 171  Must have documented relapsed, refractory, or progressive disease after treatment with systemic therapy (refractory defined as less than partial response [PR] or disease progression <6 months after last dose) but is not considered refractory to the disease-specific combination regimen. Have provided sufficient tumor tissue to test for EZH2 mutation status and cell of origin at study-specific laboratories.  Subject must meet cancer-specific criteria as follows:  Diffuse Large B Cell Lymphoma (Arms 1 and 2):  I. Have histologically confirmed DLBCL (including primary mediastinal B cell lymphoma), with R/R disease following at least 2 lines of prior standard therapy, including alkylator/anthracycline (unless anthracycline-based chemotherapy is contraindicated)/anti-CD20-based therapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or equivalent) AND must be considered unable to benefit from intensification treatment with autologous hematopoietic stem cell transplantation (HSCT), as defined by meeting at least 1 of the following criteria:  I. Relapsed following, or refractory to, previous autologous HSCT II. Did not achieve at least a partial response to a standard salvage regimen (e.g., rituximab, ifosfamide, carboplatin, and etoposide phosphate [R-ICE] or rituximab, dexamethasone, cytarabine, and cisplatin [R-DHAP]) III. Ineligible for intensification treatment due to age or significant comorbidity IV. Ineligible for intensification treatment due to failure to mobilize an acceptable number of hematopoietic stem cells V. Refused intensification treatment and/or autologous HSCT Note: patients with high grade B cell lymphoma with myc, BCL2, and/or BCL6 are eligible for these arms.  II. Have genetic sequencing results for tumor biopsy or be willing to undergo genetic testing of the malignancy III. Have measurable disease as defined by Lugano Classification (Cheson, 2014; Appendix 1) IV. Have disease requiring treatment as determined by the Investigator  Mantle Cell Lymphoma (Arm 3) I. Have received at least 2 prior lines of therapy II. Have measurable disease as defined by Lugano Classification (Cheson, 2014; Appendix 1)  III. Pathologically confirmed MCL with typical mantle cell immunophenotype: CD-positive, CD2-positive, CD10-negative, and CD23-negative with:  I. Documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) by FISH testing and/or II. Overexpress cyclin D1 based on IHC, and III. Requires treatment based on MIPI score: https://www.mdcalc.com/mantle-cell-lymphoma-international-prognostic-index-mipi c) Multiple Myeloma (Arm 4)  I. Must have a known diagnosis of multiple myeloma according to IMWG 2016 criteria (Kumar, 2016; Appendix 2) with evidence of measurable disease, as defined by at least one of the following:  I. Serum M-protein ≥0.5 g/dL, OR Note: Modification to measurable disease at screening. EZH-1501 will require serum M-protein ≥0.5 g/dL (IMWG criteria measurable disease requires of serum M-protein ≥1 g/dL).  II. Urine M-protein ≥200 mg/24 hours, OR  III. In the absence of measurable M-protein, serum immunoglobulin free light chain:  o ≥10 mg/dL, and abnormal serum immunoglobulin kappa lambda free light chain ratio (<0.26 or >1.65).  II. Must have received at least 2-3 prior lines of therapy Note: ≥1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens (e.g., 3-6 cycles of initial therapy with bortezomib-dexamethasone followed by stem cell transplantation [SCT], consolidation, and lenalidomide maintenance) will be considered 1 line.  Other Arm-Specific Requirements:  Arms 1, 2, and 4 (Containing lenalidomide or pomalidomide):  I. All subjects must be registered into the respective mandatory REMS programs and be willing and able to comply with the requirements.  II. First pregnancy test must be performed within 10 to 14 days prior to first dose of study drug and the second pregnancy test must be performed within 24 hours prior to first dose of study drug.  III. FCBP must either practice complete abstinence or agree to use two reliable methods of contraception simultaneously. This includes ONE highly effective method of contraception and ONE additional effective contraceptive method. Contraception must begin at least 28 days prior to first dose of study drug, continue during study treatment (including during dose interruptions), and for 6 months after study drug discontinuation see Section 9.3 for contraception requirements).  Exclusion Criteria:  Subjects who meet ANY of the following exclusion criteria are NOT eligible to enroll in this study:  Known symptomatic brain metastases, carcinomatous meningitis/leptomeningeal metastases, central nervous system (CNS) lymphoma. Untreated or impending spinal cord compression in patients with MM (Arm 4).  