None listed
Conditions
Brief summary
We propose to test in a phase III study (oral melphalan and dexamethasone (MDex), the standard therapy for AL patients who are not autologous candidates for stem cell transplant (ASCT), against bortezomib added to MDex (BMDex). The hematologic response rate with MDex is 60% with 30% complete responses. The median overall survival with MDex is 5.1 years and the median progression free survival is 3.8 years. The basis for the combination of BMDex includes the high activity of bortezomib in AL, particularly the high complete response rate and the rapidity of hematologic response to bortezomib and dexamethasone, and the large clinical experience in phase II and phase III studies with bortezomib, melphalan and prednisone in myeloma. Untreated patients diagnosed with AL who are not candidates for stem cell transplant with melphalan 200 mg/m2 are the target population. Patients who are eligible for SCT with melphalan 200 mg/m2 but who decline the procedure can be enrolled in the study as a subgroup with stratified randomization. Because many newly diagnosed AL patients present with limited organ reserve, the eligibility criteria take into consideration the impact of cardiac involvement on overall survival using cardiac biomarker staging. Stage I and II patients will be eligible and stage III patients will be enrolled in an ancillary phase II study.
Interventions
After stratification, patients will be randomized to receive either:
MDex: Patients will take oral melphalan at a dose of 0.22 mg/kg and oral dexamethasone at 40 mg daily for four consecutive days at the beginning of each cycle (days 1-4)every 28 days (MDex).
or
BMDex: cycles 1 and 2 = MDex (as above) with bortezomib at 1.3 mg/m2 i.v. on days 1, 4, 8 and 11 of a 28 day cycle,
cycles 3 – 8 = MDex with bortezomib at 1.3 mg/m2 i.v. on days 1, 8, 15 and 22 of a 35 day cycle.
(Experimental Arm:
After stratification, patients will be randomized to receive either: MDex: Patients will take oral melphalan at a dose of 0.22 mg/kg and oral dexamethasone at 40 mg daily for four consecutive days at the beginning of each cycle (days 1-4)every 28 days (MDex). or BMDex: cycles 1 and 2 = MDex (as above) with bortezomib at 1.3 mg/m2 i.v. on days 1, 4, 8 and 11 of a 28 day cycle, cycles 3 – 8 = MDex with bortezomib at 1.3 mg/m2 i.v. on days 1, 8, 15 and 22 of a 35 day cycle. (Experimental Arm: The combination of Bortezomib, Melphalan and Dexamethasone (BMDex))
Sponsors
Australasian Leukaemia and Lymphoma Group (ALLG)
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Histologic diagnosis of amyloidosis. Genetic testing must be negative for transthyretin mutations associated with hereditary amyloidosis or immunohistochemistry of amyloid deposits must provide clear evidence of kappa or lambda light chains in those who present with peripheral neuropathy or heart as the dominant organ involvement. Not eligible for transplant with melphalan 200 mg/m2. Patients who are eligible for transplant with melphalan 200 mg/m2 but decline the procedure, can be enrolled in the study, but are stratified in a separate stratum before randomization. Eastern Cooperative Oncology Group performance status 0, 1 or 2. Measurable disease; at least one of the following criteria: Monoclonal protein more than 10 g/L in serum, Amyloid-forming (involved) free light chains greater than 75 mg/L with an abnormal kappa-lambda ratio, Difference between involved and uninvolved free light chains grater than 50 mg/L Bone marrow with a clonal predominance. Symptomatic organ involvement (heart, kidney, liver/Gastrointestinal tract, peripheral nervous system). Hemoglobin of 11 g/dL, absolute neutrophil count of 1500/microL, platelets of 140,000/microL. Total bilirubin less than 2.5 mg/dL, alkaline phosphatase less than 5 times the upper limit of normal, Alanine transaminase 3 times the upper limit of normal (patients with a documented history of Gilbert’s disease who have a total bilirubin (predominantly unconjugated) greater than 2.5mg/L without any other liver function test abnormalities are still eligible) Estimated glomerular filtration rate by the modification of diet in renal disease formula greater than 30 ml/min.
Exclusion criteria
Amyloid-specific syndrome, such as carpal tunnel syndrome or skin purpura as the only evidence of disease. The finding of isolated vascular amyloid in a bone marrow biopsy specimen or in a plasmacytoma is not indicative of systemic amyloidosis. Isolated soft tissue involvement. Presence of non-AL amyloidosis. Previous treatment for plasma cell disease. A single previous cycle of dexamethasone or steroid equivalent (maximum cumulative dexamethasone dose 160 mg) is allowed; in this case baseline data must be obtained after steroid administration. Previous stem cell harvest is allowed, provided that mobilization is performed with granulocyte colony stimulating factor only. Bone marrow plasma cells greater than 30 percent. Cardiac stage three disease Chronic atrial fibrillation Supine systolic blood pressure less than 100mmHg or symptomatic orthostatic hypotension or clinically important autonomic disease Grade 3 sensory or grade 1 painful peripheral neuropathy. Clinically overt multiple myeloma with lytic bone lesions Patients with uncontrolled infection or active malignancy with the exception of adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years. Patients with hypersensitivity to bortezomib, boron or mannitol.
Outcome results
None listed