Multiple Myeloma
Conditions
Keywords
Treatment for patients with multiple myeloma, who have received no prior treatment
Brief summary
The purpose of this Phase 1/2 study is to evaluate the efficacy and safety of treatment with VELCADE, dexamethasone, and Revlimid® (VDR) as well as VELCADE, dexamethasone, cyclophosphamide, and Revlimid (VDCR) in patients with multiple myeloma who have received no prior treatment. This study will evaluate whether the addition of Revlimid to VELCADE and Dexamethasone will increase the complete response (CR)/ very good partial response (VGPR) rate.
Interventions
bortezomib 1.3 mg/m\^2 given via IV on days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles, then on days 1, 8, 15 and 22 of a 6-week cycle for 4 cycles (maintenance).
DRUGdexamethasone
dexamethasone 40 mg orally on days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop
DRUGcyclophosphamide
cyclophosphamide 500 mg/m\^2 orally on days 1 and 8 of a 3-week cycle for 8 cycles, then stop
lenalidomide 25 mg orally on days 1 to 14 of a 3-week cycle for 8 cycles then stop (VDR arm) lenalidomide 15 mg orally on days 1 to 14 of a 3-week cycle for 8 cycles then stop (VDCR arm)
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Millennium Pharmaceuticals, Inc.
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
* Voluntary written informed consent * Male or female subject 18 years of age or older * A Karnofsky Performance Status score of ≥50% (Eastern Cooperative Oncology Group Performance Status score ≤2) * Subjects must have symptomatic myeloma or asymptomatic myeloma with myeloma-related organ damage * Diagnosed Multiple myeloma * Subjects must have measurable disease requiring systemic therapy * Subjects must not have been treated previously with any systemic therapy for multiple myeloma * Two weeks must have elapsed since the date of the last radiotherapy treatment * Women of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 to 14 days prior to therapy and repeated within 24 hours before starting study drug. They must commit to continued abstinence from heterosexual intercourse or begin 2 acceptable methods of birth control (1 highly effective method and 1 additional effective method) used at the same time, beginning at least 4 weeks before initiation of Revlimid treatment. Women must also agree to ongoing pregnancy testing * Men must agree to not father a child and agree to use a latex condom during therapy and for 4 weeks after the last dose of study drug, even if they have had a successful vasectomy, if their partner is of childbearing potential * All subjects must agree to comply with the requirements of the RevAssistSM program
Exclusion criteria
* History of allergy to any of the study medications, their analogues, or excipients in the various formulations * ≥Grade 2 peripheral neuropathy on clinical examination * Myocardial infarction within 6 months prior to enrollment or New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or clinically significant conduction system abnormalities. * Female subject who is pregnant or breast-feeding * Clinically relevant active infection or serious comorbid medical conditions * Any condition, including laboratory abnormalities, that in the opinion of the Investigator places the subject at unacceptable risk if he/she were to participate in the study. This includes but is not limited to serious medical or psychiatric illness likely to interfere with participation in this clinical study * Active prior malignancy diagnosed or treated within the last 3 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Combined Complete Response and Very Good Partial Response | Up to 48 weeks or until disease progression | Complete response requires negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. Very good partial response requires serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \< 100 mg per 24 h |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Overall Response | Up to 48 weeks or until disease progression | Overall Response includes complete response and partial response. Complete response requires negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. Partial response requires at least 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by at least 90% or to \< 200 mg per 24 hour. |
| Number of Patients With Stringent Complete Response Rate | Up to 48 weeks or until disease progression | Stringent Complete Response is defined as complete response plus normal free light chain (kappa/lambda) ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. |
