Bortezomib and Dexamethasone With or Without Lenalidomide in Treating Patients With Multiple Myeloma Previously Treated With Dexamethasone

Study Overview
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Brief Summary
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This randomized phase III trial compares bortezomib, dexamethasone, and lenalidomide with bortezomib and dexamethasone to see how well they work in treating patients with multiple myeloma previously treated with dexamethasone. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. It is not yet known whether giving bortezomib and dexamethasone is more effective with or without lenalidomide in treating multiple myeloma.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare the progression-free survival (PFS) for two consolidation regimens: bortezomib, lenalidomide, and dexamethasone (VRD) versus bortezomib and dexamethasone (VD) only. SECONDARY OBJECTIVES: I. To determine the incremental ability of VRD versus VD in attaining a complete response or a very good partial response (VGPR) in patients receiving induction therapy with a dexamethasone based induction regimen. II. To compare the overall survival, measured from the time of study entry. III. Evaluate response rate and PFS according to cytogenetic category (by gene expression and fluorescence in situ hybridization [FISH]). IV. To evaluate the toxicity of the two regimens. V. To compare quality of life (QOL) based on the Functional Assessment of Cancer Therapy (FACT)-Neurotoxicity (Ntx) Trial Outcome Index (TOI) of patients receiving VD to those receiving VRD from registration to 6 months post consolidation treatment. VI. To examine the impact of differential treatment response (PFS), if observed, on QOL based on the FACT-Ntx TOI up to 12 months post consolidation treatment. VII. To obtain prospective data on multiple myeloma specific QOL attributes. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive bortezomib at 1.3 mg/m2 intravenously (IV) on days 1, 4, 8, and 11, lenalidomide orally (PO) once daily (QD) at 15 mg on days 1-14, and dexamethasone at 40 mg total dose per day PO QD on days 1, 8, and 15. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive bortezomib at 1.3 mg/m2 IV on days 1, 4, 8, and 11 and dexamethasone at 40 mg total dose per day PO QD on days 1, 8, and 15. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 5 years.

Official Title
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Randomized Phase III Trial of Consolidation Therapy With Bortezomib (Velcade®)-Lenalidomide (Revlimid®) -Dexamethasone (VRD) Versus Bortezomib (Velcade®)-Dexamethasone (VD) for Patients With Multiple Myeloma Who Have Completed a Dexamethasone Based Induction Regimen

Conditions
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Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

Intervention / Treatment
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* Drug: bortezomib
* Drug: lenalidomide
* Drug: dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Symptomatic multiple myeloma, that was symptomatic at time of initial diagnosis, but may be asymptomatic at the time of registration based on induction therapy For the original diagnosis of myeloma, patients must have met the following criteria at one point in their disease course: bone marrow plasmacytosis (>10% plasma cells or sheets of plasma cells) or a biopsy proven plasmacytoma, and evidence of end-organ damage due to multiple myeloma including anemia, hypercalcemia, bone disease (lytic bone lesions or pathologic fractures) or renal dysfunction. Patients may have prior exposure to bortezomib Patients must have received a minimum of 1 cycle, maximum of 6 cycles, of a dexamethasone-based regimen; patient must not have experienced progressive disease on such therapy The following induction regimens were considered adequate for enrollment: dexamethasone alone; vincristine, doxorubicin and dexamethasone; thalidomide and dexamethasone; lenalidomide and dexamethasone; liposomal doxorubicin and dexamethasone; the combination of any of the above agents and dexamethasone; or cyclophosphamide, lenalidomide and dexamethasone Patients must have received the minimum cumulative dose of dexamethasone of 160 mg (sum of induction treatment) with no maximum dose specified Patients must have been offered and refused front-line stem cell transplant OR not have been eligible for front-line stem cell transplant. Bone marrow aspiration and/or biopsy must be obtained =< 28 days prior to randomization All tests below must be performed =< 28 days prior to randomization: Kappa free light chain mg/dL Lambda free light chain mg/dL Serum M-protein by serum protein electrophoresis (SPEP) Urine M-protein light chain excretion by urine protein electrophoresis (UPEP) Adequate laboratory levels within 7 days prior to randomization: hemoglobin > 7 g/dL, platelet count > 75,000 cells/mm^3, absolute neutrophil count > 1000 cells/mm^3, creatinine < 2.5 mg/dL, creatinine clearance (measured or calculated) >= 60 mL/min, direct bilirubin =< 1.5 mg/dL, serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 times the upper limit of normal Patients may be receiving bisphosphonates or erythropoietin growth factors (erythropoietic agents) for multiple myeloma Prior palliative and/or localized radiation therapy is permitted, provided at least 14 days have passed from date of last radiation therapy to date of randomization Patients must be willing and able to take prophylaxis with either aspirin at 325 mg/day or alternative prophylaxis with either low molecular weight heparin or coumadin (patients with prior deep vein thrombosis [DVT] are eligible provided they remain on the anticoagulation regimen that was prescribed for treatment of the DVT throughout the protocol therapy) Patients must be competent to understand the study as explained in the consent form Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 Sexually active males must be willing to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking lenalidomide, and for 4 weeks after stopping treatment Patients with a history of prior malignancy are eligible provided there is no active malignancy and a low expectation of recurrence within 6 months Age >=18 years Exclusion Criteria: More than 8 weeks from the last day of last cycle of induction treatment Active, uncontrolled seizure disorder; seizures in the last 6 months Uncontrolled inter-current illness that would limit compliance with the study including uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation, prior history of Stevens Johnson syndrome Grade 2 or higher peripheral neuropathy by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 Active, uncontrolled infection Smoldering myeloma or monoclonal gammopathy of undetermined significance Pregnant or nursing women were not eligible. Women of child-bearing potential unwilling to use a dual method of contraception and men who were unwilling to use a condom were not eligible

