Multiple Myeloma and Plasma Cell Neoplasm
Conditions
Keywords
stage I multiple myeloma
Brief summary
RATIONALE: Zoledronate may prevent bone loss and stop the growth of cancer cells in bone. Thalidomide may stop the growth of cancer cells by blocking blood flow to the cancer. It is not yet know whether giving zoledronate together with thalidomide is more effective than zoledronate alone in treating multiple myeloma. PURPOSE: This randomized phase III trial is studying zoledronate and thalidomide see how well they work compared with zoledronate alone in treating patients with early stage multiple myeloma.
Detailed description
OBJECTIVES: Primary * Compare time to progression in patients with early stage multiple myeloma treated with zoledronate with or without thalidomide. Secondary * Compare the response rate, 1-year progression-free survival rate, duration of response, and time to next therapy in patients treated with these regimens. * Assess differences in toxicity of these regimens in these patients. OUTLINE: This is a multicenter, randomized study. Patients are stratified according to the presence of lytic lesions on metastatic bone survey (yes vs no), beta-2 microglobulin level (high vs normal), and bone marrow labeling index (high \[\> 1.0%\] vs low \[≤ 1.0%\]). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive oral thalidomide on days 1-28. Treatment with thalidomide repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive zoledronate IV over 15 minutes on day 1. Treatment with zoledronate repeats every 84 days for 1 year and once a year thereafter in the absence of disease progression or unacceptable toxicity. * Arm II: Patients receive zoledronate IV over 15 minutes on day 1. Treatment repeats every 84 days for 1 year and once a year thereafter in the absence of disease progression or unacceptable toxicity. Blood samples are collected for research studies at baseline and after courses 3, 6, 9, and 12. Bone marrow aspirates are performed at baseline and after courses 6 and 12. Samples are evaluated for bone marrow angiogenesis; vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR-1), and VEGFR-2 expression; bone marrow angiogenesis-VEGF relationship; bone marrow angiogenesis/apoptosis rate relationship; bone marrow angiogenesis/plasma cell (PC) proliferation rate relationship; VEGF expression/apoptosis rate relationship; and VEGFR expression/PC proliferation rate relationship. After completion of study treatment, patients are followed every 6 months for up to 5 years. PROJECTED ACCRUAL: A total of 120 patients will be accrued for this study.
Interventions
DRUGThalidomide
200 mg orally on days 1-28 of 28 day cycle
DRUGzoledronic acid
4 mg\^2 by IV on day 1 every 84 days for 1 year and once per year thereafter
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of multiple myeloma (MM) * Previously untreated asymptomatic disease * No requirement for immediate chemotherapy for active MM, such as hypercalcemia from myeloma or painful bone lesions * No solitary plasmacytoma * Measurable or evaluable disease as defined by one of the following: * Serum monoclonal protein ≥ 1.0 g by protein electrophoresis * More than 200 mg of monoclonal protein in the urine by 24-hour electrophoresis * Measurable soft tissue plasmacytoma by physical exam with ruler or by MRI or positron emission tomography/CT scan * If the only measurable lesion is the plasmacytoma, it must be ≥ 1.5 cm in 1 dimension * Must have ≥ 10% plasma cells as measured on the bone marrow aspirate, bone marrow biopsy, or labeling index * No amyloidosis PATIENT CHARACTERISTICS: * Performance status 0-2 * Absolute neutrophil count ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Hemoglobin ≥ 8.0 g/dL * Creatinine ≤ 2.0 mg/dL (elevation above normal range should not be felt to be related to myeloma) * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use 2 methods of effective contraception 4 weeks before, during, and for 4 weeks after completion of study treatment * No uncontrolled infection * No other active malignancy * No New York Heart Association class III or IV heart disease * No pre-existing neuropathy ≥ grade 2 * No concurrent major dental work PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Prior corticosteroids (for nonmalignant disorders) allowed * Prior therapy with experimental agents not shown to have significant activity in MM, such as clarithromycin, dehydroepiandrosterone, and anakinra allowed * No prior thalidomide or corticosteroids for MM * No more than 3 doses of IV zoledronate or pamidronate within the past 12 months * At least 3 months since prior radiotherapy, including radiotherapy for solitary plasmacytoma * No concurrent oral bisphosphonate therapy for osteoporosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Disease Progression (TTP) | randomization to progression (up to 5 years) | Time to disease progression (TTP) was defined as the time from randomization to the earliest documentation of disease progression. Participants were followed for a