Multiple Myeloma
Conditions
Keywords
Relapsed/Refractory Multiple Myeloma
Brief summary
The purpose of the study is to determine whether the addition of Elotuzumab to Bortezomib/ Dexamethasone will prolong the time before myeloma worsens \[progression free survival (PFS)\].
Interventions
BIOLOGICALElotuzumab
Solution; Intravenous (IV); 10 mg/kg; (Cycles 1 & 2: Days 1, 8 & 15; Cycles 3-8: Days 1 & 11; Cycle 9+: Days 1 & 15); Until subject meets criteria for discontinuation of study drug
DRUGBortezomib
Solution; IV; 1.3 mg/m2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until subject meets criteria for discontinuation of study drug
DRUGDexamethasone
Tablets; Oral; 20 mg; (Cycles 1& 2: once daily on Days 2, 4, 5, 8, 9, 11; Cycles 3-8: once daily on Days 2, 4, 5, 9, 12; Cycles 9+: once daily on Days 2, 8, 9, 16); Until subject meets criteria for discontinuation of study drug
Sponsors
AbbVie
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For additional information, please contact the BMS oncology clinical trial information service at 855-216-0126 or email MyCancerStudyConnect@emergingmed.com. Please visit www.BMSStudyConnect.com for more information on clinical trial participation. Inclusion Criteria: * Documented progression from most recent line of therapy * Measurable disease * 1 to 3 prior lines of therapy * Subjects may be proteasome inhibitor naive or have received prior proteasome inhibitor therapy provided all the following criteria are met: 1. The subject did not discontinue any proteasome inhibitor due to intolerance or grade ≥ 3 toxicity 2. The subject is not refractory to any proteasome inhibitor, defined as progression during treatment or within 60 days after the last dose 3. The subject previously achieved a partial response (PR) or better to previous proteasome inhibitor (PI)
Exclusion criteria
* Monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, or Waldenstrom's macroglobulinemia * Active plasma cell leukemia * Known Human immunodeficiency virus (HIV) infection or active hepatitis A, B, or C
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Investigator-Assessed Progression-free Survival (PFS) Time (Months) From Randomization to Date of First Tumor Progression or Death Due to Any Cause - Randomized Participants | Randomization until 111 events (disease progression or death), up to May 2014, approximately 2 years | PE was planned for after at least 103 events; it was analyzed after 111 events. Response was assessed: Day 1 (± 7 days) of each cycle per modified International Myeloma Working Group (IMWG) criteria; assessed using adequate tumor assessment (ATA) (ie, serum and urine M-protein tests performed within 14 days of each other; imaging if baseline measurable extramedullary plasmacytoma existed). Progression: Any of following: Increase of 25% from lowest response in 1 or more: serum and/or urine M-component; in those without measurable serum and urine M-protein levels, difference between involved and uninvolved free light chain (FLC) levels (absolute increase \> 100 mg/L); Bone marrow plasma cell percentage (≥10%). Definite new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing lesions or plasmacytomas. Development of hypercalcemia attributed solely to the plasma cell proliferative disorder. |
| Number of Investigator-Assessed Progression-free Survival Events From Randomization to Date of First Tumor Progression or Death Due to Any Cause - All Randomized Participants | Randomization until 111 events, up to May 2014, approximately 2 years | PE planned for after at least 103 events (progression/death); analyzed at 111 events. Those who neither progressed nor died were censored on the date of last adequate tumor assessment (ATA), which requires both serum and urine M-protein tests. If no post-baseline tumor assessments/no death, then censored on randomization day. Response assessed: Day 1 (± 7 days) each cycle; 30 and 60 days post treatment. Modified IMWG criteria used. Progression: Any of following: Increase of 25% in serum and/or urine M-component; if no measurable serum, urine M-protein levels, then difference between involved and uninvolved free light chain (FLC) levels (absolute increase \> 100 mg/L) ; Bone marrow plasma cell percentage (≥10%). New bone lesions or soft tissue plasmacytomas or increase in size of existing lesions, plasmacytomas. Development of hypercalcemia attributed solely to plasma cell proliferative disorder. First dose occurs within 3 days of randomization. |
