Multiple Myeloma
Conditions
Brief summary
This multicenter, open-label trial will randomize participants with multiple myeloma to a regimen of ibandronate or zoledronate in order to compare the incidence of nephrotoxicity, measured as creatinine clearance (CrCl) reduction greater than (\>) 30 percent (%) or an absolute value of 30 milliliters per minute (mL/min) or lower.
Interventions
DRUGIbandronate
Ibandronate will be administered via 15-minute intravenous (IV) infusion as 6 milligrams (mg) every 4 weeks for 92 weeks.
DRUGZoledronate
Zoledronate will be administered via 15-minute IV infusion as 4 mg every 4 weeks for 92 weeks.
Sponsors
Roche Pharma AG
Hoffmann-La Roche
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
* Confirmed multiple myeloma, Stage II-III as per Salmon and Durie (1975) * Indication for biphosphonate therapy
Exclusion criteria
* Previous therapy with ibandronate or zoledronate within the past 12 months * Renal insufficiency with serum creatinine \>3.0 mg/dL or \>265 micromoles per liter (µmol/L) or CrCl \<30 mL/min * Hypersensitivity to ibandronate, zoledronate, or other biphosphonates * Presence of secondary malignomas, apart from basaliomas and cervical carcinoma in situ * Severe accompanying illness with organ impairment * Osteonecrosis of the jaw at the start of the study * Life expectancy ≤12 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Deterioration in Renal Function According to Reduction in Creatinine Clearance (CrCl) From Baseline to Week 44 | Baseline, Week 44 | CrCl was calculated from blood samples using the Cockcroft-Gault formula. Relevant deterioration in renal function was defined as CrCl reduction of 30 percent (%) from Baseline or an absolute value less than or equal to (≤) 30 milliliters per minute (mL/min) at Week 44. The last available value on/before Week 44 was used in the calculation. The percentage of participants with deterioration in renal function at Week 44 was reported. |
| Percentage of Participants With Deterioration in Renal Function According to Reduction in CrCl From Baseline to Week 92 | Baseline, Week 92 | CrCl was calculated from blood samples using the Cockcroft-Gault formula. Relevant deterioration in renal function was defined as CrCl reduction of 30% from Baseline or an absolute value ≤30 mL/min at Week 92. The last available value on/before Week 92 was used in the calculation. The percentage of participants with deterioration in renal function at Week 92 was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Skeletal-Related Events (SREs) | From Baseline to end of study (up to Week 96) | SREs were defined according to the Bondronat Summary of Product Characteristics (SmPC) to include radiotherapy to bone for treatment of fractures/impending fractures, surgery to bone for treatment of fractures, vertebral fractures, and non-vertebral fractures. The percentage of participants with at least 1 SRE during the study was reported. |
| Time to First SRE | From Baseline to end of study (up to Week 96) | SREs were defined according to the Bondronat SmPC to include radiotherapy to bone for treatment of fractures/impending fractures, surgery to bone for treatment of fractures, vertebral fractures, and non-vertebral fractures. Time to first SRE was defined as the time from first dose of study drug to the time of SRE during the study. The median time to first SRE was estimated by Kaplan-Meier analysis and expressed in days. |
| Number of SREs for Each Participant | From Baseline to end of study (up to Week 96) | SREs were defined according to the Bondronat SmPC to include radiotherapy to bone for treatment of fractures/impending fractures, surgery to bone for treatment of fractures, vertebral fractures, and non-vertebral fractures. The number of SREs was averaged across all participants, including those participants who did not experience SREs during the study. |
| Percentage of Participants With Osteonecrosis of Jaw | From Baseline to end of study (up to Week 96) | The percentage of participants with at least 1 event of osteonecrosis of jaw during the study was reported. |
| Number of Events of Osteonecrosis of Jaw for Each Participant | From Baseline to end of study (up to Week 96) | The number of events of osteonecrosis of jaw was averaged across all participants, including those participants who did not experience the event during the study. |
| Percentage of Participants With Zoledronate Dose Reduction | From Baseline to end of study (up to Week 96) | The percentage of participants with at least 1 zoledronate dose reduction during the study was reported. |
| Percent Change From Baseline in Alpha (A) 1-Microglobulin | Baseline and Weeks 44, 92 | The percent change in A1-microglobulin was calculated as \[Week 44 or 92 A1-microglobulin minus Baseline A1-microglobulin\] divided by Baseline A1-microglobulin, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation. |
| Percent Change From Baseline in Gamma-Glutamyltransferase (GGT) | Baseline and Weeks 44, 92 | The percent change in GGT was calculated as \[Week 44 or 92 GGT minus Baseline GGT\] divided by Baseline GGT, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation. |
