Tandem Melphalan and Autolog. SCT in MM Patients 60 to 70 Years of Age With and Without Induction Chemotherapy (DSMM-II)

Phase III-study for Evaluation of Induction Therapy Before Stem Cell Mobilization and Tandem High-dose Melphalan in Multiple Myeloma Patients 60 to 70 Years of Age

Patients 60 to 70 years of age with newly diagnosed multiple myeloma were prospectively randomized between 4 cycles of anthracycline/dexamethasone-based induction chemotherapy (A1) or only 2 x 4 days of dexamethasone (A2). A reference arm included patients who could not be randomized (B). Tandem melphalan 140 mg/m² (MEL140) with autologous transplantation was scheduled for all patients.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Anthracycline/dexamethasone-based induction chemotherapy; Drug: Tumor-reduction chemotherapy and stem cell mobilization; Procedure: Stem cell apheresis; Drug: Tandem high-dose chemotherapy (melphalan); Procedure: Autologous peripheral blood stem cell transplantation; Drug: Dexamethasone for control of symptoms

Detailed Description

In arm A1, patients received 4 cycles of conventional induction therapy with anthracycline/dexamethasone-based regimens. Specified in the protocol were vincristine/doxorubicin/dexamethasone (VAD), idarubicin/dexamethasone (ID) and cyclophosphamide/doxorubicin/dexamethasone (CAD). In arm A2, patients were planned to receive only dexamethasone 40 mg orally on days 1-4 and 8-11 for symptom control before stem cell mobilization. For the patients in arm B, a maximum of 6 cycles of induction chemotherapy was allowed. Following this, the treatment was identical for all patients. For stem cell mobilization, an age-adjusted IEV-regimen with granulocyte-colony stimulating factor (G-CSF) was recommended. The target dose for stem cell collection was 6 x 10E+6 CD34 (cluster of differentiation 34)-positive cells/kg (2 transplants and one back-up). The standard dose for each transplantation was 2 x 10E+6 CD34-positive cells/kg. High-dose melphalan at a total dose of 140 mg/m² (MEL140) was given in two doses of 70 mg/m² on days -3 and -2. Stem cell transplantation (SCT) was performed on day 0. A second MEL140 course was planned two months after the first. Regular bisphosphonate treatment was recommended.

• Study Type: Interventional
• Enrollment (Actual): 549
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histological confirmed multiple myeloma stage II or III according to the classification of Salmon and Durie
• Aged between 60 and 70 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Signed and dated written informed consent
• No previous chemotherapy or not more than one cycle in total or previous chemotherapy of more than one cycle if paused for at least 6 months and not more than six cycles in total (arm A1 and A2 only)
• Ongoing primary chemotherapy of two to maximum six cycles (arm B only)

Exclusion Criteria:

