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

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

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 Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Thalidomide; Drug: Dexamethasone; Drug: Zoledronic acid; Drug: Cyclophosphamide; Drug: Melphalan

• Study Type: Interventional
• Enrollment (Actual): 378
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna

Publications and helpful links

General Publications

• Zamagni E, Patriarca F, Nanni C, Zannetti B, Englaro E, Pezzi A, Tacchetti P, Buttignol S, Perrone G, Brioli A, Pantani L, Terragna C, Carobolante F, Baccarani M, Fanin R, Fanti S, Cavo M. Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood. 2011 Dec 1;118(23):5989-95. doi: 10.1182/blood-2011-06-361386. Epub 2011 Sep 6. Erratum In: Blood. 2012 Sep 13;120(11):2349.

Study record dates

Study Major Dates

• Study Start: March 1, 2002
• Primary Completion (Actual): October 1, 2007
• Study Completion (Actual): January 1, 2009

Study Registration Dates

• First Submitted: March 31, 2011
• First Submitted That Met QC Criteria: April 22, 2011
• First Posted (Estimate): April 25, 2011

Study Record Updates

• Last Update Posted (Estimate): April 25, 2011
• Last Update Submitted That Met QC Criteria: April 22, 2011
• Last Verified: March 1, 2011

More Information

Terms related to this study

• Keywords: autologous stem cell transplantation; induction therapy; thalidomide
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Bone Density Conservation Agents; Dexamethasone; Cyclophosphamide; Thalidomide; Melphalan; Zoledronic Acid
• Other Study ID Numbers: MM-BO2002