| Number of Patients With Complete Response Rate + Near Complete Response Rate | Up to 48 weeks or until disease progression | Complete response requires negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. Near Complete response requires positive immunofixation on the serum and/or urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. |
| Duration of Response | Up to 48 weeks or until disease progression | Duration of response is the time from date of first documented confirmed response to date of first documented progressive disease. A confirmed response is a response that has been observed on at least two consecutive assessments. Disease progression requires any one or more of the following: serum m-protein increase \>= 25% from nadir(absolute increase \>= 0.5 g/dL); Urine m-protein increase \>= 25% from nadir(absolute increase \>= 200 mg/24 hr), bone marrow plasma cell percentage increase \>= 25% from nadir(absolute increase \>= 10%), new bone lesion or soft tissue plasmacytomas. |
| Number of Patients With Adverse Events (AEs) | From first dose of study drug through the 30 day post-treatment AE assessment visit | Evaluate the safety and tolerability of the combination therapy |
| Time to Response | Up to 48 weeks or until disease response | Time to response is defined as time from date of randomization to the date of the first documentation of a confirmed response. confirmed response is a response that has been observed on at least two consecutive assessments. |
| Progression-free Survival | Up to 48 weeks or until disease progression/death | Progression-free survival is defined as time from the date of randomization to the date of the first documented progressive disease or death. Disease progression requires any one or more of the following: serum m-protein increase \>= 25% from nadir(absolute increase \>= 0.5 g/dL); Urine m-protein increase \>= 25% from nadir(absolute increase \>= 200 mg/24 hr), bone marrow plasma cell percentage increase \>= 25% from nadir(absolute increase \>= 10%), new bone lesion or soft tissue plasmacytomas. |
| Probability of 1-year Survival | survival probability at 1 year after randomization | — |
| Overall Survival | Up to 48 weeks or until death | Overall survival is defined as time from the date of randomization to the date of death |
| Time to Disease Progression | Up to 48 weeks or until disease progression | Time to disease progression is defined as time from the date of randomization to the date of first documented progressive disease. Disease progression requires any one or more of the following: serum m-protein increase \>= 25% from nadir(absolute increase \>= 0.5 g/dL); Urine m-protein increase \>= 25% from nadir(absolute increase \>= 200 mg/24 hr), bone marrow plasma cell percentage increase \>= 25% from nadir(absolute increase \>= 10%), new bone lesion or soft tissue plasmacytomas. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| V-DR VELCADE (bortezomib), dexamethasone, and Revlimid (lenalidomide) Bortezomib: 1.3 mg/m\^2/dose IV on Days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles, then on Days 1, 8, 15, and 22 of a 6-week cycle for 4 cycles.
Dexamethasone: 40 mg orally \[PO\] on Days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop.
Lenalidomide: 25 mg PO on Days 1 through 14 of a 3-week cycle for 8 cycles, then stop. | 42 |
| VDCR VELCADE (bortezomib), dexamethasone, cyclophosphamide, Revlimid (lenalidomide) Bortezomib: 1.3 mg/m\^2/dose IV on Days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles, then on Days 1, 8, 15, and 22 of a 6-week cycle for 4 cycles.
Dexamethasone: 40 mg PO on Days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop.
Cyclophosphamide: 100 - 500 mg/m\^2 dose PO on Days 1 and 8 of a 3-week cycle for 8 cycles, then stop.
Lenalidomide: 15 mg PO on Days 1 through 14 of a 3-week cycle for 8 cycles, then stop. | 66 |
| V-DC VELCADE (bortezomib), dexamethasone, cyclophosphamide Bortezomib: 1.3 mg/m\^2/dose IV on Days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles, then on Days 1, 8, 15, and 22 of a 6-week cycle for 4 cycles.
Dexamethasone: 40 mg orally PO on Days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop.
Cyclophosphamide: 500 mg/m\^2 dose PO on Days 1 and 8 of a 3-week cycle for 8 cycles, then stop. | 33 |
| VDC-mod Modified dosing of VELCADE (bortezomib), dexamethasone, cyclophosphamide Bortezomib: 1.3 mg/m\^2/dose IV on Days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles, then on Days 1, 8, 15, and 22 of a 6-week cycle for 4 cycles.
Dexamethasone: 40 mg PO on Days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop.
