Multiple Myeloma
Conditions
Brief summary
This phase III randomized trial compares three different peripheral stem cell mobilization regimens for patients with multiple myeloma who have received primary induction therapy or other therapies. Up to 180 patients will be enrolled. Patients eligible for treatment will be randomized to one of the three following mobilization regimens: Arm A = VELCADE, CYCLOPHOSPHAMIDE, & G-CSF Arm B = VELCADE & G-CSF Arm C = CYCLOPHOSPHAMIDE & G-CSF Arm D = PLERIXAFOR & G-CSF Arm E = PLERIXAFOR, VELCADE, & G-CSF
Detailed description
PRIMARY STUDY OBJECTIVES • To compare the efficacy of the following peripheral stem cell mobilization regimens for MM: i. High dose cyclophosphamide, VELCADE, and G-CSF ii. VELCADE and G-CSF iii. High dose cyclophosphamide and G-CSF SECONDARY STUDY OBJECTIVES • To evaluate biomarkers as surrogate markers of mobilization in each arm To evaluate changes in tumor mass as defined by standard response parameters. To evaluate the safety of each of the arms. This phase III randomized trial compares three different peripheral stem cell mobilization regimens for patients with multiple myeloma who have received primary induction therapy Primary Endpoints a) Percentage of patients able to collect \>6 x 106 CD34+ cells/kg in \< 2 collections. Secondary Endpoints 1. Engrafting: Neutrophil recovery (ANC \>0.5 of \<12 days), Plt recovery (\>20K untransfused \<20 days)) after mel 200 based transplant. 2. Toxicities
Interventions
1.3 mg/m2 IVP on days 1, 4, 8 and 11
DRUGcyclophosphamide
2.0 g/m2 (day 4 for Arm A and day 1 for Arm C)
DRUGG-CSF
given for ten (+/- two) consecutive days starting on day 9 at a dose of 10 micrograms/kg/day (start on day 2 for Arm C and start on Day 1 for Arm D)
DRUGPlerixafor
plerixafor is given on day 4, approximately 11 hours prior to stem cell collection attempt on Day 5, plerixafor daily until stem cell collection is complete (Arm D), start on Day 12, approximately 11 hours prior to stem cell collection attempt and plerixafor daily until collection if complete (Arm E)
Sponsors
Millennium Pharmaceuticals, Inc.
Weill Medical College of Cornell University
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 * Confirmed diagnosis of multiple myeloma * Age \> than 18 years at the time of signing the informed consent form. * Karnofsky performance status above 60% * Patients must be within 30 days of completing induction therapy. * Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control . * Male subject agrees to use an acceptable method for contraception for the duration of the study. * Life expectancy \> 12 weeks. * Subjects must have a MUGA scan or echo with LVEF \>50% * Subjects must meet the following laboratory parameters: 1. Absolute neutrophil count (ANC) ≥1500 cells/mm3 2. Platelets count ≥ 50,000/mm3 3. Hemoglobin \> 9.0 g/dL 4. Serum SGOT/AST \<3.0 x upper limits of normal (ULN) 5. Serum SGPT/ALT \<3.0 x upper limits of normal (ULN) 6. Serum creatinine \< 2.5 mg/dL or creatinine clearance \> 40ml/min 7. Serum total bilirubin \< 1.5 x ULN
Exclusion criteria
* Patients with (no measurable monoclonal protein, free light chains, and/or M-spike in blood or urine) unless measurable disease is available with imaging techniques such as MRI and PET scan. * History of allergic reactions to compounds containing boron, mannitol, VELCADE * Prior history of other malignancies (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless disease free for \> = 5 years. * NYHA Class III or IV heart disease. History of active unstable angina, congestive heart disease, severe uncontrolled cardiac arrhythmia, electrocardiographic evidence of acute ischemia, active conduction system abnormalities or myocardial infarction within 6 months prior to enrollment. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant. * Female patients who are pregnant or breastfeeding. Women of childbearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation. * Known HIV or hepatitis A, B, or C positivity---ONLY IF ACTIVE * Active viral or bacterial infections or any coexisting medical problem that would significantly increase the risks of this treatment program. * Any concurrent, uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place him/her at unacceptable risk * Patient has \> = Grade 2 peripheral neuropathy within 14 days before enrollment. * Patient has received other investigational drugs with 14 days before enrollment * Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Able to Collect >=6 x 106 CD34+ Cells/kg in <= 2 Collections. | 36 months | The primary endpoint in all five treatment arms is the percentage of patients who are able to achieve greater than 6 x 106 CD34+ stems cells/kg harvested (defined as effectiveness). Note that no patients were enrolled Arm D and Arm E. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Achieved Neutrophil Recovery After Melphalan 200 Based Transplant | 20 days post-transplant | Number of patients who achieved neutrophil recovery after Melphalan 200 based transplant in 20 days or fewer. Neutrophil recovery is defined as an absolute neutrophil count of greater than 0.5 k/uL for three consecutive days. |
| Number of Patients Who Achieved Platelet Recovery After Melphalan 200 Based Transplant | 20 days post-transplant | Number of patients who achieved platelet recovery after Melphalan 200 based transplant in 20 days or fewer. Platelet recovery is defined as a platelet count of greater than 20,000, untransfused, for three consecutive days. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: VELCADE, CYCLOPHOSPHAMIDE, & G-CSF VELCADE at 1.3 mg/m2 IVP on days 1, 4, 8 and 11 in combination with high-dose cyclophosphamide at 2.0 g/m2 on day 4. G-CSF is given for ten (+/- two) consecutive days starting on day 9 at a dose of 10 micrograms/kg/day. Pheresis will commence once ANC of 1.5 is reached.
