Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, Bendamustine, Bortezomib, Dexamethasone
Brief summary
In this study, investigators will evaluate the activity of bendamustine, bortezomib and dexamethasone (BBD). This regimen combines 3 agents with high activity in multiple myeloma, with different mechanisms of action and non-overlapping toxicities.
Detailed description
The purpose of this study is to assess the efficacy, tolerability, and toxicity of bendamustine, bortezomib, and dexamethasone (BBD) as first-line treatment of multiple myeloma (MM) patients who are transplant ineligible or who are not candidates for high dose chemotherapy. Eligible patients will receive protocol treatment for up to 34 weeks plus the screening period (up to 2 weeks). Response assessments will occur every 4 weeks and confirmed using the International Myeloma Working Group Uniform Response Criteria. Patients having an objective response or stable disease will continue to maintenance therapy until disease progression or intolerable toxicity.
Interventions
DRUGBendamustine
Treatment: 80 mg/m2 via intravenous (IV) Days 1 and 2; repeat cycles every 28-days for 8 cycles or 2 cycles beyond confirmed complete response.
DRUGBortezomib
1.3 mg/m2 IV Days 1, 8, 15; repeat cycles every 28-days for 8 cycles or 2 cycles beyond confirmed complete response. Maintenance: 1.3 mg/m2 IV or SQ Days 1, 15
DRUGDexamethasone
20 mg orally (PO) Days 1, 2, 8, 9, 15, 16 every 28-days for 8 cycles or 2 cycles beyond confirmed complete response, Maintenance: 20 mg PO Days 1, 15
Sponsors
Millennium Pharmaceuticals, Inc.
Cephalon
SCRI Development Innovations, LLC
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
1. Patients must meet the Durie and Salmon criteria for initial diagnosis of multiple myeloma. 2. Previously histologically confirmed, multiple myeloma with indication for therapy including one of the following: * Hemoglobin \<10 g/dl or 2 g/dl below normal * Serum calcium \>11.5 mg/dl * Creatinine \>2 mg/dl * Lytic bone lesions or severe osteopenia * Extramedullary plasmacytomas 3. Patients should not be considered candidates for high dose therapy/autologous stem cell transplantation due to coexistent medical conditions, advanced age, poor performance status, refusal of high dose chemotherapy, or other reasons as judged by the patient and/or physician. 4. ECOG Performance Status 0-2. 5. WBC ≥3000/mL; ANC ≥1000/mL; platelets ≥50,000/mL (patients with platelets ≥30,000/mL are eligible if thrombocytopenia is felt to be due to extensive bone marrow involvement with myeloma). 6. Patients with adequate organ function as measured by: Renal: Serum creatinine \<2.0 mg/dL or a calculated or measured creatinine clearance of \>30 mL/minute. Hepatic: Total bilirubin \< 1.5 x ULN and ALT and AST \<2.5 x the ULN (\<5 x ULN for patients with liver involvement). 7. Patients must have measurable or evaluable disease. In patients with disease limited to bone and bone marrow, serial paraprotein measurements are acceptable for evaluable disease. 8. Patients must be accessible for treatment and follow-up procedures. 9. Male or female patients 18 years of age or older. 10. Patients must provide written informed consent prior to receiving protocol therapy. 11. Women of childbearing potential must agree to use a medically acceptable method of birth control(e.g., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study and for 12 months after their last dose of rituximab. Men must use an acceptable form/method of contraception for the duration of treatment and for 3 months after the end of treatment. 12. Patients must be able to understand the nature of this study and give written informed consent.
