R1979-ONC-2210 (OLYMPIA-5)

Adult (>=18) R/R FL1-3a or MZL after >=1 prior systemic line incl anti-CD20; measurable disease; ECOG 0-2; adequate marrow/organ function; informed consent; questionnaire/visit compliance; lenalidomide precautions.

1. Local histologic confirmation of FL grade 1-3a or MZL (nodal, splenic, or extra nodal MZL) as assessed by the investigator. Participants with subtypes of extra nodal MZL where systemic anti-lymphoma therapy is indicated will be included. Corresponding tumor biopsy sample should also be sent to central laboratory. Availability of tumor tissue for submission to central laboratory is required for study enrollment. Archival tumor tissue for histological assessment prior to enrollment is allowed. 2. Must have refractory disease or relapsed after at least 1 prior line (with a duration of at least 2 cycles) of systemic chemo-immunotherapy or immunotherapy. Prior systemic therapy should have included at least one anti-CD20 antibody, and participant should meet indication for treatment. NOTE: Prior treatment with lenalidomide is allowed if previously tolerated at the approved full dose more than 6 months before the start of cycle 1 day 1. 3. Have measurable disease on cross sectional imaging documented by diagnostic computed tomography [CT], or magnetic resonance imaging [MRI] imaging (measurable disease is defined as at least 1 bi-dimensionally measurable nodal lesion of >1.5 cm or extranodal disease of >1 cm in the greatest transverse diameter (GTD) regardless of the short axis diameter). 4. Male or female >=18 years of age or the legal age of adults to consent to participate in a clinical study per country-specific regulations, whichever is greater, at the time of consent. 5. ECOG performance status of 0 to 2. 6. Adequate hematologic function, as measured by: - Platelet count >=75 x 10^9/L (no platelet transfusion within 7 days before first dose to meet criterion) - ANC >=1.0 x 10^9/L (no G-CSF within 2 days before first dose to meet criterion) - Hemoglobin >=9 g/dL NOTE: If low counts are believed due to marrow infiltration/splenic sequestration, enrollment may be considered. NOTE (marrow involvement/splenic sequestration): - Platelet count >=25 x 10^9/L (no platelet transfusion within 3 days before first odronextamab dose) - Hemoglobin >=7.0 g/dL - ANC >=0.5 x 10^9/L (no G-CSF within 2 days before first odronextamab dose) 7. Adequate organ function: - Cardiac ejection fraction >40% by echocardiogram or MUGA - Total bilirubin <=1.5 x ULN (<=3 x ULN if due to lymphoma liver infiltration) - ALT and AST <=3 x ULN (<=5 x ULN if due to lymphoma liver infiltration) - ALP <=2.5 x ULN (<=5 x ULN if due to lymphoma liver infiltration) NOTE: AST >3 x ULN and/or ALT >3 x ULN with concurrent total bilirubin >1.5 x ULN is exclusionary. NOTE: Known Gilbert syndrome excluded if total bilirubin >4 x ULN. - Calculated creatinine clearance (Cockcroft-Gault) >=60 mL/min NOTE: If calculated CrCl <60, measured CrCl >=60 mL/min may be accepted. 8. Ability to understand study purpose/risks and provide signed/dated informed consent and privacy authorization. 9. Willing and able to comply with clinic visits, study procedures, and patient diary documentation. 10. Able to understand and complete study-related questionnaires. 11. Able and willing to receive appropriate treatment/prophylaxis for thromboembolic events per investigator judgment. 12. All participants must: a) understand lenalidomide potential teratogenic risk; b) agree not to donate blood during study drug therapy and for 28 days after lenalidomide discontinuation; c) agree not to share study medication; d) agree to counseling on pregnancy precautions and fetal exposure risk with lenalidomide.

Exclude CNS lymphoma/involvement, transformed/high-grade histology, major uncontrolled comorbidity/infection, recent disallowed therapies, active COVID/HIV-HBV-HCV uncontrolled, pregnancy/breastfeeding, and contraception noncompliance.

1. Primary CNS lymphoma or known involvement (current or prior CNS involvement) by non-primary CNS NHL. NOTE: Suspected CNS involvement must be evaluated by CNS imaging (CT/MRI) and lumbar puncture as appropriate. 2. Histological evidence of transformation to high-grade or diffuse large B-cell lymphoma, or any histology other than FL grade 1-3a or MZL. 3. History of/current relevant CNS pathology (eg epilepsy, seizure, paresis, aphasia, apoplexy, severe brain injury, cerebellar disease, organic brain syndrome, psychosis) or inflammatory CNS lesions/vasculitis on MRI. 4. Other malignancy unless adequately/definitively treated and cancer-free >=3 years, except specified allowed cancers (eg localized prostate cancer on hormonal/local RT, cervical CIS, breast CIS, definitively treated nonmelanoma skin cancer). 5. Any other significant active disease/medical condition that may interfere with study conduct or pose significant risk, including major cardiovascular/pulmonary/GI/hepatic/renal/endocrine/hematologic/autoimmune/psychiatric/neurologic disorders. 6. Known malabsorption syndrome or pre-existing GI condition that may impair lenalidomide absorption (eg gastric bypass/lap band/other gastric procedures altering absorption); NG/gastrostomy delivery of lenalidomide not allowed. 7. High thromboembolic risk participants unwilling to take VTE prophylaxis. 8. Prior treatments: a) Any anti-lymphoma therapy within 28 days or 5 half-lives (whichever shorter) before assigned treatment start b) Any investigational therapy within 28 days before assigned treatment start c) Major surgery within 4 weeks before assigned treatment start (except lymph node biopsy) d) Standard radiotherapy within 14 days before first assigned treatment dose NOTE: Palliative RT to symptomatic lesion allowed if not a target lesion for tumor assessments e) Prior lenalidomide or any CD20xCD3 bispecific antibody within past 6 months f) Continuous systemic corticosteroids >10 mg/day prednisone equivalent within 72 hours of assigned treatment start g) Prior organ transplantation 9. Allergy/hypersensitivity: a) Severe allergic reaction to compounds with similar chemical/biologic composition as study drug/excipient b) Known hypersensitivity to both allopurinol and rasburicase 10. Infections: a) Active infection at enrollment or within 2 weeks if requiring ongoing treatment and/or with risk of dissemination/severe infection under immunosuppression; must be cleared or well controlled before study therapy b) Active COVID-19 c) Uncontrolled HIV/HBV/HCV infection d) CMV detectable by PCR at screening (must be treated and show >=2 undetectable CMV PCRs >=7 days apart before reconsideration) NOTE: Controlled HIV allowed (undetectable viral load, CD4 >350 cells/uL, spontaneous or on stable ART) NOTE: HBsAg+ or HBcAb+ participants must be evaluated and have controlled HBV (DNA PCR below detection + on antiviral therapy) NOTE: HCV Ab+ participants allowed if controlled infection (undetectable HCV RNA by PCR spontaneously or after successful prior therapy) 11. Live vaccination within 28 days before assigned treatment start. 12. Institutionalization by judicial/administrative authority order. 13. Clinical site study team members/immediate family unless Sponsor-approved. 14. Pregnant or breastfeeding women. 15. WOCBP unwilling to use highly effective contraception as specified (timing/method requirements), and male participants unwilling to meet condom/contraception and sperm donation restrictions per protocol. 16. Criterion removed in Amendment 2.