maximum of 5 years from registration. The median OS with 95% CI was estimated using the Kaplan Meier method, a two-sided (stratified) log-rank test was calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Confirmed Response (Complete Response [CR], Very Good Partial Response [VGPR] or Partial Response [PR]) on Two Consecutive Evaluations at Least 2 Weeks Apart in the First 12 Months of Treatment | 12 months | Response is defined as follows: * CR: Complete disappearance of M-protein from serum & urine on immunofixation, \<5% plasma cells in bone marrow (BM) * VGPR: \>=90% reduction in serum M-component; Urine M-Component \<100 mg per 24 hours; \<=5% plasma cells in BM * PR: \>= 50% reduction in serum M-Component and/or Urine M-Component \>= 90% reduction or \<200 mg per 24 hours; or \>= 50% decrease in difference between involved and uninvolved FLC levels |
| Duration of Response (Complete Response, Partial Response, and Very Good Partial Response) | time from start of response to progression (up to 5 years) | Duration of response (DOR) is defined as the time from first documentation of response (CR, VGPR or PR) to disease progression. The median DOR with 95% CI was estimated using the Kaplan Meier method |
| 12-month Progression-free Survival (PFS) | 12 months | PFS at 12 months is a dichotomized outcome indicating whether or not a participant was progression free (and alive) at 12 months from the date of randomization. |
| Time to Treatment Failure | time from randomization to treatment failure (up to 5 years) | Time to treatment failure (TTF) was defined as the time from randomization to the date at which the patient was removed from (protocol) treatment due to disease progression, unacceptable toxicity, participant refusal or death. The median TTF with 95% CI was estimated using the Kaplan Meier method |
| Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events | During treatment (up to 5 years) | Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 2. Description of Grades: Grade 1: Mild Grade 2: Moderate Grade 3: Severe Grade 4: Life-threatening Grade 5: Death |
| Time to Subsequent Treatment | time from end of treatment to subsequent treatment (up to 5 years) | Time to subsequent treatment (TTS) was defined as time from end of active (protocol) treatment to the start of subsequent treatment for participants with progressive disease. The median TTS with 95% CI was estimated using the Kaplan Meier method |
Countries
United States
Participant flow
Recruitment details
Sixty-eight (68) participants were recruited at Mayo Clinic (Rochester) and Memorial Sloan-Kettering between July 2003 and March 2009.
Pre-assignment details
All 68 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Arm I: Thal/ZLD Thalidomide (Thal) + Zolendronic acid (ZLD) | 35 |
| Arm II: ZLD Zoledronic acid (ZLD) | 33 |
| Total | 68 |
Baseline characteristics
| Characteristic | Arm I: Thal/ZLD | Arm II: ZLD | Total |
|---|---|---|---|
| Age Continuous | 63 years | 63 years | 63 years |
| Anemia < lower limit of normal | 14 participants | 18 participants | 32 participants |
| Anemia >= lower limit of normal | 21 participants | 15 participants | 36 participants |
| Beta-2 Microglobulin High (> upper limit of normal) | 29 participants | 26 participants | 55 participants |
| Beta-2 Microglobulin Normal (<= upper limit of normal) | 6 participants | 7 participants | 13 participants |
| Bone Marrow Labeling Index High (> 1.0%) | 3 participants | 3 participants | 6 participants |
| Bone Marrow Labeling Index Low (<= 1.0%) | 31 participants | 30 participants | 61 participants |
| Bone Marrow Labeling Index Not Applicable | 1 participants | 0 participants | 1 participants |
| Lytic Bone Lesions Not Present | 33 participants | 31 participants | 64 participants |
| Lytic Bone Lesions Present | 2 participants | 2 participants | 4 participants |
| Peripheral blood circulating plasma cells No | 20 participants | 18 participants | 38 participants |
| Peripheral blood circulating plasma cells Not Applicable | 1 participants | 0 participants | 1 participants |
| Peripheral blood circulating plasma cells Not Done | 1 participants | 1 participants | 2 participants |
| Peripheral blood circulating plasma cells Yes | 13 participants | 14 participants | 27 participants |
| Region of Enrollment United States | 35 participants | 33 participants | 68 participants |
| Sex: Female, Male Female | 13 Participants | 14 Participants | 27 Participants |
| Sex: Female, Male Male | 22 Participants | 19 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 35 / 35 | 28 / 33 |
| serious Total, serious adverse events | 3 / 35 | 1 / 33 |
Outcome results
Primary
Time to Disease Progression (TTP)
Time to disease progression (TTP) was defined as the time from randomization to the earliest documentation of disease progression. Participants were followed for a maximum of 5 years from registration. The median OS with 95% CI was estimated using the Kaplan Meier method, a two-sided (stratified) log-rank test was calculated.
