Multiple Myeloma
Conditions
Keywords
Z-MAX, multiple myeloma, zoledronic acid, bone metastases
Brief summary
The purpose of this trial is to study the safety of treating patients with multiple myeloma and at least one bone lesion with zoledronic acid 4mg intravenously (IV) every 3 - 4 weeks for 2 years. Patients will receive a zoledronic acid infusion for 15 minutes or 30 minutes.
Interventions
DRUGzoledronic acid
4 mg zoledronic acid in 250 mL of calcium-free solution (i.e., 0.9% sodium chloride or 5% glucose) administered intravenously.
Sponsors
Novartis Pharmaceuticals
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
* Patients 18 years of age or older * Confirmed diagnosis of Multiple Myeloma * Stable renal function defined as two serum creatinine determinations of \< 3 mg/dL * Calculated creatinine clearance of greater than or equal to 30 mL/min * ECOG Performance Status of 0 or 1 * Life expectancy of greater than or equal to 9 months * If the patient is of child-bearing potential, a negative pregnancy test is required at screening, while postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. * Ability to comply with trial requirements and give informed consent.
Exclusion criteria
* IV Bisphosphonate therapy for more than 3 years. * Patients with a diagnosis of amyloidosis. * Known hypersensitivity to zoledronic acid or other bisphosphonates * Pregnant patients or lactating patients. * Women of childbearing potential not on a medically recognized form of contraception * Patients with uncontrolled cardiovascular disease, hypertension, and Type 2 diabetes mellitus.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants With a Significant Increase in Serum Creatinine at 12 Months | Baseline and 12 Months | The primary renal safety endpoint was the number of participants with a clinically relevant increase in serum creatinine at 12 months. Serum creatinine was determined prior to each zoledronic acid infusion for all Participants and was considered to be significantly increased if there was an increase of 0.5 mg/dL or more or a doubling of the baseline serum creatinine value. |
| The Number of Participants With Disease Progression | 24 Months | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants With a Significant Increase in Serum Creatinine at 24 Months | Baseline and 24 Months | Serum Creatinine was considered to be significantly increased if there was an increase of 0.5 mg/dL or more or a doubling of the baseline serum creatinine value. |
| Time to First Significant Increase in Serum Creatinine | Up to 24 months | Median time to event in participants who had a clinically relevant increase in serum creatinine. |
| Zoledronic Acid Concentrations | 24 months | Samples for drug concentration analysis were drawn at 10 and 15 minutes into the infusion for participants in the 15-minute infusion group and at 25 and 30 minutes into the infusion for patients in the 30-minute infusion group. The mean and median zoledronic acid concentrations were greater in the 15-minute group than in the 30-minute group at both sampling timepoints. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 15 - Minute Infusion Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks. | 88 |
| 30 - Minute Infusion Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3-4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks. | 88 |
| Total | 176 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 20 | 14 |
| Overall Study | Administrative problems | 12 | 13 |
| Overall Study | Adverse Event | 8 | 8 |
| Overall Study | Condition no longer requires study drug | 7 | 4 |
| Overall Study | Death | 9 | 6 |
| Overall Study | Lack of Efficacy | 0 | 3 |
| Overall Study | Lost to Follow-up | 3 | 7 |
| Overall Study | Protocol Violation | 5 | 2 |
| Overall Study | Withdrawal by Subject | 11 | 15 |
Baseline characteristics
| Characteristic | 15 - Minute Infusion | 30 - Minute Infusion | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 49 Participants | 41 Participants | 90 Participants |
| Age, Categorical Between 18 and 65 years | 39 Participants | 47 Participants | 86 Participants |
| Age Continuous | 64.3 years STANDARD_DEVIATION 11.95 | 64.0 years STANDARD_DEVIATION 11.54 | 64.1 years STANDARD_DEVIATION 11.7 |
| Calculated creatinine clearance | 87.3 mL/min STANDARD_DEVIATION 32.6 | 89.3 mL/min STANDARD_DEVIATION 39.5 | 88.3 mL/min STANDARD_DEVIATION 36.1 |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black | 9 participants | 13 participants | 22 participants |
| Race/Ethnicity, Customized Caucasian | 70 participants | 69 participants | 139 participants |
| Race/Ethnicity, Customized Other | 8 participants | 5 participants | 13 participants |
| Region of Enrollment United States | 88 participants | 88 participants | 176 participants |
| Sex: Female, Male Female | 32 Participants | 39 Participants | 71 Participants |
| Sex: Female, Male Male | 56 Participants | 49 Participants | 105 Participants |
| Time since diagnosis | 12.5 months STANDARD_DEVIATION 24.3 | 9.7 months STANDARD_DEVIATION 14.1 | 11.1 months STANDARD_DEVIATION 19.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 74 / 85 | 76 / 84 |
| serious Total, serious adverse events | 30 / 85 | 35 / 84 |
Outcome results
Primary
The Number of Participants With a Significant Increase in Serum Creatinine at 12 Months
The primary renal safety endpoint was the number of participants with a clinically relevant increase in serum creatinine at 12 months. Serum creatinine was determined prior to each zoledronic acid infusion for all Participants and was considered to be significantly increased if there was an increase of 0.5 mg/dL or more or a doubling of the baseline serum creatinine value.
