Mosunetuzumab With or Without Polatuzumab Vedotin and Obinutuzumab for the Treatment of Untreated Indolent B-Cell Non-Hodgkin Lymphoma

Diagnosis of indolent B-cell non-Hodgkin lymphoma with no prior systemic therapy.

\* Eligible histologies based on 2016 World Health Organization (WHO) classification include:

* Follicular lymphoma (grade 1-2 or 3a)

* Marginal zone lymphoma. Patients with mucosa-associated lymphoid tissue (MALT) subtype of marginal zone lymphoma (MZL) may have relapsed or refractory disease after a course of antibiotic therapy

Meet criteria for initiation of therapy that include one of the following:

* Symptomatic disease (including but not limited to pain/discomfort, b-symptoms)

* Threatened end-organ function

* Progressive cytopenias (leukopenia \[WBC \< 1,000/uL\] OR hemoglobin \< 10 g/dL OR platelets \< 100,000/uL)

* Steady progression

* Bulky disease (one site at least 7 cm or at least four sites of 3 cm)

* Hepatomegaly

* Splenomegaly

Be willing and able to provide written informed consent for the trial

Have had an informed discussion with the investigator as part of the consenting/screening process that included information on treatments for these conditions with known clinical benefit, and there is documented understanding that the patient is forgoing approved available therapies

Be \>= 18 years of age on day of signing informed consent

Have measurable fludeoxyglucose F-18 (FDG)-avid nodal disease, including at least 1 disease site measuring at least 1.5 cm in longest dimension on computed tomography (CT) or FDG-positron emission tomography (PET), or FDG-avid extra nodal measurable site measuring at least 1.0 cm in longest dimension

Have a performance status of 0-2 on the ECOG Performance Scale (PS)

Absolute neutrophil count (ANC) \>= 1,000/uL except in cases of marrow infiltration by lymphoma

Platelets \>= 75,000/mcL except in cases of marrow infiltration by lymphoma or hypersplenism

Hemoglobin \>= 8 g/dL except in cases of marrow infiltration by lymphoma without red blood cell (RBC) transfusion within 14 days of first treatment

Measured or calculated creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) \>= 40 mL/min; Note: Creatinine clearance should be calculated per institutional standard

Serum total bilirubin =\< 1.5 X upper limit of normal (ULN) (Patients with documented Gilbert disease may be enrolled if total bilirubin =\< 3.0 x ULN) or OR direct bilirubin =\< ULN for subjects with total bilirubin levels \> 1.5 ULN

Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT)\] (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 X ULN OR =\< 5 X ULN for subjects with liver involvement

International normalized ratio (INR) or prothrombin time (PT) =\< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants

Activated partial thromboplastin time (aPTT) =\< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants, or subject is shown to have an antiphospholipid antibody on workup

For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of =\< 1% per year during the treatment period and for at least 3 months after the last dose mosunutuzimab or 6 months after the last dose of obinutuzumab. Women must refrain from donating eggs during this same period. A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state ( =\< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements. Examples of contraceptive methods with a failure rate of =\< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception

For women of childbearing potential, a negative serum pregnancy test result during screening period. Women who are considered not to be of childbearing potential are not required to have a pregnancy test

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 5 months after the last treatment. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not acceptable methods of preventing drug exposure. Male patients considering preservation of fertility should bank sperm before study treatment

Patients on agents that modulate CYP3A4 should be aware that these agents are prohibited if they require treatment in Part B, and require discontinuation for at least 5 half-lives in order to proceed with Part B

What this study is about