Multiple Myeloma
Conditions
Keywords
multiple myeloma, bortezomib, hematology, bone marrow cancer, immunoglobulin, refractory, progression, dexamethasone, lenalidomide, cyclophosphamide
Brief summary
The purpose of this study is to test the effectiveness and safety of adding cyclophosphamide or lenalidomide to the VD combination in the treatment of patients with multiple myeloma that have achieved a stable response after 4 initial cycles of treatment with VD. Multiple myeloma is the second most common cancer of the blood. Bortezomib disrupts the life cycle of the cell, affecting numerous biologic pathways, including those related to growth and survival of cancer cells.
Detailed description
It has been shown that quality of response corresponds with clinical benefit. Stable disease is not regarded as a satisfactory result of therapy for relapsed and refractory multiple myeloma. However, there is no consensus if, when and how treatment should be continued or changed in the case of stable disease. There are different strategies of achieving an optimal quality of response in relapsed and refractory multiple myeloma. One is to treat for a longer duration with one regimen. The alternative path can be a sequential approach adding another agent to the initial regimen depending on the outcome of therapy after a defined treatment period. These two principles will be evaluated in the present study. Both Cyclophosphamide and Lenalidomide have proven to be efficacious in multiple myeloma and combinations of both agents with bortezomib and Dexamethasone have been shown to be active and tolerable. In this study patients with relapsed/progressive or refractory multiple myeloma will start treatment with bortezomiib and Dexamethasone. Response will be evaluated after four cycles. Patients with complete, very good partial response or partial response will continue treatment as initiated. Patients with stable disease will either continue treatment with the bortezomib/Dexamethasone combination for another four cycles or will receive Cyclophosphamide or Lenalidomide as an additional third agent for another four cycles. Patients with multiple myeloma that are refractory to or have relapsed/progressed after primary treatment for multiple myeloma will be enrolled in the study. All patients will receive a combination of bortezomib plus dexamethasone for a total of four cycles. Based on the response to this treatment, further study treatment is customized. Patients with a complete, a very good partial or a partial response will continue to receive bortezomib and Dexamethasone for a maximum additional four cycles, to an overall maximum of eight cycles. Patients achieving stable disease, as defined by International Myeloma Working Group 2006 (IMWG 2006) response criteria, will undergo a central randomisation to continue treatment with VD or VD plus cyclophosphamide or VD plus lenalidomide. Patients with progressive disease will go off study treatment. After randomisation, patients will receive therapy for up to four additional treatment cycles, to an overall maximum of eight cycles. Each cycle will consist of three weeks treatment. There will be a long-term follow-up period with monthly visits until relapse or progressive disease. Thereafter follow-up for survival will be continued by at least a phone call every other month. This will be performed for all patients until the last patient was treated and followed up for 1 year. Safety will be assessed by the monitoring of adverse events, physical examination (including neurological/peripheral neurological examinations), pulmonary examinations, vital signs measurements, and clinical laboratory tests. Patients will be treated in a 3-week cycle, up to a maximum of 8 cycles bortezomib 1.3 mg/m2 will be administered on day 1, 4, 8 and 11 as i.v. bolus infusion. Dexamethasone 20 mg po will be administered on days 1, 2, 4, 5, 8, 9, 11, 12. Dexamethasone will be administered as 2 tables of 8 mg plus 1 tablet of 4 mg Cyclophosphamide 500 mg po will be administered as 10 tablets of 50 mg on day 1, 8, 15 Lenalidomide will be administered as once daily 10 mg tablet from day 1 to 14
Interventions
DRUGCyclophosphamide
500 mg, p.o daily, days 1, 8 and 15 for cycles 5 to 8 cycles
DRUGBortezomib
1.3 mg/m2 IV bolus on Day 1, 4, 8, 11 for cycles 1 to 8