• Multiple myeloma stage I according to the classification of Salmon and Durie without need of any therapy
• Aged under 60 or over 70 years
• ECOG performance status >2
• Previous chemotherapy of more than six cycles
• Informed consent missing
• Myocardial infarction within the last six months
• Cardiac dysrhythmia stage IV b according to the classification of Lown
• Heart failure >NYHA II according to the classification of the New York Heart Association (NYHA), left ventricular ejection fraction <50% in ECG
• Severe restrictive or obstructive pulmonary disease (diffusing capacity <60% under normal)
• Renal insufficiency including a serum creatinine level >2mg/dl if not caused by multiple myeloma and reversible
• Liver diseases combined with an elevation of transaminases and of bilirubin of three times above normal
• Severe infections (HIV, hepatitis B/C, syphilis etc. )
• Severe psychiatric disease
• Other not curative treated malignant tumor within the last five years
• Concurrent participation in other clinical studies
• Other not curative treated malignant tumor within the last five years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A1: Induction chemotherapy; Anthracycline/dexamethasone-based induction chemotherapy Tumor-reduction chemotherapy and stem cell mobilization Stem cell apheresis Tandem high-dose chemotherapy Autologous peripheral blood stem cell transplantation	Drug: Anthracycline/dexamethasone-based induction chemotherapy; 4 cycles of anthracycline/dexamethasone-based chemotherapy; Other Names: ID, VAD, CAD; Drug: Tumor-reduction chemotherapy and stem cell mobilization; Ifosfamide (day 1-3: 1.900mg/m² iv), epirubicin (day 1: 75 mg/m² iv), etoposide (day 1-3: 120 mg/m² iv) and G-CSF (day 5 until end of apheresis: 5µg/kg sc); Other Names: IEV + G-CSF; Procedure: Stem cell apheresis; stem cell apheresis in peripheral blood, sought amount of CD34-cells: 6 * 10E6/kg; Other Names: SC-apheresis; Drug: Tandem high-dose chemotherapy (melphalan); Two cycles of high-dose melphalan (day -3 and day -2: 70mg/m²); Other Names: Tandem melphalan; Procedure: Autologous peripheral blood stem cell transplantation; Two infusions of collected stem cells (day 0: 2*10E6 CD34-cell/kg per transplantation); Other Names: PBSCT
Active Comparator: A2: No induction chemotherapy; Dexamethasone for control of symptoms Tumor-reduction chemotherapy and stem cell mobilization Stem cell apheresis Tandem high-dose chemotherapy Autologous peripheral blood stem cell transplantation	Drug: Tumor-reduction chemotherapy and stem cell mobilization; Ifosfamide (day 1-3: 1.900mg/m² iv), epirubicin (day 1: 75 mg/m² iv), etoposide (day 1-3: 120 mg/m² iv) and G-CSF (day 5 until end of apheresis: 5µg/kg sc); Other Names: IEV + G-CSF; Procedure: Stem cell apheresis; stem cell apheresis in peripheral blood, sought amount of CD34-cells: 6 * 10E6/kg; Other Names: SC-apheresis; Drug: Tandem high-dose chemotherapy (melphalan); Two cycles of high-dose melphalan (day -3 and day -2: 70mg/m²); Other Names: Tandem melphalan; Procedure: Autologous peripheral blood stem cell transplantation; Two infusions of collected stem cells (day 0: 2*10E6 CD34-cell/kg per transplantation); Other Names: PBSCT; Drug: Dexamethasone for control of symptoms; 2 x 4 days of dexamethasone (day 1-4 and day 8-11: 40mg); Other Names: dexamethasone
Other: B: Observation; Tumor-reduction chemotherapy and stem cell mobilization Stem cell apheresis Tandem high-dose chemotherapy Autologous peripheral blood stem cell transplantation	Drug: Anthracycline/dexamethasone-based induction chemotherapy; 4 cycles of anthracycline/dexamethasone-based chemotherapy; Other Names: ID, VAD, CAD; Drug: Tumor-reduction chemotherapy and stem cell mobilization; Ifosfamide (day 1-3: 1.900mg/m² iv), epirubicin (day 1: 75 mg/m² iv), etoposide (day 1-3: 120 mg/m² iv) and G-CSF (day 5 until end of apheresis: 5µg/kg sc); Other Names: IEV + G-CSF; Procedure: Stem cell apheresis; stem cell apheresis in peripheral blood, sought amount of CD34-cells: 6 * 10E6/kg; Other Names: SC-apheresis; Drug: Tandem high-dose chemotherapy (melphalan); Two cycles of high-dose melphalan (day -3 and day -2: 70mg/m²); Other Names: Tandem melphalan; Procedure: Autologous peripheral blood stem cell transplantation; Two infusions of collected stem cells (day 0: 2*10E6 CD34-cell/kg per transplantation); Other Names: PBSCT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event free survival	Calculated according to the method of Kaplan and Meier	From randomization to 10 years follow up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Calculated according to the method of Kaplan and Meier	From randomization to 10 years follow up
Rate of remission (Evaluation of the overall response rate)	Evaluation of the overall response rate. Overall repose is defined as complete response + partial response. The definition of remission followed the criteria of Bladé.	After last therapy to at least 6 weeks thereafter
Quality of remission (Evaluation of the best response)	Evaluation of the best response. Response is evaluated after induction therapy, tumor-reduction chemotherapy and stem cell mobilization and each high-dose chemotherapy. The definition of remission followed the criteria of Bladé.	After last therapy to at least 6 weeks thereafter
Short and long time toxicity according to NCI Common Terminology Criteria for Adverse Events (CTCAE)	Examination of the maximum grade of toxicity according to NCI Common Terminology Criteria for Adverse Events (CTCAE)	From randomization until 2 years after last therapy
Cytogenetic examination (Univariate analysis according to the method of Kaplan and Meier. Multivariate analysis according to the method of Cox´s proportional hazards regression analysis.)	Examination of cytogenetic abnormalities wich are of major importance to define longer or shorter survival. Univariate analysis according to the method of Kaplan and Meier. Multivariate analysis according to the method of Cox´s proportional hazards regression analysis.	From randomization to 10 years follow up

