Multiple Myeloma
Conditions
Keywords
stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, refractory multiple myeloma
Brief summary
RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as thalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. It may also stop the growth of cancer by blocking blood flow to the cancer. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with thalidomide and dexamethasone may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving bortezomib together with thalidomide and dexamethasone works in treating patients with relapsed or refractory multiple myeloma.
Detailed description
OBJECTIVES: * Determine the confirmed overall response rate (complete remission, remission, and partial remission) in patients with relapsed or refractory multiple myeloma treated with bortezomib, thalidomide, and dexamethasone. * Determine overall and progression-free survival of patients treated with this regimen. * Determine the qualitative and quantitative toxic effects of this regimen in these patients. * Correlate, preliminarily, treatment with bortezomib with the activation of osteoblasts in these patients. OUTLINE: This is a multicenter study. * Induction therapy: Patients receive bortezomib IV on days 1, 4, 8, and 11, oral thalidomide once daily on days 1-21, and oral dexamethasone once daily on days 1, 2, 4, 5, 8, 9, 11, and 12. Treatment repeats every 21 days until achievement of confirmed complete remission (CR), remission (R), or partial remission (PR) OR for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving confirmed CR, R, or PR who reach a plateau prior to receiving the maximum 8 courses of induction therapy OR who achieve confirmed CR, R, or PR after receiving the maximum 8 courses of induction therapy proceed to maintenance therapy. Patients achieving stable disease after receiving the maximum 8 courses of induction therapy either proceed to maintenance therapy or receive further treatment with bortezomib, thalidomide, and dexamethasone off-study. * Maintenance therapy: Patients receive oral dexamethasone on days 1-4. Courses repeat every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed within 30 days and then every 6 months for up to 5 years. PROJECTED ACCRUAL: A total of 90 patients will be accrued for this study within 18 months.
Interventions
DRUGbortezomib
induction: 1 mg/m2 IV push days 1, 4, 8, 11 every 21 days
DRUGdexamethasone
induction: 20 mg/d PO days 1, 2, 4, 5, 8, 9, 11, 12 every 21 days maintenance: 40 mg days 1-4 every 28 days until progression
DRUGthalidomide
100 mg/d PO days 1-21 every 21 days
Sponsors
National Cancer Institute (NCI)
SWOG Cancer Research Network
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of multiple myeloma (MM) * Active disease * Relapsed or refractory disease after ≥ 1 prior therapy for MM, that may have included autologous or allogeneic stem cell transplantation * Relapse is defined as the occurrence of any of the following during or after prior treatment: * Myeloma protein level increase by \> 100% from the lowest previously recorded level * Myeloma protein level increase above the defined response criteria for partial remission * Reappearance of any myeloma peak that had disappeared during the prior treatment * Increase in the size and number of lytic bone lesions and/or focal lesions by x-ray, MRI, positron emission tomography, and/or CT scan * Refractory disease is defined as no response (i.e., not achieving complete remission, remission, or partial remission) to prior therapy * Measurable disease * No evidence of POEMS (polyneuropathy, organomegaly, endocrinopathy, presence of M-protein, and skin changes) syndrome * Must be registered on protocol SWOG-S0334 PATIENT CHARACTERISTICS: Age * 18 and over Performance status * Zubrod 0-2 (unless due to bone pain) Life expectancy * Not specified Hematopoietic * Absolute neutrophil count \> 1,000/mm\^3 * Platelet count \> 50,000/mm\^3 Hepatic * AST or ALT ≤ 3 times upper limit of normal (ULN) * Bilirubin ≤ 3 times ULN Renal * Creatinine clearance \> 30 mL/min Cardiovascular * No New York Heart Association class III or IV congestive heart failure * No myocardial infarction within the past 6 months * No poorly controlled hypertension Other * Not pregnant or nursing * Negative pregnancy test * Fertile female patients must use effective double method contraception for ≥ 4 weeks before, during, and for ≥ 4 weeks after completion of study treatment (during and for 4 weeks after completion of study treatment for male patients) * No blood, ova, or sperm donation during study treatment * No active infection requiring antibiotics * No neurotoxicity ≥ grade 2 * No diabetes mellitus * No other serious medical or psychiatric illness that would preclude study treatment * No other malignancy within the past 3 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix PRIOR CONCURRENT THERAPY: Biologic therapy * See Disease Characteristics Chemotherapy * At least 14 days since prior chemotherapy (28 days for nitrosoureas) and recovered Endocrine therapy * Not specified Radiotherapy * At least 14 days since prior radiotherapy and recovered Surgery * Not specified Other * No prior bortezomib alone or combined with thalidomide * Concurrent participation on protocol SWOG-S0309 allowed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate Complete Remission (CR), Remission (R), and Partial Remission (PR). | 1 year | Responses are defined as follows: Complete Remission: Absence of bone marrow or blood findings of multiple myeloma. This includes disappearance of all evidence of serum and urine M-proteins on immunofixation electrophoresis studies. Normalization of serum concentrations of normal immunoglobulins is not required for CR. There must also be no evidence of increasing anemia. Bone marrow cellularity must be ≥ 20% with plasma cells ≤ 5%. Remission: A ≥ 75% reduction in the serum M-protein, and if a urine M-protein (Bence-Jones protein) is present, either a ≥ 90% reduction in this protein, or a urine M-protein \< 0.2gm/day. Bone marrow plasma cells must be ≤ 5%. Partial Remission: A ≥ 50% reduction in the serum M-protein, and if present, a ≥ 50% reduction in the urine M-protein (Bence-Jones protein). Bone marrow plasma cells must not be increased from baseline level. