Multiple Myeloma
Conditions
Brief summary
The purpose of this study is to determine whether the combination of AMD3100 (plerixafor) and granulocyte colony-stimulating factor (G-CSF, generic name of filgrastim) is better than G-CSF alone to mobilize and collect the optimal number of stem cells in multiple myeloma patients for autologous transplantation.
Detailed description
A peripheral stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. Currently filgrastim (G-CSF), a colony stimulating factor, is used to cause the growth and mobilization of stem cells from bone marrow to peripheral blood, which can then be collected from the peripheral blood by a process called apheresis. Plerixafor aids in the release of the stem cells from the bone marrow into the peripheral blood, possibly allowing for a more rapid collection of a larger number of stem cells from the peripheral blood. Larger stem cell doses for transplantation correlate to faster recovery times after high dose chemotherapy followed with stem cell transplantation. This study is intended to determine whether the combination of plerixafor with filgrastim (G-CSF)is better than filgrastim (G-CSF) alone in helping multiple myeloma patients collect at least 6 million stem cells in two or less apheresis sessions. This study was previously posted by AnorMED, Inc. In November 2006, AnorMED, Inc. was acquired by Genzyme Corporation. Genzyme Corporation is the sponsor of the trial.
Interventions
Participants underwent mobilization with granulocyte colony-stimulating factor (G-CSF) (10 µg/kg/day) for 4 days, administered by subcutaneous (SC) injection. On the evening of Day 4, participants received plerixafor (240 µg/kg), administered by SC injection. On Day 5, participants received a morning dose of G-CSF (10 µg/kg) and underwent apheresis approx. 10 to 11 hours after the dose of plerixafor (within 60 minutes of G-CSF administration). Participants continued to receive an evening dose of plerixafor followed by a morning dose of G-CSF and apheresis for up to 4 aphereses or until ≥ 6\*10\^6 CD34+ cells/kg were collected. Participants who participated in the rescue procedure underwent an additional daily treatment with plerixafor (240 µg/kg) and apheresis for up to 4 days.
Participants underwent mobilization with granulocyte colony-stimulating factor (G-CSF) (10 µg/kg/day) for 4 days, administered by subcutaneous (SC) injection. On the evening of Day 4, participants received placebo, administered by SC injection. On Day 5, participants received a morning dose of G-CSF (10 µg/kg) and underwent apheresis approx. 10 to 11 hours after the dose of placebo (within 60 minutes of G-CSF administration). Participants continued to receive an evening dose of placebo followed by a morning dose of G-CSF and apheresis for up to 4 aphereses or until ≥ 6\*10\^6 CD34+ cells/kg were collected. Participants who participated in the rescue procedure underwent an additional daily treatment with plerixafor (240 µg/kg) and apheresis for up to 4 days.
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 78 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of multiple myeloma in first or second complete or partial remission * \>= 4 weeks since last cycle of chemotherapy (thalidomide, dexamethasone, and Velcade were not considered prior chemotherapy for the purpose of this study) * Recovered from all acute toxic effects of prior chemotherapy * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * White Blood Cell count (WBC) \> 2.5\*10\^9/L * Absolute polymorphonuclear leukocytes (PMN) count \> 1.5\*10\^9/L * Platelet (PLT) \> 100\*10\^9/L * Serum creatinine \<=2.2 mg/dL * Cardiac and pulmonary status sufficient to undergo apheresis and transplantation * Negative for HIV
Exclusion criteria
): * Failed previous stem cell collection * Previous stem cell transplantation * Brain metastases or myelomatous meningitis * Radiation to ≥ 50% of the pelvis * Abnormal electrocardiogram (ECG) with rhythm disturbance (ventricular arrhythmias) or other conduction abnormality * Received bone-seeking radionuclides (e.g. holmium) * A residual acute medical condition resulting from prior chemotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Achieving a Target of ≥ 6*10^6 CD34+ Cells/kg in 2 or Fewer Days of Apheresis. | up to Day 6 | Proportion of participants achieving a target of ≥ 6\*10\^6 CD34+ cells/kg in 2 or fewer days of apheresis. Central lab data were taken from Days 5 to 6 of the Treatment/Apheresis period. Each participant's value was calculated as the sum of all daily values collected over the 2 apheresis days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Achieving a Target of ≥ 6*10^6 CD34+ Cells/kg in 4 or Fewer Days of Apheresis. | up to Day 8 | Proportion of participants achieving a target of ≥ 6\*10\^6 CD34+ cells/kg in 4 or fewer days of apheresis. Central lab data were taken from Days 5 to 8 of the Treatment/Apheresis period. Each participant's value was calculated as the sum of all daily values collected over the 4 apheresis days. |
