This is an open label, multi-center, international, randomized phase III trial to compare the efficacy of Mosunetuzumab-Lenalidomide with investigator choices exclusively in R/R MZL patients. Patients with a proven diagnosis of EMZL, SMZL or NMZL subtypes and previously treated with at least one prior systemic treatment and not more than three prior lines are eligible. Previous treatment line must include at least one systemic line with a drug targeting CD20 (monoclonal antibody at least 2 cycles) with or without chemotherapy (R-CHOP, R-Bendamustine, R-CVP, R-Chlorambucil at least 2 cycles) or targeted treatment such as Ibrutinib.

The patients will be Randomized as follows:

Arm A - Experimental arm:

• Mosunetuzumab-Lenalidomide

Arm B - Comparator arms ( Investigator Choices):

• Rituximab-Lenalidomide
• Rituximab-Bendamustine
• Rituximab-CHOP

This is an open label, multi-center, international, randomized phase III trial to compare the efficacy of Mosunetuzumab-Lenalidomide with investigator choices exclusively in R/R MZL patients. Patients with a proven diagnosis of EMZL, SMZL or NMZL subtypes and previously treated with at least one prior systemic treatment and not more than three prior lines are eligible. Previous treatment line must include at least one systemic line with a drug targeting CD20 (monoclonal antibody at least 2 cycles) with or without chemotherapy (R-CHOP, R-Bendamustine, R-CVP, R-Chlorambucil at least 2 cycles) or targeted treatment such as Ibrutinib.

Patients are stratified according to MZL subtypes and time to progression of disease after first-line within 2 years (POD24) < 2 years or > 2 years.

Mosunetuzumab will be administered sub-cutaneously (SC) (21 days first cycle, then 28 days next cycles) and Lenalidomide will be given PO 20 mg/day from Day 1 to Day 21 from cycles C2 to C6. For each patient, investigator choice had to be decided before randomization between Rituximab-Lenalidomide and Rituximab-chemotherapy (R-Bendamustine or R-CHOP).

The primary efficacy endpoint for comparison is the Progression-free survival (PFS) as determined by investigator (Lugano criteria 2014). Secondary objectives include CR24 as determined by investigator (at 24 months) according to Lugano criteria 2014 and by central review based on PET result, Overall response rate (ORR) and CR other than CR24 as determined by investigator, or by central review based on PET result according to Lugano Criteria 2014. 260 patients are planned to be enrolled in France, Belgium, Germany, Italy and Portugal

Inclusion criteria:

1. Have a biopsy proven diagnosis of MZL, extranodal (EMZL) or nodal (NMZL) Or have a diagnosis of splenic MZL (SMZL) based on mandatory 13 flow cytometry markers: surface immunoglobulins (SmIg), CD5, CD23, FMC7, CD22 or CD79b, CD200, CD180, CD20, CD43, CD11c, CD10,CD103 and CD123 and validated by a centralized review.

   In case of large dissemination, disseminated MZL (as evaluated by investigator; please contact the Sponsor to discuss any doubt) will be included as DMZL and included in NMZL subtype. Participants with high tumor burden criteria are eligible.

   Participants with borderline or related entities, such as splenic diffuse red pulp lymphoma (SDRPL), typical hairy cell leukemia (HCL), and HCL variant (HCLv), are not eligible.

2. Have been treated with at least one prior systemic treatment and not more than three prior lines. Previous line must include at least one systemic line with a drug targeting CD20 (monoclonal antibody at least 2 cycles; participants treated with monoclonal antibody monotherapy should have received at least 4 weekly injections) with or without chemotherapy (R-CHOP, R-Bendamustine, R-CVP, R-Chlorambucil at least 2 cycles) or targeted treatment such as BTK inhibitors (at least 1 month). Participants previously treated by lenalidomide are eligible if the last administration of lenalidomide is superior to 12 months before C1D1. When randomized in comparator arm, those participants should require R-chemo. Prior local therapy (including surgery, radiotherapy antibiotics for H. pylori-positive gastric lymphoma, and antiviral for hepatitis C virus) is not considered as one line of treatment

3. Signed Informed Consent Form

4. Age ≥ 18 years at the time of signing the informed consent form

5. Ability to comply with the study protocol and procedures and required hospitalizations, in the investigator's judgement

6. Eastern Cooperative Oncology Group (ECOG) performance score (PS) of ≤ 2

7. Have a symptomatic disease requiring a systemic treatment

8. Not eligible for a local treatment including radiotherapy or surgery

9. Stage I disease of EMZL, SMZL or NMZL may be eligible only if not candidate to local therapy (surgery or radiotherapy).

