Multiple Myeloma
Conditions
Brief summary
The primary objective of this study is to assess the safety and tolerability of bendamustine as combination therapy with bortezomib for patients with relapsed/refractory multiple myeloma (MM).
Interventions
DRUGbendamustine
Bendamustine was administered to 3 cohorts of patients at escalating doses of 50 (cohort 1), 70 (cohort 2) and 90 mg/m\^2/dose (cohort 3). Doses were administered by intravenous (iv) infusion once daily on days 1 and 4 of each 28-day cycle. Each iv was administered over 60 minutes and followed the injection of bortezomib. Bortezomib will be administered to patients at a dose of 1.0 mg/m2/dose as an iv push over 3 to 5 seconds followed by a standard saline flush or through a running iv line. Doses are to be administered to patients on days 1, 4, 8 and 11 of the 28-day cycle.
DRUGbortezomib
Bortezomib was administered at a dose of 1.0 mg/m\^2/dose as an intravenous (iv) push over 3 to 5 seconds followed by a standard saline flush or through a running iv line. Doses are to be administered on days 1, 4, 8 and 11 of each 28-day cycle.
Sponsors
Cephalon
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
The patient: * has a diagnosis of multiple myeloma. * currently has multiple myeloma with measurable disease. * must have received at least 1 previous treatment regimen and shows signs of progressive disease at the time of study entry. * if a woman of child bearing potential (not surgically sterile or at least 12 months naturally postmenopausal), must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 30 days after participation in the study. * if a man, must agree to use an acceptable method of contraception throughout the study and for 90 days after last dose study drug. * must have an Eastern Cooperative Oncology Group (ECOG) performance status not greater than 2. * must have a life-expectancy of greater than 3 months. * must meet specific protocol-related hematological and laboratory criteria within 14 days of enrollment.
Exclusion criteria
The patient has: * had a prior malignancy within the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix). * plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes (POEMS) syndrome. * plasma cell leukemia. * non-measurable multiple myeloma. * Common Terminology Criteria for Adverse Events (CTCAE) grade 2 (or greater) peripheral neuropathy within 14 days before enrollment. * previously participated in a Cephalon-sponsored clinical study with bendamustine. * impaired cardiac function or clinically significant cardiac diseases. * undergone major surgery within 4 weeks prior to screening or has not recovered from side effects of such therapy. * severe hypercalcemia. * other concurrent severe and/or uncontrolled medical or psychiatric conditions. * known positivity for human immunodeficiency virus (HIV) or hepatitis B or C. * a history of allergic reaction attributable to compounds of similar chemical or biological composition to bendamustine, bortezomib, boron, or mannitol. * received chemotherapy within 3 weeks before enrollment, with the exception of nitrosoureas, which should be discontinued at least 6 weeks before enrollment. * received corticosteroids (greater than 10 mg/day prednisone or equivalent) within 3 weeks before enrollment. * received immunotherapy, antibody, or radiation therapy within 4 weeks before enrollment. * a status as a pregnant or lactating woman. Any women becoming pregnant during the study will be withdrawn from the study. * a status as a male whose sexual partner is a woman of childbearing potential not using effective birth control. * used an investigational drug within 1 month before the screening visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Dose Limiting Toxicity (DLT) | Day 1 - 28 | Maximum tolerated dose was the dose that was 1 step lower than the dose where at least one third of patients experienced DLT. A DLT was defined as any of the following occurring during the first cycle: * grade 4 hematologic toxicity without regard for relationship to study drug treatment * thrombocytopenia grade 3 with grade 3 or grade 4 hemorrhage * grade 3 febrile neutropenia * grade 3 or grade 4 nausea and vomiting refractory to anti emetic therapy * any study drug related grade 3 or grade 4 nonhematologic toxicity * any drug related death Toxicity grades (3=severe AE and 4=life-threatening or disabling AE) were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants' Best