The marked activity of thalidomide (thal) and dexamethasone (dex) in relapsed and refractory multiple myeloma (MM) provided the basis for this phase 2 clinical study aimed at investigating the efficacy and toxicity of thal-dex incorporated into melphalan-based double autologous stem cell transplantation (ASCT)for patients less than 65 years old with newly diagnosed symptomatic MM. Thal-dex was given as primary induction therapy and was then continued throughout the subsequent treatment phases until the day before the second autotransplantation. Primary study endpoints,as evaluated on an intention to treat basis, are response rates to the different treatment phases (induction, first and second ASCT), best response whenever achieved, duration of response (DOR), time to progression (TTP), progression free survival (PFS)and toxicity profile of thal-dex. Secondary endpoints, as evaluated on an intention to treat basis, are overall survival (OS) and clinical outcomes (DOR, TTP, PFS and OS)according to prognostic factors, including cytogenetic abnormalities and imaging features, as detected by 18F-FDG PET/CT.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
378
* INDUCTION THERAPY: 100 mg/d on days 1-14, 200 mg/d on days 15-120 (in case of delay of HD-CTX , Thalidomide will be continued until the day before Cyclophosphamide as priming therapy for PBSC collection) * AFTER PBSC COLLECTION: 200 mg/d from day after last PBSC collection until the day before first course of MEL-200 * AFTER FIRST TRANSPLANTATION: 200 mg/d from recovery of hematopoiesis until the day before the second course of MEL-200
* INDUCTION THERAPY: 40 mg/d days 1-4, 9-12 and 17-20 (cycles 1 and 3, 30 days each); 40 mg/d days 1-4 (cycles 2 and 4, 30 days each) * AFTER PBSC COLLECTION: 40 mg/d days 1-4 (starting the same day of resumption of Thalidomide) * AFTER FIRST TRANSPLANTATION: 40 mg/d days 1-4 (starting the same day of resumption of Thalidomide) for 3 cycles (30 days each)
* INDUCTION THERAPY: 4 mg i.v. once a cycle for 4 cycles (30 days each) * AFTER PBSC COLLECTION: 4 mg i.v. once (the same day of resumption of Thalidomide) * AFTER FIRST TRANSPLANTATION: 4 mg i.v. once a cycle (starting the same day of resumption of Thalidomide) for 3 cycles (30 days each)
Cyclophosphamide 7 g/sqm + G-CSF 5 mcg/Kg from the day +6 for stem cell mobilisation
Melphalan 200 mg/sqm on day -1 for first and second ASCT
Response rate (at least PR, VGPR, nCR and CR) to thal-dex induction
Responses are reported by study investigators and centrally reassessed by study coordinator(s). Criteria are those initially proposed by the European Group for Blood and Marrow Transplantation (EBMT), with the addition of nCR (100% M-protein reduction by electrophoresis, but immunofixation-positive)and VGPR (at least 90% reduction of M component).
Time frame: 120 days after the start day of tal-dex induction therapy
duration of response (partial response, PR, very good partial response, VGPR, complete response, CR)
Duration of response is calculated from the first achievement of the response (at least PR, at least VGPR, at least CR) to relapse/progression
Time frame: Average time period between the day of first achievement of response and the day of first relapse or progression
time to progression (TTP)
TTP is calculated from the start date of induction therapy to the date of relapse/progression
Time frame: Average time period between the start day of induction therapy and the day of relapse or progression
progression free survival (PFS)
PFS is calculated from the start date of induction therapy to the date of relapse/progression or death for any cause, whichever occurs first
Time frame: Average time period between the start day of induction therapy and the day of relapse or progression or death, whichever occurs firstly
toxicity of thal-dex (induction and subsequent treatment phases)
Adverse events are assessed monthly and graded according to the National Cancer Institute Common Toxicity Criteria, version 2. Safety is monitored until 30 days after the last dose of study drug.
Time frame: Within 30 days after the last dose of study drug
Response rate (at least PR, VGPR, nCR and CR) to first ASCT
Responses are reported by study investigators and centrally reassessed by study coordinator(s). Criteria are those initially proposed by the European Group for Blood and Marrow Transplantation (EBMT), with the addition of nCR (100% M-protein reduction by electrophoresis, but immunofixation-positive)and VGPR (at least 90% reduction of M component).
Time frame: 90 days after first ASCT
Response rate (at least PR, VGPR, nCR and CR) to second ASCT
Responses are reported by study investigators and centrally reassessed by study coordinator(s). Criteria are those initially proposed by the European Group for Blood and Marrow Transplantation (EBMT), with the addition of nCR (100% M-protein reduction by electrophoresis, but immunofixation-positive)and VGPR (at least 90% reduction of M component).
Time frame: 90 days after second ASCT
Overall survival (OS)
OS is measured from the start date of induction therapy until death from any cause
Time frame: Average time period between the start day of induction therapy and the day of death, due to any cause
OS by cytogenetic abnormalities
OS is calculated as defined above in patients with or without high risk cytogenetic abnormalities (translocation t(4;14), deletion chromosome 17p, deletion chromosome 13q)
Time frame: Average time period between the start day of induction therapy and the day of death, due to any cause
OS by 18F-FDG PET/CT imaging
OS is calculated as defined above in patients with different PET/CT patterns (normal, focal, diffuse, presence or absence of extramedullary disease)
Time frame: Average time period between the start day of induction therapy and the day of death, due to any cause
TTP by cytogenetic abnormalities
TTP is calculated as defined above in patients with or without high risk cytogenetic abnormalities (translocation t(4;14), deletion chromosome 17p, deletion chromosome 13q)
Time frame: Average time period between the start day of induction therapy and the day of relapse or progression
PFS by cytogenetic abnormalities
PFS is calculated as defined above in patients with or without high risk cytogenetic abnormalities (translocation t(4;14), deletion chromosome 17p, deletion chromosome 13q)
Time frame: Average time period between the start day of induction therapy and the day of relapse or progression or death, whichever occurs firstly
TTP by 18F-FDG PET/CT imaging
TTP is calculated as defined above in patients with different PET/CT patterns (normal, focal, diffuse, presence or absence of extramedullary disease)
Time frame: Average time period between the start day of induction therapy and the day of relapse or progression
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PFS by 18F-FDG PET/CT imaging
PFS is calculated as defined above in patients with different PET/CT patterns (normal, focal, diffuse, presence or absence of extramedullary disease)
Time frame: Average time period between the start day of induction therapy and the day of relapse or progression or death, whichever occurs firstly