10. Measurable disease in at least two perpendicular dimensions on an imaging scan is defined as: lymph node or nodal mass bi-dimensional measurement with ≥ 15 mm in longest transverse diameter or the short diameter must measure ≥ 10 mm regardless of the longest transverse diameter.

    Spleen is considered as a measurable disease if vertical axis is higher than 130 mm.

11. Adequate hematopoietic function at screening as follows unless cytopenia is clearly due to marrow involvement of MZL or hypersplenism or autoimmune thrombocytopenia:

    11.1. Platelet count ≥ 75 G/L; in cases of thrombocytopenia clearly due to marrow involvement of MZL or hypersplenism or auto-immune thrombocytopenia, platelet count should be ≥ 30 G/L. Washout platelet transfusion is 7 days between transfusion and D1 of starting treatment 11.2. Absolute Neutrophil Count (ANC) ≥ 1 G/L unless neutropenia is clearly due to marrow involvement of MZL or hypersplenism. G-CSF is not allowed within 7 days before starting treatment 11.3. Total hemoglobin ≥ 8 g/dL unless anemia is clearly due to marrow involvement of MZL or hypersplenism or autoimmune hemolytic anemia. Washout erythrocyte transfusion is 7 days between transfusion and D1 of starting treatment

12. Serum total bilirubin ≤ 1.5 x the upper limit of normal (ULN) (or ≤3 x ULN for participants with Gilbert syndrome),

13. AST or ALT ≤ 2.5 x ULN, unless directly attributable to the participant's MZL

14. Measured or estimated creatinine clearance ≥ 40 mL/min by institutional standard method

15. Participants who are hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (HBcAb) positive, must be negative for hepatitis B virus (HBV) polymerase chain reaction (PCR) to be eligible for study participation. Participants who are hepatitis B surface antigen (HBsAg) negative, hepatitis B surface antibody (anti-HBsAb) positive and hepatitis B core antibody (HBcAb) negative are eligible,

16. Contraception:

    16.1. For women of childbearing potential (WOCBP) (refer to section 14.6.1):

    • must have a negative result for pregnancy test (highly sensitive serum) within 7 days before randomization and within 7 days before initiation of study treatment.
    • must agree to abstain from becoming pregnant or breastfeeding, and agree to use highly effective contraceptive methods during study participation, and for at least 28 days after the final dose of lenalidomide (if applicable), 3 months after the final dose of mosunetuzumab and tocilizumab (if applicable), 12 months after the final dose of CHOP (if applicable), 6 months after the final dose of bendamustine (if applicable) and 12 months after the final dose of rituximab (if applicable).

    16.2. For men: with a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period (including periods of treatment interruption), and for at least 28 days after the final dose of lenalidomide (if applicable), 2 months after the final dose of tocilizumab (if applicable), 6 months after the final dose of CHOP (if applicable), 3 months after the final dose of bendamustine and 12 months after the final dose of rituximab (if applicable). ). Men must also agree to refrain from donating sperm from the first day of treatment until at least 7 days after the final dose of lenalidomide (if applicable), 2 months after the final dose of tocilizumab (if applicable), 6 months after the final dose of CHOP (if applicable), 3 months after the final dose of bendamustine (if applicable), and 12 months after the final dose of rituximab (if applicable)

17. Participants covered by any social security system (France).

18. Participants who understand and speak one of the country official languages.

19. LVEF within normal range (i.e. > 50% as evaluated by Transthoracic Echocardiography or > 45% as evaluated by isotopic method (MUGA scan)).

Exclusion criteria:

1. MZL with histologic transformation to high-grade lymphoma

2. Participants who have received any of the following treatments prior to study entry:

   • Treatment with mosunetuzumab or other CD20/CD3-directed bispecific antibodies
   • Allogeneic stem cell transplant

3. Participants who have received any of the following treatments, whether investigational or approved, within the respective time periods prior to initiation of study treatment:

   • Radiotherapy within 2 weeks prior to the first dose of study treatment
   • Autologous stem cell transplant within 100 days prior to first study treatment
   • Use of monoclonal antibodies within 4 weeks prior to first study treatment
   • Systemic immunosuppressive medications (including, but not limited to, Cyclophosphamide, Azathioprine, Methotrexate, Thalidomide, and anti-tumor necrosis factor agents) and corticosteroids on the long run with the following exceptions: inhaled steroids for asthma, topical steroids, or replacement or stress corticosteroids during the study at any time. Participants who require lymphoma symptom control during screening may receive corticosteroid < or = 1mg/kg/day prednisone or equivalent for a maximum of 10 days prior to first dose of study treatment.
   • Any other anti-cancer investigational therapy within 4 weeks prior to initiation of study treatment.