bortezomib (Velcade): 1.3 mg/m2 IVP on days 1, 4, 8 and 11
cyclophosphamide: 2.0 g/m2 (day 4 for Arm A and day 1 for Arm C)
G-CSF: given for ten (+/- two) consecutive days starting on day 9 at a dose of 10 micrograms/kg/day (start on day 2 for Arm C and start on Day 1 for Arm D) | 20 |
| Arm B: VELCADE & G-CSF VELCADE at 1.3 mg/m2 IVP on days 1, 4, 8 and 11. G-CSF is given for ten (+/- two) consecutive days starting on day 9 at a dose of 10 micrograms/kg/day. Day 12 start pheresis collection
bortezomib (Velcade): 1.3 mg/m2 IVP on days 1, 4, 8 and 11
G-CSF: given for ten (+/- two) consecutive days starting on day 9 at a dose of 10 micrograms/kg/day (start on day 2 for Arm C and start on Day 1 for Arm D) | 4 |
| Arm C: CYCLOPHOSPHAMIDE & G-CSF High-dose cyclophosphamide at 2.0 g/m2 on day 1. G-CSF is given for ten (+/- two) consecutive days starting on day 2 at a dose of 10 micrograms/kg/day. Pheresis will commence once ANC of 1.5 is reached.
cyclophosphamide: 2.0 g/m2 (day 4 for Arm A and day 1 for Arm C)
G-CSF: given for ten (+/- two) consecutive days starting on day 9 at a dose of 10 micrograms/kg/day (start on day 2 for Arm C and start on Day 1 for Arm D) | 23 |
| Arm D: PLERIXAFOR & G-CSF G-CSF is given for ten (+/- two) consecutive days starting on day 1 at a dose of 10 micrograms/kg/day. Plerixafor is given on day 4, approximately 11 hours prior to stem cell collection attempt on Day 5. Both G-CSF and plerixafor are continued daily until collection is complete. Pheresis will commence for everyone on Day 5 regardless of ANC status.
G-CSF: given for ten (+/- two) consecutive days starting on day 9 at a dose of 10 micrograms/kg/day (start on day 2 for Arm C and start on Day 1 for Arm D)
Plerixafor: plerixafor is given on day 4, approximately 11 hours prior to stem cell collection attempt on Day 5, plerixafor daily until stem cell collection is complete (Arm D), start on Day 12, approximately 11 hours prior to stem cell collection attempt and plerixafor daily until collection if complete (Arm E) | 0 |
| Arm E: PLERIXAFOR, VELCADE, & G-CSF Bortezomib at 1.3 mg/m2 IVP on days 1, 4, 8 and 11. G-CSF is given for ten (+/- wo) consecutive days starting on day 9 at a dose of 10 micrograms/kg/day.
Plerixafor is given on day 12, approximately 11 hours prior to stem cell collection attempt and is continued daily until collection is complete. Pheresis will commence for everyone on Day 13 regardless of ANC status.
bortezomib (Velcade): 1.3 mg/m2 IVP on days 1, 4, 8 and 11
G-CSF: given for ten (+/- two) consecutive days starting on day 9 at a dose of 10 micrograms/kg/day (start on day 2 for Arm C and start on Day 1 for Arm D)
Plerixafor: plerixafor is given on day 4, approximately 11 hours prior to stem cell collection attempt on Day 5, plerixafor daily until stem cell collection is complete (Arm D), start on Day 12, approximately 11 hours prior to stem cell collection attempt and plerixafor daily until collection if complete (Arm E) | 0 |
| Total | 47 |
Baseline characteristics
| Characteristic | Total | Arm C: CYCLOPHOSPHAMIDE & G-CSF | Arm B: VELCADE & G-CSF | Arm A: VELCADE, CYCLOPHOSPHAMIDE, & G-CSF |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 17 Participants | 12 Participants | 0 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants | 11 Participants | 4 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 22 Participants | 3 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 8 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 27 Participants | 12 Participants | 1 Participants | 14 Participants |
| Sex: Female, Male Female | 17 Participants | 5 Participants | 2 Participants | 10 Participants |
| Sex: Female, Male Male | 30 Participants | 18 Participants | 2 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 4 | 0 / 23 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 8 / 20 | 4 / 4 | 18 / 23 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 20 | 0 / 4 | 1 / 23 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Number of Patients Able to Collect >=6 x 106 CD34+ Cells/kg in <= 2 Collections.
