Multiple Myeloma
Conditions
Keywords
Relapsed Multiple Myeloma, Refractory Multiple Myeloma
Brief summary
The current study is being conducted to evaluate the possibility that a different schedule of bortezomib, doxorubicin HCl liposome, and dexamethasone might decrease the incidence of peripheral neuropathy yet maintain similar efficacy and allow maintenance of bortezomib dosing for a longer period.
Interventions
DRUGbortezomib
Patients will be treated with bortezomib at 1.3mg/m\^2 on Days 1, 4, 15, and 18 every 28 days (cycle).
DRUGdexamethasone
Dexamethasone tablets will be given at 20mg daily on Days 1, 2, 4, 5, 15, 16, 18, and 19 every 28 days (cycle).
Patients will receive intravenous doxorubicin HCl liposome injection given at 30 mg/m\^2 on Day 4 every 28 days (cycle).
Sponsors
Millennium Pharmaceuticals, Inc.
Accelerated Community Oncology Research Network
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient is at least 18 years of age. * Patient has confirmed diagnosis of relapsed/refractory multiple myeloma with measurable disease by serum or urine. Measurable disease defined as monoclonal protein of ≥ 1g/dl on serum protein electrophoresis (SPEP) or \> 200 mg urine M protein/ 24 hours * Patient has received at least 1 prior treatment regimen. (Prior treatment with bortezomib is allowed.) * Patient has ECOG ≤ 2 * Patient provides voluntary written informed consent before performance of any study-relates procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. * Patients who have received prior high dose chemotherapy with stem cell support are eligible for this study. * Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. * Male subject agrees to use an acceptable method for contraception for the duration of the study.
Exclusion criteria
* Patient has a platelet count of \< 50, 000 cells/mm³, within 14 days before enrollment. * Patient has an absolute neutrophil count (ANC) ≤ 750/mm³ within 14 days before enrollment. * Patient has a calculated or measured creatinine clearance of \< 20 mL/min within 14 days before enrollment and/or serum creatinine ≥ 2.5 mg/dl. * Patient has hemoglobin \< 7.5 g/dl. * Patient has ≥ Grade 2 peripheral neuropathy within 14 days before enrollment. * Myocardial infarction within 6 months prior to enrollment or has (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant. * Patient has received a total cumulative dosage of anthracyclines exceeding 550 mg/m2. * Patient has hypersensitivity to boron or mannitol. * Patient has history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL. * Patient has clinically significant coexisting illness unrelated to myeloma. * Patient has uncontrolled diabetes. * Patient has plasma cell leukemia. * Patient has serum bilirubin \> 1.5 x upper normal limit, alanine aminotransaminase (ALT), aspartate aminotransferase (AST) \> 2.5 x upper normal limit (ULN), or alkaline phosphatase \> 2.5 x ULN. * Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (B-hCG)pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. * Patient has received other investigational drugs within 14 days before enrollment. * Patient has serious medical or psychiatric illness likely to interfere with participation in this clinical study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of Treatment-emergent Peripheral Neuropathy | Every 4 weeks from start of treatment until end of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) | TTP was measured from day 1 of treatment until time of progression, assessed up to 40 months | — |
| Number of Participants With Treatment Response | Every 8 weeks from start of treatment until end of treatment | Complete Response (CR), Partial Response (PR), and Minor Response (MR) each required stable bone disease and normal calcium levels. CR also required 100% serum protein electrophoresis (SPEP) reduction, negative immunofixation (IF), 100% urine protein electrophoresis (UPEP)reduction, and \<5% plasma cells in bone marrow. PR also required \>=50% SPEP reduction, \>=90% UPEP reduction, and \>=50% reduction in plasma cells in bone marrow. MR also required \>=25% SPEP reduction, \>=50% UPEP reduction, and \> 25% reduction in plasma cells. |
| Relative Dose Intensity of Bortezomib | Each dose of bortezomib (days 1, 4, 15, and 18 every 28 days) | Relative dose intensity is defined as actual dose/scheduled dose. Bortezomib is administered on Days 1, 4, 15, and 18 every 28 days. |
Countries
United States
Participant flow
Recruitment details
15 community oncology research sites across the US within the ACORN network participated in this study. Enrollment started in July 2006 but was stopped in December 2008 at the point when it became clear that enrollment was too slow to complete the planned enrollment target of 45 patients within the time frame allowed.
Pre-assignment details
Informed consent was obtained from all subjects. All subjects underwent screening procedures to verify eligibility.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Group All subjects received bortezomib 1.3mg/m\^2 on Days 1, 4, 15, and 18 every 28 days and dexamethasone 20mg daily on Days 1, 2, 4, 5, 15, 16, 18, and 19 every 28 days. Following US FDA approval of doxorubicin HCl liposome injection in combination with bortezomib in May 2007, the study was amended to allow combination treatment with both bortezomib and doxorubicin HCl liposome injection 30 mg/m\^2 on Day 4 every 28 days with dexamethasone. The target goal was 8 cycles of treatment. | 32 |
| Total | 32 |
Baseline characteristics
| Characteristic | Treatment Group |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 18 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Age Continuous | 63.7 years STANDARD_DEVIATION 10.05 |
| Region of Enrollment United States | 32 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 28 / 32 |
| serious Total, serious adverse events | 10 / 32 |
Outcome results
Primary
Incidence of Treatment-emergent Peripheral Neuropathy
Time frame: Every 4 weeks from start of treatment until end of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Group | Incidence of Treatment-emergent Peripheral Neuropathy | 11 Participants |
Secondary
Number of Participants With Treatment Response
Complete Response (CR), Partial Response (PR), and Minor Response (MR) each required stable bone disease and normal calcium levels. CR also required 100% serum protein electrophoresis (SPEP) reduction, negative immunofixation (IF), 100% urine protein electrophoresis (UPEP)reduction, and \<5% plasma cells in bone marrow. PR also required \>=50% SPEP reduction, \>=90% UPEP reduction, and \>=50% reduction in plasma cells in bone marrow. MR also required \>=25% SPEP reduction, \>=50% UPEP reduction, and \> 25% reduction in plasma cells.
