Treatment With Velcade (Bortezomib) Plus Dexamethasone (VD) or VD Plus Cyclophosphamide or VD Plus Lenalidomide in Patients With Multiple Myeloma Stabilized After 4 Cycles of VD

Study Overview
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Brief Summary
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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
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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

Official Title
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Efficacy and Safety of Velcade Plus Dexamethasone (VD), VD+Cyclophosphamide or VD Plus Lenalidomide in MMY Patients Who Are Refractory or Have Relapsed After Their Primary Therapy for MMY and Have Achieved Stable Disease After 4 Cycles of VD

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Bortezomib
* Drug: Dexamethasone
* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stable Disease: VD<br>Stable disease after 4 cycles bortezomib + dexamethasone: 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 cycle 1 to 8 | Drug: Bortezomib<br>* 1.3 mg/m2 IV bolus on Day 1, 4, 8, 11 for cycles 1 to 8<br>Drug: Dexamethasone<br>* 20 mg orally daily, on Days 1, 2, 4, 5, 8, 9, 11, 12 for cycles 1 to 8<br>|
| Experimental: Stable Disease: VDC<br>Stable disease after 4 cycles bortezomib + dexamethasone: bortezomib 1.3 mg/m2 IV bolus on Day 1, 4, 8 and 11 in combination with dexamethasone 20 mg orally daily, on Days 1, 2, 4, 5, 8, 9, 11, 12 for cycle 1 to 8 and cyclophosphamide 500 mg, orally daily, days 1, 8 and 15 for cycle 5 to 8 | Drug: Cyclophosphamide<br>* 500 mg, p.o daily, days 1, 8 and 15 for cycles 5 to 8 cycles<br>Drug: Bortezomib<br>* 1.3 mg/m2 IV bolus on Day 1, 4, 8, 11 for cycles 1 to 8<br>Drug: Dexamethasone<br>* 20 mg orally daily, on Days 1, 2, 4, 5, 8, 9, 11, 12 for cycles 1 to 8<br>|
| Experimental: Stable Disease: VDL<br>Stable disease after 4 cycles bortezomib + dexamethasone: bortezomib 1.3 mg/m2 IV bolus on Day 1, 4, 8 and 11 in combination with dexamethasone 20 mg orally daily, on Days 1, 2, 4, 5, 8, 9, 11, 12 for cycle 1 to 8 and lenalidomide 10 mg orally daily from day 1 to day 14 for cycle 5 to 8 | Drug: Bortezomib<br>* 1.3 mg/m2 IV bolus on Day 1, 4, 8, 11 for cycles 1 to 8<br>Drug: Dexamethasone<br>* 20 mg orally daily, on Days 1, 2, 4, 5, 8, 9, 11, 12 for cycles 1 to 8<br>Drug: Lenalidomide<br>* 10 mg orally daily, days 1-14 for cycles 5 to 8<br>|
| Experimental: Complete to Partial Response: VD<br>Complete, very good partial or partial response after 4 cycles bortezomib + dexamethasone: 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 cycle 1 to 8 | Drug: Bortezomib<br>* 1.3 mg/m2 IV bolus on Day 1, 4, 8, 11 for cycles 1 to 8<br>Drug: Dexamethasone<br>* 20 mg orally daily, on Days 1, 2, 4, 5, 8, 9, 11, 12 for cycles 1 to 8<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Prior to treatment at day 1 of each cycle and at the end of treatment (day 21 of cycle 8), up to 168 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 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). | 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 | 
| One Year Survival | Percent Probability of Survival at 1 year from the start of treatment, estimated using Kaplan-Meier analysis. | 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 | 
| 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple myeloma, bortezomib, hematology, bone marrow cancer, immunoglobulin, refractory, progression, dexamethasone, lenalidomide, cyclophosphamide