The purpose of this study is to assess the efficacy and safety of of tafasitamab plus lenalidomide in adults with diffuse large B-cell lymphoma (DLBCL) who have relapsed or are refractory to at least 1 but no more than 3 previous systemic DLBCL treatment regimens and who are not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT).

Inclusion Criteria:

• Histologically-confirmed diagnosis of any of the following:

  1. Diffuse large B-cell lymphoma not otherwise specified
  2. T cell/histiocyte-rich large B-cell lymphoma
  3. Epstein-Barr virus positive DLBCL of the elderly
  4. Grade 3b follicular lymphoma
  5. Composite lymphoma with a DLBCL component with a subsequent DLBCL relapse
  6. Evidence of histological transformation from an earlier diagnosis of low grade lymphoma (ie, an indolent pathology such as follicular lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia) into DLBCL, with a subsequent DLBCL relapse

• Willingness to undergo tumor biopsy requirements for the study, (or have archival lymph node or tissue block from the most recent biopsy, not to exceed 3 years prior to C1D1).

• Willingness to undergo bone marrow biopsy/aspirate collections.

• History of relapsed/progressive/recurrent disease according to the International Working Group response criteria after the most recent systemic therapy.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

• Adequate hematologic, hepatic, and renal function,

• Left ventricular ejection fraction (LVEF) ≥ 50%,

• Willingness to avoid pregnancy or fathering children,

Exclusion Criteria:

• Any other histological type of lymphoma according to the WHO 2016 classification of lymphoid neoplasms, including:

  1. primary mediastinal (thymic) large B-cell lymphoma,
  2. Burkitt lymphoma,
  3. Primary refractory diffuse large B-cell lymphoma (DLBCL),
  4. History of double- or triple-hit DLBCL.

• Participants who, within 30 days prior to Cycle 1 Day 1, have:

  1. Not discontinued CD20-targeted therapy, chemotherapy, radiotherapy, investigational anticancer therapy or other lymphoma-specific therapy
  2. Undergone major surgery or suffered from significant traumatic injury
  3. Received live vaccines or have an anticipated need for such vaccination while receiving study treatment
  4. Required parenteral antimicrobial therapy for active, intercurrent infections

• Have undergone ASCT within the period ≤ 3 months prior to signing consent.

• Have undergone previous allogenic stem cell transplantation.

• Inadequate recovery (> Grade 1) from prior treatment toxicity and/or complications from major surgery before Cycle 1 Day 1.

• Have a history of deep venous thrombosis/embolism, threatening thromboembolism or known thrombophilia or are at high risk for a thromboembolic event in the opinion of the investigator and who are not willing/able to take venous thromboembolic event prophylaxis during the entire treatment period.

• Prior history of malignancies other than DLBCL, unless disease-free for ≥ 5 years prior to screening.

• Clinically significant cardiac disease, including unstable angina, acute myocardial infarction, New York Heart Association Class II to IV congestive heart failure, uncontrolled arrhythmia, and/or cardiac conduction issues, within 6 months of Cycle 1 Day 1.

• Any of the following positive tests:

  1. Known seropositive for or history of active viral infection with HIV.
  2. Known positive test result for hepatitis C (HCV antibody serology testing) and a positive test result for HCV RNA.
  3. Known positive test results for chronic HBV infection (defined by HBsAg positivity). Participants with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA was undetectable