| 1 Year Progression-Free Survival Rate - Randomized Participants | Year 1 after last participant was randomized | PFS rate=Percentage probability of participants experiencing no progression or death up to 1 year, estimated using the Kaplan-Meier method. Response assessed by the investigator: Day 1 (± 7 days) of each cycle per modified IMWG criteria; assessed using ATA (ie, serum and urine M-protein tests performed within 14 days of each other; imaging done if baseline measurable extramedullary plasmacytoma existed). Progression: Any of the following: Increase of 25% from lowest response in 1 or more: serum and/or urine M-component; in those without measurable serum and urine M-protein levels, difference between involved and uninvolved FLC levels (absolute increase \> 100 mg/L) ; Bone marrow plasma cell percentage (≥10%). Definite new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing lesions or plasmacytomas. Development of hypercalcemia attributed solely to the plasma cell proliferative disorder. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-free Survival Time (Months) From Randomization to Date of First Tumor Progression or Death Due to Any Cause, in Randomized Participants With at Least One FcγRIIIa V Allele | Randomization until 111 events, up to May 2014, approximately 2 years | PE was planned for after at least 103 events; it was analyzed after 111 events. Response was assessed: Day 1 (± 7 days) of each cycle per modified IMWG criteria; assessed using adequate tumor assessment (ATA) (ie, serum and urine M-protein tests performed within 14 days of each other; imaging if baseline measurable extramedullary plasmacytoma existed). Progression: Any of following: Increase of 25% from lowest response in 1 or more: serum and/or urine M-component; in those without measurable serum and urine M-protein levels, difference between involved and uninvolved FLC levels (absolute increase \> 100 mg/L); Bone marrow plasma cell percentage (≥10%). Definite new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing lesions or plasmacytomas. Development of hypercalcemia attributed solely to the plasma cell proliferative disorder. Randomized participants with at least 1 FcγRIIIa V allele were a sub-set of all randomized participants. |
| Investigator-Assessed Objective Response Rate (ORR) - All Randomized Participants | Randomization until 111 events, up to May 2014, approximately 2 years | ORR was calculated for participants with a best overall response (BOR) of partial response (PR) or better, including stringent complete response (sCR), complete response (CR), and very good partial response (VGPR). BOR was determined by the investigator based on myeloma tumor assessments using IMWG criteria: CR=Negative immunofixation of serum and urine and disappearance of any soft tissue plasmacytomas, and \< 5% plasma cells in bone marrow; sCR= CR + normal FLC ratio and absence of clonal cells in bone marrow; VGPR=Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein level + urine M-protein level \< 100 mg per 24 hour; PR= ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hour. ORR= number of participants responding divided by total number of participants randomized, measured as a percentage. |
| Investigator-Assessed Objective Response Rate in Randomized Participants With at Least One FcγRIIIa V Allele | Randomization until 111 events, up to May 2014, approximately 2 years | ORR was calculated for participants with a BOR of PR or better, sCR, CR, and VGPR. BOR was determined by the investigator based on myeloma tumor assessments using IMWG criteria: CR=Negative immunofixation of serum and urine and disappearance of any soft tissue plasmacytomas, and \< 5% plasma cells in bone marrow; sCR= CR + normal FLC ratio and absence of clonal cells in bone marrow; VGPR=Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein level + urine M-protein level \< 100 mg per 24 hour; PR= ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hour. ORR= number of participants responding divided by total number of participants randomized, measured as a percentage. Randomized participants with at least 1 FcγRIIIa V allele were a sub-set of all randomized participants. |
Countries
Canada, France, Italy, Spain, United States
Participant flow
Pre-assignment details
185 participants were enrolled, 152 participants were randomized. Reasons not randomized: 23 no longer met study criteria, 5 withdrew consent, 2 died, 3 had poor/non-compliance. 150 were treated with study drug. 2 participants were not treated: 1 withdrawal by subject and 1 physician decision.