Exclusion criteria
1. Previous therapy for multiple myeloma with the exception of an initial 4-day course of pulsed dexamethasone. 2. Patients with ≥NCI CTCAE v4.0 grade 2 peripheral neuropathy ≤14 days prior to study enrollment. 3. Treatment with investigational agent(s) ≤14 days prior to study enrollment. 4. Active infection or infection requiring intravenous antibiotic treatment at the time of accrual. 5. Known to be HIV positive (HIV test is not required for participation in the trial). 6. Patients with class III/IV cardiac problems as defined by the New York Heart Association (NYHA)criteria: * History of uncontrolled or symptomatic angina * History of arrhythmias requiring medications, or clinically significant, with the exception of asymptomatic atrial fibrillation requiring anticoagulation * Myocardial infarction \< 6 months from study entry * Uncontrolled or symptomatic congestive heart failure * Ejection fraction below the institutional normal limit * Any other cardiac condition that, in the opinion of the treatment physician, would make this protocol unreasonably hazardous for the patient * Uncontrolled hypertension (systolic blood pressure \[BP\] \>180 or diastolic BP \>100mm Hg)or uncontrolled cardiac arrhythmias. * Prior to study entry, any ECG abnormality at Screening must be documented by the investigator as not medically relevant. 7. Other serious medical conditions or psychiatric illness that would potentially interfere with patient participation in this trial. 8. A second malignancy, other than basal cell carcinoma of the skin or in situ carcinoma of the cervix,unless the tumor was treated with curative intent at least 2 years previously or low-risk prostate cancer after curative therapy. 9. Known hypersensitivity to bortezomib, boron, or mannitol. 10. Female patient is pregnant or lactating. Confirmation that female patients of childbearing potential are not pregnant must be established by a negative serum pregnancy test ≤7 days prior to start of treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate | every 8 weeks for approximately 48 months | Defined as the percent of patients having a complete response (CR) to treatment, assessed using the International Myeloma Working Group (IMWG) Uniform Response Criteria. CR=disappearance of soft tissue plasmacytomas and 5% or less plasma cells in bone marrow. |
| Number of Patients Who Experienced Serious and Non-serious Adverse Events | approximately 36 weeks | All serious adverse events (SAEs) and non-serious adverse events (AEs) were assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0, and were collected from start of study treatment until 30 days after last dose of study medication. Refer to the Adverse Event module for specific terms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | every 8 weeks for up to 48 months | Defined as the interval of time (in months) that patient are alive from date of first protocol treatment to date of documented tumor progression or date of death from any cause. Progressive disease, assessed according to International Myeloma Working Group Uniform Response Criteria, is defined as at least a 25% increase from the nadir in any one of the following criteria: serum M-protein, urine M-protein, or bone marrow plasma cell percentage of 10% or greater. |
| Overall Survival | every 4 weeks until progressive disease then every 12 weeks, projected 48 months | Defined as the interval of time, in months, from first study treatment until the earlier of the date of death or date last known alive. |
| Overall Response Rate | every 4 weeks for approximately 2 years | The number of patients with observed complete or partial response (CR or PR) assessed by International Myeloma Working Group (IMWG) Uniform Response Criteria. PR=50% or greater reduction from baseline in serum M-protein and 90% or greater reduction from baseline in 24-hour urinary M-protein. |
Countries
United States
Participant flow
Recruitment details
Between May 2010 and May 2014, 59 patients with transplant-ineligible Multiple Myeloma (MM) were enrolled at 9 investigational sites in the U.S. The original treatment plan was modified during the trial to decrease intensity but increase treatment duration. Of 59 enrolled patients, 18 were treated on the initial regimen; 41 on the modified plan.
Participants by arm
| Arm | Count |
|---|---|
| Original BBD Regimen Bendamustine, Bortezomib,and Dexamethasone (BBD) every 28 days for 8 cycles or 2 cycles beyond a confirmed complete response, assessed by International Myeloma Working Group (IMWG) Uniform Response Criteria. No maintenance therapy.
Bendamustine: 80 mg/m2 via intravenous (IV) Days 1 and 4 Bortezomib: 1.3 mg/m2 IV Days 1, 4, 8, 11 Dexamethasone: 40 mg orally (PO) Days 1, 2, 3, 4 | 18 |
| Modified BBD Regimen Bendamustine, Bortezomib,and Dexamethasone (BBD) every 28 days for 8 cycles or 2 cycles beyond a confirmed complete response, assessed by International Myeloma Working Group (IMWG) Uniform Response Criteria criteria. Patients with stable disease and no intolerable toxicity may continue maintenance therapy with Bortezomib and Dexamethasone every 28 days for 4 cycles. After cycle 4, dexamethasone may be discontinued at the physician's discretion.