Cyclophosphamide: 500 mg/m\^2 dose PO on Days 1, 8, and 15 of a 3-week cycle for 8 cycles, then stop. | 17 |
| Total | 158 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 11 | 4 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Other | 2 | 5 | 2 | 2 |
| Overall Study | Physician Decision | 0 | 2 | 4 | 1 |
| Overall Study | Progressive Disease | 2 | 4 | 2 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 4 | 2 | 1 |
Baseline characteristics
| Characteristic | VDCR | V-DC | V-DR | VDC-mod | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 24 Participants | 12 Participants | 15 Participants | 6 Participants | 57 Participants |
| Age, Categorical Between 18 and 65 years | 42 Participants | 21 Participants | 27 Participants | 11 Participants | 101 Participants |
| Age Continuous | 60.9 years STANDARD_DEVIATION 8.97 | 61.4 years STANDARD_DEVIATION 8.32 | 59.5 years STANDARD_DEVIATION 8.76 | 59.6 years STANDARD_DEVIATION 9.16 | 60.5 years STANDARD_DEVIATION 8.75 |
| Region of Enrollment United States | 66 participants | 33 participants | 42 participants | 17 participants | 158 participants |
| Sex: Female, Male Female | 28 Participants | 14 Participants | 18 Participants | 10 Participants | 70 Participants |
| Sex: Female, Male Male | 38 Participants | 19 Participants | 24 Participants | 7 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 41 / 42 | 65 / 66 | 33 / 33 | 17 / 17 |
| serious Total, serious adverse events | 17 / 42 | 26 / 66 | 7 / 33 | 7 / 17 |
Outcome results
Primary
Number of Patients With Combined Complete Response and Very Good Partial Response
Complete response requires negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. Very good partial response requires serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \< 100 mg per 24 h
Time frame: Up to 48 weeks or until disease progression
Population: The response-evaluable population is defined as phase 2 patients with measurable disease at baseline and with at least 1 post baseline response assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V-DR | Number of Patients With Combined Complete Response and Very Good Partial Response | 21 participants |
| VDCR | Number of Patients With Combined Complete Response and Very Good Partial Response | 23 participants |
| V-DC | Number of Patients With Combined Complete Response and Very Good Partial Response | 13 participants |
| VDC-mod | Number of Patients With Combined Complete Response and Very Good Partial Response | 9 participants |
Secondary
Duration of Response
Duration of response is the time from date of first documented confirmed response to date of first documented progressive disease. A confirmed response is a response that has been observed on at least two consecutive assessments. Disease progression requires any one or more of the following: serum m-protein increase \>= 25% from nadir(absolute increase \>= 0.5 g/dL); Urine m-protein increase \>= 25% from nadir(absolute increase \>= 200 mg/24 hr), bone marrow plasma cell percentage increase \>= 25% from nadir(absolute increase \>= 10%), new bone lesion or soft tissue plasmacytomas.
Time frame: Up to 48 weeks or until disease progression
Population: Responders (patients achieved complete and partial response) in the response evaluable population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| V-DR | Duration of Response | NA days |
| VDCR | Duration of Response | NA days |
| V-DC | Duration of Response | NA days |
| VDC-mod | Duration of Response | NA days |
Secondary
Number of Patients With Adverse Events (AEs)
Evaluate the safety and tolerability of the combination therapy
Time frame: From first dose of study drug through the 30 day post-treatment AE assessment visit
Population: The safety population includes patients received any dose of any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V-DR | Number of Patients With Adverse Events (AEs) | 42 participants |
| VDCR | Number of Patients With Adverse Events (AEs) | 65 participants |
| V-DC | Number of Patients With Adverse Events (AEs) | 33 participants |
| VDC-mod | Number of Patients With Adverse Events (AEs) | 17 participants |
Secondary
Number of Patients With Complete Response Rate + Near Complete Response Rate
Complete response requires negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. Near Complete response requires positive immunofixation on the serum and/or urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow.
Time frame: Up to 48 weeks or until disease progression
Population: The response-evaluable population is defined as phase 2 patients with measurable disease at baseline and with at least 1 post baseline response assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V-DR | Number of Patients With Complete Response Rate + Near Complete Response Rate | 17 participants |
| VDCR | Number of Patients With Complete Response Rate + Near Complete Response Rate | 14 participants |
| V-DC | Number of Patients With Complete Response Rate + Near Complete Response Rate | 10 participants |
| VDC-mod | Number of Patients With Complete Response Rate + Near Complete Response Rate | 8 participants |
Secondary
Number of Patients With Overall Response
Overall Response includes complete response and partial response. Complete response requires negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow. Partial response requires at least 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by at least 90% or to \< 200 mg per 24 hour.