Participants by arm
| Arm | Count |
|---|---|
| Elotuzumab + Bortezomib + Dexamethasone Elotuzumab: Solution; Intravenous (IV); 10 mg/kg; (Cycles 1 & 2: Days 1, 8 & 15; Cycles 3-8: Days 1 & 11; Cycle 9+: Days 1 & 15); Until participant meets criteria for discontinuation of drug Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of drug. Days of Elotuzumab infusion: Dexamethasone (8mg IV + 8mg Oral) administered. Other days Dexamethasone 20 mg Oral administered Dexamethasone: Tablets; 20 mg; (Cycles 1& 2: once daily on Days 2, 4, 5, 8, 9, 11; Cycles 3-8: once daily on Days 2, 4, 5, 9, 12; Cycles 9+: once daily on Days 2, 8, 9, 16); Until criteria met for discontinuation. Dexamethasone: Tablets; 8 mg; (Cycles 1& 2: Days 1, 8, 15; Cycles 3-8: Days 1 &11; Cycles 9+; Days 1 & 15); Until criteria met for discontinuation of drug. Dexamethasone: Solution; IV; 8 mg; (Cycles 1& 2: Days 1, 8, 15; Cycles 3-8: Days 1 &11; Cycles 9+; Days 1 & 15); Until criteria met for discontinuation | 77 |
| Bortezomib + Dexamethasone Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of study drug. Dexamethasone: Tablets; 20 mg; (Cycles 1-8 once daily on Days 1, 2, 4, 5, 8, 9, 11, 12; Cycles 9+ once daily on Days 1, 2, 8, 9, 15, 16); Until criteria is met for discontinuation of study drug | 75 |
| Total | 152 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 11 |
| Overall Study | Disease Progression | 52 | 35 |
| Overall Study | no longer meets study criteria | 1 | 0 |
| Overall Study | non-specified | 6 | 4 |
| Overall Study | poor/non-compliance | 0 | 1 |
| Overall Study | study drug toxicity | 11 | 14 |
| Overall Study | subject request to discontinue treatment | 3 | 5 |
| Overall Study | Withdrawal by Subject | 2 | 5 |
Baseline characteristics
| Characteristic | Bortezomib + Dexamethasone | Elotuzumab + Bortezomib + Dexamethasone | Total |
|---|---|---|---|
| Age, Continuous | 65.1 years STANDARD_DEVIATION 10.34 | 65.4 years STANDARD_DEVIATION 9.48 | 65.3 years STANDARD_DEVIATION 9.88 |
| Age, Customized ≥65 and <75 years | 28 Participants | 28 Participants | 56 Participants |
| Age, Customized < 65 years | 33 Participants | 34 Participants | 67 Participants |
| Age, Customized >= 75 years | 14 Participants | 15 Participants | 29 Participants |
| Number of Prior Lines of Therapy 1 line of prior therapy | 51 Participants | 55 Participants | 106 Participants |
| Number of Prior Lines of Therapy 2 or 3 lines of prior therapy | 24 Participants | 22 Participants | 46 Participants |
| Presence of At Least 1 FcγRIIIa V allele No | 21 Participants | 22 Participants | 43 Participants |
| Presence of At Least 1 FcγRIIIa V allele Yes | 54 Participants | 55 Participants | 109 Participants |
| Prior Protease Inhibitor Use No | 38 Participants | 39 Participants | 77 Participants |
| Prior Protease Inhibitor Use Yes | 37 Participants | 38 Participants | 75 Participants |
| Region of Enrollment France | 11 Participants | 10 Participants | 21 Participants |
| Region of Enrollment Italy | 32 Participants | 34 Participants | 66 Participants |
| Region of Enrollment Spain | 9 Participants | 8 Participants | 17 Participants |
| Region of Enrollment United States | 23 Participants | 25 Participants | 48 Participants |
| Sex: Female, Male Female | 38 Participants | 35 Participants | 73 Participants |
| Sex: Female, Male Male | 37 Participants | 42 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 37 / 75 | 39 / 75 |
| other Total, other adverse events | 72 / 75 | 71 / 75 |
| serious Total, serious adverse events | 39 / 75 | 31 / 75 |
Outcome results
Primary
1 Year Progression-Free Survival Rate - Randomized Participants
PFS rate=Percentage probability of participants experiencing no progression or death up to 1 year, estimated using the Kaplan-Meier method. Response assessed by the investigator: Day 1 (± 7 days) of each cycle per modified IMWG criteria; assessed using ATA (ie, serum and urine M-protein tests performed within 14 days of each other; imaging done if baseline measurable extramedullary plasmacytoma existed). Progression: Any of the following: Increase of 25% from lowest response in 1 or more: serum and/or urine M-component; in those without measurable serum and urine M-protein levels, difference between involved and uninvolved FLC levels (absolute increase \> 100 mg/L) ; Bone marrow plasma cell percentage (≥10%). Definite new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing lesions or plasmacytomas. Development of hypercalcemia attributed solely to the plasma cell proliferative disorder.
