Multiple Myeloma Stage I
Conditions
Keywords
Multiple Myeloma, Stage I, Zoledronic acid, Progression
Brief summary
Multiple myeloma is a disease of B-lymphocytes producing malignant plasma cells. Malignant plasma cells induce osteolytic lesions, which is characteristic for progression of multiple myeloma. It is the aim of this study to investigate whether zoledronic acid has an influence on the progression of multiple myeloma.
Interventions
DRUGZoledronic acid
Zoledronic acid administered via normal saline intravenous infusion (over 15 minutes) every 4 weeks. Dosage was according to calculated creatinine clearance: patients with baseline creatinine clearance \> 60 ml/min received 4 mg; for patients with mild to moderate renal impairment, doses were calculated to achieve the same AUC as that achieved in patients with creatinine clearance of 75 ml/min, assuming target AUC of 0.66 (mg\*hr/l).
DIETARY_SUPPLEMENTCalcium / Vitamin D
Patients on zoledronic acid received 500 mg calcium and 400-500 IU vitamin D combination tablet daily.
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
* Evidence of myeloma according to the criteria of the British Columbia Cancer Agency (for the diagnosis, 2 of the 3 criteria must be met): * Evidence of paraprotein in the serum or urine * Bone marrow infiltration with plasma cells which represent more than 10% of the nucleated cells * Radiologically, at least one osteolytic lesion * Asymptomatic patients with Stage I (Durie and Salmon) multiple myeloma
Exclusion criteria
* Patients with more than one osteolytic lesion on conventional skeletal radiography * Previous treatment with bisphosphonates * bilirubin \> 2.5 mg/dl * Abnormal renal function as evidenced by: A calculated creatinine clearance \< 30 ml/minute. Creatinine clearance (CrCl) is calculated using the Cockcroft-Gault formula: * CrCl= \[140-age(years)\] x weight(kg)/\[72xserumcreatinine(mg/dL)\] X {0.85 for female patients} * Patients with other malignant diseases or severe concomitant diseases * Potentially fertile patients who are not using a reliable and appropriate method of contraception * Pregnancy or breast-feeding * Participation in another clinical study with an investigational drug within 12 weeks of study entry * Current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures. * Recent (within 6 weeks) or planned dental or jaw surgery (e.g.. extraction, implants) Other protocol-defined inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Days of Progression Free Survival | 48 months | Progression-free survival was defined as time from date of randomization to death from any cause or one of the following events: * progression to stage II or III according to Salmon & Durie classification * skeletal related events (pathologic fracture, initiation of radiotherapy or surgery on bone, spinal cord compression or hypercalcemia) * unequivocal progression of osteolytic lesions (at least a 20% increase in the largest diameter of one existing osteolytic lesion which is measured in at least one dimension as 20 mm with conventional techniques), determined radiologically. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Progression by Individual Criteria | 48 months | Number of patients with progression by individual criteria consisting of Progression of disease overall, Skeletal-related events (including pathological fracture, initiation of radiotherapy or surgery on bone, spinal cord compression or Hypercalcemia), Progression to stage II or III according to Salmon & Durie classification, and unequivocal progression of osteolytic lesion. Patients are counted separately for every type of progression, but only once for Overall Progression. |
| The Number of Participants With the Development of Skeletal Complications | 48 months | * Pathologic fracture: bone fractures that occur spontaneously or from trivial trauma. New vertebral compression fracture defined as a decrease in vertebral height of 25% from baseline * Spinal cord compression: the impingement of tumor on the spinal cord confirmed by radiography * Bone Radiotherapy: Bone irradiation to palliate painful lesions, treat or prevent pathologic fractures or spinal cord compression * Surgery on bone: surgical procedures performed to set, stabilize or prevent pathologic fractures or areas of spinal cord compression * Hypercalcemia: Corrected serum calcium ≥ 12.0 mg/dl |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid (ZOL446) Participants received intravenous infusion of Zoledronic acid every 4 weeks for 48 weeks, and calcium and Vitamin D daily. | 72 |
| Control No Treatment with study medication. | 71 |
| Total | 143 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 10 | 11 |
| Overall Study | Adverse Event | 10 | 6 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 9 |
Baseline characteristics
| Characteristic | Zoledronic Acid (ZOL446) | Control | Total |
|---|---|---|---|
| Age Continuous | 58.8 years STANDARD_DEVIATION 12.02 | 62.1 years STANDARD_DEVIATION 10.79 | 60.4 years STANDARD_DEVIATION 11.5 |
| Race/Ethnicity, Customized Caucasian | 69 participants | 70 participants | 139 participants |
| Race/Ethnicity, Customized Oriental | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Other | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Germany | 72 participants | 71 participants | 143 participants |
| Sex: Female, Male Female | 42 Participants | 31 Participants | 73 Participants |
| Sex: Female, Male Male | 30 Participants | 40 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 61 / 72 | 51 / 71 |
| serious Total, serious adverse events | 28 / 72 | 12 / 71 |
Outcome results
Primary
Days of Progression Free Survival
Progression-free survival was defined as time from date of randomization to death from any cause or one of the following events: * progression to stage II or III according to Salmon & Durie classification * skeletal related events (pathologic fracture, initiation of radiotherapy or surgery on bone, spinal cord compression or hypercalcemia) * unequivocal progression of osteolytic lesions (at least a 20% increase in the largest diameter of one existing osteolytic lesion which is measured in at least one dimension as 20 mm with conventional techniques), determined radiologically.
