Multiple Myeloma
Conditions
Keywords
hematologic malignancy
Brief summary
Investigators planned to accrue 176 participants, to compare the response rate, overall response rate and survival of patients with multiple myeloma (MM) when randomized to two regimens (thalidomide+Dexamethasone versus Vincristine+Adriamycin+Dexamethasone). Investigators also planned to test if treatment with zoledronate immediately prior to chemotherapy results in an enhanced response to treatment (i.e. increase in complete response rates).
Detailed description
Patients Randomized to receive VAD (vincristine, adriamycin, dexamethasone): All patients received four cycles of VAD repeated every 4 weeks. Chemotherapy was administered by continuous IV Infusion for 96 hours: vincristine at a dose of 0.4 mg/day and doxorubicin at a dose of 9 mg/m\^2/day. Patients were administered dexamethasone 40 mg by mouth (PO) on days 1 to 4, 9 to 12, and 17 to 20 of the initial two cycles. Dexamethasone was given only on days 1-4 of all subsequent cycles. Patients were randomized to receive zoledronic acid IV on either Day 1 or 15 of each cycle. This schedule continued monthly as long as the patient remained on study. The dose was calculated based on the patients' monthly creatinine clearance. Upon initiation of Zometa therapy, the following guidelines were applied: For patients with creatinine clearance \>60 mL/min, the recommended dose remained at 4mg. For patients with reduced creatinine clearance, dosing was calculated to achieve the same area under curve (AUC) as in patients with creatinine clearance of 75 mL/min. Creatinine clearance was calculated using the Cockcroft-Gault formula.
Interventions
DRUGzoledronic acid
Patients were randomized to receive zoledronic acid I.V. on either Day 1 or 15 of each cycle. This schedule continued monthly as long as the patient remained on study. The dose was calculated based on the patients' monthly creatinine clearance.
DRUGdexamethasone
As outlined in VAD Treatment arm and Thalidomide and Dexamethasone Treatment arm
DRUGthalidomide
As outlined in Thalidomide and Dexamethasone Treatment arm
DRUGvincristine
As outlined in VAD Treatment Arm
DRUGadriamycin
As outlined in VAD Treatment arm
Sponsors
Novartis
H. Lee Moffitt Cancer Center and Research Institute
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 must have newly diagnosed MM confirmed by the presence of bone marrow plasmacytosis with \> 10 percent plasma cells, sheets of plasma cells, or biopsy-proven plasmacytoma. Patients must have Durie-Salmon Stage IIA-B or IIIA-B. Patients with non-secretory myeloma are eligible. (These patients will not be included in the analysis of response rates, but will be assessed for toxicity and survival). * Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, 2, or 3 * ≥ 18 years of age. * Signed informed consent form * Expected survival of greater than 8 weeks * Capable of swallowing study medication tablets * Capable of following directions regarding taking study medication, or has a daily care provider who will be responsible for administering study medication. * Patients will be eligible for study even if they lack socioeconomic access to autologous transplantation. (These patients will be identified prior to randomization so as not to confound study results). * All patients (in the event that they are randomized to the thalidomide/dexamethasone arm) must agree to take part in the System for Education and Prescribing Safety (S.T.E.P.S.)™. They must sign a separate informed consent for this program.