4. Pregnant or breastfeeding or intending to become pregnant during the study or within 28 days after the final dose of lenalidomide, 3 months after the final dose of mosunetuzumab and tocilizumab (if applicable), 12 months after the final dose of CHOP, 6 months after the final dose of bendamustine and 12 months after the final dose of rituximab (if applicable).

5. Received a live, attenuated vaccine within 4 weeks before first dose of study treatment, or in whom it is anticipated that such a live attenuated vaccine will be required during the study period or within 6 months after the final dose of study treatment, except for acute pandemic situation such as COVID19

6. Active or history of CNS lymphoma or leptomeningeal infiltration

7. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibody therapy (or recombinant antibody-related fusion proteins) - grade 3 and 4

8. Known hypersensitivity to biopharmaceuticals produced in CHO cells or any component of the mosunetuzumab, rituximab, tocilizumab, lenalidomide, or thalidomide formulation, including Mannitol

9. Participants unable to receive adequate prophylaxis and/or therapy for thromboembolic events (aspirin or low molecular weight heparin or direct oral anticoagulants)

10. History of prior malignancy, except for conditions as listed below if participants have recovered from the acute side effects incurred as a result of previous therapy and only with a single occurrence of the following conditions:

    • Malignancies treated with curative intent and with no known active disease present for ≥ 2 years before enrollment
    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    • Adequately treated cervical carcinoma in situ without evidence of disease
    • Surgically/adequately treated low grade, early stage I, localized prostate in situ carcinoma

11. Participants with infections requiring IV treatment with antibiotics or hospitalization (Grade 3 or 4) within the last 4 weeks prior to inclusion or known active bacterial, viral (including SARS-CoV-2), fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds),

12. Evidence of any significant, concomitant disease that could affect compliance with the protocol or interpretation of results, including, but not limited to:

    • Significant cardiovascular disease [e.g., Objective Class C or D heart diseases (cf. Classes of Heart Failure | American Heart Association)], myocardial infarction within the previous 6 months, unstable arrhythmia, or unstable angina)
    • Significant pulmonary disease (such as obstructive pulmonary disease or history of bronchospasm)
    • Clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis
    • Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease. Participants with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 1 year and have no residual neurologic deficits as judged by the investigator are allowed. Participants with a history of epilepsy who have had no seizures in the past 2 years with or without anti-epileptic medications can be eligible.

13. History of confirmed progressive multifocal leukoencephalopathy (PML)

14. Known Positive serologic HIV test at screening

15. Acute or chronic hepatitis C virus (HCV) infection Participants who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation.

16. Known or suspected history of hemophagocytic lymphohistiocytosis

17. Known or suspected chronic active Epstein-Barr virus (EBV) infection within the last 4 weeks prior to inclusion

18. History of erythema multiforme, Grade ≥3 rash, or blistering following prior treatment with immunomodulatory derivatives

19. History of interstitial lung disease (ILD), drug-induced pneumonitis, and autoimmune pneumonitis

20. Active autoimmune disease requiring treatment

21. History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis; except:

    • Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.
    • Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
    • Patients with a history of disease-related immune thrombocytopenic purpura or autoimmune hemolytic anemia may be eligible
    • Participants with a remote history of, or well-controlled autoimmune disease, with a treatment-free interval from immunosuppressive therapy for 12 months may be eligible after review and discussion with the Medical Monitor.

22. Recent major surgery with risk of bleeding within 4 weeks prior to first study treatment administration (C1D1)

23. History of solid organ transplantation

24. Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes an individual's safe participation in and completion of the study

25. Person deprived of his/her liberty by a judicial or administrative decision

26. Person hospitalized without consent

27. Adult person under legal protection

28. Adult person unable to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness

29. Participant unable to receive at least one of the three regimens of the comparator arm. As in usual practice, physician has to verify the absence of contraindication to the use of the drugs, hypersensitivity, and to take into account the lymphoma history and previous treatment scheme used

30. Suspicion or clinical evidence of transformed lymphoma at enrollment by investigator assessment (e.g. very high SUV (SUV > 20 or double compared to SUV of other lesions) in at least one lesion that was not biopsied, and discordant with SUV of biopsied lesion, LDH > 2.5 ULN in a context of rapidly progressive disease, etc). Please contact the Coordinating Investigators / Sponsor to discuss such cases or if there is any doubt before considering enrollment.

31. Uncontrolled symptomatic pleural or serous effusion requiring urgent treatment within 48 hours (participants with controlled disease after adequate pleural/serous drainage and/or effective pleurX™ or similar system are eligible only if control system is in place before randomization).

32. Uncontrolled symptomatic ureterohydronephrosis resulting in renal failure (participants with adequate management i.e. ureteral catheter or double J stent allowing renal failure control are eligible only if control system is in place before randomization).