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: Arm A (VRD)<br>Patients were given consolidation therapy for 8 cycles (1 cycle = 21 days) with the combination bortezomib, dexamethasone and lenalidomide. Patients received each cycle: the standard dose of bortezomib (1.3 mg/m2) on days 1, 4, 8 and 11; fixed dose of lenalidomide at 15 mg orally on days 1-14; and 3 days of dexamethasone at 40 mg total dose per day given on days 1, 8 and 15. Aspirin 325 mg/day orally on days 1-21 of each cycle was required unless the patient was treated with alternate prophylaxis of either low molecular weight heparin or coumadin. | Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Drug: lenalidomide<br>* Given PO<br>* Other names: Revlimid® (formerly Revimid®);Drug: dexamethasone<br>* Given PO<br>* Other names: DXM;|
| Active Comparator: Arm B (VD)<br>Patients were given consolidation therapy for 8 cycles (1 cycle = 21 days) with the combination bortezomib plus dexamethasone. Patients received each cycle: the standard dose of bortezomib (1.3 mg/m2) on days 1, 4, 8 and 11 and 3 days of dexamethasone at 40 mg total dose per day given on days 1, 8 and 15. | Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Drug: dexamethasone<br>* Given PO<br>* Other names: DXM;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression-free survival was defined as the time from randomization to the earliest documentation of disease progression (PD) or death. If a patient died without evidence of PD, the patient was considered an event if death occurred within 3 months of the last disease assessment. Patients who died outside of the specified interval or patients who were alive without evidence of PD were censored at the date of last disease assessment. The PFS results are based on data as of August 2012, while overall survival (OS) was updated in April 2014. Given the early termination and limited sample size, data management efforts to update PFS were not pursued. | Assessed every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from study entry, every 12 months if patient is 6-10 years from study entry, up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rates (Complete Response [CR] or Very Good Partial Response [VGPR]) | CR: Patients with complete disappearance of an M-protein and no evidence of myeloma in the bone marrow are considered to have CR. To be considered CR, patients must meet all of the following criteria: Negative immunofixation on the serum and urine at two consecutive times Disappearance of any soft tissue plasmacytomas ≤5% plasma cells in bone marrow If serum and urine M protein are unmeasurable and the immunoglobulin free light chain (FLC) parameter is being used, patients must have a normal ratio of 0.26-1.65 at two consecutive times VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis OR >=90% reduction in serum M-component plus urine M-component <100 mg per 24 hours (by SPEP and UPEP) If the serum and urine M protein are unmeasurable and the immunoglobulin FLC parameter is being used, a >90% decrease in the difference between involved and uninvolved FLC levels is required in place of the M protein criteria | Assessed at the end of each cycle, every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from study entry, every 12 months if patient is 6-10 years from study entry, up to 10 years | 
| Overall Survival (OS) | Overall survival is defined as the time from randomization to death or date of last known alive. The OS results are based on data as of April 2014. | Assessed every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from study entry, every 12 months if patient is 6-10 years from study entry, up to 10 years | 
| Change in Quality of Life (QOL) From Baseline to 6 Months Post Consolidation as Assessed by the Functional Assessment of Cancer Therapy-Neurotoxicity Trial Outcome Index (FACT-Ntx TOI) | The combined score on the FACT-Ntx TOI is of interest. The FACT-Ntx TOI has 25 items and the score ranges from 0 (worst possible quality of life) -100 (best possible quality of life). The primary QOL endpoint is defined as the change in the FACT-Ntx TOI score from registration to 6 months post consolidation treatment. | Baseline and 6 months post consolidation treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Consolidation therapy, First-line therapy, Proteasome inhibitor, Thalidomide analogue, Quality of life