Background: Most patients with the indolent non-Hodgkin lymphoma (NHL) subtypes FL or MZL respond to first-line treatment but relapse is common, and there is no single standard treatment for patients with R/R FL or MZL. Tafasitamab is an Fc-engineered humanized monoclonal antibody (mAb) against CD19 which is broadly expressed in FL and MZL, and regulates B-cell proliferation via B-cell receptor signaling. In preclinical studies, tafasitamab has shown activity against NHL cell lines in combination with rituximab (anti-CD20 mAb) and lenalidomide (LEN). Tafasitamab monotherapy has shown promising clinical activity in a phase 2a study in patients with R/R NHL (NCT01685008), with an ORR of 29% (n/N = 10/34) in patients with FL and 33% (n/N = 3/9) in patients with MZL. In an ongoing phase 2, single-arm study (L-MIND, NCT02399085), tafasitamab plus LEN followed by tafasitamab alone demonstrated an ORR of 57.5% (n/N = 46/80) in patients with R/R diffuse large B-cell lymphoma (FDA approved indication). These preclinical and clinical observations from phase 2 trials suggest a potential clinical benefit of tafasitamab plus LEN and rituximab for patients with R/R FL or MZL. Methods: This phase 3 double-blind, placebo-controlled, randomized study is designed to investigate whether tafasitamab plus LEN and rituximab provides improved clinical benefit compared with LEN and rituximab in patients with R/R FL or R/R MZL. Patients will be randomized 1:1 to receive tafasitamab (12 mg/kg IV on days 1, 8, 15, and 22 of a 28-day cycle [cycles 1–3], then days 1 and 15 [cycles 4–12]) plus LEN (20 mg PO QD, days 1–21/ cycle for 12 cycles) and rituximab (375 mg/m² IV on days 1, 8, 15, and 22 of cycle 1, then day 1 of cycles 2–5), or placebo (0.9% saline solution IV) plus LEN and rituximab. The primary study endpoint is PFS (investigator assessed [INV] by Lugano 2014 criteria) for patients with FL. Key secondary endpoints are PFS (INV) in overall population (FL and MZL), PET-CR rate (INV) at end of treatment (4–8 weeks after last treatment) and OS in patients with FL. Inclusion criteria include age ≥18 y, histologically confirmed FL (grade 1, 2, or 3a) or MZL (nodal, splenic, or extranodal), documented R/R disease, ≥1 prior systemic anti-CD20 therapy (including anti-CD20 refractory disease), ECOG PS ≤2, adequate systemic organ function, and high tumor burden (per GELF criteria). Exclusion criteria include prior rituximab plus LEN treatment, history of radiotherapy for other diseases (≥25% of bone marrow), nonhematologic malignancy, congestive heart failure (LVEF < 50%), active systemic infection, known CNS lymphoma, or severe immunocompromised state. inMIND (NCT04680052, EudraCT2020-004407-13) is currently enrolling patients; planned enrollment is 528 patients with R/R FL and 60–90 patients with R/R MZL. Clinical trial information: NCT04680052