| Percentage of Participants With Elevation of Serum Creatinine (SCr) From Baseline | Baseline and Weeks 44, 92 | Elevation in SCr was defined as an increase greater than (\>) 0.5 milligrams per deciliter (mg/dL) for participants with Baseline SCr less than (\<) 1.4 mg/dL, or an increase \>1.0 mg/dL for participants with Baseline SCr greater than or equal to (≥) 1.4 mg/dL. For the Week 44 analysis, the last available value on/before Week 44 was used. For the Week 92 analysis, the last available value on/before Week 92 was used. The percentage of participants with elevation of SCr at Weeks 44 and 92 was reported. |
| Percent Change From Baseline in CrCl | Baseline and Weeks 44, 92 | CrCl was calculated from blood samples using the Cockcroft-Gault formula, and was also measured by urinalysis. The percent change in CrCl was calculated as \[Week 44 or 92 CrCl minus Baseline CrCl\] divided by Baseline CrCl, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation. |
| Percent Change From Baseline in N-Acetyl-Beta-D-Glucosaminidase (B-NAG) | Baseline and Weeks 44, 92 | The percent change in B-NAG was calculated as \[Week 44 or 92 B-NAG minus Baseline B-NAG\] divided by Baseline B-NAG, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation. |
| Number of Zoledronate Dose Reductions for Each Participant | From Baseline to end of study (up to Week 96) | The number of zoledronate dose reductions was averaged across all participants, including those participants who did not have any dose reductions during the study. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ibandronate Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment. | 41 |
| Zoledronate Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment. | 40 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative Reasons | 1 | 3 |
| Overall Study | Death | 4 | 2 |
| Overall Study | Elevated Serum Creatinine | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other | 6 | 2 |
| Overall Study | Protocol Violation | 5 | 6 |
| Overall Study | Renal Insufficiency | 4 | 6 |
| Overall Study | Undesired Event | 3 | 4 |
| Overall Study | Violation of Eligibility Criteria | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Ibandronate | Zoledronate | Total |
|---|---|---|---|
| Age, Continuous | 65.3 years STANDARD_DEVIATION 9.4 | 69.1 years STANDARD_DEVIATION 9.1 | 67.2 years STANDARD_DEVIATION 9.4 |
| Sex: Female, Male Female | 15 Participants | 14 Participants | 29 Participants |
| Sex: Female, Male Male | 26 Participants | 26 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 43 / 46 | 34 / 43 |
| serious Total, serious adverse events | 27 / 46 | 18 / 43 |
Outcome results
Primary
Percentage of Participants With Deterioration in Renal Function According to Reduction in CrCl From Baseline to Week 92
CrCl was calculated from blood samples using the Cockcroft-Gault formula. Relevant deterioration in renal function was defined as CrCl reduction of 30% from Baseline or an absolute value ≤30 mL/min at Week 92. The last available value on/before Week 92 was used in the calculation. The percentage of participants with deterioration in renal function at Week 92 was reported.
Time frame: Baseline, Week 92
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibandronate | Percentage of Participants With Deterioration in Renal Function According to Reduction in CrCl From Baseline to Week 92 | 14.6 percentage of participants |
| Zoledronate | Percentage of Participants With Deterioration in Renal Function According to Reduction in CrCl From Baseline to Week 92 | 12.5 percentage of participants |
Primary
Percentage of Participants With Deterioration in Renal Function According to Reduction in Creatinine Clearance (CrCl) From Baseline to Week 44
CrCl was calculated from blood samples using the Cockcroft-Gault formula. Relevant deterioration in renal function was defined as CrCl reduction of 30 percent (%) from Baseline or an absolute value less than or equal to (≤) 30 milliliters per minute (mL/min) at Week 44. The last available value on/before Week 44 was used in the calculation. The percentage of participants with deterioration in renal function at Week 44 was reported.
Time frame: Baseline, Week 44
Population: Intent-to-Treat (ITT) Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibandronate | Percentage of Participants With Deterioration in Renal Function According to Reduction in Creatinine Clearance (CrCl) From Baseline to Week 44 | 9.8 percentage of participants |
| Zoledronate | Percentage of Participants With Deterioration in Renal Function According to Reduction in Creatinine Clearance (CrCl) From Baseline to Week 44 | 12.5 percentage of participants |
Secondary
Number of Events of Osteonecrosis of Jaw for Each Participant
The number of events of osteonecrosis of jaw was averaged across all participants, including those participants who did not experience the event during the study.
