THAL-DEX Incorporated Into Double PBSC Autotransplantation for Untreated Multiple Myeloma (MM)

Study Overview
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Brief Summary
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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.

Official Title
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Thalidomide-Dexamethasone Incorporated Into Double Autologous Stem-Cell Transplantation for Patients Less Than 65 Years of Age With Newly Diagnosed Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Thalidomide
* Drug: Dexamethasone
* Drug: Zoledronic acid
* Drug: Cyclophosphamide
* Drug: Melphalan


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Confirmed diagnosis of symptomatic MM based on standard criteria. No prior or current systemic therapy for MM, with exception of steroids. At least 18 years and less than 65 years of age. Presence of quantifiable M protein in serum or urine. Durie & Salmon stage II-III or I with disease progression. Adequate organ function (heart, lung). No previous deep vein thrombosis and/or recurring thrombophlebitis and/or pulmonary embolisms, confirmed by doppler ultrasound or computed tomography scan. Willing and able to comply with the protocol requirements. Exclusion criteria: Diagnosis of smouldering or asymptomatic MM, plasmacell leukemia, solitary plasmocytoma of the bone o extramedullary plasmocytoma. Diagnosis of non-secretory MM. Prior or current systemic therapy for MM, with exception of steroids. More than 65 years of age. Female subjects pregnant. Non adequate organ function (heart, lung). Patient has a prior history of thrombosis or venous thromboembolism or pulmonary embolism.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Thalidomide|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|
|Drug: Dexamethasone|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)|
|Drug: Zoledronic acid|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)|
|Drug: Cyclophosphamide|Cyclophosphamide 7 g/sqm + G-CSF 5 mcg/Kg from the day +6 for stem cell mobilisation|
|Drug: Melphalan|Melphalan 200 mg/sqm on day -1 for first and second ASCT|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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 | 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 | 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 | 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. | 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). | 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). | 90 days after second ASCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS is measured from the start date of induction therapy until death from any cause | 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) | 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) | 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) | 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) | 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) | Average time period between the start day of induction therapy and the day of relapse or progression | 
| 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) | Average time period between the start day of induction therapy and the day of relapse or progression or death, whichever occurs firstly | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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autologous stem cell transplantation, thalidomide, induction therapy