| Proportion of Participants Achieving a Target of ≥ 2*10^6 CD34+ Cells/kg in 4 or Fewer Days of Apheresis. | up to Day 8 | Proportion of participants achieving a target of ≥ 2\*10\^6 CD34+ cells/kg in 4 or fewer days of apheresis. Central lab data were taken from Days 5 to 8 of the Treatment/Apheresis period. Each participant's value was calculated as the sum of all daily values collected over the 4 apheresis days. |
| Median Number of Days to ≥6*10^6 CD34+ Cells/kg | up to Day 8 | The Kaplan Meier estimate of median number of days (number of days at which 50% of participants have experienced the event, accounting for censored values) in each treatment arm to collect an optimum number of cells (≥6\*10\^6 CD34+ cells/kg) for transplantation. |
| Median Number of Days to Polymorphonuclear (PMN) Cell Engraftment | Up to Month 13 | The Kaplan Meier estimate of median number of days to PMN engraftment (number of days at which 50% of participants have experienced the event, accounting for censored values) was a secondary efficacy endpoint. Engraftment was defined as PMN counts ≥ 0.5\*10\^9/L for 3 consecutive days or ≥ 1.0\*10\^9/L for 1 day. Time to engraftment corresponded to the first day that the criteria were met and was evaluated up to 12 months post transplant. |
| Number of Participants With Adverse Events | up to Day 38 | Number of participants with treatment emergent adverse events (AEs). The timeframe for treatment emergent AEs is defined as Day 1 (start of G-CSF Mobilization) to the day before starting chemotherapy (approximately 38 days later). AEs were reported regardless of relationship to study treatment. The investigator graded each AE using the World Health Organization (WHO) Adverse Event Grading Scale. AEs of Grade 3 were considered severe and Grade 4 were considered life-threatening. |
| Graft Durability at 100 Days Post Transplantation | approximately Day 138 | The proportion of participants maintaining a durable graft at 100 days post-transplantation by at least 2 of the following criteria (without erythropoietin (EPO), G-CSF, or transfusions): (1) a platelet count \>50000/µL without transfusion for at least 2 weeks, (2) hemoglobin \>=10g/dL for at least 1 month, (3) and absolute neutrophil count \>1000/µL for at least 1 week. |
| Graft Durability at 6 Months Post Transplantation | approximately Month 7 | The proportion of participants maintaining a durable graft at 6 months post-transplantation by at least 2 of the following criteria (without erythropoietin (EPO), G-CSF, or transfusions): (1) a platelet count \>50000/µL without transfusion for at least 2 weeks, (2) hemoglobin \>=10g/dL for at least 1 month, (3) and absolute neutrophil count \>1000/µL for at least 1 week. |
| Graft Durability at 12 Months Post Transplantation | approximately Month 13 | The proportion of participants maintaining a durable graft at 12 months post-transplantation by at least 2 of the following criteria (without erythropoietin (EPO), G-CSF, or transfusions): (1) a platelet count \>50000/µL without transfusion for at least 2 weeks, (2) hemoglobin \>=10g/dL for at least 1 month, (3) and absolute neutrophil count \>1000/µL for at least 1 week. |
| Median Number of Days to Platelet (PLT) Engraftment | Up to Month 13 | The Kaplan Meier estimate of median number of days to PLT engraftment (number of days at which 50% of participants have experienced the event, accounting for censored values) was a secondary efficacy endpoint. Engraftment was defined as ≥ 20\*10\^9/L without transfusion for the preceding 7 days. Time to engraftment corresponded to the first day that the criteria were met and was evaluated up to 12 months post transplant. |
Countries
Canada, Germany, United States
Participant flow
Recruitment details
Participants with multiple myeloma (MM) eligible for autologous hematopoietic stem cell transplant were recruited from 40 centers (38 in the U.S., 1 in Germany, 1 in Canada). The first participant was randomized on 04 February 2005 and the last participant's last study visit occurred on 22 January 2008. A total of 302 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| G-CSF Plus Plerixafor Participants underwent mobilization with G-CSF for 4 days. On the evening of Day 4, participants received a dose of plerixafor. On each subsequent day, participants received a morning dose of G-CSF followed by apheresis and an evening dose of plerixafor for a maximum of 4 aphereses or until ≥ 6\*10\^6 CD34+ cells/kg were collected. | 148 |
