The purpose of this study is to evaluate the safety, tolerability, and preliminary clinical activity of CC-95251 alone and in combination with antineoplastic agents in participants with relapsed or refractory acute myeloid leukemia and relapsed or refractory and treatment-naive higher risk melodysplastic syndromes.

N/A

Inclusion Criteria:

• Eastern Cooperative Oncology Group Performance Status of 0 to 2

For Parts A & B:

Relapsed or refractory (R/R) acute myeloid leukemia (AML) as defined by the 2016 WHO Classification R/R myelodysplastic syndromes (MDS) as defined by the 2016 WHO Classification with intermediate, high or very high risk by Revised International Prognostic Scoring System (IPSS-R)

For Part C:

• Treatment-naïve (ie, previously untreated) MDS as defined by the 2016 WHO Classification with intermediate, high or very high risk by IPSS-R

Exclusion Criteria:

Acute promyelocytic leukemia Immediately life-threatening, severe complications of leukemia such as disseminated/uncontrolled infection, uncontrolled bleeding, and/or uncontrolled disseminated intravascular coagulation Participants who have received prior treatment with a CD47 or SIRPα targeting agent Participant is on chronic systemic immunosuppressive therapy or corticosteroids Prior systemic cancer-directed treatments or investigational modalities ≤ 5 half-lives or 4 weeks prior to starting study treatment, whichever is shorter (relapsed or refractory participants only). Any condition including, active or uncontrolled infection, or the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study Pregnant or nursing participants.

Other protocol-defined inclusion/exclusion criteria apply

Contact: BMS Study Connect Contact Center http://www.bmsstudyconnect.com/ 855-907-3286 Clinical.Trials@bms.com

Contact: First line of the email MUST contain the NCT# and Site #.