This is a multicenter, open-label, Phase 1b study to determine the recommended dose and regimen of durvalumab either as monotherapy or in combination with POM with or without low dose dex in subjects with RRMM. The study will consist of a dose-finding portion as well as a parallel dose-expansion portion to determine the optimal dose and regimen.

On 05 Sep 2017, a Partial Clinical Hold was placed on this study by the United States (US) Food and Drug Administration (FDA). The decision by the FDA was based on data related to risks of anti-programmed cell death-1 (PD-1) antibody, pembrolizumab, in combination with IMiDs® immunomodulatory drugs in patients with multiple myeloma. As a result, enrollment into this study has been discontinued. Subjects who are receiving clinical benefit, based on the discretion of the investigator, may remain on study treatment after being reconsented.

Inclusion Criteria:

• Has a confirmed diagnosis of active multiple myeloma and measurable disease.
• Must have undergone prior treatment with ≥2 treatment lines of anti-myeloma therapy
• Must have failed last line of treatment (refractory to last line of treatment).
• Must have achieved at least a stable disease (SD) for at least 1 cycle of treatment to at least 1 prior anti-myeloma regimen before developing Progressive disease (PD) (relapsed)
• Prior anti-myeloma treatments must have included a lenalidomide AND proteasome inhibitor alone or in combination.
• Has performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
• The extramedullary plasmacytoma (EMP) sub-group, must have radiologically measurable EMP disease (soft tissue or bone related) that is amenable to biopsy and does not need to have measurable disease.

Exclusion Criteria:

• Has non-secretory or oligosecretory multiple myeloma
• Has had prior anti-myeloma therapy within 2 weeks prior to study Day 1
• Has undergone prior organ or allogeneic hematopoetic stem cell transplantation
• Has received previous therapy with pomalidomide and did not achieve at least a stable disease
• Has received prior therapy with an anti-programmed cell death 1 receptor (anti-PD-1), antiprogrammed death-ligand 1 (anti-PD-L1), antiprogrammed death-ligand 2 (anti-PD-L2), anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways).
• Has received prior treatment with a monoclonal antibody within 5 half-lives of Study Day 1
• Has received investigational agents within 28 days or 5 half-lives (whichever is longer) of Study Day 1
• Has received live, attenuated vaccine within 30 days prior to Study Day 1
• Had rash ≥ Grade 3 during prior thalidomide, lenalidomide, or pomalidomide therapy
• Has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, POM, or dex
• Has peripheral neuropathy ≥ Grade 2
• Has a known additional malignancy that is progressing or requires active treatment (except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy).
• Is positive for human immunodeficiency virus (HIV), chronic or active hepatitis B or active hepatitis A or C
• Has a prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years (with the exception Basal cell carcinoma of the skin, Squamous cell carcinoma of the skin, Carcinoma in situ of the cervix, Carcinoma in situ of the breast, Incidental histologic finding of prostate cancer [T1a or T1b] or prostate cancer that is curative)
• Has clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS multiple myeloma
• Has clinically significant cardiac disease
• Is a female who is pregnant, nursing, or breastfeeding, or who intends to become pregnant during the participation in the study
• Is a current smoker