| G-CSF Plus Placebo Participants underwent mobilization with G-CSF for 4 days. On the evening of Day 4, participants received a dose of placebo. On each subsequent day, participants received a morning dose of G-CSF followed by apheresis and an evening dose of placebo for a maximum of 4 aphereses or until ≥ 6\*10\^6 CD34+ cells/kg were collected. | 154 |
| Total | 302 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 7 | 7 |
| Overall Study | Elective Withdrawal | 5 | 5 |
| Overall Study | Entered Rescue Procedure | 0 | 7 |
| Overall Study | Failed mobilization | 0 | 4 |
| Overall Study | Intercurrent illness | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other | 6 | 9 |
Baseline characteristics
| Characteristic | G-CSF Plus Plerixafor | G-CSF Plus Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.2 years STANDARD_DEVIATION 8.4 | 58.4 years STANDARD_DEVIATION 8.6 | 58.3 years STANDARD_DEVIATION 8.5 |
| Race/Ethnicity, Customized African-American | 18 participants | 14 participants | 32 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 3 participants | 4 participants |
| Race/Ethnicity, Customized Caucasian | 117 participants | 128 participants | 245 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 11 participants | 4 participants | 15 participants |
| Race/Ethnicity, Customized Other | 1 participants | 5 participants | 6 participants |
| Sex: Female, Male Female | 48 Participants | 47 Participants | 95 Participants |
| Sex: Female, Male Male | 100 Participants | 107 Participants | 207 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 140 / 147 | 140 / 151 |
| serious Total, serious adverse events | 4 / 147 | 6 / 151 |
Outcome results
Primary
Proportion of Participants Achieving a Target of ≥ 6*10^6 CD34+ Cells/kg in 2 or Fewer Days of Apheresis.
Proportion of participants achieving a target of ≥ 6\*10\^6 CD34+ cells/kg in 2 or fewer days of apheresis. Central lab data were taken from Days 5 to 6 of the Treatment/Apheresis period. Each participant's value was calculated as the sum of all daily values collected over the 2 apheresis days.
Time frame: up to Day 6
Population: Intent-to-Treat Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G-CSF Plus Plerixafor | Proportion of Participants Achieving a Target of ≥ 6*10^6 CD34+ Cells/kg in 2 or Fewer Days of Apheresis. | Proportion achieving target in ≤2 days | 0.716 proportion of participants |
| G-CSF Plus Plerixafor | Proportion of Participants Achieving a Target of ≥ 6*10^6 CD34+ Cells/kg in 2 or Fewer Days of Apheresis. | Proportion not achieving target in ≤2 days | 0.284 proportion of participants |
| G-CSF Plus Placebo | Proportion of Participants Achieving a Target of ≥ 6*10^6 CD34+ Cells/kg in 2 or Fewer Days of Apheresis. | Proportion achieving target in ≤2 days | 0.344 proportion of participants |
| G-CSF Plus Placebo | Proportion of Participants Achieving a Target of ≥ 6*10^6 CD34+ Cells/kg in 2 or Fewer Days of Apheresis. | Proportion not achieving target in ≤2 days | 0.656 proportion of participants |
Secondary
Graft Durability at 100 Days Post Transplantation
The proportion of participants maintaining a durable graft at 100 days post-transplantation by at least 2 of the following criteria (without erythropoietin (EPO), G-CSF, or transfusions): (1) a platelet count \>50000/µL without transfusion for at least 2 weeks, (2) hemoglobin \>=10g/dL for at least 1 month, (3) and absolute neutrophil count \>1000/µL for at least 1 week.
Time frame: approximately Day 138
Population: Participants who received a stem cell transplant and were evaluable at 100 days post-transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G-CSF Plus Plerixafor | Graft Durability at 100 Days Post Transplantation | Proportion of participants with a durable graft | 0.986 proportion of participants |
| G-CSF Plus Plerixafor | Graft Durability at 100 Days Post Transplantation | Proportion of participants without a durable graft | 0.014 proportion of participants |
| G-CSF Plus Placebo | Graft Durability at 100 Days Post Transplantation | Proportion of participants with a durable graft | 0.978 proportion of participants |
| G-CSF Plus Placebo | Graft Durability at 100 Days Post Transplantation | Proportion of participants without a durable graft | 0.022 proportion of participants |
Secondary
Graft Durability at 12 Months Post Transplantation
The proportion of participants maintaining a durable graft at 12 months post-transplantation by at least 2 of the following criteria (without erythropoietin (EPO), G-CSF, or transfusions): (1) a platelet count \>50000/µL without transfusion for at least 2 weeks, (2) hemoglobin \>=10g/dL for at least 1 month, (3) and absolute neutrophil count \>1000/µL for at least 1 week.