Time frame: From Baseline to end of study (up to Week 96)
Population: ITT Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibandronate | Number of Events of Osteonecrosis of Jaw for Each Participant | 0.0 events of osteonecrosis of jaw | Standard Deviation 0 |
| Zoledronate | Number of Events of Osteonecrosis of Jaw for Each Participant | 0.0 events of osteonecrosis of jaw | Standard Deviation 0 |
Secondary
Number of SREs for Each Participant
SREs were defined according to the Bondronat SmPC to include radiotherapy to bone for treatment of fractures/impending fractures, surgery to bone for treatment of fractures, vertebral fractures, and non-vertebral fractures. The number of SREs was averaged across all participants, including those participants who did not experience SREs during the study.
Time frame: From Baseline to end of study (up to Week 96)
Population: ITT Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibandronate | Number of SREs for Each Participant | 0.3 SREs | Standard Deviation 0.6 |
| Zoledronate | Number of SREs for Each Participant | 0.5 SREs | Standard Deviation 1.1 |
Secondary
Number of Zoledronate Dose Reductions for Each Participant
The number of zoledronate dose reductions was averaged across all participants, including those participants who did not have any dose reductions during the study.
Time frame: From Baseline to end of study (up to Week 96)
Population: ITT Population; only the Zoledronate arm was included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibandronate | Number of Zoledronate Dose Reductions for Each Participant | 0.8 dose reductions | Standard Deviation 1.4 |
Secondary
Percentage of Participants With Elevation of Serum Creatinine (SCr) From Baseline
Elevation in SCr was defined as an increase greater than (\>) 0.5 milligrams per deciliter (mg/dL) for participants with Baseline SCr less than (\<) 1.4 mg/dL, or an increase \>1.0 mg/dL for participants with Baseline SCr greater than or equal to (≥) 1.4 mg/dL. For the Week 44 analysis, the last available value on/before Week 44 was used. For the Week 92 analysis, the last available value on/before Week 92 was used. The percentage of participants with elevation of SCr at Weeks 44 and 92 was reported.
Time frame: Baseline and Weeks 44, 92
Population: ITT Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ibandronate | Percentage of Participants With Elevation of Serum Creatinine (SCr) From Baseline | Week 44 | 2.4 percentage of participants |
| Ibandronate | Percentage of Participants With Elevation of Serum Creatinine (SCr) From Baseline | Week 92 | 7.3 percentage of participants |
| Zoledronate | Percentage of Participants With Elevation of Serum Creatinine (SCr) From Baseline | Week 44 | 2.5 percentage of participants |
| Zoledronate | Percentage of Participants With Elevation of Serum Creatinine (SCr) From Baseline | Week 92 | 2.5 percentage of participants |
Secondary
Percentage of Participants With Osteonecrosis of Jaw
The percentage of participants with at least 1 event of osteonecrosis of jaw during the study was reported.
Time frame: From Baseline to end of study (up to Week 96)
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibandronate | Percentage of Participants With Osteonecrosis of Jaw | 0.0 percentage of participants |
| Zoledronate | Percentage of Participants With Osteonecrosis of Jaw | 0.0 percentage of participants |
Secondary
Percentage of Participants With Skeletal-Related Events (SREs)
SREs were defined according to the Bondronat Summary of Product Characteristics (SmPC) to include radiotherapy to bone for treatment of fractures/impending fractures, surgery to bone for treatment of fractures, vertebral fractures, and non-vertebral fractures. The percentage of participants with at least 1 SRE during the study was reported.
Time frame: From Baseline to end of study (up to Week 96)
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibandronate | Percentage of Participants With Skeletal-Related Events (SREs) | 22.0 percentage of participants |
| Zoledronate | Percentage of Participants With Skeletal-Related Events (SREs) | 30.0 percentage of participants |
Secondary
Percentage of Participants With Zoledronate Dose Reduction
The percentage of participants with at least 1 zoledronate dose reduction during the study was reported.
Time frame: From Baseline to end of study (up to Week 96)
Population: ITT Population; only the Zoledronate arm was included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibandronate | Percentage of Participants With Zoledronate Dose Reduction | 30.0 percentage of participants |
Secondary
Percent Change From Baseline in Alpha (A) 1-Microglobulin
The percent change in A1-microglobulin was calculated as \[Week 44 or 92 A1-microglobulin minus Baseline A1-microglobulin\] divided by Baseline A1-microglobulin, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation.
Time frame: Baseline and Weeks 44, 92
Population: ITT Population. The Number of Participants Analyzed reflects the total number of participants who provided evaluable data for the endpoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ibandronate | Percent Change From Baseline in Alpha (A) 1-Microglobulin | Week 44 | 0.0 percent change |
| Ibandronate | Percent Change From Baseline in Alpha (A) 1-Microglobulin | Week 92 | 0.0 percent change |
| Zoledronate | Percent Change From Baseline in Alpha (A) 1-Microglobulin | Week 44 | 0.0 percent change |
| Zoledronate | Percent Change From Baseline in Alpha (A) 1-Microglobulin | Week 92 | 0.0 percent change |
Secondary
Percent Change From Baseline in CrCl
CrCl was calculated from blood samples using the Cockcroft-Gault formula, and was also measured by urinalysis. The percent change in CrCl was calculated as \[Week 44 or 92 CrCl minus Baseline CrCl\] divided by Baseline CrCl, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation.