Tumor Response as Assessed by the Investigator | up to 7.5 months (eight 28-day cycles) | Abbreviated criteria for response categories: CR includes the disappearance of the original monoclonal protein (M-protein) from blood and urine, and \<5% plasma cells in the bone marrow, and no increase in size/number of lytic bone lesions, and disappearance of soft tissue plasmacytomas for \>=4 weeks. VGPR includes serum and urine M-protein detectable by immunofixation but not electrophoresis, and reduction in 24-hr urinary light chain excretion by \<100 mg, and disappearance of soft tissue plasmacytomas for \>= 4 weeks, and no increase in size/number of lytic bone lesions. PR includes a \>=50% reduction in serum M-protein, and reduction in 24-hr urinary light chain excretion by either \>=90% or to \<200 mg, and \>=50% reduction in size of soft tissue plasmacytomas, and no increase in size/number of lytic bone lesions. MR includes a \>=25% and \<=49% reduction in serum M-protein. SD does not meet criteria for the other response categories. See outcome #4 for a definition of PD. |
| Kaplan-Meier Estimate for Time to Progression (TTP) | up to 8.6 months | Time to progression was defined as the time from initiation of therapy to progressive disease (PD). PD requires at least one of the following: * \>25% increase in serum monoclonal paraprotein (which must also be an absolute increase of at least 5 g/L), * \>25% increase in 24-hour urinary light chain excretion (which must also be an absolute increase of at least 200 mg/24 h), * \>25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy (which must also be an absolute increase of at least 10%), * definite increase in the size of existing lytic bone lesions or soft tissue plasmacytomas, * the development of new bone lesions or soft tissue plasmacytomas, * the development of hypercalcemia (corrected serum calcium \> 11.5 mg/dL or 2.8 mmol/L not attributable to any other cause). |
| Kaplan-Meier Estimate for Progression-Free Survival | up to 23 months | Progression free survival is the time between the date of initiation of therapy to progressive disease (PD) or death from any cause, whichever occurs first. See outcome #4 for a definition of PD. |
| Percentage of Participants With An Overall Tumor Response As Assessed By the Investigator | Up to 7.5 months (eight 28-day cycles) | Overall tumor response is the sum of a complete response (CR), very good partial response (VGPR), partial response (PR) and minimal response (MR). A modified version of the Bladé criteria for response was used. Abbreviated definitions for the response categories can be found in the description of outcome #3. |
| Kaplan-Meier Estimate for Duration of Response | up to 8.5 months | Duration of response (DR) is defined as the time from the first response to progressive disease (PD). See outcome #4 for a PD definition. |
| Kaplan-Meier Estimate for Overall Survival (OS) | up to 23 months | Overall survival is defined as the time from initiation of therapy to death from any cause or last follow-up visit. |
| Summary of Participants With Adverse Events (AEs) | up to 8.5 months. Deaths are reported up to 18 months | Counts of participants who had AEs are summarized in a variety of categories. Severity and relatedness to study drug are in the opinion of the investigator according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0. Severity is rated on a 5-point scale: 1=mild, 2=moderate, 3=severe, 4=life threatening or disabling, and 5= death related to AE. Relatedness is assessed on a 5-point scale: not related, unlikely, possible, probable and definite. Definite, probable and possible answers are reported as 'related' to study medication. Deaths are reported up to 18 months. All the deaths occurred beyond the treatment-emergent timeframe since they occurred 6.5-16 months after the final dosing. All other parts of the summary represent the treatment-emergent timeframe (up to 8.5 months) which is the treatment period plus 30 days. |
| Time to the First Response | up to 8.5 months | Time to first response is defined as the time from the initiation of therapy to the first evidence of a confirmed response (ie, CR, VGPR, PR, or MR). |
Countries
United States
Participant flow
Pre-assignment details
Fifty-one patients were screened and forty from 10 U.S. centers were enrolled. Reasons for not enrolling were failed to meet inclusion and/or exclusion criteria (10) and an adverse event (1).
