Multiple Myeloma
Conditions
Brief summary
PRIMARY STUDY OBJECTIVES * To evaluate the efficacy of the combination of bortezomib, dexamethasone, with and without DOXIL, followed by high-dose cyclophosphamide as a therapy for two different subsets of multiple myeloma patients: 1. Patients post first line therapy 2. Patients with relapsed/refractory disease who are bortezomib-naïve * To evaluate the safety of the combination of bortezomib and dexamethasone, with and without DOXIL, followed by high-dose cyclophosphamide as therapy for patients with multiple myeloma. SECONDARY STUDY OBJECTIVES * To evaluate the role of the combination of bortezomib dexamethasone, with and without DOXIL, followed by high-dose cyclophosphamide on the ability to collect \> 10 x 106 CD34+ cells/kg in \< 7 collections (for both subsets of multiple myeloma patients). * To evaluate the survival of patients who receive the combination of bortezomib dexamethasone, with and without DOXIL, followed by high-dose cyclophosphamide (for both subsets of patients).
Interventions
DRUGBortezomib
During Induction Phase (6 cycles): Bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 During 21-day mobilization cycle (1 cycle): Bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11
DRUGdexamethasone
During Induction Phase (6 cycles): dexamethasone 40 mg on days 1-4, 8-11, and 15-18
DRUGliposomal doxorubicin
If patients achieve less then a PR during the induction phase after 2 cycles, or less then a CR after 4 cycles: Liposomal doxorubicin was added at 30 mg/m2 on day 4 for the remaining cycles
DRUGcyclophoshamide
During the 21 day mobilization phase (1 cycle): cyclophosphamide at 3 g/m2 on day 8
DRUGfilgrastim
During the 21 day mobilization phase (1 cycle): 10 μg/kg/day for 10 consecutive days starting 24 hours after cyclophosphamide administration on day 9
Sponsors
Millennium Pharmaceuticals, Inc.
Weill Medical College of Cornell University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Consolidation: All patients will receive 2 cycles of bortezomib (VEL) and dexamethasone (DEX). Patients who achieve a complete response after 2 cycles will receive 4 additional cycles of VEL/DEX before mobilization. Patients who do not achieve at least a partial response after 2 cycles will receive 4 more cycles of VEL/DEX plus DOXIL. Patients who achieve a partial response after 2 cycles on VEL/DEX, will continue this combination for 2 more cycles. Patients who achieve a complete response after 4 cycles will receive 2 additional cycles of VEL/DEX before mobilization. Patients who remain with a partial response after 4 cycles of VEL/DEX will receive 2 additional cycles of the combination of VEL/DEX plus DOXIL. Mobilization: Patients who complete 6 cycles of consolidation will proceed to mobilization. Patients will receive one cycle of VEL plus high dose CYTOXAN followed by G-CSF beginning 24 hours after CYTOXAN given for a total of 10 daily doses.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject must voluntarily sign and understand written informed consent. * Confirmed diagnosis of multiple myeloma as specified by the SWOG criteria and is detailed in Appendix I. * Measurable disease as defined the following: 1. For patients post induction therapy, any measurable paraprotein in the serum or urine and/or any plasmacytoma present on physical exam or imaging. 2. For patients with relapsed/refractory disease, \> 0.5 g/dL serum monoclonal protein, \> 0.1 g/dL serum free light chains, \> 0.2 g/24 hrs urinary M-protein excretion, and/or measurable plasmacytoma(s). * Age \> or = than 18 years at the time of signing the informed consent form. * Karnofsky performance status\> or =70% (\>60% if due to bony involvement of myeloma). * Group A (post-induction therapy)- patients who have received only one prior treatment regimen (eg VAD, Thal/Dex, BLT-D, MP, BiRD, or DVd) with at least 20 patients having received a Revlimid based regimen or Group B(\>1st line of therapy)- patients with relapsed/refractory multiple myeloma who have received two or more prior treatment regimens . * If the patient is a woman of childbearing age, she must have a negative serum or urine pregnancy test within 7 days of starting study and must use effective contraception throughout the course of the study. * Life expectancy \> 12 weeks. * Absolute neutrophil count (ANC)\> or = 1500 cells/mm3 (\> or = 1000 for patients with bone marrow biopsy displaying \> 50% involvement by myeloma) * Platelets count \> or = 50,000/mm3 (\> or = 30,000 for patients with bone marrow biopsy displaying \> 50% involvement by myeloma) * Hemoglobin \> 9.0 g/dL * Serum SGOT/AST \<3.0 x upper limits of normal (ULN) * Serum SGPT/ALT \<3.0 x upper limits of normal (ULN) * Serum creatinine \< 2.5 mg/dL or creatinine clearance \> 40ml/min * Serum total bilirubin \< 1.5 x ULN * Patients must have a MUGA scan with LVEF \>50%
Exclusion criteria