Time frame: Baseline and Weeks 44, 92
Population: ITT Population. The Number of Participants Analyzed reflects the total number of participants who provided evaluable data for the endpoint. The number of participants who provided data within the specified timeframe for each analysis (n) is shown in the table.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ibandronate | Percent Change From Baseline in CrCl | Week 44, Calculated/Blood (n=41,40) | -0.5 percent change | Standard Deviation 28.5 |
| Ibandronate | Percent Change From Baseline in CrCl | Week 44, Measured/Urinalysis (n=37,37) | 6.9 percent change | Standard Deviation 53 |
| Ibandronate | Percent Change From Baseline in CrCl | Week 92, Calculated/Blood (n=41,40) | -0.7 percent change | Standard Deviation 31.9 |
| Ibandronate | Percent Change From Baseline in CrCl | Week 92, Measured/Urinalysis (n=37,37) | 3.1 percent change | Standard Deviation 45.6 |
| Zoledronate | Percent Change From Baseline in CrCl | Week 92, Measured/Urinalysis (n=37,37) | 2.0 percent change | Standard Deviation 39.1 |
| Zoledronate | Percent Change From Baseline in CrCl | Week 44, Calculated/Blood (n=41,40) | -0.4 percent change | Standard Deviation 21.7 |
| Zoledronate | Percent Change From Baseline in CrCl | Week 92, Calculated/Blood (n=41,40) | -4.3 percent change | Standard Deviation 20.3 |
| Zoledronate | Percent Change From Baseline in CrCl | Week 44, Measured/Urinalysis (n=37,37) | 3.9 percent change | Standard Deviation 37.3 |
Secondary
Percent Change From Baseline in Gamma-Glutamyltransferase (GGT)
The percent change in GGT was calculated as \[Week 44 or 92 GGT minus Baseline GGT\] divided by Baseline GGT, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation.
Time frame: Baseline and Weeks 44, 92
Population: ITT Population. The Number of Participants Analyzed reflects the total number of participants who provided evaluable data for the endpoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ibandronate | Percent Change From Baseline in Gamma-Glutamyltransferase (GGT) | Week 44 | -6.0 percent change |
| Ibandronate | Percent Change From Baseline in Gamma-Glutamyltransferase (GGT) | Week 92 | -2.5 percent change |
| Zoledronate | Percent Change From Baseline in Gamma-Glutamyltransferase (GGT) | Week 44 | 3.8 percent change |
| Zoledronate | Percent Change From Baseline in Gamma-Glutamyltransferase (GGT) | Week 92 | 3.8 percent change |
Secondary
Percent Change From Baseline in N-Acetyl-Beta-D-Glucosaminidase (B-NAG)
The percent change in B-NAG was calculated as \[Week 44 or 92 B-NAG minus Baseline B-NAG\] divided by Baseline B-NAG, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation.
Time frame: Baseline and Weeks 44, 92
Population: ITT Population. The Number of Participants Analyzed reflects the total number of participants who provided evaluable data for the endpoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ibandronate | Percent Change From Baseline in N-Acetyl-Beta-D-Glucosaminidase (B-NAG) | Week 44 | -15.7 percent change |
| Ibandronate | Percent Change From Baseline in N-Acetyl-Beta-D-Glucosaminidase (B-NAG) | Week 92 | -17.2 percent change |
| Zoledronate | Percent Change From Baseline in N-Acetyl-Beta-D-Glucosaminidase (B-NAG) | Week 44 | 10.6 percent change |
| Zoledronate | Percent Change From Baseline in N-Acetyl-Beta-D-Glucosaminidase (B-NAG) | Week 92 | 9.3 percent change |
Secondary
Time to First SRE
SREs were defined according to the Bondronat SmPC to include radiotherapy to bone for treatment of fractures/impending fractures, surgery to bone for treatment of fractures, vertebral fractures, and non-vertebral fractures. Time to first SRE was defined as the time from first dose of study drug to the time of SRE during the study. The median time to first SRE was estimated by Kaplan-Meier analysis and expressed in days.
Time frame: From Baseline to end of study (up to Week 96)
Population: ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibandronate | Time to First SRE | 393.0 days |
| Zoledronate | Time to First SRE | 244.5 days |