A Study of Durvalumab in Combination With Lenalidomide With and Without Dexamethasone in Adults With Newly Diagnosed Multiple Myeloma

Inclusion Criteria

• Subjects must satisfy the following criteria to be enrolled into the study:
• Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF)
• Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements
• Subject must have documented diagnosis with previously untreated (for cohort C, the induction and consolidation treatment along with the first autologous stem cell transplantation (ASCT) are allowed), symptomatic multiple myeloma (MM) as defined by the criteria below:

MM diagnostic criteria (all 3 required);

• Monoclonal protein present in the serum and/or urine
• Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma
• Any one or more of the following myeloma defining events:
• one or more of the following Myeloma-related organ dysfunction (at least one of the following);
• (C) Calcium elevation (serum calcium >11.5 mg/dl )(>2.65 mmol/L)
• (R) Renal insufficiency (serum creatinine >2 mg/dl)(177 µmol/L or more) or creatinine clearance 2 g/dL below the lower limit of laboratory normal)
• (B) Bone lesions (lytic or osteopenic) one or more bone lesions on skeletal radiography, computed tomography (CT), or positron emission tomography-computed tomography (PET-CT)
• one or more of the following biomarkers of malignancy:
• Clonal bone marrow plasma cell percentage ≥60%
• Abnormal serum free light-chain ratio ≥100 (involved kappa) or 1 focal lesions detected by functional imaging including PET/CT and/or whole body magnetic resonance imaging (MRI)

AND have measurable disease by protein electrophoresis analyses as defined by the following:

• Immunoglobulin G (IgG) MM: Serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dl or urine Mprotein level ≥ 200 mg/24 hours
• Immunoglobulin A (IgA) MM: Serum M-protein level ≥ 0.5 g/dl or urine M-protein level ≥ 200 mg/24 hours
• Immunoglobulin M (IgM) MM (IgM M-protein plus lytic bone disease documented by skeletal survey plain films): Serum M-protein level ≥ 1.0 g/dl or urine M-protein level ≥ 200 mg/24 hours
• Immunoglobulin D (IgD) MM: Serum M-protein level ≥ 0.05 g/dl or urine M-protein level ≥ 200 mg/24 hours
• Light chain MM: Serum M-protein level ≥ 1.0 g/dl or urine M-protein level ≥ 200 mg/24 hours
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Females of childbearing potential (FCBP) must:

a. Have two negative pregnancy tests as verified by the investigator prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.

b. She must either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and be source documented) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study treatment, during the study therapy (including dose interruptions), and for 90 days after discontinuation of study treatment.

c. Refrain from egg cell and blood donation for 90 days after the final dose of durvalumab.

• Male subjects must :

a. Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a FCBP while participating in the study, during dose interruptions and for at least 90 days following study treatment discontinuation, even if he has undergone a successful vasectomy.

b. Refrain from sperm and blood donation for at least 90 days after the final dose of durvalumab.

• For Cohort A subject must be transplant non-eligible (TNE) and meet at least one of the following high risk factors:

a. Cytogenetic abnormalities finding in malignant myeloma clone with t(4; 14); a