Collaborators and Investigators

• Sponsor: WiSP Wissenschaftlicher Service Pharma GmbH
• Investigators: Principal Investigator: Christian Straka, Prof. Dr., Schön Klink Starnberger See

Publications and helpful links

General Publications

• Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, Gertz M, Giralt S, Jagannath S, Vesole D. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998 Sep;102(5):1115-23. doi: 10.1046/j.1365-2141.1998.00930.x. No abstract available.
• Alexanian R, Barlogie B, Tucker S. VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol. 1990 Feb;33(2):86-9. doi: 10.1002/ajh.2830330203.
• Clark AD, Douglas KW, Mitchell LD, McQuaker IG, Parker AN, Tansey PJ, Franklin IM, Cook G. Dose escalation therapy in previously untreated patients with multiple myeloma following Z-Dex induction treatment. Br J Haematol. 2002 Jun;117(3):605-12. doi: 10.1046/j.1365-2141.2002.03519.x. Erratum In: Br J Haematol 2002 Sep;118(4):1201.
• Straka C, Hebart H, Adler-Reichel S, Werding N, Emmerich B, Einsele H. Blood stem cell collections after mobilization with combination chemotherapy containing ifosfamide followed by G-CSF in multiple myeloma. Oncology. 2003;65 Suppl 2:94-8. doi: 10.1159/000073368.
• Szelenyi H, Kreuser ED, Keilholz U, Menssen HD, Keitel-Wittig C, Siehl J, Knauf W, Thiel E. Cyclophosphamide, adriamycin and dexamethasone (CAD) is a highly effective therapy for patients with advanced multiple myeloma. Ann Oncol. 2001 Jan;12(1):105-8. doi: 10.1023/a:1008362107080.
• Straka C, Liebisch P, Salwender H, Hennemann B, Metzner B, Knop S, Adler-Reichel S, Gerecke C, Wandt H, Bentz M, Bruemmendorf TH, Hentrich M, Pfreundschuh M, Wolf HH, Sezer O, Bargou R, Jung W, Trumper L, Hertenstein B, Heidemann E, Bernhard H, Lang N, Frickhofen N, Hebart H, Schmidmaier R, Sandermann A, Dechow T, Reichle A, Schnabel B, Schafer-Eckart K, Langer C, Gramatzki M, Hinke A, Emmerich B, Einsele H. Autotransplant with and without induction chemotherapy in older multiple myeloma patients: long-term outcome of a randomized trial. Haematologica. 2016 Nov;101(11):1398-1406. doi: 10.3324/haematol.2016.151860. Epub 2016 Aug 4.

Study record dates

Study Major Dates

• Study Start: August 1, 2001
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: October 23, 2014
• First Submitted That Met QC Criteria: November 6, 2014
• First Posted (Estimate): November 11, 2014

Study Record Updates

• Last Update Posted (Estimate): November 11, 2014
• Last Update Submitted That Met QC Criteria: November 6, 2014
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Keywords: elderly patients; induction chemotherapy; high-dose chemotherapy; autologous blood stem-cell transplantation
• 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; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dexamethasone; Dexamethasone acetate; BB 1101; Melphalan
• Other Study ID Numbers: WiSP_AM71; protocol version 08/01/2001 (Other Identifier: DSMM)