Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, Pomalidomide
Brief summary
The purpose of this study is to compare the efficacy of the combination of pomalidomide, bortezomib and low dose dexamethasone to the combination of bortezomib and low dose dexamethasone in participants with relapsed/refractory multiple myeloma. This study will also assess how safe the combination of pomalidomide, bortezomib and low dose dexamethasone is compared to the combination of bortezomib and low dose dexamethasone.
Interventions
DRUGPomalidomide
Pomalidomide 4 mg will be taken orally on Days 1-14 of a 21-day cycle.
DRUGBortezomib
Bortezomib 1.3 mg/m2 will be administered subcutaneously on Days 1, 4, 8 and 11 of 21 days for cycles 1 -8 and on Days 1, 8 of 21 days for cycle 9 and onward until disease progression.
DRUGDexamethasone
Dexamethasone 20 mg/day \[≤ 75 years old\] or 10 mg/day \[\>75 years old\] will be taken orally on Days 1, 2, 4, 5, 8, 9, 11, 12 of 21 days for cycles 1-8 and on Days 1, 2, 8, 9 of 21 days for cycles 9 and onward until disease progression.
Sponsors
Celgene
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
* Must be ≥ 18 years at the time of signing informed consent. * Must have documented diagnosis of multiple myeloma and have measureable disease by serum and urine protein electrophoresis. * Must have had at least 1 but no greater than 3 prior anti-myeloma regimens. * Must have documented disease progression during or after their last anti-myeloma therapy. * All subjects must have received prior treatment with a lenalidomide containing regimen for at least 2 consecutive cycles.
Exclusion criteria
* Documented progressive disease during therapy or within 60 days of the last dose of a bortezomib-containing therapy under the 1.3 mg/m\^2 dose twice weekly dosing schedule. * Peripheral neuropathy Grade 3, Grade 4 or Grade 2 with pain within 14 days prior to randomization. * Non-secretory multiple myeloma. * Subjects with severe renal impairment requiring dialysis. * Previous therapy with pomalidomide.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival by Independent Response Adjudication Committee (IRAC) | From randomization to progressive disease or death during the IRAC assessment period, up to approximately 42 months | Progression free survival (PFS) will be calculated as the time between the randomization and progressive disease (PD) or death. Progressive Disease is defined as an Increase of ≥ 25% from nadir in: * Serum M-component and/or (the absolute increase must be ≥ 0.5 g/dL)g * Urine M-component and/or (the absolute increase must be ≥ 200 mg/24 hours) * In patients without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels, the absolute increase must be \> 100 mg/dL. * Bone marrow plasma cell percentage, the absolute % must be ≥ 10%h * Definite development of new bone lesions or soft tissue plasmacytomas increase in the size of existing bone lesions or soft tissue plasmacytomas. -Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization to date of death, up to approximately 65 months | Overall survival (OS) is calculated as the time from randomization to death from any cause. |
| Overall Response Rate by Independent Response Adjudication Committee (IRAC) | From randomization to progressive disease or death during the IRAC assessment period, up to approximately 42 months | The ORR together with the relative proportions in each response category (ie, stringent CR \[sCR\], CR, very good PR \[VGPR\], PR, SD, and PD) by treatment using the IMWG criteria will be examined. Complete Response: Negative immunofixation on the 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 by immunohistochemistry or immunofluorescence VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine Mprotein level \< 100 mg per 24 hours PR: ≥ 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hours Progressive Disease: Please refer to Primary outcome measure for definition SD: Not meeting criteria for CR, VGPR, PR, or progressive disease |
| Duration of Response by Independent Response Adjudication Committee (IRAC) | From randomization to progressive disease or death during the IRAC assessment period, up to approximately 42 months | Duration of myeloma response is defined as the duration from the time when the IMWG response criteria are first met for sCR or CR or VGPR or PR until the first date the response criteria are met for PD or until the subject died from any cause, whichever occurs first. Complete Response: Negative immunofixation on the 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 by immunohistochemistry or immunofluorescence VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine Mprotein level \< 100 mg per 24 hours PR: ≥ 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hours Progressive Disease: Please refer to Primary outcome measure for definition SD: Not meeting criteria for CR, VGPR, PR, or progressive disease |
| Number of Participants With Grade 3-4 Treatment Emergent Adverse Events (TEAE) | From first dose to 28 days after the last dose (up to approximately 44 months | Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening on or after the first dose date of the study treatment and within 28 days after the last dose date. |
| Number of Participants With Grade 5 Treatment Emergent Adverse Events (TEAE) | From first dose to 28 days after the last dose (up to approximately 44 months | Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening on or after the first dose date of the study treatment and within 28 days after the last dose date. |
Countries
Austria, Canada, Denmark, Finland, France, Germany, Greece, Ireland, Israel, Italy, Japan, Netherlands, Norway, Poland, Portugal, Puerto Rico, Russia, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Pre-assignment details
548 participants treated
Participants by arm
| Arm | Count |
|---|---|
| Treatment 1: POM+BTZ+LD-DEX POM (Pomalidomide)
* 4 mg/day on Days 1 to 14 of each 21-day treatment cycle BTZ (Bortezomib)
* For Cycles 1 - 8: 1.3 mg/m2/dose on Days 1, 4, 8, and 11 of a 21-day cycle
* For Cycles 9 onwards: 1.3 mg/m2/dose on Days 1 and 8 of a 21-day cycle DEX (Dexamethasone)
* For Cycles 1 to 8, 20 mg/day (≤ 75 years old) or 10 mg/day (\> 75 years old) on Days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle.
