Inclusion Criteria:

• Subjects must be ≥ 18 years of age at the time of screening.
• Written informed consent and any locally required authorization (e.g., data privacy) must be obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
• Subjects must have a confirmed diagnosis of MM as per IMWG criteria (Rajkumar et al, 2014) requiring systemic therapy.
• Subjects must have measurable disease defined as at least one of the IMWG criteria.
• FLC ratio is abnormal.
• Subjects must be deemed relapsed/refractory, as defined by IMWG consensus recommendations (Rajkumar et al, 2011), and have exhausted standard-of-care regimens with proven clinical benefit, which include agents from the following anti-myelomatherapies: PIs, IMIDs, and mAbs.
• Relapsed myeloma: previously treated myeloma that progresses and requires the initiation of salvage therapy but does not meet criteria for either “primary refractory myeloma” or “relapsed-and-refractory myeloma” categories.
• Refractory myeloma: disease that is nonresponsive while on primary or salvage therapy, or progresses within 60 days of last therapy. Nonresponsive disease is defined as either failure to achieve minimal response or development of progressive disease while on therapy.
• Subjects must either be ineligible for or post-autologous stem cell transplant.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Adequate organ and marrow functions.
• All subjects must consent to and undergo pretreatment (baseline) fresh BM aspirate and biopsy collection. On-treatment BM aspirate and biopsy collection on Day 8 or Day 43 is mandatory for subjects enrolled in the optional pharmacodynamic cohort only. Ontreatment Day 8 or Day 43 BM aspirate and biopsy collection is optional for all other dose-escalation and dose-expansion subjects enrolled.
• Female subjects of childbearing potential who are sexually active with a nonsterilized male partner must use at least one highly effective method of contraception for definition of females of childbearing potential and for a description of highly effective methods of contraception) post-screening, and must agree to continue using such precautions for 90 days after the final dose of investigational product. 
• Nonsterilized male subjects who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide post-screening and for 90 days after receipt of the last dose of investigational product. It is strongly recommended for the female partner of a male subject to also use a highly effective method of contraception throughout this period. In addition, male  subjects must refrain from sperm donation while on study and for 90 days after the final dose of investigational product.

Exclusion Criteria:

Target Disease

• Subjects who have previously received an autologous stem cell transplant if less than 90 days have elapsed from the time of transplant or the subject has not recovered from transplant-associated toxicities prior to the first scheduled dose of MEDI2228;
• Subjects who have previously received an allogeneic stem cell transplant;
• Subjects who have previously received another BCMA-targeted therapy;
• Central nervous system (CNS) involvement (including meningeal involvement) by MRI or cerebrospinal fluid exam;
• Known history of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome, plasma cell leukemia, Waldenstrom’s macroglobulinemia, or amyloidosis.

Medical History and Concurrenr Diseases

• Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.
• Subject has a history of malignancy (other than MM) within 3 years prior to the first scheduled dose of investigational product (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, with concurrence with the sponsor's Medical Monitor, is considered cured with minimal risk of recurrence within 3 years).
• Subjects requiring concomitant treatment with corticosteroids > 10 mg of prednisone or equivalent for the treatment of other medical conditions.
  • NOTE:  A brief (< 3 weeks) course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
  • The use of topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption) is permitted.
• Chronic or ongoing active infections requiring systemic treatment such as, but not restricted to, tuberculosis, chronic lung infection/bronchiectasis, or chronic renal infection.
• Known history of human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infections at the time of screening which are defined as:
  • Positive hepatitis B surface antigen (HBsAg) or positive hepatitis B core (HBc) antibody;
  • Positive HCV antibody followed by positive confirmatory test (e.g., quantitative HCV RNA test).
    • NOTE: Subjects with positive HBsAg or HBc antibody who are receiving prophylactic antiviral therapy with entecavir, adefovir, telbivudine or tenofovir (either prophylactic or for management) are eligible if the HBV load is undetectable by quantitative PCR. Subjects who are HCV antibody positive are eligible if HCV by quantitative PCR is undetectable on 2 occasions 4 weeks apart.
• Current severe systemic disease (including, but not limited to clinically significant renal, hepatic, hematological [except MM], gastrointestinal, pulmonary, endocrine, or neurological disease) or intercurrent illness (eg, ongoing or active infection, flare of autoimmune disease) that could substantially increase risk of incurring AEs from MEDI2228.
• Subject has clinically significant cardiac disease, including:
  • Myocardial infarction within 6 months before date of randomization, or unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class IIIIV);
  • Cardiac arrhythmia (Grade 2 or higher [NCI CTCAE version 4.03]) or clinically significant ECG abnormalities;
  • Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 480 msec (NOTE: If QTcF > 480 msec, then this must be confirmed based on average QTcF value from at least 3 manually overread 12-lead ECGs performed over a short period of time [ie, within 30 minutes]).
• Subjects at risk of non-disease related major bleeding (eg, recent gastrointestinal hemorrhage or neurosurgery, within previous 21 days).
• Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder) or the subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise their well-being) or that could prevent, limit, or confound protocol-specified assessments.
• Subject has known allergies or hypersensitivity to mAbs or human proteins, or their excipients or known sensitivity to mammalian-derived products.
• Subject is a woman who is pregnant or breastfeeding or planning to become pregnant while enrolled in this study or within 6 months after the last dose of investigational product.
• Subject has history of hepatic veno-occlusive disease (sinusoidal occlusive syndrome); e.g., related to prior autologous stem cell transplant.