Time frame: approximately Month 13
Population: Participants who received a stem cell transplant and were evaluable at 12 months post-transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G-CSF Plus Plerixafor | Graft Durability at 12 Months Post Transplantation | Proportion of participants with a durable graft | 0.992 proportion of participants |
| G-CSF Plus Plerixafor | Graft Durability at 12 Months Post Transplantation | Proportion of participants without a durable graft | 0.008 proportion of participants |
| G-CSF Plus Placebo | Graft Durability at 12 Months Post Transplantation | Proportion of participants with a durable graft | 0.992 proportion of participants |
| G-CSF Plus Placebo | Graft Durability at 12 Months Post Transplantation | Proportion of participants without a durable graft | 0.008 proportion of participants |
Secondary
Graft Durability at 6 Months Post Transplantation
The proportion of participants maintaining a durable graft at 6 months post-transplantation by at least 2 of the following criteria (without erythropoietin (EPO), G-CSF, or transfusions): (1) a platelet count \>50000/µL without transfusion for at least 2 weeks, (2) hemoglobin \>=10g/dL for at least 1 month, (3) and absolute neutrophil count \>1000/µL for at least 1 week.
Time frame: approximately Month 7
Population: Participants who received a stem cell transplant and were evaluable at 6 months post-transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G-CSF Plus Plerixafor | Graft Durability at 6 Months Post Transplantation | Proportion of participants with a durable graft | 0.985 proportion of participants |
| G-CSF Plus Plerixafor | Graft Durability at 6 Months Post Transplantation | Proportion of participants without a durable graft | 0.015 proportion of participants |
| G-CSF Plus Placebo | Graft Durability at 6 Months Post Transplantation | Proportion of participants with a durable graft | 0.984 proportion of participants |
| G-CSF Plus Placebo | Graft Durability at 6 Months Post Transplantation | Proportion of participants without a durable graft | 0.016 proportion of participants |
Secondary
Median Number of Days to ≥6*10^6 CD34+ Cells/kg
The Kaplan Meier estimate of median number of days (number of days at which 50% of participants have experienced the event, accounting for censored values) in each treatment arm to collect an optimum number of cells (≥6\*10\^6 CD34+ cells/kg) for transplantation.
Time frame: up to Day 8
Population: Intent-to-treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| G-CSF Plus Plerixafor | Median Number of Days to ≥6*10^6 CD34+ Cells/kg | 1.0 Days |
| G-CSF Plus Placebo | Median Number of Days to ≥6*10^6 CD34+ Cells/kg | 4.0 Days |
Secondary
Median Number of Days to Platelet (PLT) Engraftment
The Kaplan Meier estimate of median number of days to PLT engraftment (number of days at which 50% of participants have experienced the event, accounting for censored values) was a secondary efficacy endpoint. Engraftment was defined as ≥ 20\*10\^9/L without transfusion for the preceding 7 days. Time to engraftment corresponded to the first day that the criteria were met and was evaluated up to 12 months post transplant.
Time frame: Up to Month 13
Population: Participants who received a stem cell transplant
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| G-CSF Plus Plerixafor | Median Number of Days to Platelet (PLT) Engraftment | 18.0 Days |
| G-CSF Plus Placebo | Median Number of Days to Platelet (PLT) Engraftment | 18.0 Days |
Secondary
Median Number of Days to Polymorphonuclear (PMN) Cell Engraftment
The Kaplan Meier estimate of median number of days to PMN engraftment (number of days at which 50% of participants have experienced the event, accounting for censored values) was a secondary efficacy endpoint. Engraftment was defined as PMN counts ≥ 0.5\*10\^9/L for 3 consecutive days or ≥ 1.0\*10\^9/L for 1 day. Time to engraftment corresponded to the first day that the criteria were met and was evaluated up to 12 months post transplant.
Time frame: Up to Month 13
Population: Participants who received a stem cell transplant.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| G-CSF Plus Plerixafor | Median Number of Days to Polymorphonuclear (PMN) Cell Engraftment | 11.0 Days |
| G-CSF Plus Placebo | Median Number of Days to Polymorphonuclear (PMN) Cell Engraftment | 11.0 Days |
Secondary
Number of Participants With Adverse Events
Number of participants with treatment emergent adverse events (AEs). The timeframe for treatment emergent AEs is defined as Day 1 (start of G-CSF Mobilization) to the day before starting chemotherapy (approximately 38 days later). AEs were reported regardless of relationship to study treatment. The investigator graded each AE using the World Health Organization (WHO) Adverse Event Grading Scale. AEs of Grade 3 were considered severe and Grade 4 were considered life-threatening.
