Multiple Myeloma
Conditions
Keywords
Multiple myeloma, zoledronic acid, skeletal complications, bone
Brief summary
This study evaluated the effectiveness and safety of a dosing method for zoledronic acid in preventing skeletal complications in multiple myeloma participants who have been on an intravenous (IV) bisphosphonate for about one to two years.
Interventions
DRUGzoledronic acid
Zoledronic acid concentrate (4 mg/5 milliliters \[ml\]) was diluted in 100 mL sterile 0.9% calcium-free sodium chloride or 5% dextrose injection, administered IV, either 4 or 12 weeks for 96 weeks.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of multiple myeloma * Have been on zoledronic acid or pamidronate for 1-2 years and therapy must have been initiated for osteolytic lesion, bone fracture, spinal compression, or osteopenia due to multiple myeloma * Stable renal function
Exclusion criteria
* Known sensitivity to bisphosphonates * Receiving investigational drugs considered not safe for co-administration or have a significant effect on bone turnover * Current active dental problems * Had bone marrow transplant or blood stem cell transplant within 2 months before study entry or planned transplant within 2 months following enrollment Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ≥1 SRE at the End of 1 Year on Study | 1 year | SRE was defined as pathological bone fracture, initiation of radiotherapy or surgery on bone, spinal cord compression, or hypercalcemia of malignancy (HCM). SRE was assessed by centrally read radiographic bone surveys. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced Pathologic Bone Fracture | Years 1 and 2 | Pathologic bone fractures are defined as bone fractures that occur spontaneously or as a result of trivial trauma. |
| Percentage of Participants Who Experienced Spinal Cord Compression | Years 1 and 2 | Spinal cord compression is caused by the impingement of a tumor on the spinal cord and is associated with neurologic impairment and/or back pain. |
| Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 and 100/End of Study (EOS) | uNTx is a biomarker used to measure the rate of bone turnover found in urine. |
| Percentage of Participants Who Experienced Radiation to Bone | Years 1 and 2 | Radiation therapy to bone events includes irradiation of bone to palliate painful lesions, to treat or prevent pathologic fractures, or to treat or prevent spinal cord compression. |
| Time to First SRE on Study | Up to 2 years | The time to first SRE is defined as the date of enrollment to the date of the first occurrence of any SRE on the study. SRE includes pathological fracture, initiation of radiotherapy or surgery on bone, spinal cord compression, or HCM. Participants who drop-out was treated as censored observations. Time to first SRE on the study was assessed by the Kaplan-Meier method. |
| Percentage of Participants Who Experienced HCM | Years 1 and 2 | HCM is defined as corrected serum calcium ≥ 12.0 milligrams per deciliter (mg/dL) (3.00 millimoles per liter \[mmol/L\]), or a lower level of hypercalcemia that was symptomatic and required active treatment other than rehydration. |
| Skeletal Related Event (SRE) Rate | Years 1 and 2 | The SRE rate for each participant was calculated as the number of SREs/total follow-up time. SRE included pathological bone fracture, initiation of radiotherapy or surgery on bone, spinal cord compression, or HCM. |
| Time to Death | Up to 2 years | Time to death was defined as the time from the date of enrollment to the date of death. Participants who dropped out or completed the study were considered censored observations. Time to death was assessed by Kaplan-Meier method. |
| Percentage of Participants Who Experienced Surgery to Bone | Years 1 and 2 | Surgery to bone events includes surgical procedures that are performed to set or stabilize pathologic fractures or areas of spinal cord compression and surgical procedures that are performed to prevent an imminent pathologic fracture or spinal cord compression. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 67 centers in the United States (US) from 07 November 2007 to 03 April 2012.
Pre-assignment details
A total of 121 participants with Advanced Multiple Myeloma were enrolled in this study. By study design, any participants who had a Skeletal-related Event (SRE) in Zoledronic Acid Every 12 Weeks group was switched to Zoledronic Acid Every 4 Weeks or 12 Weeks group and reported as Zoledronic Acid Every 4 Weeks or 12 Weeks group, respectively.
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid Every 12 Weeks Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement ( \<50 nmol/mmol creatinine). | 79 |
| Zoledronic Acid Every 4 Weeks or 12 Weeks Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 4 weeks or every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement (≥ 50 nmol/mmol creatinine or \<50 nmol/mmol creatinine, respectively). | 42 |
| Total | 121 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal Laboratory Value(s) | 3 | 5 |
| Overall Study | Abnormal Test Procedure Result(s) | 1 | 0 |
| Overall Study | Administrative Problems | 2 | 4 |
| Overall Study | Adverse Event | 9 | 7 |
| Overall Study | Death | 2 | 2 |
| Overall Study | Withdrawal by Subject | 12 | 5 |
Baseline characteristics
| Characteristic | Zoledronic Acid Every 12 Weeks | Zoledronic Acid Every 4 Weeks or 12 Weeks | Total |
|---|---|---|---|
| Age, Continuous | 62.8 years STANDARD_DEVIATION 9.91 | 65.8 years STANDARD_DEVIATION 12.66 | 63.8 years STANDARD_DEVIATION 10.99 |
| Sex: Female, Male Female | 36 Participants | 21 Participants | 57 Participants |
| Sex: Female, Male Male | 43 Participants | 21 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 79 | 2 / 42 |
| other Total, other adverse events | 70 / 79 | 41 / 42 |
| serious Total, serious adverse events | 23 / 79 | 25 / 42 |
Outcome results
Primary
Percentage of Participants With ≥1 SRE at the End of 1 Year on Study
SRE was defined as pathological bone fracture, initiation of radiotherapy or surgery on bone, spinal cord compression, or hypercalcemia of malignancy (HCM). SRE was assessed by centrally read radiographic bone surveys.
