Multiple Myeloma
Conditions
Keywords
Multiple myeloma
Brief summary
The purpose of this study is to assess the efficacy of bortezomib in combination with melphalan and prednisone to achieve complete responses for patients with previously untreated multiple myeloma compared to an historical control group. This trial will also evaluate the safety and toxicity of this regimen as well as evaluate the duration of response of this regimen.
Detailed description
Based on the need to improve front-line therapy for patients less likely to undergo transplant, the promising recent in vitro and clinical work on melphalan and bortezomib, we propose a prospective trial with bortezomib added to standard melphalan and prednisone therapy for previously untreated patients with multiple myeloma. Bortezomib 1.3 mg/m2 will be given twice weekly for two weeks and will be added to standard melphalan and prednisone on a 4-week cycle. This three-drug combination will be compared to historical data. We have treated 2 patients with relapsed disease following \>2 prior regimens including high-dose therapy with autologous stem cell support. Each patient received melphalan, prednisone, and bortezomib as described below and both had marked declines in M-protein within 2 cycles. These responses have been sustained for at least 3 months and treatment was well tolerated. Eligible patients will have histologically confirmed Multiple Myeloma (MM) having not received prior systemic therapy given with the intent to induce remission, be adults, have life expectancy greater than 3 months, adequate performance status, organ and marrow function as described in the protocol, not be pregnant, HIV positive, or taking any investigational agents. Patients must not have history of allergic reactions to study drugs or similar compounds or have uncontrolled intercurrent illness or social situation that would limit compliance with study requirements. Patients must also have the ability to give informed consent. Study drugs will be administered on an inpatient or outpatient basis. Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle. Supportive care measures such as antiemetics and growth factors may be given.
Interventions
DRUGBortezomib
DRUGMelphalan
DRUGPrednisone
Sponsors
Duke University
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
* Patients must have histologically confirmed multiple myeloma, defined as at least one of the following major criteria and one minor criterion or at least three minor criteria: Major Criteria Minor Criteria Plasmacytoma on tissue biopsy Marrow plasmacytosis 10-29% Marrow plasmacytosis ≥ 30% Monoclonal protein present, less than major criteria Monoclonal protein: Lytic bone lesions Immunoglobulin G (IgG) \> 3.5 g/dl Decrease in uninvolved immunoglobulins: Immunoglobulin A (IgA) \> 2 g/dl Immunoglobulin M (IgM) \< 50 mg/dl Bence Jones ≥ 1 g/24 hr IgA \< 100 mg/dl IgG \< 600 mg/dl * No prior therapy * Life expectancy greater than 3 months * Eastern Cooperative Oncology Group (ECOG) performance status \<3 (Karnofsky \>40% * Patients must have normal organ and marrow function. Patients with severe pancytopenia due to myeloma involvement of the bone marrow and patients with renal insufficiency (creatinine \> 2 mg/dl) due to myeloma will also be included. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Pregnant women * Patients may not be receiving any other investigational agents. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to bortezomib, melphalan, or other agents used in the study. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy. Therefore, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with bortezomib or other agents administered during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response | 6 weeks following completion of treatment | Overall response rate equals complete response and partial response per Southwest Oncology Group Criteria. Measurable, quantifiable protein criteria must be present. Acceptable protein criteria are quantitative immunoglobulin IgG, IgA, IgD, IgE or IgM and/or urine M-component (Bence-Jones protein). If both are present, the quantitative immunoglobulin will be followed for response. Complete Remission: The absence of bone marrow or blood findings of multiple myeloma. This includes disappearance of all evidence of serum and urine M-components on electrophoresis as by immunofixation studies. There must also be no evidence of increasing anemia. Partial Remission: A 50-74% reduction in the quantitative immunoglobulin, and if present, a 50-89% reduction in the urine M-component (Bence-Jones protein). Stable/No Remission): A \<50% reduction I nthe quantitative immunoglobulin, or if the patient has light-chain disease only, a \<50% reduction in the urine M-component (Bence-Jones protein. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Any Grade or Severe Adverse Event | At any time during the study and up to 30 days after stopping the study drug | Number of patients with any grade or severe, defined as ≥ grade 3 by Common Terminology Criteria for Adverse Events (CTCAE) v4.0, adverse events as a measure of safety |
| Median Duration of Response | up to 4 years | Duration of response is measured from date of first confirmed response until date of disease progression. |
Countries
United States
Participant flow
Recruitment details
Recruitment period occurred from July 2004 to December 2007 at Duke University Medical Center.
Participants by arm
| Arm | Count |
|---|---|
| Bortezomib+Melphalan+Prednisone Bortezomib 1.3 mg/m2 is administered intravenously in a 3-5 second bolus on days 1, 4, 8, and 11 of a 28 day cycle. Six cycles are planned. On days when both melphalan and bortezomib are given, melphalan is given at least one hour prior to bortezomib. Melphalan 6 mg/m2 is administered orally on an empty stomach daily on days 1-7 of each cycle. Prednisone 60 mg/m2 is administered orally daily on days 1-7 of each cycle. | 45 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Bortezomib+Melphalan+Prednisone |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 18 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 30 / 45 |
| serious Total, serious adverse events | 6 / 45 |
Outcome results
Primary
Response
Overall response rate equals complete response and partial response per Southwest Oncology Group Criteria. Measurable, quantifiable protein criteria must be present. Acceptable protein criteria are quantitative immunoglobulin IgG, IgA, IgD, IgE or IgM and/or urine M-component (Bence-Jones protein). If both are present, the quantitative immunoglobulin will be followed for response. Complete Remission: The absence of bone marrow or blood findings of multiple myeloma. This includes disappearance of all evidence of serum and urine M-components on electrophoresis as by immunofixation studies. There must also be no evidence of increasing anemia. Partial Remission: A 50-74% reduction in the quantitative immunoglobulin, and if present, a 50-89% reduction in the urine M-component (Bence-Jones protein). Stable/No Remission): A \<50% reduction I nthe quantitative immunoglobulin, or if the patient has light-chain disease only, a \<50% reduction in the urine M-component (Bence-Jones protein.
Time frame: 6 weeks following completion of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bortezomib+Melphalan+Prednisone | Response | 42 participants |
Secondary
Median Duration of Response
Duration of response is measured from date of first confirmed response until date of disease progression.
Time frame: up to 4 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bortezomib+Melphalan+Prednisone | Median Duration of Response | 19.8 months |
| Bortezomib+Melphalan+Prednisone: ASCT | Median Duration of Response | 27.9 months |
Secondary
Number of Patients With Any Grade or Severe Adverse Event
Number of patients with any grade or severe, defined as ≥ grade 3 by Common Terminology Criteria for Adverse Events (CTCAE) v4.0, adverse events as a measure of safety
Time frame: At any time during the study and up to 30 days after stopping the study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bortezomib+Melphalan+Prednisone | Number of Patients With Any Grade or Severe Adverse Event | 34 participants |