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity Evaluation | From date of protocol therapy start to date of protocol therapy end, i.e., up to about 3.5 years | To evaluate the qualitative and quantitative toxicities associated with this regimen. |
| Progression-Free Survival | about 12-18 months | From date of initial registration to date of progression/relapse of disease (\> 25% increase from baseline in myeloma protein production or other signs of disease progression such as hypercalcemia, etc.) or death from any cause, whichever came first, up to 5 years |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bortezomib With Thalidomide and Dexamethasone Induction (per 21-day cycle): Bortezomib - 1.0 mg/m2 (Days 1, 4, 8, and 11). Dexamethasone - 20 mg/d PO (Days 1, 2, 4, 5, 8, 9, 11, and 12). Thalidomide 100 mg (Days 1-21).
Maintenance (per 28-day cycle): thalidomide 100mg (Days 1-28). Dexamethasone 40 mg Days 1-4. | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Bortezomib With Thalidomide and Dexamethasone |
|---|---|
| Age, Continuous | 63.7 years |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 1 / 7 |
Outcome results
Primary
Overall Response Rate Complete Remission (CR), Remission (R), and Partial Remission (PR).
Responses are defined as follows: Complete Remission: Absence of bone marrow or blood findings of multiple myeloma. This includes disappearance of all evidence of serum and urine M-proteins on immunofixation electrophoresis studies. Normalization of serum concentrations of normal immunoglobulins is not required for CR. There must also be no evidence of increasing anemia. Bone marrow cellularity must be ≥ 20% with plasma cells ≤ 5%. Remission: A ≥ 75% reduction in the serum M-protein, and if a urine M-protein (Bence-Jones protein) is present, either a ≥ 90% reduction in this protein, or a urine M-protein \< 0.2gm/day. Bone marrow plasma cells must be ≤ 5%. Partial Remission: A ≥ 50% reduction in the serum M-protein, and if present, a ≥ 50% reduction in the urine M-protein (Bence-Jones protein). Bone marrow plasma cells must not be increased from baseline level.
Time frame: 1 year
Population: Ninety patients is sufficient to distinguish between the null hypothesis that the response rate is 45% versus the alternative of a response rate of 60% with 89% power, using a one-sided test based on the binomial distribution with a significance level of 5%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bortezomib + Thal/Dex | Overall Response Rate Complete Remission (CR), Remission (R), and Partial Remission (PR). | 14 percentage of participants |
Secondary
Progression-Free Survival
From date of initial registration to date of progression/relapse of disease (\> 25% increase from baseline in myeloma protein production or other signs of disease progression such as hypercalcemia, etc.) or death from any cause, whichever came first, up to 5 years
Time frame: about 12-18 months
Population: With ninety patients, we will have 82% power to rule out a null hypothesis of a 12-month median survival versus an alternative hypothesis of an 18-month median survival at a significance level of 5%.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bortezomib + Thal/Dex | Progression-Free Survival | 8 Months |
Secondary
Toxicity Evaluation
To evaluate the qualitative and quantitative toxicities associated with this regimen.
Time frame: From date of protocol therapy start to date of protocol therapy end, i.e., up to about 3.5 years
Population: All participants receiving at least one dose of induction therapy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bortezomib + Thal/Dex | Toxicity Evaluation | Neutrophils/granulocytes (ANC/AGC) | 2 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Platelets | 1 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Albumin, serum-low (hypoalbuminemia) | 1 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Allergy/Immunology-Other | 1 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Bilirubin (hyperbilirubinemia) | 1 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Edema: limb | 1 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Extremity-lower (gait/walking) | 1 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Fatigue (asthenia, lethargy, malaise) | 1 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Hemoglobin | 1 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Inf (clin/microbio) w/Gr 3-4 neuts - Lung | 1 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Leukocytes (total WBC) | 1 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Lymphopenia | 1 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Muscle weakness, not d/t neuropathy - Extrem-lower | 1 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Muscle weakness, not d/t neuropathy - body/general | 1 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Neuropathy: motor | 1 Participants |
| Bortezomib + Thal/Dex | Toxicity Evaluation | Neuropathy: sensory | 1 Participants |