Participants by arm
| Arm | Count |
|---|---|
| Bendamustine 50 mg/m^2 Cohort Bortezomib 1.0 mg/m\^2/dose (days 1, 4, 8 and 11) by intravenous push and Bendamustine 50 mg/m\^2/dose (days 1 and 4) intravenously for up to eight 28 day cycles. | 5 |
| Bendamustine 70 mg/m^2 Cohort Bortezomib 1.0 mg/m\^2/dose (days 1, 4, 8 and 11) by intravenous push and Bendamustine 70 mg/m\^2/dose (days 1 and 4) intravenously for up to eight 28 day cycles. | 4 |
| Bendamustine 90 mg/m^2 Cohort Bortezomib 1.0 mg/m\^2/dose (days 1, 4, 8 and 11) by intravenous push and Bendamustine 90 mg/m\^2/dose (days 1 and 4) intravenously for up to eight 28 day cycles. | 31 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 4 |
| Overall Study | Disease progression | 2 | 1 | 10 |
| Overall Study | Noncompliance to study medication | 0 | 0 | 1 |
| Overall Study | Response plateau; started maintenance | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 6 |
Baseline characteristics
| Characteristic | Bendamustine 50 mg/m^2 Cohort | Bendamustine 70 mg/m^2 Cohort | Bendamustine 90 mg/m^2 Cohort | Total |
|---|---|---|---|---|
| Age Continuous | 62.8 years STANDARD_DEVIATION 18.17 | 67.0 years STANDARD_DEVIATION 9.49 | 64.5 years STANDARD_DEVIATION 10.68 | 64.6 years STANDARD_DEVIATION 11.38 |
| Body Surface Area (BSA) | 1.76 m^2 STANDARD_DEVIATION 0.234 | 1.81 m^2 STANDARD_DEVIATION 0.177 | 1.90 m^2 STANDARD_DEVIATION 0.265 | 1.87 m^2 STANDARD_DEVIATION 0.254 |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black | 1 participants | 0 participants | 5 participants | 6 participants |
| Race/Ethnicity, Customized Other | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 4 participants | 4 participants | 24 participants | 32 participants |
| Region of Enrollment United States | 5 participants | 4 participants | 31 participants | 40 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 12 Participants | 17 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 19 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 5 | 4 / 4 | 31 / 31 |
| serious Total, serious adverse events | 0 / 5 | 1 / 4 | 7 / 31 |
Outcome results
Primary
Participants With Dose Limiting Toxicity (DLT)
Maximum tolerated dose was the dose that was 1 step lower than the dose where at least one third of patients experienced DLT. A DLT was defined as any of the following occurring during the first cycle: * grade 4 hematologic toxicity without regard for relationship to study drug treatment * thrombocytopenia grade 3 with grade 3 or grade 4 hemorrhage * grade 3 febrile neutropenia * grade 3 or grade 4 nausea and vomiting refractory to anti emetic therapy * any study drug related grade 3 or grade 4 nonhematologic toxicity * any drug related death Toxicity grades (3=severe AE and 4=life-threatening or disabling AE) were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.
Time frame: Day 1 - 28
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bendamustine 50 mg/m^2 Cohort | Participants With Dose Limiting Toxicity (DLT) | 0 participants |
| Bendamustine 70 mg/m^2 Cohort | Participants With Dose Limiting Toxicity (DLT) | 0 participants |
| Bendamustine 90 mg/m^2 Cohort | Participants With Dose Limiting Toxicity (DLT) | 0 participants |
Secondary
Kaplan-Meier Estimate for Duration of Response
Duration of response (DR) is defined as the time from the first response to progressive disease (PD). See outcome #4 for a PD definition.
Time frame: up to 8.5 months
Population: Participants who had a response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine 50 mg/m^2 Cohort | Kaplan-Meier Estimate for Duration of Response | NA months |
Secondary
Kaplan-Meier Estimate for Overall Survival (OS)
Overall survival is defined as the time from initiation of therapy to death from any cause or last follow-up visit.