Time frame: Every 8 weeks from start of treatment until end of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Group | Number of Participants With Treatment Response | NA Participants |
Secondary
Relative Dose Intensity of Bortezomib
Relative dose intensity is defined as actual dose/scheduled dose. Bortezomib is administered on Days 1, 4, 15, and 18 every 28 days.
Time frame: Each dose of bortezomib (days 1, 4, 15, and 18 every 28 days)
Population: Note that the sample sized varied at each dose and ranged from 32 patients to 1 patient.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 8 / Week 29 | 1.05 Relative dose intensity | Standard Deviation 0.213 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 1 / Week 1 | 0.97 Relative dose intensity | Standard Deviation 0.158 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 1 / Week 1 Day 4 | 0.98 Relative dose intensity | Standard Deviation 0.159 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 1 / Week 3 | 0.97 Relative dose intensity | Standard Deviation 0.158 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 1 / Week 3 Day 18 | 0.97 Relative dose intensity | Standard Deviation 0.154 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 2 / Week 5 | 0.95 Relative dose intensity | Standard Deviation 0.144 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 2 / Week 5 Day 4 | 0.96 Relative dose intensity | Standard Deviation 0.148 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 2 / Week 7 | 0.95 Relative dose intensity | Standard Deviation 0.14 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 2 / Week 7 Day 18 | 0.96 Relative dose intensity | Standard Deviation 0.146 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 3 / Week 9 | 0.99 Relative dose intensity | Standard Deviation 0.147 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 3 / Week 9 Day 4 | 0.97 Relative dose intensity | Standard Deviation 0.121 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 3 / Week 11 | 0.97 Relative dose intensity | Standard Deviation 0.142 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 3 / Week 11 Day 18 | 0.95 Relative dose intensity | Standard Deviation 0.104 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 4 / Week 13 | 0.99 Relative dose intensity | Standard Deviation 0.152 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 4 / Week 13 Day 4 | 0.96 Relative dose intensity | Standard Deviation 0.111 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 4 / Week 15 | 0.99 Relative dose intensity | Standard Deviation 0.154 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 4 / Week 15 Day 18 | 0.96 Relative dose intensity | Standard Deviation 0.111 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 5 / Week 17 | 0.98 Relative dose intensity | Standard Deviation 0.151 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 5 / Week 17 Day 4 | 0.96 Relative dose intensity | Standard Deviation 0.11 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 5 / Week 19 | 1.00 Relative dose intensity | Standard Deviation 0.157 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 5 / Week 19 Day 18 | 0.97 Relative dose intensity | Standard Deviation 0.111 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 6 / Week 21 | 1.01 Relative dose intensity | Standard Deviation 0.162 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 6 / Week 21 Day 4 | 0.98 Relative dose intensity | Standard Deviation 0.114 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 6 / Week 23 | 1.01 Relative dose intensity | Standard Deviation 0.169 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 6 / Week 23 Day 18 | 0.99 Relative dose intensity | Standard Deviation 0.115 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 7 / Week 25 | 1.11 Relative dose intensity | Standard Deviation 0.154 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 7 / Week 25 Day 4 | 1.03 Relative dose intensity | Standard Deviation 0.148 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 7 / Week 27 | 1.08 Relative dose intensity | Standard Deviation 0.198 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 7 / Week 27 Day 18 | 1.03 Relative dose intensity | Standard Deviation 0.148 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 8 / Week 29 Day 4 | 0.99 Relative dose intensity | Standard Deviation 0.14 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 8 / Week 31 | 1.05 Relative dose intensity | Standard Deviation 0.213 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 8 / Week 31 Day 18 | 1.04 Relative dose intensity | Standard Deviation 0.085 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 9 / Week 33 | 1.10 Relative dose intensity | Standard Deviation 0.488 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 9 / Week 33 Day 4 | 0.75 Relative dose intensity | — |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 9 / Week 35 | 1.15 Relative dose intensity | Standard Deviation 0.417 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 10 / Week 37 | 1.22 Relative dose intensity | Standard Deviation 0.311 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 10 / Week 37 Day 4 | 1.00 Relative dose intensity | — |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 10 / Week 39 | 1.22 Relative dose intensity | Standard Deviation 0.311 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 10 / Week 39 Day 18 | 1.00 Relative dose intensity | — |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 11 / Week 41 | 1.22 Relative dose intensity | Standard Deviation 0.311 |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 11 / Week 41 Day 4 | 1.00 Relative dose intensity | — |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 11 / Week 43 | 1.44 Relative dose intensity | — |
| Treatment Group | Relative Dose Intensity of Bortezomib | Cycle 11 / Week 43 Day 18 | 1.00 Relative dose intensity | — |
Secondary
Time to Progression (TTP)
Time frame: TTP was measured from day 1 of treatment until time of progression, assessed up to 40 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Group | Time to Progression (TTP) | 23.07 Months | Standard Deviation 3.2 |