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

A Dose Review Team (DRT) evaluated DLTs to determine the recommended dose (RD) of Durvalumab to use in the Expansion Period. A DLT was defined as: a. Grade 4 neutropenia for \>= 5 days. b. Grade 3 neutropenia associated with fever (≥ 38.5°C / 101.3°F) of any duration. c. Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, or platelets transfusion. d. Grade 4 hematologic toxicity that does not resolve to baseline level \<=72 hours. e. Grade 4 anemia, unexplained by underlying disease. f. Any nonhematologic toxicity Grade ≥ 3 except for alopecia and nausea. g. Treatment interruption \>= 2 weeks due to AE. If ≤ 1 of the 6 initial participants in each cohort experience a DLT during cycle 1, the RD was Durvalumab 1500 mg; If \>=2 of the 6 initial participants in any cohort experience a DLT during cycle 1, the maximum tolerated dose (MTD) was exceeded and the dose level of Durvalumab was de-escalated to 750 mg

Time frame: First treatment cycle: Day 1 to Day 28

Population: Dose-Determining Population consists of all participants from the Safety Population of the Dose Determining Period who received at least one dose of Durvalumab. Cohort B's Dose-Determining Population was 7 participants as one was considered non-evaluable and was therefore replaced per protocol

Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100\*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.

Time frame: pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 4 hours, 168 hours (Day 8), 336 hours (Day 15) and 504 hours (Day 22) after administration of DURVA on Day 1

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100\*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.

Time frame: pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 4 hours, 168 hours (Day 8), 336 hours (Day 15) and 504 hours (Day 22) after administration of DURVA on Day 1

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100\*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.

Time frame: pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 4 hours, 168 hours (Day 8), 336 hours (Day 15) and 504 hours (Day 22) after administration of DURVA on Day 1

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100\*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.

Time frame: pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 4 hours, 168 hours (Day 8), 336 hours (Day 15) and 504 hours (Day 22) after administration of DURVA on Day 1

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100\*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.

Time frame: pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 4 hours, 168 hours (Day 8), 336 hours (Day 15) and 504 hours (Day 22) after administration of DURVA on Day 1

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Time to maximum observed concentration of Durvalumab (DURVA) after multiple doses on day 1 obtained from the observed concentration versus time data

Time frame: pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 4 hours, 168 hours (Day 8), 336 hours (Day 15) and 504 hours (Day 22) after administration of DURVA on Day 1

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100\*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.

Time frame: pre-infusion (-60 to -5 minutes prior to dose), end of infusion (EOI), 4 hours, 168 hours (Day 8), 336 hours (Day 15) and 504 hours (Day 22) after administration of DURVA on Day 1

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Duration of response (for responders only) was defined as the time from earliest date of documented response (PR or better) to the earliest date of disease progression (DP) as determined by the investigator per IMWG Uniform Response criteria or death during study treatment, whichever occurred first.

Time frame: Day 1 of each cycle starting with Cycle 2 up to Cycle 17 plus one week for the end of treatment visit (Day 29 up to Week 73)

Population: Efficacy Evaluable Population: Participants in Cohorts A + B who had a response.

Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100\*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.

Time frame: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Time to maximum observed concentration of Lenalidomide (LEN) after multiple doses on day 15 obtained from the observed concentration versus time data

Time frame: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100\*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.

Time frame: Cycle 1 Day 1: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100\*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.

Time frame: Cycle 1 Day 1: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100\*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.

Time frame: Cycle 1 Day 1: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100\*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.

Time frame: Cycle 1 Day 1: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100\*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.

Time frame: Cycle 1 Day 1: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100\*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.

Time frame: Cycle 1 Day 1: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Time to maximum observed concentration of Lenalidomide (LEN) after multiple doses on day 1 obtained from the observed concentration versus time data

Time frame: Cycle 1 Day 1: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Geometric mean was obtained by computing the arithmetic mean of the logarithm-transformed values of concentration/PK parameters and then using the exponentiation to return the computation to the original scales. Geometric CV% was calculated as follows: CV% = 100\*SQRT(EXP(σ2)-1), where σ2 denotes the variance of the log-transformed values.

Time frame: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, and 8 hours post LEN dose

Population: The PK Population included participants who received \>=1 dose of study treatment and had \>=1 measurable PK assessment. If participants were noncompliant with respect to dosing, had incomplete data, or other circumstances that would affect PK evaluation, inclusion was made on a case-by-case basis.