Time frame: up to Day 38
Population: Primary Safety population of all participants who received at least 1 mobilization dose of G-CSF or study treatment (plerixafor or placebo). Four participants did not receive G-CSF or any study treatment and were excluded from the safety analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G-CSF Plus Plerixafor | Number of Participants With Adverse Events | Grade 3 (severe) or 4 (life-threatening) AEs | 11 participants |
| G-CSF Plus Plerixafor | Number of Participants With Adverse Events | AEs Leading to early termination | 3 participants |
| G-CSF Plus Plerixafor | Number of Participants With Adverse Events | Adverse Events (AEs) | 140 participants |
| G-CSF Plus Plerixafor | Number of Participants With Adverse Events | AEs Leading to early treatment termination | 1 participants |
| G-CSF Plus Plerixafor | Number of Participants With Adverse Events | Serious Adverse Events (SAEs) | 4 participants |
| G-CSF Plus Plerixafor | Number of Participants With Adverse Events | Related AEs | 95 participants |
| G-CSF Plus Placebo | Number of Participants With Adverse Events | Serious Adverse Events (SAEs) | 6 participants |
| G-CSF Plus Placebo | Number of Participants With Adverse Events | Adverse Events (AEs) | 140 participants |
| G-CSF Plus Placebo | Number of Participants With Adverse Events | Related AEs | 67 participants |
| G-CSF Plus Placebo | Number of Participants With Adverse Events | AEs Leading to early treatment termination | 2 participants |
| G-CSF Plus Placebo | Number of Participants With Adverse Events | AEs Leading to early termination | 0 participants |
| G-CSF Plus Placebo | Number of Participants With Adverse Events | Grade 3 (severe) or 4 (life-threatening) AEs | 11 participants |
Secondary
Proportion of Participants Achieving a Target of ≥ 2*10^6 CD34+ Cells/kg in 4 or Fewer Days of Apheresis.
Proportion of participants achieving a target of ≥ 2\*10\^6 CD34+ cells/kg in 4 or fewer days of apheresis. Central lab data were taken from Days 5 to 8 of the Treatment/Apheresis period. Each participant's value was calculated as the sum of all daily values collected over the 4 apheresis days.
Time frame: up to Day 8
Population: Intent-to-Treat Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G-CSF Plus Plerixafor | Proportion of Participants Achieving a Target of ≥ 2*10^6 CD34+ Cells/kg in 4 or Fewer Days of Apheresis. | Proportion achieving target in ≤4 days | 0.953 proportion of participants |
| G-CSF Plus Plerixafor | Proportion of Participants Achieving a Target of ≥ 2*10^6 CD34+ Cells/kg in 4 or Fewer Days of Apheresis. | Proportion not achieving target in ≤4 days | 0.047 proportion of participants |
| G-CSF Plus Placebo | Proportion of Participants Achieving a Target of ≥ 2*10^6 CD34+ Cells/kg in 4 or Fewer Days of Apheresis. | Proportion achieving target in ≤4 days | 0.883 proportion of participants |
| G-CSF Plus Placebo | Proportion of Participants Achieving a Target of ≥ 2*10^6 CD34+ Cells/kg in 4 or Fewer Days of Apheresis. | Proportion not achieving target in ≤4 days | 0.117 proportion of participants |
Secondary
Proportion of Participants Achieving a Target of ≥ 6*10^6 CD34+ Cells/kg in 4 or Fewer Days of Apheresis.
Proportion of participants achieving a target of ≥ 6\*10\^6 CD34+ cells/kg in 4 or fewer days of apheresis. Central lab data were taken from Days 5 to 8 of the Treatment/Apheresis period. Each participant's value was calculated as the sum of all daily values collected over the 4 apheresis days.
Time frame: up to Day 8
Population: Intent-to-Treat Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| G-CSF Plus Plerixafor | Proportion of Participants Achieving a Target of ≥ 6*10^6 CD34+ Cells/kg in 4 or Fewer Days of Apheresis. | Proportion achieving target in ≤4 days | 0.757 proportion of participants |
| G-CSF Plus Plerixafor | Proportion of Participants Achieving a Target of ≥ 6*10^6 CD34+ Cells/kg in 4 or Fewer Days of Apheresis. | Proportion not achieving target in ≤4 days | 0.243 proportion of participants |
| G-CSF Plus Placebo | Proportion of Participants Achieving a Target of ≥ 6*10^6 CD34+ Cells/kg in 4 or Fewer Days of Apheresis. | Proportion achieving target in ≤4 days | 0.513 proportion of participants |
| G-CSF Plus Placebo | Proportion of Participants Achieving a Target of ≥ 6*10^6 CD34+ Cells/kg in 4 or Fewer Days of Apheresis. | Proportion not achieving target in ≤4 days | 0.487 proportion of participants |