* Patients with non-secretory MM (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. * Prior treatment with bortezomib. * Peripheral neuropathy of \> Grade 2 as defined by CTCAE Version 3.0 (see Appendix II) * History of allergic reactions to compounds containing mannitol, bortezomib, conventional formulation of doxorubicin HCL or the components of DOXIL. * 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 ³ 5 years. * NYHA Class III or IV heart disease. History of active unstable angina, congestive heart disease, serious uncontrolled cardiac arrhythmia or myocardial infarction within 6 months. * 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 * 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, including, but not limited to, uncontrolled hypertension, uncontrolled diabetes, active uncontrolled infection, and/or acute chronic liver disease (i.e., hepatitis, cirrhosis). * No prior anti-myeloma therapy within 2 weeks of treatment initiation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Drug Combination as Therapy for Myeloma (Overall Response Rate) | Best response at any point during each respective study phase was collected - once after consolidation/prior to mobilization (approximately 6 cycles after start of treatment), and once after mobilization | Myeloma response criteria developed by Bladé et al. was used to categorize response. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Yield of CD34+ Stem Cells | Occurred after mobilization, and prior to Stem cell transplant; a 7 day limit was imposed on stem cell collection | This is the yield of CD34+ stem cells collection after high dose cyclophosphamide. |
| Progression Free Survival | Date of progression, assessed from start of trial to Final data cut off date (15 April 2011) | Response was assessed using IMWG guidelines, which for progressive disease are as follows: Increase of \> 25% from lowest response value in any one or more of the following: * Serum M-component and/or (the absolute increase must be \> 0.5 g/dL)\* * Urine M-component and/or (the absolute increase must be \> 200 mg/24 h) * Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be \> 10 mg/dL * Bone marrow plasma cell percentage; the absolute percentage must be \> 10% * Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas * Development of hypercalcaemia (corrected serum calcium \> 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder IF starting M protein component is \> 5g/dL, then absolute increase of 1g is sufficient for progression. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Arm (All Patients) Bortezomib, Dexamethasone, Pegylated Liposomal Doxorubicin, Cyclophosphamide: Bortezomib 1.3 mg/m2 days 1, 4, 8, 11 (initial cycles) Dexamethasone 40 mg Days 1-4, 8-11, 15-18 (initial cycles) Doxil 30 mg/m2 Day 4 of subsequent cycles | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Mobilization (VEL+CYTOXAN+FILGRASTIM) | Adverse Event | 8 |
| Mobilization (VEL+CYTOXAN+FILGRASTIM) | Lack of Efficacy | 2 |
| Mobilization (VEL+CYTOXAN+FILGRASTIM) | unable to tolerate | 1 |
Baseline characteristics
| Characteristic | Treatment Arm (All Patients) |
|---|---|
| Abnormalities by FISH del (17p) | 1 participants |
| Abnormalities by FISH hyperdiploidy | 7 participants |
| Abnormalities by FISH none | 16 participants |
| Abnormalities by FISH p53 | 4 participants |
| Abnormalities by FISH t (11;14) | 5 participants |
| Abnormalities by FISH t (14;16) | 2 participants |
| Abnormalities by FISH t (4;14) | 4 participants |
| Abnormalities by FISH trisomy 11 | 10 participants |
| Age, Continuous | 61 years |
| Age, Customized Age <70 years | 34 Participants |
| Age, Customized Age > or = 70 | 4 Participants |
| Best response prior to induction therapy Complete Response | 1 participants |
| Best response prior to induction therapy partial Response | 27 participants |
| Best response prior to induction therapy Stable Disease | 10 participants |
| Beta-2 Microglubilin | 2.05 mg/L |
| Durie Salmon Staging System 1a | 1 participants |
| Durie Salmon Staging System 2a | 19 participants |
| Durie Salmon Staging System 3a | 17 participants |
| Durie Salmon Staging System 3b | 1 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| International Staging System I | 18 participants |
| International Staging System II | 17 participants |
| International Staging System III | 3 participants |
| Prior induction therapy dexamethasone, then single-agent lenalidomide | 1 participants |
| Prior induction therapy lenalidomide + dexamethasone ± BIAXIN | 21 participants |
| Prior induction therapy melphalan + cyclophosphamide | 1 participants |
| Prior induction therapy pulsed dexamethasone only | 2 participants |
| Prior induction therapy Thalidomide + dexamethasone | 3 participants |
| Prior induction therapy Thalidomide + lenalidomide + dexamethasone± BIAXIN | 8 participants |
| Prior induction therapy thalidomide only | 2 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 26 Participants |
| Serum Albumin | 3.5 g/dL |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 38 / 38 |
| serious Total, serious adverse events | 1 / 38 |
Outcome results
Primary
Efficacy of Drug Combination as Therapy for Myeloma (Overall Response Rate)
Myeloma response criteria developed by Bladé et al. was used to categorize response.
