Testing the Role of DNA Released From Tumor Cells Into the Blood in Guiding the Use of Immunotherapy After Surgical Removal of the Bladder, Kidney, Ureter, and Urethra for Urothelial Cancer Treatment, MODERN Study

Exclusion Criteria

• •PRE-REGISTRATION: No gross cancer at the surgical margins. Microscopic invasive urothelial carcinoma at the surgical margins (i.e., "positive margins") are allowed. Carcinoma in situ (CIS) at margins is considered negative margins
• •PRE-REGISTRATION: No evidence of residual cancer or metastasis after radical cystectomy or nephroureterectomy or ureterectomy (imaging is not required prior to pre-registration but is required prior to registration)
• •PRE-REGISTRATION: Have undergone a radical cystectomy nephroureterectomy, or ureterectomy with pathological evidence of urothelial carcinoma at high risk of recurrence as described in one of the two scenarios below (i or ii). The 7th edition of American Joint Committee on Cancer (AJCC) staging will be utilized.:
• •* (i) Patients ineligible for cisplatin due to at least one of the following criteria and reason for ineligibility should be documented:
• •* (i) Creatinine Clearance (using Cockcroft-Gault): \< 60 mL/min
• •* (i) Common Terminology Criteria for Adverse Events (CTCAE) version 5, grade \>= 2 audiometric hearing loss
• •* (i) CTCAE version 5, grade \>= 2 or above peripheral neuropathy
• •* New York Heart Association Class III heart failure
• •* (i) Eastern Cooperative Oncology Group (ECOG) performance status = 2
• •* (i) Patients who are eligible for cisplatin may be candidates if they refuse adjuvant cisplatin-based chemotherapy, despite being informed by the investigator about the treatment options. The patient's refusal must be documented.
• •* (i) Patients with pT2N0 urothelial cancer on radical surgery specimen (without prior neoadjuvant systemic therapy) with ctDNA(+) Signatera results based on an assay performed post-radical surgery as part of routine care outside of the study may proceed with pre-registration but require confirmation of ctDNA(+) Signatera testing on repeat "central testing" in the context of A032103 testing. Patients with pT2N0 with central testing not confirming ctDNA(+) will not be eligible for A032103 (Note: this is distinct from patients with ypT2N0 who are eligible based on ii).
• •* (ii) Patients who received neoadjuvant systemic therapy: ypT2-T4a and/or ypN+ on radical surgery (i.e., cystectomy. , nephroureterectomy, or ureterectomy) pathology specimen. Neoadjuvant systemic therapy may have included cisplatin-based chemotherapy, cisplatin-based chemotherapy plus PD-1/PD-L1 blockade, or enfortumab vedotin plus PD-1/PD-L1 blockade
• •PRE-REGISTRATION: Available tumor tissue for central Signatera testing to be submitted at pre-registration. Central testing is defined as testing performed as part of the A032103 study prior to registration and is provided by the study and not routine standard commercial testing. Patients who have already had local Signatera testing performed as part of routine care will require repeat central testing as part of the A032103 study to be eligible for registration/randomization. Tumor tissue from the radical surgery specimen is preferred over tissue from prior diagnostic biopsy specimen (e.g., transurethral resection of bladder tumor specimen)
• •PRE-REGISTRATION: Age \>= 18 years
• •PRE-REGISTRATION: ECOG Performance Status 0-2
• •PRE-REGISTRATION: Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects
• •PRE-REGISTRATION: No postoperative/adjuvant systemic therapy after radical surgery
• •PRE-REGISTRATION: No adjuvant radiation after radical surgery
• •PRE-REGISTRATION: No treatment with any other type of investigational agent =\< 4 weeks before pre-registration
• •PRE-REGISTRATION: Not have ever received prior treatment with LAG-3 blockade
• •PRE-REGISTRATION: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• •PRE-REGISTRATION: Absolute Neutrophil Count (ANC) \>= 1,200/mm\^3
• •PRE-REGISTRATION: Platelet count \>= 100,000/mm\^3
• •PRE-REGISTRATION: Hemoglobin \>= 8 g/dL
• •PRE-REGISTRATION: Creatinine =\< 1.5 x upper limit of normal (ULN) or calculated (calc.) creatinine clearance \> 30 mL/min (using either Cockcroft-Gault formula or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
• •PRE-REGISTRATION: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 3 x ULN
• •PRE-REGISTRATION: Total bilirubin =\< 1.5 x upper limit of normal (ULN) (except in patients with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)
• •PRE-REGISTRATION: For women of childbearing potential only: A negative urine or serum pregnancy test done =\< 14 days prior to pre-registration is required
• •PRE-REGISTRATION: Not currently requiring hemodialysis
• •PRE-REGISTRATION: No current or prior history of myocarditis
• •PRE-REGISTRATION: No grade ≥ 3 immune related adverse event with prior PD-1/PD-L1 blockade
• •PRE-REGISTRATION: No active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens- Johnson syndrome, or phospholipid syndrome because of the risk of recurrence or exacerbation of disease.
• •PRE-REGISTRATION: Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible.
• •PRE-REGISTRATION: Patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.
• •PRE-REGISTRATION: No current pneumonitis or prior history of non-infectious pneumonitis that required steroids within the previous 5 years.
• •PRE-REGISTRATION: No known active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (e.g., hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] \[qualitative\] is detected).