A Study to Compare the Administration of Pembrolizumab After Surgery Versus Administration Both Before and After Surgery for High-Risk Melanoma

Exclusion Criteria

• •STEP 1 REGISTRATION (RANDOMIZATION): Patients are eligible for this trial either at initial presentation of their melanoma or at the time of the first detected nodal, satellite/in-transit, distant metastases, or recurrent disease in prior lymphadenectomy basin or distant site. Nodal, satellite/in-transit metastasis, distant metastases or disease in a prior complete lymphadenectomy basin must have been confirmed histologically by hematoxylin (H) \& eosin (E) stained slides.
• •STEP 1 REGISTRATION (RANDOMIZATION): Patients with multiple regional nodal basin involvement are eligible. Gross or microscopic extracapsular nodal extension is permitted.
• •STEP 1 REGISTRATION (RANDOMIZATION): Patients must have histologically proven stage IIIB or higher. This would entail pathologic confirmation beyond the primary or initial diagnosis of melanoma involving fine needle aspiration cytology or biopsy confirmation of any N-category or M-category resectable site.
• •STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have received previous neoadjuvant treatment for their melanoma. Patients may have received prior non-immunotherapy adjuvant therapy. Patients must not have had prior immunotherapy including, but not limited to ipilimumab, interferon alfa-2b, high dose interleukin (IL)-2, pegylated-interferon (PEG-IFN), anti-PD-1, anti-PD-L1 intra-tumoral, or vaccine therapies. Patients must not be planning to receive any of the prohibited therapies during treatment phases on the study.
• •STEP 1 REGISTRATION (RANDOMIZATION): Patients must not be planning to receive concomitant other biologic therapy, hormonal therapy, other chemotherapy, surgery, while on protocol therapy.
• •STEP 1 REGISTRATION (RANDOMIZATION): Patients may have received prior radiation therapy, including after prior surgical resection. All adverse events associated with prior surgery and radiation therapy must have resolved to =\< grade 1 prior to randomization.
• •STEP 1 REGISTRATION (RANDOMIZATION): Patients must be \>= 18 years of age
• •STEP 1 REGISTRATION (RANDOMIZATION): All patients must have disease status documented by a complete physical examination and imaging studies within 42 days prior to randomization. Imaging studies must include a CT of the chest, abdomen and pelvis with intravenous contrast (unless contraindicated). For patients with melanoma arising from the head and neck, dedicated neck imaging (CT with intravenous contrast is required. If the patient has unknown primary with disease in the axilla, neck imaging is required CT imaging must be done with intravenous contrast if there are no contraindications for it. Extremity melanomas must be imaged using CT with intravenous contrast or MRI with and without gadolinium
• •* Note: PET-CT scans are NOT acceptable to establish eligibility. Non-iodinated CT scans that are part of common PET-CT imaging protocols do not provide contrast for difficult to ascertain areas such as the neck and liver, and do not provide enough CT detail to perform appropriate RECIST 1.1 measurements. As such, a PET-CT with non-contrast CT or non-diagnostic quality CT images is considered insufficient for the detection of melanoma.
• •STEP 1 REGISTRATION (RANDOMIZATION): All patients must have a CT or magnetic resonance imaging (MRI) of the brain within 42 days prior to randomization. The brain CT or MRI should be performed with intravenous contrast (unless contraindicated).
• •STEP 1 REGISTRATION (RANDOMIZATION): Absolute neutrophil count (ANC) \>= 1,500/microliter (mcL) (within 42 days prior to randomization).
• •STEP 1 REGISTRATION (RANDOMIZATION): Platelets \>= 100,000/mcL (within 42 days prior to randomization).
• •STEP 1 REGISTRATION (RANDOMIZATION): Hemoglobin \>= 10 g/dL (within 42 days prior to randomization).
• •STEP 1 REGISTRATION (RANDOMIZATION): Total bilirubin =\< 1.5 x institutional upper limit of normal (IULN) (except patients with Gilbert's syndrome, who must have a total bilirubin \< 3.0 mg/dL) (within 42 days prior to randomization).
• •STEP 1 REGISTRATION (RANDOMIZATION): Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) =\< 2 x IULN (within 42 days prior to randomization).
• •STEP 1 REGISTRATION (RANDOMIZATION): Alkaline phosphatase =\< 2 x IULN (within 42 days prior to randomization).
• •STEP 1 REGISTRATION (RANDOMIZATION): Patients must have lactate dehydrogenase (LDH) performed within 42 days prior to randomization.
• •STEP 1 REGISTRATION (RANDOMIZATION): Patients must have adequate renal function as evidenced by calculated creatinine clearance \> 30 mL/min. The creatinine level (mg/dL) used in the calculation must be obtained within 42 days prior to randomization.
• •STEP 1 REGISTRATION (RANDOMIZATION): Patients must have Zubrod performance status =\< 2.
• •STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• •STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have an active infection requiring systemic therapy.
• •STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• •STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have received live vaccines within 42 days prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed.
• •* NOTE: The COVID-19 vaccines (currently available and those in the pipeline for FDA emergency use authorization or FDA approval) do not contain live virus, and therefore, COVID-19 vaccination does not affect or preclude eligibility for the S1801 trial. For patients who have undergone lymphadenectomy, vaccines should be delivered to a limb with an intact lymph node basin (Sentinel lymph node biopsy in a limb is acceptable). The vaccine should not be administered in a limb that has undergone lymphadenectomy.
• •* Patients with microscopic residual disease (i.e., positive margins) can be treated with re-excision or radiation, per site discretion, to render the patient disease-free prior to registration of adjuvant therapy.
• •* Disease-free status must be documented by a complete physical examination and radiographic imaging studies within 42 days prior to Step 3 registration. Imaging studies must include a CT of the chest, abdomen, and pelvis (unless contraindicated). Extremity melanomas must be imaged using CT with intravenous contrast or MRI with and without gadolinium. CT imaging must be done with intravenous contrast if there are no contraindications for it.
• •* For patients with melanoma arising from the head and neck, dedicated neck imaging (CT with IV contrast, unless contraindicated) is required.
• •* If the patient has had unknown primary with disease in the axilla, neck imaging is required to assure the region is clear of cancer.
• •* Any other clinically indicated imaging studies if performed (e.g., bone scan) must show no evidence of disease.
• •STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients must be registered to step 3 no more than 84 days after date of surgery.
• •STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients with R0 or R1 resections must have disease-free status documented by a complete physical examination and imaging studies within 42 days prior to step 3 registration. These patients must have disease assessments by CT chest/abdomen/pelvis with IV contrast, and neck CT with IV contrast if primary head and neck melanoma. MRI combined with non-contrast CT is an acceptable alternative for patients with CT contrast allergy, but imaging must encompass total body.