Time frame: Up to 48 weeks or until disease progression
Population: The response-evaluable population is defined as phase 2 patients with measurable disease at baseline and with at least 1 post baseline response assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V-DR | Number of Patients With Overall Response | 35 participants |
| VDCR | Number of Patients With Overall Response | 35 participants |
| V-DC | Number of Patients With Overall Response | 24 participants |
| VDC-mod | Number of Patients With Overall Response | 17 participants |
Secondary
Number of Patients With Stringent Complete Response Rate
Stringent Complete Response is defined as complete response plus normal free light chain (kappa/lambda) ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence.
Time frame: Up to 48 weeks or until disease progression
Population: The response-evaluable population is defined as phase 2 patients with measurable disease at baseline and with at least 1 post baseline response assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V-DR | Number of Patients With Stringent Complete Response Rate | 7 participants |
| VDCR | Number of Patients With Stringent Complete Response Rate | 6 participants |
| V-DC | Number of Patients With Stringent Complete Response Rate | 3 participants |
| VDC-mod | Number of Patients With Stringent Complete Response Rate | 5 participants |
Secondary
Overall Survival
Overall survival is defined as time from the date of randomization to the date of death
Time frame: Up to 48 weeks or until death
Population: The modified intent-to-treat population is defined as phase 2 patients received at least one dose of any drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| V-DR | Overall Survival | NA days |
| VDCR | Overall Survival | NA days |
| V-DC | Overall Survival | NA days |
| VDC-mod | Overall Survival | NA days |
Secondary
Probability of 1-year Survival
Time frame: survival probability at 1 year after randomization
Population: The modified intent-to-treat population is defined as phase 2 patients received at least one dose of any drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V-DR | Probability of 1-year Survival | 100 percentage of patients |
| VDCR | Probability of 1-year Survival | 91.6 percentage of patients |
| V-DC | Probability of 1-year Survival | 100 percentage of patients |
| VDC-mod | Probability of 1-year Survival | 100 percentage of patients |
Secondary
Progression-free Survival
Progression-free survival is defined as time from the date of randomization to the date of the first documented progressive disease or death. Disease progression requires any one or more of the following: serum m-protein increase \>= 25% from nadir(absolute increase \>= 0.5 g/dL); Urine m-protein increase \>= 25% from nadir(absolute increase \>= 200 mg/24 hr), bone marrow plasma cell percentage increase \>= 25% from nadir(absolute increase \>= 10%), new bone lesion or soft tissue plasmacytomas.
Time frame: Up to 48 weeks or until disease progression/death
Population: The modified intent-to-treat population is defined as phase 2 patients received at least one dose of any drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| V-DR | Progression-free Survival | NA days |
| VDCR | Progression-free Survival | 631 days |
| V-DC | Progression-free Survival | NA days |
| VDC-mod | Progression-free Survival | NA days |
Secondary
Time to Disease Progression
Time to disease progression is defined as time from the date of randomization to the date of first documented progressive disease. Disease progression requires any one or more of the following: serum m-protein increase \>= 25% from nadir(absolute increase \>= 0.5 g/dL); Urine m-protein increase \>= 25% from nadir(absolute increase \>= 200 mg/24 hr), bone marrow plasma cell percentage increase \>= 25% from nadir(absolute increase \>= 10%), new bone lesion or soft tissue plasmacytomas.
Time frame: Up to 48 weeks or until disease progression
Population: The modified intent-to-treat population is defined as phase 2 patients received at least one dose of any drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| V-DR | Time to Disease Progression | NA days |
| VDCR | Time to Disease Progression | NA days |
| V-DC | Time to Disease Progression | NA days |
| VDC-mod | Time to Disease Progression | NA days |
Secondary
Time to Response
Time to response is defined as time from date of randomization to the date of the first documentation of a confirmed response. confirmed response is a response that has been observed on at least two consecutive assessments.
Time frame: Up to 48 weeks or until disease response
Population: Responders (patients achieved complete and partial response) in the response evaluable population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| V-DR | Time to Response | 49 days |
| VDCR | Time to Response | 50 days |
| V-DC | Time to Response | 55 days |
| VDC-mod | Time to Response | 49 days |