Time frame: randomization to progression (up to 5 years)
Population: Time to disease progression was analyzed on all randomized participants on an intent to treat basis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I: Thal/ZLD | Time to Disease Progression (TTP) | 2.4 years |
| Arm II: ZLD | Time to Disease Progression (TTP) | 1.2 years |
p-value: 0.02Log Rank
Secondary
12-month Progression-free Survival (PFS)
PFS at 12 months is a dichotomized outcome indicating whether or not a participant was progression free (and alive) at 12 months from the date of randomization.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I: Thal/ZLD | 12-month Progression-free Survival (PFS) | 30 participants |
| Arm II: ZLD | 12-month Progression-free Survival (PFS) | 18 participants |
p-value: 0.0048Chi-squared
Secondary
Duration of Response (Complete Response, Partial Response, and Very Good Partial Response)
Duration of response (DOR) is defined as the time from first documentation of response (CR, VGPR or PR) to disease progression. The median DOR with 95% CI was estimated using the Kaplan Meier method
Time frame: time from start of response to progression (up to 5 years)
Population: Participants who achieved a confirmed response (CR, VGPR, or PR) as described above were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I: Thal/ZLD | Duration of Response (Complete Response, Partial Response, and Very Good Partial Response) | 3.3 years |
Secondary
Number of Participants With a Confirmed Response (Complete Response [CR], Very Good Partial Response [VGPR] or Partial Response [PR]) on Two Consecutive Evaluations at Least 2 Weeks Apart in the First 12 Months of Treatment
Response is defined as follows: * CR: Complete disappearance of M-protein from serum & urine on immunofixation, \<5% plasma cells in bone marrow (BM) * VGPR: \>=90% reduction in serum M-component; Urine M-Component \<100 mg per 24 hours; \<=5% plasma cells in BM * PR: \>= 50% reduction in serum M-Component and/or Urine M-Component \>= 90% reduction or \<200 mg per 24 hours; or \>= 50% decrease in difference between involved and uninvolved FLC levels
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I: Thal/ZLD | Number of Participants With a Confirmed Response (Complete Response [CR], Very Good Partial Response [VGPR] or Partial Response [PR]) on Two Consecutive Evaluations at Least 2 Weeks Apart in the First 12 Months of Treatment | 13 participants |
| Arm II: ZLD | Number of Participants With a Confirmed Response (Complete Response [CR], Very Good Partial Response [VGPR] or Partial Response [PR]) on Two Consecutive Evaluations at Least 2 Weeks Apart in the First 12 Months of Treatment | 0 participants |
p-value: <0.001Chi-squared
Secondary
Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events
Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 2. Description of Grades: Grade 1: Mild Grade 2: Moderate Grade 3: Severe Grade 4: Life-threatening Grade 5: Death
Time frame: During treatment (up to 5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I: Thal/ZLD | Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events | 17 participants |
| Arm II: ZLD | Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events | 13 participants |
Secondary
Time to Subsequent Treatment
Time to subsequent treatment (TTS) was defined as time from end of active (protocol) treatment to the start of subsequent treatment for participants with progressive disease. The median TTS with 95% CI was estimated using the Kaplan Meier method
Time frame: time from end of treatment to subsequent treatment (up to 5 years)
Population: This data was not (and will never be) analyzed as it was not submitted consistently across all participants.
Secondary
Time to Treatment Failure
Time to treatment failure (TTF) was defined as the time from randomization to the date at which the patient was removed from (protocol) treatment due to disease progression, unacceptable toxicity, participant refusal or death. The median TTF with 95% CI was estimated using the Kaplan Meier method
Time frame: time from randomization to treatment failure (up to 5 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I: Thal/ZLD | Time to Treatment Failure | 16.5 months |
| Arm II: ZLD | Time to Treatment Failure | 11.1 months |