Tumor response, including progressive disease, was assessed by the investigators and captured the best assessment of response during the treatment period. ORR was defined as partial response (PR) or better which includes PR, very good partial response (VGPR), complete response (CR), or stringent complete response (sCR). A PR required ≥ 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hours. If present at baseline, a ≥ 50% reduction in the size of soft tissue plasmacytomas was also required. sCR required - a negative immunofixation of serum and urine and - disappearance of any soft tissue plasmacytomas and - ≤ 5% plasma cells in bone marrow and normal free light-chain (FLC) ratio and - absence of clonal plasma cells by immunohistochemistry or 2- to 4-color flow cytometry.

Time frame: Day 1 of each cycle starting with Cycle 2 up to Cycle 17 plus one week for the end of treatment visit (Day 29 up to Week 73)

Population: Efficacy Evaluable Population which consisted of enrolled participants who received at least 1 dose of the study medications and had at least 1 evaluable postbaseline response assessment. See the Response Improvement Rate outcome for an efficacy measure for Cohort C.

The number of participants who develop antidrug antibody against durvalumab at any of the sampling timepoints during the study.

Time frame: Pre-dose samples on Day 1 of cycles 1, 2, 4, 6, 10, and 14 (study days 1, 29, 85, 141, 253, 393)

Population: The Safety Population was defined as all enrolled participants who receive at least 1 dose of the study medications.

This outcome was originally defined as a Kaplan-Meier estimate of overall survival (OS) and was defined as the time between first date of dosing of study medication and death due to any cause. However due to the early study termination and limited follow-up time, the majority of participants were censored for OS analysis. Data reported instead represent the number of participants who died due to any cause from Day 1 up to data cut-off.

Time frame: Day 1 up to Week 87

Population: Safety population

This outcome was originally defined as a Kaplan-Meier estimate of progression-free survival (PFS) which estimated the time between first date of dosing of study medication and disease progression, as determined by the investigator using the IMWG Uniform Response Criteria, or death during study treatment, whichever occurred earlier. However due to the early study termination and limited follow-up time, the majority of participants were censored for PFS analysis. Data reported instead represent the number of participants who died during study treatment or had disease progression within 90 days of the last dose of durvalumab.

Time frame: Day 1 up to Week 84

Population: Safety population

An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. A TEAE includes AEs between the first dose date of either study drug and 90 days after the last dose of study drug. A serious AE is any AE occurring at any dose that: • Results in death; • Is life-threatening; • Requires or prolongs existing inpatient hospitalization; • Results in persistent or significant disability/incapacity; • Is a congenital anomaly/birth defect; • Constitutes an important medical event. The Investigator assessed the relationship of each AE to study drug and graded the severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03): - Grade 1 = Mild - Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention required) - Grade 3 = Severe (limitation in activity; medical intervention required) - Grade 4 = Life-threatening - Grade 5 = Death

Time frame: Day 1 up to Week 84 (the longer of 90 days after discontinuing treatment with DURVA, or 28 days after the last dose of LEN or dex)

Population: Safety population. The Safety Population is defined as all enrolled subjects who receive at least 1 dose of the study medications.

Response Improvement Rate is defined as the percentage of participants who achieved a response from treatment as compared to the pre-autologous stem cell transplantation \[ASCT\] diseases measurement used as baseline for response assessment. IMWG response categories could be stable disease (SD), partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR), as long as it represented an improvement compared to prior to transplant.

Time frame: Baseline (Cycle 1 Day 1); Treatment: Day 1 of each cycle starting with Cycle 2 up to Cycle 15 plus one week for the end of treatment visit (Day 29 up to Week 61)

Population: Efficacy Evaluable Population which consists of all enrolled participants who received at least 1 dose of the study medications and had at least 1 evaluable postbaseline response assessment.

Time to response (for responders only, per IMWG Uniform Response Criteria) is calculated as the time from the first date of dosing of study medication to the first date of documented response (PR or better).

Time frame: Day 1 of each cycle starting with Cycle 2 up to Cycle 17 plus one week for the end of treatment visit (Day 29 up to Week 73)

Population: Efficacy Evaluable Population: Participants in Cohorts A + B who had a response