Time frame: 48 months
Population: Intent to Treat Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid (ZOL446) | Days of Progression Free Survival | 1078.1 Days | Standard Error 59.53 |
| Control | Days of Progression Free Survival | 992.80 Days | Standard Error 61.83 |
Secondary
Number of Patients With Progression by Individual Criteria
Number of patients with progression by individual criteria consisting of Progression of disease overall, Skeletal-related events (including pathological fracture, initiation of radiotherapy or surgery on bone, spinal cord compression or Hypercalcemia), Progression to stage II or III according to Salmon & Durie classification, and unequivocal progression of osteolytic lesion. Patients are counted separately for every type of progression, but only once for Overall Progression.
Time frame: 48 months
Population: Intent to Treat Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zoledronic Acid (ZOL446) | Number of Patients With Progression by Individual Criteria | Progression of disease overall | 19 Participants |
| Zoledronic Acid (ZOL446) | Number of Patients With Progression by Individual Criteria | Skeletal-related events | 0 Participants |
| Zoledronic Acid (ZOL446) | Number of Patients With Progression by Individual Criteria | Progression to stage II or III | 17 Participants |
| Zoledronic Acid (ZOL446) | Number of Patients With Progression by Individual Criteria | Unequivocal progression of osteolytic lesion | 3 Participants |
| Control | Number of Patients With Progression by Individual Criteria | Unequivocal progression of osteolytic lesion | 10 Participants |
| Control | Number of Patients With Progression by Individual Criteria | Progression of disease overall | 26 Participants |
| Control | Number of Patients With Progression by Individual Criteria | Progression to stage II or III | 24 Participants |
| Control | Number of Patients With Progression by Individual Criteria | Skeletal-related events | 4 Participants |
Secondary
The Number of Participants With the Development of Skeletal Complications
* Pathologic fracture: bone fractures that occur spontaneously or from trivial trauma. New vertebral compression fracture defined as a decrease in vertebral height of 25% from baseline * Spinal cord compression: the impingement of tumor on the spinal cord confirmed by radiography * Bone Radiotherapy: Bone irradiation to palliate painful lesions, treat or prevent pathologic fractures or spinal cord compression * Surgery on bone: surgical procedures performed to set, stabilize or prevent pathologic fractures or areas of spinal cord compression * Hypercalcemia: Corrected serum calcium ≥ 12.0 mg/dl
Time frame: 48 months
Population: Intent to treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zoledronic Acid (ZOL446) | The Number of Participants With the Development of Skeletal Complications | Pathological fracture | 0 Participants |
| Zoledronic Acid (ZOL446) | The Number of Participants With the Development of Skeletal Complications | Spinal cord compression | 0 Participants |
| Zoledronic Acid (ZOL446) | The Number of Participants With the Development of Skeletal Complications | Initiation of radiotherapy or surgery on bone | 0 Participants |
| Zoledronic Acid (ZOL446) | The Number of Participants With the Development of Skeletal Complications | Hypercalcemia | 0 Participants |
| Zoledronic Acid (ZOL446) | The Number of Participants With the Development of Skeletal Complications | Skeletal events overall | 0 Participants |
| Control | The Number of Participants With the Development of Skeletal Complications | Hypercalcemia | 0 Participants |
| Control | The Number of Participants With the Development of Skeletal Complications | Skeletal events overall | 4 Participants |
| Control | The Number of Participants With the Development of Skeletal Complications | Pathological fracture | 1 Participants |
| Control | The Number of Participants With the Development of Skeletal Complications | Initiation of radiotherapy or surgery on bone | 1 Participants |
| Control | The Number of Participants With the Development of Skeletal Complications | Spinal cord compression | 2 Participants |