Treatment:
Bendamustine: 80 mg/m2 via intravenous (IV) Days 1 and 2 Bortezomib: 1.3 mg/m2 IV Days 1, 8, 15 Dexamethasone: 20 mg orally (PO) Days 1, 2, 8, 9, 15,16
Maintenance:
Bortezomib: 1.3 mg/m2 IV or SQ Days 1, 15 Dexamethasone: 20 mg PO Days 1, 15 | 41 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Maintenance Therapy | Continuing maintenance therapy | 0 | 14 |
| Maintenance Therapy | Intercurrent Illness | 0 | 1 |
| Maintenance Therapy | Physician Decision | 0 | 1 |
| Maintenance Therapy | Progressive Disease | 0 | 9 |
| Maintenance Therapy | Toxicity | 0 | 2 |
| Maintenance Therapy | Withdrawal by Subject | 0 | 1 |
| Treatment Period-Cycles 1-8 | Death | 3 | 1 |
| Treatment Period-Cycles 1-8 | Disease Progression | 2 | 2 |
| Treatment Period-Cycles 1-8 | Intercurrent Illness | 1 | 2 |
| Treatment Period-Cycles 1-8 | Lost to Follow-up | 1 | 0 |
| Treatment Period-Cycles 1-8 | Physician Decision | 3 | 0 |
| Treatment Period-Cycles 1-8 | Toxicity | 2 | 1 |
| Treatment Period-Cycles 1-8 | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Original BBD Regimen | Modified BBD Regimen |
|---|---|---|---|
| Age, Continuous | 75 years | 75 years | 75 years |
| Race/Ethnicity, Customized American Indian/Alaskan Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black/African American | 13 Participants | 3 Participants | 10 Participants |
| Race/Ethnicity, Customized Caucasian | 41 Participants | 14 Participants | 27 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment United States | 59 participants | 18 participants | 41 participants |
| Sex/Gender, Customized female | 19 Participants | 5 Participants | 14 Participants |
| Sex/Gender, Customized male | 39 Participants | 13 Participants | 26 Participants |
| Sex/Gender, Customized unknown | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 18 / 18 | 38 / 41 |
| serious Total, serious adverse events | 7 / 18 | 17 / 41 |
Outcome results
Primary
Complete Response Rate
Defined as the percent of patients having a complete response (CR) to treatment, assessed using the International Myeloma Working Group (IMWG) Uniform Response Criteria. CR=disappearance of soft tissue plasmacytomas and 5% or less plasma cells in bone marrow.
Time frame: every 8 weeks for approximately 48 months
Population: All patients evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Original BBD Regimen | Complete Response Rate | 0 percentage of participants |
| Modified BBD Regimen | Complete Response Rate | 13 percentage of participants |
Primary
Number of Patients Who Experienced Serious and Non-serious Adverse Events
All serious adverse events (SAEs) and non-serious adverse events (AEs) were assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0, and were collected from start of study treatment until 30 days after last dose of study medication. Refer to the Adverse Event module for specific terms.
Time frame: approximately 36 weeks
Population: All patients who received at least one dose of BBD treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Original BBD Regimen | Number of Patients Who Experienced Serious and Non-serious Adverse Events | SAEs | 7 participants |
| Original BBD Regimen | Number of Patients Who Experienced Serious and Non-serious Adverse Events | AEs | 18 participants |
| Modified BBD Regimen | Number of Patients Who Experienced Serious and Non-serious Adverse Events | SAEs | 17 participants |
| Modified BBD Regimen | Number of Patients Who Experienced Serious and Non-serious Adverse Events | AEs | 38 participants |
Secondary
Overall Response Rate
The number of patients with observed complete or partial response (CR or PR) assessed by International Myeloma Working Group (IMWG) Uniform Response Criteria. PR=50% or greater reduction from baseline in serum M-protein and 90% or greater reduction from baseline in 24-hour urinary M-protein.
Time frame: every 4 weeks for approximately 2 years
Population: All patients evaluable for response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Original BBD Regimen | Overall Response Rate | CR | 0 participants |
| Original BBD Regimen | Overall Response Rate | PR | 5 participants |
| Modified BBD Regimen | Overall Response Rate | CR | 5 participants |
| Modified BBD Regimen | Overall Response Rate | PR | 8 participants |
Secondary
Overall Survival
Defined as the interval of time, in months, from first study treatment until the earlier of the date of death or date last known alive.
Time frame: every 4 weeks until progressive disease then every 12 weeks, projected 48 months
Population: All patients evaluable for response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Original BBD Regimen | Overall Survival | NA months |
| Modified BBD Regimen | Overall Survival | NA months |
Secondary
Progression Free Survival
Defined as the interval of time (in months) that patient are alive from date of first protocol treatment to date of documented tumor progression or date of death from any cause. Progressive disease, assessed according to International Myeloma Working Group Uniform Response Criteria, is defined as at least a 25% increase from the nadir in any one of the following criteria: serum M-protein, urine M-protein, or bone marrow plasma cell percentage of 10% or greater.
Time frame: every 8 weeks for up to 48 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Original BBD Regimen | Progression Free Survival | 11.1 months |
| Modified BBD Regimen | Progression Free Survival | 18.9 months |