Time frame: up to 23 months
Population: Safety population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine 50 mg/m^2 Cohort | Kaplan-Meier Estimate for Overall Survival (OS) | 17.82 months |
Secondary
Kaplan-Meier Estimate for Progression-Free Survival
Progression free survival is the time between the date of initiation of therapy to progressive disease (PD) or death from any cause, whichever occurs first. See outcome #4 for a definition of PD.
Time frame: up to 23 months
Population: Safety population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine 50 mg/m^2 Cohort | Kaplan-Meier Estimate for Progression-Free Survival | 15.21 months |
Secondary
Kaplan-Meier Estimate for Time to Progression (TTP)
Time to progression was defined as the time from initiation of therapy to progressive disease (PD). PD requires at least one of the following: * \>25% increase in serum monoclonal paraprotein (which must also be an absolute increase of at least 5 g/L), * \>25% increase in 24-hour urinary light chain excretion (which must also be an absolute increase of at least 200 mg/24 h), * \>25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy (which must also be an absolute increase of at least 10%), * definite increase in the size of existing lytic bone lesions or soft tissue plasmacytomas, * the development of new bone lesions or soft tissue plasmacytomas, * the development of hypercalcemia (corrected serum calcium \> 11.5 mg/dL or 2.8 mmol/L not attributable to any other cause).
Time frame: up to 8.6 months
Population: Safety population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine 50 mg/m^2 Cohort | Kaplan-Meier Estimate for Time to Progression (TTP) | 8.4 months |
Secondary
Participants' Best Tumor Response as Assessed by the Investigator
Abbreviated criteria for response categories: CR includes the disappearance of the original monoclonal protein (M-protein) from blood and urine, and \<5% plasma cells in the bone marrow, and no increase in size/number of lytic bone lesions, and disappearance of soft tissue plasmacytomas for \>=4 weeks. VGPR includes serum and urine M-protein detectable by immunofixation but not electrophoresis, and reduction in 24-hr urinary light chain excretion by \<100 mg, and disappearance of soft tissue plasmacytomas for \>= 4 weeks, and no increase in size/number of lytic bone lesions. PR includes a \>=50% reduction in serum M-protein, and reduction in 24-hr urinary light chain excretion by either \>=90% or to \<200 mg, and \>=50% reduction in size of soft tissue plasmacytomas, and no increase in size/number of lytic bone lesions. MR includes a \>=25% and \<=49% reduction in serum M-protein. SD does not meet criteria for the other response categories. See outcome #4 for a definition of PD.
Time frame: up to 7.5 months (eight 28-day cycles)
Population: Efficacy population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bendamustine 50 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Complete response (CR) | 0 participants |
| Bendamustine 50 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Very good partial response (VGPR) | 0 participants |
| Bendamustine 50 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Partial response (PR) | 1 participants |
| Bendamustine 50 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Minimal response (MR) | 1 participants |
| Bendamustine 50 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Progressive disease (PD) | 1 participants |
| Bendamustine 50 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Stable disease (SD) | 2 participants |
| Bendamustine 70 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Partial response (PR) | 0 participants |
| Bendamustine 70 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Complete response (CR) | 0 participants |
| Bendamustine 70 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Minimal response (MR) | 1 participants |
| Bendamustine 70 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Progressive disease (PD) | 1 participants |
| Bendamustine 70 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Very good partial response (VGPR) | 0 participants |
| Bendamustine 70 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Stable disease (SD) | 2 participants |
| Bendamustine 90 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Very good partial response (VGPR) | 2 participants |
| Bendamustine 90 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Partial response (PR) | 8 participants |
| Bendamustine 90 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Stable disease (SD) | 13 participants |
| Bendamustine 90 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Minimal response (MR) | 5 participants |
| Bendamustine 90 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Complete response (CR) | 1 participants |
| Bendamustine 90 mg/m^2 Cohort | Participants' Best Tumor Response as Assessed by the Investigator | Progressive disease (PD) | 2 participants |
Secondary
Percentage of Participants With An Overall Tumor Response As Assessed By the Investigator
Overall tumor response is the sum of a complete response (CR), very good partial response (VGPR), partial response (PR) and minimal response (MR). A modified version of the Bladé criteria for response was used. Abbreviated definitions for the response categories can be found in the description of outcome #3.
