Inclusion Criteria: 

• Participants who are ≥ 12 years of age and < 18 years of age (adolescents) must weigh ≥ 40 kg at the time of signing the informed consent (assent).
• Participants must have an Eastern Cooperative Oncology Group performance status of ≤ 1/Lansky Performance Score ≥ 80% for adolescents (≥ 12 to < 18 years of age).
• Participants must have histologically confirmed Stage III (unresectable) or Stage IV (metastatic) melanoma, per the American Joint Committee on Cancer staging system (8th edition).
• Participants must be treatment-naïve (ie, no prior systemic anticancer therapy for unresectable or metastatic melanoma).
  • Note that the following prior adjuvant or neoadjuvant melanoma therapies are allowed if all related adverse events have either returned to baseline or stabilized.
• Anti-PD-1 or anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) therapy with at least 6 months between the last dose and date of recurrence.
• Interferon therapy with the last dose at least 6 weeks prior to randomization. 
• BRAF- or MEK-inhibitor-containing adjuvant therapy regimens with at least 6 months between the last dose and date of recurrence.
• Participants must have measurable disease by computed tomography or magnetic resonance imaging per Response Evaluation Criteria In Solid Tumors version 1 (RECIST v1.1).
• Participants must have a documented LDH result during the screening period within 14 days prior to randomization to be used for randomization.
• Participants with known BRAF V600 mutation status, or who consent to BRAF V600 mutation testing per local institutional standards during the Screening Period with the sample collected within 3 months prior to randomization. All BRAF statuses (ie, BRAF wild-type or BRAF 600 mutation positive) are eligible.
• A formalin-fixed paraffin-embedded tissue block or a minimum of 15 unstained slides (20 preferred) of tumor tissue from core biopsy, punch biopsy, excisional biopsy, or surgical specimen obtained during screening or prior to randomization (within 3 months of enrollment with no intervening systemic anti-cancer treatment between time of acquisition and enrollment), with an associated pathology report, must be sent to the central laboratory prior to randomization. Fine needle aspirates or other cytology samples are not acceptable. Biopsies of bone lesions that do not have a soft tissue component are not acceptable. If an insufficient amount of tumor tissue from an unresectable or metastatic site is available prior to the start of the screening phase, participants must consent to allow the acquisition of additional tumor tissue during the screening period for biomarker testing. Assessment of tumor-cell PD-L1 expression by immunohistochemistry (IHC) also must be performed by central laboratory using pre-treatment tissue sample and results must be reported to IRT prior to randomization. PD-L1 status as determined using a 1% threshold will be a stratification criterion for randomization. Participants with indeterminate or unevaluable PD-L1 results will not be permitted to randomize to a treatment arm.
• Participant Re-enrollment: This study permits the re-enrollment of a participant that has discontinued the study as a pre-treatment failure (ie, participant has not been randomized). If re-enrolled, the participant must re-consent.

Exclusion Criteria:

• Participants must not have active brain metastases or leptomeningeal metastases. Participants with brain metastases are eligible if these are:
  • Asymptomatic;
  • Have been treated and participants have neurologically returned to baseline (except for residual signs or symptoms related to the central nervous system [CNS] treatment); and
  • There is no MRI evidence of progression for at least 4 weeks after CNS directed therapy is complete and within 28 days prior to first dose of study treatment administration;
  • In addition, participants must have been either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to randomization;
  • Participants with brain disease treated with whole brain radiation are not eligible.
• Participants must not have ocular melanoma.
• Participants must not have an active, known, or suspected autoimmune disease. Participants may enroll with the following conditions:
  • Type 1 diabetes mellitus;
  • Hypothyroidism only requiring hormone replacement therapy;
  • Skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment;
  • Conditions not expected to recur in the absence of an external trigger.
• Participants must not have a history of myocarditis, regardless of etiology.
• Participants must not have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Participants must not have a concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to randomization (i.e., participants with a history of prior malignancy are eligible if treatment was completed at least 2 years before randomization and the participant has no evidence of disease). Participants with history of prior early stage basal/squamous cell skin cancer or non-invasive or in situ cancers that have undergone definitive treatment at any time are also eligible.
• Participant must not have had prior treatment with an anti-PD-1 (except if given as adjuvant or neoadjuvant therapy for melanoma), anti- PD-L1, anti-programmed death-ligand 2, antiCTLA-4 antibody (except if given as adjuvant or neoadjuvant therapy for melanoma), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways (except for interferon given as adjuvant or neoadjuvant therapy for melanoma) within 6 months prior to start of study treatment.
• Participant must not have had prior treatment with relatlimab or any other lymphocyte activation gene 3-targeted agents.
• Prior radiation therapy within 2 weeks prior to first study treatment. Participants must have recovered (i.e., Grade ≤ 1 or at baseline) from radiation-related toxicities prior to first study treatment.
• Participants who are pregnant or breastfeeding.
• Troponin T (TnT) or I (TnI) > 2 × institutional upper limit of normal (ULN). Participants with TnT or TnI levels between > 1 × to 2 × ULN will be permitted if repeat levels within 24 hours are ≤ 1 × ULN. If TnT or TnI levels are between > 1 × to 2 × ULN within 24 hours, the participant may undergo a cardiac evaluation and be considered for treatment, based on a favorable benefit/risk assessment by the Investigator. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 × ULN, the participant may undergo a cardiac evaluation and be considered for treatment, based on a favorable benefit/risk assessment by the Investigator. Notification of the decision to enroll the participant has to be made by the BMS Medical Monitor or designee.
• Left ventricular ejection fraction (LVEF) assessment with documented LVEF < 50% by either transthoracic echocardiogram (TTE) or multigated acquisition scan (TTE preferred test) within 6 months prior to start of study treatment.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 11/16/22. Questions regarding updates should be directed to the study team contact.