Time frame: Best response at any point during each respective study phase was collected - once after consolidation/prior to mobilization (approximately 6 cycles after start of treatment), and once after mobilization
Population: All 38 patients were treated with DoVeD consolidation therapy (Vel + DEX with or without DOXIL). Of the 38 patients enrolled, 27 proceeded to mobilization (11 did not undergo mobilization). Responses were assessed prior to mobilization (post DoVED), and again after mobilization, to see if mobilization improved patient response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment Arm - Post Mobilization | Efficacy of Drug Combination as Therapy for Myeloma (Overall Response Rate) | Complete Response (CR) | 3 participants |
| Treatment Arm - Post Mobilization | Efficacy of Drug Combination as Therapy for Myeloma (Overall Response Rate) | Partial Response (PR) | 13 participants |
| Treatment Arm - Post Mobilization | Efficacy of Drug Combination as Therapy for Myeloma (Overall Response Rate) | Very Good Partial response (VGPR) | 6 participants |
| Treatment Arm - Post Mobilization | Efficacy of Drug Combination as Therapy for Myeloma (Overall Response Rate) | Other Response (progression, stable disease, etc) | 1 participants |
| Treatment Arm - Post Mobilization | Efficacy of Drug Combination as Therapy for Myeloma (Overall Response Rate) | Stringent Complete Response (sCR) | 4 participants |
| Treatment Arm - Responses Prior to Mobilization | Efficacy of Drug Combination as Therapy for Myeloma (Overall Response Rate) | Other Response (progression, stable disease, etc) | 6 participants |
| Treatment Arm - Responses Prior to Mobilization | Efficacy of Drug Combination as Therapy for Myeloma (Overall Response Rate) | Stringent Complete Response (sCR) | 0 participants |
| Treatment Arm - Responses Prior to Mobilization | Efficacy of Drug Combination as Therapy for Myeloma (Overall Response Rate) | Complete Response (CR) | 1 participants |
| Treatment Arm - Responses Prior to Mobilization | Efficacy of Drug Combination as Therapy for Myeloma (Overall Response Rate) | Very Good Partial response (VGPR) | 1 participants |
| Treatment Arm - Responses Prior to Mobilization | Efficacy of Drug Combination as Therapy for Myeloma (Overall Response Rate) | Partial Response (PR) | 2 participants |
Secondary
Progression Free Survival
Response was assessed using IMWG guidelines, which for progressive disease are as follows: Increase of \> 25% from lowest response value in any one or more of the following: * Serum M-component and/or (the absolute increase must be \> 0.5 g/dL)\* * Urine M-component and/or (the absolute increase must be \> 200 mg/24 h) * Only in patients without measurable serum and urine M-protein levels; the difference between involved and uninvolved FLC levels. The absolute increase must be \> 10 mg/dL * Bone marrow plasma cell percentage; the absolute percentage must be \> 10% * Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas * Development of hypercalcaemia (corrected serum calcium \> 11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma cell proliferative disorder IF starting M protein component is \> 5g/dL, then absolute increase of 1g is sufficient for progression.
Time frame: Date of progression, assessed from start of trial to Final data cut off date (15 April 2011)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Arm - Post Mobilization | Progression Free Survival | 46.6 months |
Secondary
Yield of CD34+ Stem Cells
This is the yield of CD34+ stem cells collection after high dose cyclophosphamide.
Time frame: Occurred after mobilization, and prior to Stem cell transplant; a 7 day limit was imposed on stem cell collection
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Arm - Post Mobilization | Yield of CD34+ Stem Cells | 23.2 10^6 cells/kg |