Treatment with any of the following for cancer within the indicated timeframe of a specific treatment prior to first dose of study treatment:  Cytotoxic chemotherapy within 21 days for Arms 1-3 or 14 days for Arm 4 Noncytotoxic chemotherapy (e.g., small molecule inhibitor) within 14 days Nitrosoureas within 6 weeks Prior immunotherapy within 4 weeks Radiotherapy within 6 weeks from prior radioisotope therapy; at least 12 weeks from 50% pelvic or total body irradiation Autologous HSCT within 100 days Chimeric antigen receptor T-cell therapy (CAR-T) within 30 days. Note: all treatment-related toxicities must resolve prior to enrollment. Any investigational treatment within 4 weeks or at least 5 half-lives, whichever is shorter Live vaccine within 4 weeks Subjects with prior allogeneic HSCT. History of solid organ transplant. Major surgery within 4 weeks of the start of study drug. Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment, e.g., inadequately controlled thyroid function, active infection requiring systemic therapy, autoimmune anemia, or autoimmune thrombocytopenia.  Significant cardiac or cardiovascular impairment, defined as:  Congestive heart failure (New York Heart Association class 3 or 4), or a history of congestive heart failure (New York Heart Association class 3 or 4), unless a screening echocardiogram or multigated acquisition scan performed within 3 months before the start of study drug demonstrates a left ventricular ejection fraction ≥50% (Appendix 6). Uncontrolled hypertension Unstable angina Myocardial infarction or stroke within 6 months of first dose Cardiac ventricular arrhythmia Resting electrocardiogram (ECG) with corrected QT using Fridericia's formula (QTcF) ≥ 470 msec on 2 or more time points within a 24-hour period or a documented history of long QT syndrome. Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat prior to enrollment whereas subjects greater than 3 months since deep vein thrombosis/pulmonary embolism are eligible but recommended to receive prophylaxis at Investigator discretion. History of any bleeding disorder, peptic ulcer disease, or significant bleeding within the last 1 month prior to enrollment Are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, vomiting) that might impair the bioavailability of tazemetostat.  Subjects with known active infection, or reactivation of a latent infection, whether  bacterial, viral (including, but not limited to, Epstein-Barr virus, cytomegalovirus, hepatitis B, hepatitis C, and human immunodeficiency virus), fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with intravenous (IV) antibiotics (for IV antibiotics this pertains to completion of last course of antibiotic treatment) within 4 weeks of dosing) Hypersensitivity reaction to the active pharmaceutical ingredient of tazemetostat, CD20/CD3 BsAbs, tafasitamab-cxix, lenalidomide, acalabrutinib, pomalidomide, dexamethasone or any of the other relevant components of each combination regimen under study. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruits from the diet and all foods that contain those fruits from time of enrollment to while on study. Subjects taking medications that are known strong CYP3A inhibitors and strong or moderate CYP3A inducers (including St. John's wort) (See Section 9.2.1 and https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers; https://drug-interactions.medicine.iu.edu/MainTable.aspx). Is currently taking any prohibited medication(s) as described in Section 9.2.3 and is unable to discontinue or switch to an alternative treatment. Has had prior exposure to tazemetostat or other inhibitor(s) of EZH2. History of another invasive cancer within 3 years of the start of study drug, with the exception of treated non-melanoma skin cancer, treated superficial bladder cancer, or fully treated cancers with a remote probability of recurrence in the opinion of both the Medical Monitor and Investigator. Has prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN). Has cytogenetic abnormalities known to be associated with myeloid malignancies, such as those for MDS (e.g., del 5q, chr 7, abn) or MPN (e.g., JAK2 V617F). Has a prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL) Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the subject's participation in this study OR interfere with their ability to receive study treatment or complete the study. Female subjects who are pregnant or lactating/breastfeeding.  Cancer-specific criteria as follows:  Diffuse Large B Cell Lymphoma (Arm 1):  I. Patients with prior exposure to tafasitamab-cxix. II. Prior exposure to a regimen containing or single agent lenalidomide.  Diffuse Large B Cell Lymphoma (Arm 2):  I. Prior exposure to a regimen containing or single agent lenalidomide.  Mantle Cell Lymphoma (Arm 3):  I. Subjects unable to be transitioned off of proton pump inhibitors II. Subjects with known mutations that confer resistance to a BTK inhibitor (e.g. BTK C481S, C481R mutations).  III. Subjects who experienced an anaphylactic or hypersensitivity reaction related to BTKi or who progressed while on BTKi therapy will be excluded from the study.  Multiple Myeloma (Arm 4):  I. Prior exposure to pomalidomide