The primary endpoint in all five treatment arms is the percentage of patients who are able to achieve greater than 6 x 106 CD34+ stems cells/kg harvested (defined as effectiveness). Note that no patients were enrolled Arm D and Arm E.
Time frame: 36 months
Population: Arm A: 20 patients were enrolled but only 17 were evaluable. Arm C: 23 patients enrolled but only 21 were evaluable. Arm D and Arm E of the study did not accrue any subjects, therefore the number of participants analyzed for this outcome measure is 0 for both arms.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: VELCADE, CYCLOPHOSPHAMIDE, & G-CSF | Number of Patients Able to Collect >=6 x 106 CD34+ Cells/kg in <= 2 Collections. | 11 Participants |
| Arm B: VELCADE & G-CSF | Number of Patients Able to Collect >=6 x 106 CD34+ Cells/kg in <= 2 Collections. | 0 Participants |
| Arm C: CYCLOPHOSPHAMIDE & G-CSF | Number of Patients Able to Collect >=6 x 106 CD34+ Cells/kg in <= 2 Collections. | 14 Participants |
Comparison: Arm B was initially closed due to low accrual, and Arms D and E were also closed due to no accrual. Arms A and C also had very low accrual. Therefore, the comparison of the primary outcome between Arms A and C is for exploratory purposes only.p-value: 0.995% CI: [-0.32, 0.28]Chi-squared
Secondary
Number of Patients Who Achieved Neutrophil Recovery After Melphalan 200 Based Transplant
Number of patients who achieved neutrophil recovery after Melphalan 200 based transplant in 20 days or fewer. Neutrophil recovery is defined as an absolute neutrophil count of greater than 0.5 k/uL for three consecutive days.
Time frame: 20 days post-transplant
Population: Data analyzed only for patients who went on to receive a stem cell transplant after mobilization. 25 subject did not receive a stem cell transplant after mobilization and therefore are not included in the analysis. However, no statistical test can be performed because the outcome proportion was 100% in each group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: VELCADE, CYCLOPHOSPHAMIDE, & G-CSF | Number of Patients Who Achieved Neutrophil Recovery After Melphalan 200 Based Transplant | 7 Participants |
| Arm B: VELCADE & G-CSF | Number of Patients Who Achieved Neutrophil Recovery After Melphalan 200 Based Transplant | 4 Participants |
| Arm C: CYCLOPHOSPHAMIDE & G-CSF | Number of Patients Who Achieved Neutrophil Recovery After Melphalan 200 Based Transplant | 11 Participants |
| Arm D: PLERIXAFOR & G-CSF | Number of Patients Who Achieved Neutrophil Recovery After Melphalan 200 Based Transplant | 0 Participants |
| Arm E: PLERIXAFOR, VELCADE, & G-CSF | Number of Patients Who Achieved Neutrophil Recovery After Melphalan 200 Based Transplant | 0 Participants |
Secondary
Number of Patients Who Achieved Platelet Recovery After Melphalan 200 Based Transplant
Number of patients who achieved platelet recovery after Melphalan 200 based transplant in 20 days or fewer. Platelet recovery is defined as a platelet count of greater than 20,000, untransfused, for three consecutive days.
Time frame: 20 days post-transplant
Population: Data analyzed only for patients who went on to receive a stem cell transplant after mobilization. 25 subject did not receive a stem cell transplant after mobilization and therefore are not included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: VELCADE, CYCLOPHOSPHAMIDE, & G-CSF | Number of Patients Who Achieved Platelet Recovery After Melphalan 200 Based Transplant | 4 Participants |
| Arm B: VELCADE & G-CSF | Number of Patients Who Achieved Platelet Recovery After Melphalan 200 Based Transplant | 1 Participants |
| Arm C: CYCLOPHOSPHAMIDE & G-CSF | Number of Patients Who Achieved Platelet Recovery After Melphalan 200 Based Transplant | 9 Participants |
| Arm D: PLERIXAFOR & G-CSF | Number of Patients Who Achieved Platelet Recovery After Melphalan 200 Based Transplant | 0 Participants |
| Arm E: PLERIXAFOR, VELCADE, & G-CSF | Number of Patients Who Achieved Platelet Recovery After Melphalan 200 Based Transplant | 0 Participants |
p-value: 0.2595% CI: [-0.68, 0.18]Fisher Exact