* For Cycles 9 and onward, 20 mg/day (≤ 75 years old) or 10 mg/day (\> 75 years old) on Days 1, 2, 8, and 9 of a 21-day cycle. | 281 |
| Treatment 2: BTZ+LD-DEX BTZ ((Bortezomib)
* For Cycles 1 - 8: 1.3 mg/m2/dose on Days 1, 4, 8, and 11 of a 21-day cycle
* For Cycles 9 onwards: 1.3 mg/m2/dose on Days 1 and 8 of a 21-day cycle DEX (Dexamethasone)
* For Cycles 1 to 8, 20 mg/day (≤ 75 years old) or 10 mg/day (\> 75 years old) on Days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle.
* For Cycles 9 and onward, 20 mg/day (≤ 75 years old) or 10 mg/day (\> 75 years old) on Days 1, 2, 8, and 9 of a 21-day cycle. | 278 |
| Total | 559 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Randomization | clinical progression | 0 | 1 |
| Randomization | Death | 1 | 0 |
| Randomization | Lost to Follow-up | 1 | 0 |
| Randomization | Physician Decision | 0 | 1 |
| Randomization | progressive disease | 0 | 2 |
| Randomization | Randomization error | 1 | 0 |
| Randomization | Withdrew informed consent | 0 | 4 |
| Treatment Period | Adverse Event | 39 | 52 |
| Treatment Period | Death | 20 | 9 |
| Treatment Period | Lost to Follow-up | 0 | 2 |
| Treatment Period | Other Reasons | 27 | 19 |
| Treatment Period | Pregnancy | 0 | 1 |
| Treatment Period | Progressive Disease | 167 | 165 |
| Treatment Period | Withdrawal of Consent | 25 | 22 |
Baseline characteristics
| Characteristic | Treatment 2: BTZ+LD-DEX | Total | Treatment 1: POM+BTZ+LD-DEX |
|---|---|---|---|
| Age, Continuous | 66.1 Years STANDARD_DEVIATION 10.16 | 66.0 Years STANDARD_DEVIATION 10.14 | 65.9 Years STANDARD_DEVIATION 10.13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 31 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 241 Participants | 485 Participants | 244 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 23 Participants | 43 Participants | 20 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 22 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 21 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 23 Participants | 45 Participants | 22 Participants |
| Race (NIH/OMB) White | 234 Participants | 471 Participants | 237 Participants |
| Sex: Female, Male Female | 131 Participants | 257 Participants | 126 Participants |
| Sex: Female, Male Male | 147 Participants | 302 Participants | 155 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 197 / 281 | 193 / 278 |
| other Total, other adverse events | 276 / 278 | 260 / 270 |
| serious Total, serious adverse events | 177 / 278 | 119 / 270 |
Outcome results
Primary
Progression Free Survival by Independent Response Adjudication Committee (IRAC)
Progression free survival (PFS) will be calculated as the time between the randomization and progressive disease (PD) or death. Progressive Disease is defined as an Increase of ≥ 25% from nadir in: * Serum M-component and/or (the absolute increase must be ≥ 0.5 g/dL)g * Urine M-component and/or (the absolute increase must be ≥ 200 mg/24 hours) * In patients without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels, the absolute increase must be \> 100 mg/dL. * Bone marrow plasma cell percentage, the absolute % must be ≥ 10%h * Definite development of new bone lesions or soft tissue plasmacytomas increase in the size of existing bone lesions or soft tissue plasmacytomas. -Development of hypercalcemia (corrected serum calcium \> 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder.
Time frame: From randomization to progressive disease or death during the IRAC assessment period, up to approximately 42 months
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment 1: POM+BTZ+LD-DEX | Progression Free Survival by Independent Response Adjudication Committee (IRAC) | 11.20 Months |
| Treatment 2: BTZ+LD-DEX | Progression Free Survival by Independent Response Adjudication Committee (IRAC) | 7.10 Months |
p-value: 0.00195% CI: [0.49, 0.77]Based on Cox proportional hazards model
Secondary
Duration of Response by Independent Response Adjudication Committee (IRAC)
Duration of myeloma response is defined as the duration from the time when the IMWG response criteria are first met for sCR or CR or VGPR or PR until the first date the response criteria are met for PD or until the subject died from any cause, whichever occurs first. Complete Response: Negative immunofixation on the 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 by immunohistochemistry or immunofluorescence VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine Mprotein level \< 100 mg per 24 hours PR: ≥ 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hours Progressive Disease: Please refer to Primary outcome measure for definition SD: Not meeting criteria for CR, VGPR, PR, or progressive disease
Time frame: From randomization to progressive disease or death during the IRAC assessment period, up to approximately 42 months
Population: All randomized participants with a response (sCR or CR or VGPR or PR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment 1: POM+BTZ+LD-DEX | Duration of Response by Independent Response Adjudication Committee (IRAC) | 13.70 Months |
| Treatment 2: BTZ+LD-DEX | Duration of Response by Independent Response Adjudication Committee (IRAC) | 10.94 Months |
p-value: 0.06495% CI: [0.56, 1.02]Unstratified log-rank test
Secondary
Number of Participants With Grade 3-4 Treatment Emergent Adverse Events (TEAE)
Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening on or after the first dose date of the study treatment and within 28 days after the last dose date.