DRUGDexamethasone
20 mg orally daily, on Days 1, 2, 4, 5, 8, 9, 11, 12 for cycles 1 to 8
DRUGLenalidomide
10 mg orally daily, days 1-14 for cycles 5 to 8
Sponsors
Janssen-Cilag International NV
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
* Patient has relapsed/progressed or is refractory for multiple myeloma following 1 previous line of therapy * Measurable secretory multiple myeloma: measurable disease for secretory multiple myeloma is defined by at least one of the following measurements: serum monoclonal protein greater than or equal to 1 g/dl (\> 10 gm/l) \[10g/l\], urine M-protein of ≥200 mg/24 hours * Patient has a Karnofsky performance status of ≥ 60 * Patient has a life expectancy estimated at screening of at least 6 months * Patient fulfills defined pretreatment laboratory requirements at and within 14 days before baseline
Exclusion criteria
* Patient received more than 1 previous line of therapy for multiple myeloma * Patient has known allergy or hypersensitivity to bortezomib, Dexamethasone and/or Cyclophosphamide and/or Lenalidomide or any of the constituent compounds such as boron, mannitol, or lactose * Patient has oligosecretory or non-secretory multiple myeloma * Patient received nitrosoureas or any other chemotherapy (including thalidomide), clarithromycin, interferon within 6 weeks before enrolment. Note: subjects can have received thalidomide or interferon as maintenance therapy, according to local standard of care * Patient received corticosteroids (\> 10 mg/day prednisone or equivalent) within 3 weeks before enrolment. Note: subjects can have received steroids (dexamethasone or equivalent) as maintenance therapy according to local standard of care. In addition, subjects can have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy within 3 weeks prior to study entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Best Confirmed Response | Prior to treatment at day 1 of each cycle and at the end of treatment (day 21 of cycle 8), up to 168 days | Overall Best Confirmed Response is the best Overall Response Rate with borezomib-dexamathasone (+/-cyclophosphamide or lenalidomide) recorded between baseline and end of treatment. Response was assessed using the International Myeloma working Group (IMWG) Uniform Response Criteria and validated by an Independent Monitoring Committee. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to First Confirmed Response | At Day 1 of each treatment cycle, at the End of Treatment visit until there is evidence of Progressive Disease or relapse from Complete Response (CR), up to 168 days | Time from start of treatment to the date of the first documentation of a confirmed response. Estimated using the Kaplan-Meier method. Response was assessed using the International Myeloma Working Group (IMWG) Uniform Response Criteria and validated by an Independent Monitoring Committee. |
| Progression Free Survival | At Day 1 of each treatment cycle, at the End of Treatment visit until there is evidence of Progressive Disease or relapse from Complete Response (CR). Median Follow-Up of 16.9 months | Time from start of treatment to date of disease progression, relapse from CR or death. Estimated using the kaplan-meier method. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions, or similar definition as accurate and appropriate. |
| Time to Progression | At Day 1 of each treatment cycle, at the End of Treatment visit until there is evidence of Progressive Disease or relapse from Complete Response (CR), Median Follow-up of 16.9 months | Is calculated as the time from start of treatment to the date of the first observation of disease progression or relapse from CR. Deaths owing to causes other than progression not counted, but censored. Subjects who withdraw from the study or die will be censored at the time of last disease assessment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). |
| One Year Survival | At each visit from baseline to end of treatment. After treatment, monthly visit until progression or relapse or until the start of alternative MMY therapy, up to 1 year | Percent Probability of Survival at 1 year from the start of treatment, estimated using Kaplan-Meier analysis. |