Time frame: Up to 7.5 months (eight 28-day cycles)
Population: Efficacy population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bendamustine 50 mg/m^2 Cohort | Percentage of Participants With An Overall Tumor Response As Assessed By the Investigator | 40.0 percentage of participants |
| Bendamustine 70 mg/m^2 Cohort | Percentage of Participants With An Overall Tumor Response As Assessed By the Investigator | 25.0 percentage of participants |
| Bendamustine 90 mg/m^2 Cohort | Percentage of Participants With An Overall Tumor Response As Assessed By the Investigator | 51.6 percentage of participants |
Secondary
Summary of Participants With Adverse Events (AEs)
Counts of participants who had AEs are summarized in a variety of categories. Severity and relatedness to study drug are in the opinion of the investigator according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0. Severity is rated on a 5-point scale: 1=mild, 2=moderate, 3=severe, 4=life threatening or disabling, and 5= death related to AE. Relatedness is assessed on a 5-point scale: not related, unlikely, possible, probable and definite. Definite, probable and possible answers are reported as 'related' to study medication. Deaths are reported up to 18 months. All the deaths occurred beyond the treatment-emergent timeframe since they occurred 6.5-16 months after the final dosing. All other parts of the summary represent the treatment-emergent timeframe (up to 8.5 months) which is the treatment period plus 30 days.
Time frame: up to 8.5 months. Deaths are reported up to 18 months
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bendamustine 50 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Withdrawn from study due to AE | 2 participants |
| Bendamustine 50 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Severe adverse event (grade 3 or 4) | 3 participants |
| Bendamustine 50 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Deaths | 1 participants |
| Bendamustine 50 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Treatment-related adverse events | 4 participants |
| Bendamustine 50 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Any adverse event | 5 participants |
| Bendamustine 50 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Serious adverse events | 0 participants |
| Bendamustine 50 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Any non-haematologic adverse event | 5 participants |
| Bendamustine 70 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Withdrawn from study due to AE | 2 participants |
| Bendamustine 70 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Severe adverse event (grade 3 or 4) | 3 participants |
| Bendamustine 70 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Any adverse event | 4 participants |
| Bendamustine 70 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Any non-haematologic adverse event | 4 participants |
| Bendamustine 70 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Treatment-related adverse events | 4 participants |
| Bendamustine 70 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Deaths | 0 participants |
| Bendamustine 70 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Serious adverse events | 1 participants |
| Bendamustine 90 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Withdrawn from study due to AE | 5 participants |
| Bendamustine 90 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Deaths | 5 participants |
| Bendamustine 90 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Any adverse event | 31 participants |
| Bendamustine 90 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Any non-haematologic adverse event | 31 participants |
| Bendamustine 90 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Serious adverse events | 7 participants |
| Bendamustine 90 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Treatment-related adverse events | 31 participants |
| Bendamustine 90 mg/m^2 Cohort | Summary of Participants With Adverse Events (AEs) | Severe adverse event (grade 3 or 4) | 22 participants |
Secondary
Time to the First Response
Time to first response is defined as the time from the initiation of therapy to the first evidence of a confirmed response (ie, CR, VGPR, PR, or MR).
Time frame: up to 8.5 months
Population: Participants who had a response
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bendamustine 50 mg/m^2 Cohort | Time to the First Response | 1.9 months | Standard Deviation 1.51 |