Time frame: Year 1 after last participant was randomized
Population: All randomized participants were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Elotuzumab + Bortezomib + Dexamethasone | 1 Year Progression-Free Survival Rate - Randomized Participants | 0.39 percentage probability |
| Bortezomib + Dexamethasone | 1 Year Progression-Free Survival Rate - Randomized Participants | 0.33 percentage probability |
Primary
Median Investigator-Assessed Progression-free Survival (PFS) Time (Months) From Randomization to Date of First Tumor Progression or Death Due to Any Cause - Randomized Participants
PE was planned for after at least 103 events; it was analyzed after 111 events. Response was assessed: Day 1 (± 7 days) of each cycle per modified International Myeloma Working Group (IMWG) criteria; assessed using adequate tumor assessment (ATA) (ie, serum and urine M-protein tests performed within 14 days of each other; imaging if baseline measurable extramedullary plasmacytoma existed). Progression: Any of following: Increase of 25% from lowest response in 1 or more: serum and/or urine M-component; in those without measurable serum and urine M-protein levels, difference between involved and uninvolved free light chain (FLC) levels (absolute increase \> 100 mg/L); Bone marrow plasma cell percentage (≥10%). Definite new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing lesions or plasmacytomas. Development of hypercalcemia attributed solely to the plasma cell proliferative disorder.
Time frame: Randomization until 111 events (disease progression or death), up to May 2014, approximately 2 years
Population: Intent to treat (ITT), all randomized participants were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Elotuzumab + Bortezomib + Dexamethasone | Median Investigator-Assessed Progression-free Survival (PFS) Time (Months) From Randomization to Date of First Tumor Progression or Death Due to Any Cause - Randomized Participants | 9.7 Months |
| Bortezomib + Dexamethasone | Median Investigator-Assessed Progression-free Survival (PFS) Time (Months) From Randomization to Date of First Tumor Progression or Death Due to Any Cause - Randomized Participants | 6.9 Months |
p-value: 0.092395% CI: [0.49, 1.06]Log Rank
Primary
Number of Investigator-Assessed Progression-free Survival Events From Randomization to Date of First Tumor Progression or Death Due to Any Cause - All Randomized Participants
PE planned for after at least 103 events (progression/death); analyzed at 111 events. Those who neither progressed nor died were censored on the date of last adequate tumor assessment (ATA), which requires both serum and urine M-protein tests. If no post-baseline tumor assessments/no death, then censored on randomization day. Response assessed: Day 1 (± 7 days) each cycle; 30 and 60 days post treatment. Modified IMWG criteria used. Progression: Any of following: Increase of 25% in serum and/or urine M-component; if no measurable serum, urine M-protein levels, then difference between involved and uninvolved free light chain (FLC) levels (absolute increase \> 100 mg/L) ; Bone marrow plasma cell percentage (≥10%). New bone lesions or soft tissue plasmacytomas or increase in size of existing lesions, plasmacytomas. Development of hypercalcemia attributed solely to plasma cell proliferative disorder. First dose occurs within 3 days of randomization.