Time frame: 1 year
Population: ITT analysis set included all participants who were enrolled in this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid Every 12 Weeks | Percentage of Participants With ≥1 SRE at the End of 1 Year on Study | 0 percentage of participants |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Percentage of Participants With ≥1 SRE at the End of 1 Year on Study | 0.17 percentage of participants |
Secondary
Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx)
uNTx is a biomarker used to measure the rate of bone turnover found in urine.
Time frame: Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 and 100/End of Study (EOS)
Population: Safety analysis set included all enrolled participants who received at least 1 dose of zoledronic acid. Number analyzed signifies the number of participants with data available for analysis at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid Every 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 12 | 0.2 nmol/mmol creatinine | Standard Deviation 11.5 |
| Zoledronic Acid Every 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 60 | -2.5 nmol/mmol creatinine | Standard Deviation 12.3 |
| Zoledronic Acid Every 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 36 | -2.0 nmol/mmol creatinine | Standard Deviation 9.77 |
| Zoledronic Acid Every 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 72 | -3.5 nmol/mmol creatinine | Standard Deviation 10.99 |
| Zoledronic Acid Every 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 24 | -1.4 nmol/mmol creatinine | Standard Deviation 8.72 |
| Zoledronic Acid Every 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 84 | -3.0 nmol/mmol creatinine | Standard Deviation 10.73 |
| Zoledronic Acid Every 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 48 | -2.3 nmol/mmol creatinine | Standard Deviation 9.24 |
| Zoledronic Acid Every 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 100 | -5.2 nmol/mmol creatinine | Standard Deviation 9.25 |
| Zoledronic Acid Every 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Baseline | 19.8 nmol/mmol creatinine | Standard Deviation 8.82 |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 100 | -7.4 nmol/mmol creatinine | Standard Deviation 17.68 |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Baseline | 24.1 nmol/mmol creatinine | Standard Deviation 15.63 |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 12 | 4.3 nmol/mmol creatinine | Standard Deviation 19.47 |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 24 | -0.5 nmol/mmol creatinine | Standard Deviation 15.66 |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 36 | -0.9 nmol/mmol creatinine | Standard Deviation 13.92 |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 48 | 1.7 nmol/mmol creatinine | Standard Deviation 18.39 |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 60 | -0.8 nmol/mmol creatinine | Standard Deviation 17.54 |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 72 | -6.7 nmol/mmol creatinine | Standard Deviation 15.5 |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) | Change from Baseline to Week 84 | -7.6 nmol/mmol creatinine | Standard Deviation 18.51 |
Secondary
Percentage of Participants Who Experienced HCM
HCM is defined as corrected serum calcium ≥ 12.0 milligrams per deciliter (mg/dL) (3.00 millimoles per liter \[mmol/L\]), or a lower level of hypercalcemia that was symptomatic and required active treatment other than rehydration.
Time frame: Years 1 and 2
Population: ITT analysis set includes all participants who were enrolled in this study. Number analyzed signifies the number of participants with data available for analysis at given time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zoledronic Acid Every 12 Weeks | Percentage of Participants Who Experienced HCM | Year 1 | 0.00 percentage of participants |
| Zoledronic Acid Every 12 Weeks | Percentage of Participants Who Experienced HCM | Year 2 | 0.00 percentage of participants |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Percentage of Participants Who Experienced HCM | Year 1 | 0.02 percentage of participants |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Percentage of Participants Who Experienced HCM | Year 2 | 0.00 percentage of participants |
Secondary
Percentage of Participants Who Experienced Pathologic Bone Fracture
Pathologic bone fractures are defined as bone fractures that occur spontaneously or as a result of trivial trauma.
Time frame: Years 1 and 2
Population: ITT analysis set included all participants who were enrolled in the study. Number analyzed signifies the number of participants with data available for analysis at given time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zoledronic Acid Every 12 Weeks | Percentage of Participants Who Experienced Pathologic Bone Fracture | Year 2 | 0.00 percentage of participants |
| Zoledronic Acid Every 12 Weeks | Percentage of Participants Who Experienced Pathologic Bone Fracture | Year 1 | 0.00 percentage of participants |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Percentage of Participants Who Experienced Pathologic Bone Fracture | Year 1 | 0.07 percentage of participants |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Percentage of Participants Who Experienced Pathologic Bone Fracture | Year 2 | 0.03 percentage of participants |
Secondary
Percentage of Participants Who Experienced Radiation to Bone
Radiation therapy to bone events includes irradiation of bone to palliate painful lesions, to treat or prevent pathologic fractures, or to treat or prevent spinal cord compression.