Exclusion criteria
* Elevated direct bilirubin \> 2 mg/dl * Serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) \> 2 times the upper limit of normal (ULN) * Absolute neutrophil count (ANC) \<1000/mL, unless felt to be secondary to myeloma * Ongoing radiation therapy, or radiation therapy within 3 weeks prior to first treatment, unless the acute side effects associated with such therapy are resolved. * Prior treatment for multiple myeloma * Prior bisphosphonate use is allowed but they must be discontinued before starting treatment. * Concurrent uncontrolled serious infection * Patients with peripheral (sensory) neuropathy, grade 3 or higher * Life-threatening illness (unrelated to tumor) * History of any other ACTIVE and INVASIVE cancer other than the present condition (except non-melanoma skin cancer), unless in complete remission and off of all therapy for that disease for a minimum of 3 years. * Women of childbearing potential (unless utilizing birth control) or who are pregnant or nursing will be excluded from this study. * Patients with comorbid conditions that would contraindicate the use of vincristine, doxorubicin, dexamethasone, thalidomide, or zoledronate. * Plasma Cell Leukemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rates of VAD vs. Thalidomide/Dexamethasone | End of Cycle 4 - 4 Months per Participant | Blade (15) criteria for remission in multiple myeloma was used to assess response. Complete Response (CR)includes: Disappearance of the original monoclonal protein from the blood and urine on at least two determinations for a minimum of 6 weeks by immunofixation studies. Partial Response (PR) includes: At least a 50% reduction in the level of serum monoclonal protein for at least two determinations 6 weeks apart. Minimal Response (MR)includes: At least a 25% to 49% reduction in the level of serum monoclonal protein for at least 2 determinations 2 weeks apart. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events, by Group | 4 Years, 7 Months | Number of participants with toxicities of Thalidomide/Dexamethasone vs. VAD as induction regimens in newly diagnosed multiple myeloma (MM). |
| Number of Participants With Progression Free Survival (PFS), by Treatment Arm | 4 Months | Number of participants with PFS for thalidomide/Dexamethasone vs. VAD with respect to progression free survival in newly diagnosed MM. Progressive Disease (PD): (for patients not in CR) Requires one or more of the following; \> 25% increase in the level of serum monoclonal paraprotein, which must also be an absolute increase of at least 5 g/L and confirmed on a repeat investigation. \> 25% increase in 24-hour urinary light chain excretion, which must also be an absolute increase of at least 200mg and confirmed on a repeat investigation. \>25% increase in plasma cells in a bone marrow aspirate, which also must be an absolute increase of at least 10%. Definite increase in the size of existing lytic lesions or plasmacytomas. Development of new bone lesions or plasmacytomas (except compression fractures). Development of hypercalcemia (corrected calcium \> 11.5 mg/dL not attributable to other causes). |
| Overall Survival (OS), by Treatment Arm | Up to 10 Years | Median OS for thalidomide/Dexamethasone participants vs. VAD participants. Months from On Study to Expired/Last Date Known Alive. Investigators had planned to accrue 176 participants to calculate median overall survival. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Recruitment began at Moffitt Cancer Center in June of 2003 and ended prematurely in December of 2007.
Pre-assignment details
90 participants were consented. 83 were eligible and randomized to treatment arms. 2 became ineligible after randomization and prior to treatment. 8 withdrew prior to treatment. 73 began treatment.
Participants by arm
| Arm | Count |
|---|---|
| Active Comparator: VAD Treatment VAD (vincristine, adriamycin, dexamethasone). Vincristine and adriamycin was administered by continuous infusion via a venous catheter for 96 hours every 28 days. Each 28 days is considered one cycle of therapy. Patients were to receive 4 to 6 cycles of therapy. Dexamethasone was taken in pill form. During the first 2 cycles it was taken on days 1-4, 9-12, 17-20. For all other cycles dexamethasone was taken only on days 1-4. Patients were randomized to receive zoledronic acid IV on either Day 1 or 15 of each cycle. | 36 |
| Active Comparator: Thalidomide and Dexamethasone Treatment Thalidomide was taken orally once every day in the evening for four to six months. The dexamethasone was taken in a pill form. During the first 2 cycles it was taken on days 1-4, 9-12, 17-20. For all other cycles dexamethasone was taken only on days 1-4. | 37 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 6 |
| Overall Study | Alternate therapy | 0 | 1 |
| Overall Study | Disease Progression | 3 | 5 |
| Overall Study | Other complications | 3 | 1 |
| Overall Study | Other disease | 0 | 1 |
Baseline characteristics
| Characteristic | Active Comparator: VAD Treatment | Active Comparator: Thalidomide and Dexamethasone Treatment | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 11 Participants | 10 Participants | 21 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 27 Participants | 52 Participants |
| Region of Enrollment United States | 36 participants | 37 participants | 73 participants |
| Sex: Female, Male Female | 15 Participants | 14 Participants | 29 Participants |
| Sex: Female, Male Male | 21 Participants | 23 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 36 / 36 | 37 / 37 |
| serious Total, serious adverse events | 0 / 36 | 1 / 37 |
Outcome results
Primary
Response Rates of VAD vs. Thalidomide/Dexamethasone
Blade (15) criteria for remission in multiple myeloma was used to assess response. Complete Response (CR)includes: Disappearance of the original monoclonal protein from the blood and urine on at least two determinations for a minimum of 6 weeks by immunofixation studies. Partial Response (PR) includes: At least a 50% reduction in the level of serum monoclonal protein for at least two determinations 6 weeks apart. Minimal Response (MR)includes: At least a 25% to 49% reduction in the level of serum monoclonal protein for at least 2 determinations 2 weeks apart.