Time frame: Randomization until 111 events, up to May 2014, approximately 2 years
Population: Intent to treat (ITT), all randomized participants were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Elotuzumab + Bortezomib + Dexamethasone | Number of Investigator-Assessed Progression-free Survival Events From Randomization to Date of First Tumor Progression or Death Due to Any Cause - All Randomized Participants | 52 Events (progression or death) |
| Bortezomib + Dexamethasone | Number of Investigator-Assessed Progression-free Survival Events From Randomization to Date of First Tumor Progression or Death Due to Any Cause - All Randomized Participants | 59 Events (progression or death) |
Secondary
Investigator-Assessed Objective Response Rate in Randomized Participants With at Least One FcγRIIIa V Allele
ORR was calculated for participants with a BOR of PR or better, sCR, CR, and VGPR. BOR was determined by the investigator based on myeloma tumor assessments using IMWG criteria: CR=Negative immunofixation of serum and urine and disappearance of any soft tissue plasmacytomas, and \< 5% plasma cells in bone marrow; sCR= CR + normal FLC ratio and absence of clonal cells in bone marrow; VGPR=Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein level + urine M-protein level \< 100 mg per 24 hour; PR= ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hour. ORR= number of participants responding divided by total number of participants randomized, measured as a percentage. Randomized participants with at least 1 FcγRIIIa V allele were a sub-set of all randomized participants.
Time frame: Randomization until 111 events, up to May 2014, approximately 2 years
Population: All randomized participants who had at least one FcγRIIIa V allele at randomization were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Elotuzumab + Bortezomib + Dexamethasone | Investigator-Assessed Objective Response Rate in Randomized Participants With at Least One FcγRIIIa V Allele | 60.0 percentage of participants |
| Bortezomib + Dexamethasone | Investigator-Assessed Objective Response Rate in Randomized Participants With at Least One FcγRIIIa V Allele | 61.1 percentage of participants |
Secondary
Investigator-Assessed Objective Response Rate (ORR) - All Randomized Participants
ORR was calculated for participants with a best overall response (BOR) of partial response (PR) or better, including stringent complete response (sCR), complete response (CR), and very good partial response (VGPR). BOR was determined by the investigator based on myeloma tumor assessments using IMWG criteria: CR=Negative immunofixation of serum and urine and disappearance of any soft tissue plasmacytomas, and \< 5% plasma cells in bone marrow; sCR= CR + normal FLC ratio and absence of clonal cells in bone marrow; VGPR=Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein level + urine M-protein level \< 100 mg per 24 hour; PR= ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hour. ORR= number of participants responding divided by total number of participants randomized, measured as a percentage.
Time frame: Randomization until 111 events, up to May 2014, approximately 2 years
Population: All randomized participants were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Elotuzumab + Bortezomib + Dexamethasone | Investigator-Assessed Objective Response Rate (ORR) - All Randomized Participants | 64.9 percentage of participants |
| Bortezomib + Dexamethasone | Investigator-Assessed Objective Response Rate (ORR) - All Randomized Participants | 62.7 percentage of participants |
95% CI: [-13.2, 17.8]
Secondary
Median Progression-free Survival Time (Months) From Randomization to Date of First Tumor Progression or Death Due to Any Cause, in Randomized Participants With at Least One FcγRIIIa V Allele
PE was planned for after at least 103 events; it was analyzed after 111 events. Response was assessed: Day 1 (± 7 days) of each cycle per modified IMWG criteria; assessed using adequate tumor assessment (ATA) (ie, serum and urine M-protein tests performed within 14 days of each other; imaging if baseline measurable extramedullary plasmacytoma existed). Progression: Any of following: Increase of 25% from lowest response in 1 or more: serum and/or urine M-component; in those without measurable serum and urine M-protein levels, difference between involved and uninvolved FLC levels (absolute increase \> 100 mg/L); Bone marrow plasma cell percentage (≥10%). Definite new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing lesions or plasmacytomas. Development of hypercalcemia attributed solely to the plasma cell proliferative disorder. Randomized participants with at least 1 FcγRIIIa V allele were a sub-set of all randomized participants.
Time frame: Randomization until 111 events, up to May 2014, approximately 2 years
Population: All randomized participants who had at least one FcγRIIIa V allele were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Elotuzumab + Bortezomib + Dexamethasone | Median Progression-free Survival Time (Months) From Randomization to Date of First Tumor Progression or Death Due to Any Cause, in Randomized Participants With at Least One FcγRIIIa V Allele | 9.9 Months |
| Bortezomib + Dexamethasone | Median Progression-free Survival Time (Months) From Randomization to Date of First Tumor Progression or Death Due to Any Cause, in Randomized Participants With at Least One FcγRIIIa V Allele | 8.1 Months |