| Overall Survival | At each visit from baseline to end of treatment. After treatment, monthly visit until progression or relapse or until the start of alternative MMY therapy. Further follow up by monthly phone call until the last patient was treated and followed for 1 year | Is defined as the time interval from start of treatment to the date of death due to any cause. In the absence of confirmation of death (including subjects lost to follow-up), survival time will be censored at the last date the subject is known to be alive |
Countries
France, Germany, Greece, Hungary, Lithuania, Poland, Serbia, Spain, Turkey (Türkiye), United Kingdom
Participant flow
Pre-assignment details
190 patients screened, 163 enrolled and received Bortezomib-Dexamethasone (VD) . Participants that completed cycles 1 to 4 were assessed for Response. Complete or Partial Responders were not randomized and continued on VD for cycles 5-8. Participants with Stable Disease (SD) were randomized to either VD, VDC, or VDR for cycles 5-8.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants bortezomib 1.3 mg/m2 IV bolus on Day 1, 4, 8, 11 in combination with dexamethasone 20 mg orally daily, on Days 1, 2, 4, 5, 8, 9, 11, 12 for 4 cycles | 163 |
| Total | 163 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Cycle 1 to 4 | Adverse Event | 12 | 0 | 0 | 0 |
| Cycle 1 to 4 | Death | 5 | 0 | 0 | 0 |
| Cycle 1 to 4 | Other | 1 | 0 | 0 | 0 |
| Cycle 1 to 4 | Progressive Disease | 6 | 0 | 0 | 0 |
| Cycle 1 to 4 | Withdrawal by Subject | 4 | 0 | 0 | 0 |
| Randomization (Cycle 5) to Cycle 8 | Adverse Event | 17 | 2 | 0 | 0 |
| Randomization (Cycle 5) to Cycle 8 | Complete Response/Partial Response | 1 | 0 | 0 | 0 |
| Randomization (Cycle 5) to Cycle 8 | Death | 2 | 0 | 0 | 0 |
| Randomization (Cycle 5) to Cycle 8 | Other | 3 | 1 | 0 | 0 |
| Randomization (Cycle 5) to Cycle 8 | Physician Decision | 2 | 0 | 0 | 0 |
| Randomization (Cycle 5) to Cycle 8 | Progressive Disease | 5 | 0 | 0 | 0 |
| Randomization (Cycle 5) to Cycle 8 | Protocol Violation | 1 | 0 | 0 | 0 |
| Randomization (Cycle 5) to Cycle 8 | Withdrawal by Subject | 4 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 63.7 years STANDARD_DEVIATION 11.04 |
| Region of Enrollment France | 20 participants |
| Region of Enrollment Germany | 15 participants |
| Region of Enrollment Greece | 23 participants |
| Region of Enrollment Hungary | 2 participants |
| Region of Enrollment Lithuania | 9 participants |
| Region of Enrollment Poland | 19 participants |
| Region of Enrollment Serbia | 15 participants |
| Region of Enrollment Spain | 20 participants |
| Region of Enrollment Turkey | 19 participants |
| Region of Enrollment United Kingdom | 21 participants |
| Sex: Female, Male Female | 77 Participants |
| Sex: Female, Male Male | 86 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 137 / 144 | 19 / 19 |
| serious Total, serious adverse events | 59 / 144 | 6 / 19 |
Outcome results
Primary
Overall Best Confirmed Response
Overall Best Confirmed Response is the best Overall Response Rate with borezomib-dexamathasone (+/-cyclophosphamide or lenalidomide) recorded between baseline and end of treatment. Response was assessed using the International Myeloma working Group (IMWG) Uniform Response Criteria and validated by an Independent Monitoring Committee.
Time frame: Prior to treatment at day 1 of each cycle and at the end of treatment (day 21 of cycle 8), up to 168 days
Population: mITT: All patients with at least 1 dose and 1 post baseline assessment. Low powered study because necessary sample size for the randomized part could not be reached. Thus, data were analyzed and reported by combining the randomized groups with SD, (n=19). Data are missing for 21 patients in the non-randomized CR/PR group, n=123.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Complete to Partial Response: Bortezomib + Dexamethasone | Overall Best Confirmed Response | 101 number of participants |
| Stable Disease After 4 Cycles: VD, VDC, VDL | Overall Best Confirmed Response | 6 number of participants |
Secondary
Median Time to First Confirmed Response
Time from start of treatment to the date of the first documentation of a confirmed response. Estimated using the Kaplan-Meier method. Response was assessed using the International Myeloma Working Group (IMWG) Uniform Response Criteria and validated by an Independent Monitoring Committee.
