Inclusion Criteria:
* Patients must have histologically documented history of large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
* Adult males or females must be of age ≥18 years or older at time of signing informed consent.
* Patients must be capable of understanding the protocol with willingness to comply with all study procedures including availability for the duration of the study.
* Patients must be able to understand and willing to sign a written informed consent form (ICF) document.
* Measurable PET/CT positive disease (partial response or stable disease per the 2014 Lugano Classification) on PET/CT obtained at least 21 days after, but no more than 60 days after CAR-T with axicabtagene-ciloleucel.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
* Participants must have adequate organ and bone marrow function.
* Patients must have adequate hepatic function.
* Patients must have adequate renal function.
* Baseline Oxygen Saturation \>92% on room air.
* Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning lenalidomide therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with lenalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of lenalidomide therapy.
Exclusion Criteria:
* Patients who are currently receiving or who have received any investigational study agent ≤4 weeks prior to the screening visit are ineligible.
* Detectable cerebrospinal fluid malignant cells, brain metastases, or active central nervous system (CNS) lymphoma after CAR T cell administration.
* History or presence of CNS disorder, such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
* Presence of bacterial, viral, fungal, and/or other infection of any origin that is uncontrolled and/or requires intravenous (IV) antimicrobials for treatment.
* Known cardiac atrial or cardiac ventricular lymphoma involvement.
* History of symptomatic pulmonary embolism within 6 months of enrollment.
* Known primary immunodeficiency.
* History of autoimmune disease (e.g. Crohn's disease, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.
* History of hypersensitivity, allergy or severe skin reactions to lenalidomide (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis).
* History of hypersensitivity, allergy or previous exposure to tafasitamab.
* Any medical condition deemed by the treating physician likely to interfere with assessment of safety or efficacy of study treatment.