Time frame: Baseline and 12 Months
Population: Safety Population: enrolled patients who received at least one dose of study medication, exluding site 74.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 15 - Minute Infusion | The Number of Participants With a Significant Increase in Serum Creatinine at 12 Months | 17 Participants |
| 30 - Minute Infusion | The Number of Participants With a Significant Increase in Serum Creatinine at 12 Months | 13 Participants |
Primary
The Number of Participants With Disease Progression
Time frame: 24 Months
Population: Safety Population; enrolled patients who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 15 - Minute Infusion | The Number of Participants With Disease Progression | 28 Participants |
| 30 - Minute Infusion | The Number of Participants With Disease Progression | 20 Participants |
Secondary
The Number of Participants With a Significant Increase in Serum Creatinine at 24 Months
Serum Creatinine was considered to be significantly increased if there was an increase of 0.5 mg/dL or more or a doubling of the baseline serum creatinine value.
Time frame: Baseline and 24 Months
Population: Safety Population; enrolled patients who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 15 - Minute Infusion | The Number of Participants With a Significant Increase in Serum Creatinine at 24 Months | 24 Participants |
| 30 - Minute Infusion | The Number of Participants With a Significant Increase in Serum Creatinine at 24 Months | 23 Participants |
Secondary
Time to First Significant Increase in Serum Creatinine
Median time to event in participants who had a clinically relevant increase in serum creatinine.
Time frame: Up to 24 months
Population: Safety Population; enrolled patients who received at least one dose of study medication. The medians shown are only for patients who had a significant increase by 24 months.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| 15 - Minute Infusion | Time to First Significant Increase in Serum Creatinine | 21.6 weeks | Full Range 19.88 |
| 30 - Minute Infusion | Time to First Significant Increase in Serum Creatinine | 24.4 weeks | Full Range 31.48 |
Secondary
Zoledronic Acid Concentrations
Samples for drug concentration analysis were drawn at 10 and 15 minutes into the infusion for participants in the 15-minute infusion group and at 25 and 30 minutes into the infusion for patients in the 30-minute infusion group. The mean and median zoledronic acid concentrations were greater in the 15-minute group than in the 30-minute group at both sampling timepoints.
Time frame: 24 months
Population: The pharmacokinetic (PK) population was analyzed for zoledronic acid concentration. Participants were considered to be in the PK population if they had evaluable PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 15 - Minute Infusion | Zoledronic Acid Concentrations | Second Collection (15 minutes, 30 minutes) | 248.8 ng/mL | Standard Deviation 92 |
| 15 - Minute Infusion | Zoledronic Acid Concentrations | First Collection (10 minutes, 25 minutes) | 231.1 ng/mL | Standard Deviation 185.4 |
| 30 - Minute Infusion | Zoledronic Acid Concentrations | Second Collection (15 minutes, 30 minutes) | 172.0 ng/mL | Standard Deviation 48.3 |
| 30 - Minute Infusion | Zoledronic Acid Concentrations | First Collection (10 minutes, 25 minutes) | 186.3 ng/mL | Standard Deviation 54.4 |