Time frame: At Day 1 of each treatment cycle, at the End of Treatment visit until there is evidence of Progressive Disease or relapse from Complete Response (CR), up to 168 days
Population: mITT: All patients with at least 1 dose and 1 post baseline assessment. The non- randomized CR/PR group, n=144 for Time to First confirmed Response. Low powered study because necessary sample size for the randomized part could not be reached. Thus, data were analyzed and reported by combining the randomized groups with SD, (n=19).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Complete to Partial Response: Bortezomib + Dexamethasone | Median Time to First Confirmed Response | 43.0 days |
| Stable Disease After 4 Cycles: VD, VDC, VDL | Median Time to First Confirmed Response | NA days |
Secondary
One Year Survival
Percent Probability of Survival at 1 year from the start of treatment, estimated using Kaplan-Meier analysis.
Time frame: At each visit from baseline to end of treatment. After treatment, monthly visit until progression or relapse or until the start of alternative MMY therapy, up to 1 year
Population: mITT: All patients with at least 1 dose and 1 post baseline assessment. The non- randomized CR/PR group, n=144 for Time to First confirmed Response. Low powered study because necessary sample size for the randomized part could not be reached. Thus, data were analyzed and reported by combining the randomized groups with SD, (n=19).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Complete to Partial Response: Bortezomib + Dexamethasone | One Year Survival | 80 percent probability |
| Stable Disease After 4 Cycles: VD, VDC, VDL | One Year Survival | 89 percent probability |
Secondary
Overall Survival
Is defined as the time interval from start of treatment to the date of death due to any cause. In the absence of confirmation of death (including subjects lost to follow-up), survival time will be censored at the last date the subject is known to be alive
Time frame: At each visit from baseline to end of treatment. After treatment, monthly visit until progression or relapse or until the start of alternative MMY therapy. Further follow up by monthly phone call until the last patient was treated and followed for 1 year
Population: mITT: All patients with at least 1 dose and 1 post baseline assessment. The non-randomized CR/PR group, n=144 for Time to First confirmed Response. Low powered study because necessary sample size for the randomized part could not be reached. Thus, data were analyzed and reported by combining the randomized groups with SD, (n=19).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Complete to Partial Response: Bortezomib + Dexamethasone | Overall Survival | NA days |
| Stable Disease After 4 Cycles: VD, VDC, VDL | Overall Survival | NA days |
Secondary
Progression Free Survival
Time from start of treatment to date of disease progression, relapse from CR or death. Estimated using the kaplan-meier method. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions, or similar definition as accurate and appropriate.
Time frame: At Day 1 of each treatment cycle, at the End of Treatment visit until there is evidence of Progressive Disease or relapse from Complete Response (CR). Median Follow-Up of 16.9 months
Population: mITT: All patients with at least 1 dose and 1 post baseline assessment. The non-randomized CR/PR group, n=144. Low powered study because necessary sample size for the randomized part could not be reached. Thus, data were analyzed and reported by combining the randomized groups with SD, (n=19).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Complete to Partial Response: Bortezomib + Dexamethasone | Progression Free Survival | 311.0 days |
| Stable Disease After 4 Cycles: VD, VDC, VDL | Progression Free Survival | 214.0 days |
Secondary
Time to Progression
Is calculated as the time from start of treatment to the date of the first observation of disease progression or relapse from CR. Deaths owing to causes other than progression not counted, but censored. Subjects who withdraw from the study or die will be censored at the time of last disease assessment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0).
Time frame: At Day 1 of each treatment cycle, at the End of Treatment visit until there is evidence of Progressive Disease or relapse from Complete Response (CR), Median Follow-up of 16.9 months
Population: mITT: All patients with at least 1 dose and 1 post baseline assessment. The non-randomized CR/PR group, n=144 for Time to First confirmed Response. Low powered study because necessary sample size for the randomized part could not be reached. Thus, data were analyzed and reported by combining the randomized groups with SD, (n=19).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Complete to Partial Response: Bortezomib + Dexamethasone | Time to Progression | 366.0 days |
| Stable Disease After 4 Cycles: VD, VDC, VDL | Time to Progression | 214.0 days |