Time frame: Years 1 and 2
Population: ITT analysis set included all participants who were enrolled in the study. Number analyzed signifies the number of participants with data available for analysis at given time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zoledronic Acid Every 12 Weeks | Percentage of Participants Who Experienced Radiation to Bone | Year 1 | 0.00 percentage of participants |
| Zoledronic Acid Every 12 Weeks | Percentage of Participants Who Experienced Radiation to Bone | Year 2 | 0.00 percentage of participants |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Percentage of Participants Who Experienced Radiation to Bone | Year 1 | 0.10 percentage of participants |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Percentage of Participants Who Experienced Radiation to Bone | Year 2 | 0.11 percentage of participants |
Secondary
Percentage of Participants Who Experienced Spinal Cord Compression
Spinal cord compression is caused by the impingement of a tumor on the spinal cord and is associated with neurologic impairment and/or back pain.
Time frame: Years 1 and 2
Population: ITT analysis set included all participants who were enrolled in the study. Number analyzed signifies the number of participants with data available for analysis at given time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zoledronic Acid Every 12 Weeks | Percentage of Participants Who Experienced Spinal Cord Compression | Year 1 | 0.00 percentage of participants |
| Zoledronic Acid Every 12 Weeks | Percentage of Participants Who Experienced Spinal Cord Compression | Year 2 | 0.00 percentage of participants |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Percentage of Participants Who Experienced Spinal Cord Compression | Year 1 | 0.07 percentage of participants |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Percentage of Participants Who Experienced Spinal Cord Compression | Year 2 | 0.00 percentage of participants |
Secondary
Percentage of Participants Who Experienced Surgery to Bone
Surgery to bone events includes surgical procedures that are performed to set or stabilize pathologic fractures or areas of spinal cord compression and surgical procedures that are performed to prevent an imminent pathologic fracture or spinal cord compression.
Time frame: Years 1 and 2
Population: ITT analysis set includes all participants who were enrolled in this study. Number analyzed signifies the number of participants with data available for analysis at given time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zoledronic Acid Every 12 Weeks | Percentage of Participants Who Experienced Surgery to Bone | Year 1 | 0.00 percentage of participants |
| Zoledronic Acid Every 12 Weeks | Percentage of Participants Who Experienced Surgery to Bone | Year 2 | 0.00 percentage of participants |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Percentage of Participants Who Experienced Surgery to Bone | Year 1 | 0.02 percentage of participants |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Percentage of Participants Who Experienced Surgery to Bone | Year 2 | 0.00 percentage of participants |
Secondary
Skeletal Related Event (SRE) Rate
The SRE rate for each participant was calculated as the number of SREs/total follow-up time. SRE included pathological bone fracture, initiation of radiotherapy or surgery on bone, spinal cord compression, or HCM.
Time frame: Years 1 and 2
Population: ITT analysis set includes all participants who were enrolled in this study. Number analyzed signifies the number of participants with data available for analysis at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid Every 12 Weeks | Skeletal Related Event (SRE) Rate | Year 1 | 0.00 number of SRE/total follow-up time | Standard Deviation 0 |
| Zoledronic Acid Every 12 Weeks | Skeletal Related Event (SRE) Rate | Year 2 | 0.00 number of SRE/total follow-up time | Standard Deviation 0 |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Skeletal Related Event (SRE) Rate | Year 1 | 0.03 number of SRE/total follow-up time | Standard Deviation 0.08 |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Skeletal Related Event (SRE) Rate | Year 2 | 0.02 number of SRE/total follow-up time | Standard Deviation 0.049 |
Secondary
Time to Death
Time to death was defined as the time from the date of enrollment to the date of death. Participants who dropped out or completed the study were considered censored observations. Time to death was assessed by Kaplan-Meier method.
Time frame: Up to 2 years
Population: ITT analysis set included all participants who were enrolled in this study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid Every 12 Weeks | Time to Death | NA years |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Time to Death | NA years |
Secondary
Time to First SRE on Study
The time to first SRE is defined as the date of enrollment to the date of the first occurrence of any SRE on the study. SRE includes pathological fracture, initiation of radiotherapy or surgery on bone, spinal cord compression, or HCM. Participants who drop-out was treated as censored observations. Time to first SRE on the study was assessed by the Kaplan-Meier method.
Time frame: Up to 2 years
Population: ITT analysis set included all participants who were enrolled in this study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid Every 12 Weeks | Time to First SRE on Study | NA years |
| Zoledronic Acid Every 4 Weeks or 12 Weeks | Time to First SRE on Study | NA years |