Time frame: From first dose to 28 days after the last dose (up to approximately 44 months
Population: All Treated Participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment 1: POM+BTZ+LD-DEX | Number of Participants With Grade 3-4 Treatment Emergent Adverse Events (TEAE) | 259 Participants |
| Treatment 2: BTZ+LD-DEX | Number of Participants With Grade 3-4 Treatment Emergent Adverse Events (TEAE) | 194 Participants |
Secondary
Number of Participants With Grade 5 Treatment Emergent Adverse Events (TEAE)
Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening on or after the first dose date of the study treatment and within 28 days after the last dose date.
Time frame: From first dose to 28 days after the last dose (up to approximately 44 months
Population: All Treated Participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment 1: POM+BTZ+LD-DEX | Number of Participants With Grade 5 Treatment Emergent Adverse Events (TEAE) | 29 Participants |
| Treatment 2: BTZ+LD-DEX | Number of Participants With Grade 5 Treatment Emergent Adverse Events (TEAE) | 12 Participants |
Secondary
Overall Response Rate by Independent Response Adjudication Committee (IRAC)
The ORR together with the relative proportions in each response category (ie, stringent CR \[sCR\], CR, very good PR \[VGPR\], PR, SD, and PD) by treatment using the IMWG criteria will be examined. Complete Response: Negative immunofixation on the 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 by immunohistochemistry or immunofluorescence VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine Mprotein level \< 100 mg per 24 hours PR: ≥ 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hours Progressive Disease: Please refer to Primary outcome measure for definition SD: Not meeting criteria for CR, VGPR, PR, or progressive disease
Time frame: From randomization to progressive disease or death during the IRAC assessment period, up to approximately 42 months
Population: All randomized participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment 1: POM+BTZ+LD-DEX | Overall Response Rate by Independent Response Adjudication Committee (IRAC) | Very Good Partial Response | 104 Participants |
| Treatment 1: POM+BTZ+LD-DEX | Overall Response Rate by Independent Response Adjudication Committee (IRAC) | Stable Disease | 32 Participants |
| Treatment 1: POM+BTZ+LD-DEX | Overall Response Rate by Independent Response Adjudication Committee (IRAC) | Complete Reponse | 35 Participants |
| Treatment 1: POM+BTZ+LD-DEX | Overall Response Rate by Independent Response Adjudication Committee (IRAC) | Progressive Disease | 11 Participants |
| Treatment 1: POM+BTZ+LD-DEX | Overall Response Rate by Independent Response Adjudication Committee (IRAC) | Partial Response | 83 Participants |
| Treatment 1: POM+BTZ+LD-DEX | Overall Response Rate by Independent Response Adjudication Committee (IRAC) | Not Evaluable | 7 Participants |
| Treatment 1: POM+BTZ+LD-DEX | Overall Response Rate by Independent Response Adjudication Committee (IRAC) | Stringent complete response | 9 Participants |
| Treatment 2: BTZ+LD-DEX | Overall Response Rate by Independent Response Adjudication Committee (IRAC) | Not Evaluable | 17 Participants |
| Treatment 2: BTZ+LD-DEX | Overall Response Rate by Independent Response Adjudication Committee (IRAC) | Stringent complete response | 2 Participants |
| Treatment 2: BTZ+LD-DEX | Overall Response Rate by Independent Response Adjudication Committee (IRAC) | Complete Reponse | 9 Participants |
| Treatment 2: BTZ+LD-DEX | Overall Response Rate by Independent Response Adjudication Committee (IRAC) | Very Good Partial Response | 40 Participants |
| Treatment 2: BTZ+LD-DEX | Overall Response Rate by Independent Response Adjudication Committee (IRAC) | Partial Response | 88 Participants |
| Treatment 2: BTZ+LD-DEX | Overall Response Rate by Independent Response Adjudication Committee (IRAC) | Stable Disease | 106 Participants |
| Treatment 2: BTZ+LD-DEX | Overall Response Rate by Independent Response Adjudication Committee (IRAC) | Progressive Disease | 16 Participants |
Secondary
Overall Survival (OS)
Overall survival (OS) is calculated as the time from randomization to death from any cause.
Time frame: From randomization to date of death, up to approximately 65 months
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment 1: POM+BTZ+LD-DEX | Overall Survival (OS) | 35.58 Months |
| Treatment 2: BTZ+LD-DEX | Overall Survival (OS) | 31.61 Months |
p-value: 0.57195% CI: [0.77, 1.15]Log Rank