A PHASE 1/2 MULTICENTER, OPEN-LABEL STUDY TO DETERMINE THE RECOMMENDED DOSE AND REGIMEN OF DURVALUMAB (MEDI4736) IN COMBINATION WITH LENALIDOMIDE (LEN) WITH AND WITHOUT DEXAMETHASONE (DEX) IN SUBJECTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM)

1. Subject is >= 18 years of age at the time of signing the informed
consent form (ICF)
2. Subject must understand and voluntarily sign an ICF prior to any
study-related assessments/procedures being conducted
3. Subject is willing and able to adhere to the study visit schedule and
other protocol requirements
4. Subject must have documented diagnosis with previously untreated
(for cohort C, the induction and consolidation treatment along with the
first ASCT are allowed), symptomatic multiple myeloma (MM) as defined
in the protocol
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0,
1, or 2
6. 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.
7. 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
8. 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); and / or del(17p); and / or 1q amplification; and / or
t(14:16);or
b. ISS Stage III; or
c. Serum LDH > 2 x ULN
9. For Cohort B subject must be >= 65 years of age at the time of signing
the informed consent form (ICF) and transplant non-eligible (TNE);
excluding the subjects who meet the Cohort A criteria
10. For Cohort C subject must be after first autologous stem cell
transplantation (ASCT) for NDMM and meet the following criteria:
a. Have a post-transplant response as PR or better at the time of
enrollment to this study;
b. Have one of the following high risk factors at the time of NDMM
diagnosis:
- Cytogenetic abnormalities finding in malignant myeloma clone with t(4;
14); and/ or del(17p); and / or 1q amplification; and / or t(14; 16); or
- ISS stage III; or
- Serum LDH > 2 x ULN;
c. MRD positive (defined as more than 1 malignant cell in 10^5 cells)
measured by ClonoSIGHT* NGS assay of a BMA sample) at the time of
enrollment to this study; BMA sample collected at the time of multiple
myeloma diagnosis, prior to induction therapy available for central MRD
assessment by ClonoSIGHT* NGS assay

1. Previous treatment with anti-myeloma therapy (does not include
radiotherapy, bisphosphonates, or a single short course of steroid [ie,
less than or equal to the equivalent of dexamethasone 40 mg/day for 4
days; such a short course of steroid treatment must not have been given
within 14 days of Cycle 1 Day 1], for Cohort C, the induction and
consolidation treatment along with the first ASCT are allowed)
2. Any of the following laboratory abnormalities:
a. Absolute neutrophil count (ANC) < 1,000/µL
b. Untransfused platelet count < 75,000 cells/µL
c. Serum aspartate aminotransferase/serum glutamic oxaloacetic
transaminase (SGOT/AST) or alanine aminotransferase (SGPT/ALT) >
2.5 × upper limit of normal (ULN)
d. Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with
documented Gilbert's syndrome
e. Corrected serum calcium >13.5 mg/dL (> 3.4 mmol/L)
3. Renal failure requiring hemodialysis or peritoneal dialysis
4. Any serious medical condition that places the subject at an
unacceptable risk if he or she participates in this study. Examples of
such a medical condition are, but are not limited to, subject with
unstable cardiac disease as defined by: cardiac events such as
myocardial infarction (MI) within the past 6 months, NYHA (New York
Heart Association) heart failure class III-IV, uncontrolled atrial
fibrillation or hypertension; subjects with conditions requiring chronic
steroid or immunosuppressive treatment, such as rheumatoid arthritis,
multiple sclerosis and lupus, that likely need additional steroid or
immunosuppressive treatments in addition to the study treatment
5. Peripheral neuropathy >= Grade 2
6. Primary AL (immunoglobulin light-chain) amyloidosis and myeloma
complicated by amyloidosis
7. Prior history of malignancies, other than MM, unless the subject has
been free of the disease for >= 5 years with the exception of the following
non-invasive malignancies:
a. Basal cell carcinoma of the skin
b. Squamous cell carcinoma of the skin
c. Carcinoma in situ of the cervix
d. Carcinoma in situ of the breast
e. Incidental histologic finding of prostate cancer (T1a or T1b using the
TNM [tumor, nodes, metastasis] clinical staging system) or prostate
cancer that is curative
8. Subjects is positive for human immunodeficiency virus (HIV); chronic
or active hepatitis B or active hepatitis A, or C
9. Subject had prior exposure to immunotherapy, including, but not
limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1 monoclonal antibody
or inhibitor, cell-based therapies, or cancer vaccines
10. Subjects had history of organ or allogeneic stem cell transplantation
11. Subjects who have had clinical evidence of central nervous system
(CNS) or pulmonary leukostasis, disseminated intravascular coagulation,
or CNS multiple myeloma, or plasma cell leukemia
12. Known or suspected hypersensitivity to the excipients contained in
the formulation of durvalumab, lenalidomide, or dexamethasone
13. Major surgery (as defined by the investigator) within the 28 days
prior to the first dose of study treatment
14. Received prior treatment (for any reason)with a monoclonal
antibody within 5 half-lives of initiating study treatment
15. Use of any investigational agents within 28 days or 5 half-lives
(whichever is longer) of initiating study treatment
16. Current or prior use of immunosuppressive medication within 14
days prior to the first dose of study treatment. Exceptions to this
criterion are detailed in the protocol
17. Active or prior documented autoimmune or inflammatory disorders
within the past 3 years prior to the start of treatment. Exceptions to this
criterion are detailed in the protocol
18. History of primary immunodeficiency
19. Subject has incidence of gastrointestinal disease that may
significantly alter the absorption of LEN
20. Receipt of live, attenuated vaccine within 30 days prior to the first
dose of durvalumab
21. Unable or unwilling to undergo protocol required thromboembolism
prophylaxis(for Cohort C, this will be only for the subjects who have a
history of VTE)
22. Females who are pregnant, nursing or breastfeeding, or intend to
become pregnant during the participation to the study
23. Any significant medical condition, laboratory abnormality, or
psychiatric illness that would prevent the subject from participating in
the study
24. Any condition including the presence of laboratory abnormalities,
which places the subject at unacceptable risk if he/she were to
participate in the study
25. Any condition that confounds the ability to interpret data from the
study