Time frame: End of Cycle 4 - 4 Months per Participant
Population: All evaluable participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Active Comparator: VAD Treatment | Response Rates of VAD vs. Thalidomide/Dexamethasone | Complete Response | 1 participants |
| Active Comparator: VAD Treatment | Response Rates of VAD vs. Thalidomide/Dexamethasone | Partial Response | 9 participants |
| Active Comparator: VAD Treatment | Response Rates of VAD vs. Thalidomide/Dexamethasone | Minimal Response | 6 participants |
| Active Comparator: Thalidomide and Dexamethasone Treatment | Response Rates of VAD vs. Thalidomide/Dexamethasone | Complete Response | 1 participants |
| Active Comparator: Thalidomide and Dexamethasone Treatment | Response Rates of VAD vs. Thalidomide/Dexamethasone | Partial Response | 16 participants |
| Active Comparator: Thalidomide and Dexamethasone Treatment | Response Rates of VAD vs. Thalidomide/Dexamethasone | Minimal Response | 2 participants |
Secondary
Number of Participants With Adverse Events, by Group
Number of participants with toxicities of Thalidomide/Dexamethasone vs. VAD as induction regimens in newly diagnosed multiple myeloma (MM).
Time frame: 4 Years, 7 Months
Population: All evaluable participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Active Comparator: VAD Treatment | Number of Participants With Adverse Events, by Group | Serious Adverse Events (SAEs) | 0 participants |
| Active Comparator: VAD Treatment | Number of Participants With Adverse Events, by Group | Adverse Events (AEs) | 36 participants |
| Active Comparator: Thalidomide and Dexamethasone Treatment | Number of Participants With Adverse Events, by Group | Serious Adverse Events (SAEs) | 1 participants |
| Active Comparator: Thalidomide and Dexamethasone Treatment | Number of Participants With Adverse Events, by Group | Adverse Events (AEs) | 37 participants |
Secondary
Number of Participants With Progression Free Survival (PFS), by Treatment Arm
Number of participants with PFS for thalidomide/Dexamethasone vs. VAD with respect to progression free survival in newly diagnosed MM. Progressive Disease (PD): (for patients not in CR) Requires one or more of the following; \> 25% increase in the level of serum monoclonal paraprotein, which must also be an absolute increase of at least 5 g/L and confirmed on a repeat investigation. \> 25% increase in 24-hour urinary light chain excretion, which must also be an absolute increase of at least 200mg and confirmed on a repeat investigation. \>25% increase in plasma cells in a bone marrow aspirate, which also must be an absolute increase of at least 10%. Definite increase in the size of existing lytic lesions or plasmacytomas. Development of new bone lesions or plasmacytomas (except compression fractures). Development of hypercalcemia (corrected calcium \> 11.5 mg/dL not attributable to other causes).
Time frame: 4 Months
Population: All evaluable participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active Comparator: VAD Treatment | Number of Participants With Progression Free Survival (PFS), by Treatment Arm | 2 participants |
| Active Comparator: Thalidomide and Dexamethasone Treatment | Number of Participants With Progression Free Survival (PFS), by Treatment Arm | 1 participants |
Secondary
Overall Survival (OS), by Treatment Arm
Median OS for thalidomide/Dexamethasone participants vs. VAD participants. Months from On Study to Expired/Last Date Known Alive. Investigators had planned to accrue 176 participants to calculate median overall survival.
Time frame: Up to 10 Years
Population: All participants with evaluable follow-up data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Comparator: VAD Treatment | Overall Survival (OS), by Treatment Arm | 57 months |
| Active Comparator: Thalidomide and Dexamethasone Treatment | Overall Survival (OS), by Treatment Arm | 56.5 months |