Tandem Melphalan and Autolog. SCT in MM Patients 60 to 70 Years of Age With and Without Induction Chemotherapy

Multiple Myeloma Clinical Trial

— DSMM-II  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02288741
• Other study ID #: WiSP_AM71
• Secondary ID: protocol version
• Status: Completed
• Phase: Phase 3
• First received: October 23, 2014
• Last updated: November 6, 2014
• Start date: August 2001
• Est. completion date: September 2012

Study information

• Verified date: November 2014
• Source: WiSP Wissenschaftlicher Service Pharma GmbH
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 549
• Est. completion date: September 2012
• Est. primary completion date: September 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 60 Years to 70 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Anthracycline/dexamethasone-based induction chemotherapy
4 cycles of anthracycline/dexamethasone-based chemotherapy
• Dexamethasone for control of symptoms
2 x 4 days of dexamethasone (day 1-4 and day 8-11: 40mg)
• 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)

Procedure:
• Stem cell apheresis
stem cell apheresis in peripheral blood, sought amount of CD34-cells: 6 * 10E6/kg

Drug:
• Tandem high-dose chemotherapy (melphalan)
Two cycles of high-dose melphalan (day -3 and day -2: 70mg/m²)

Procedure:
• Autologous peripheral blood stem cell transplantation
Two infusions of collected stem cells (day 0: 2*10E6 CD34-cell/kg per transplantation)

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
WiSP Wissenschaftlicher Service Pharma GmbH

References & Publications (5)

Alexanian R, Barlogie B, Tucker S. VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol. 1990 Feb;33(2):86-9. — View Citation

Bladé J, Samson D, Reece D, Apperley J, Björkstrand 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. — View Citation

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. Erratum in: Br J Haematol 2002 Sep;118(4):1201. — View Citation

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. — View Citation

Szelényi 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event free survival	Calculated according to the method of Kaplan and Meier	From randomization to 10 years follow up	No
Secondary	Overall survival	Calculated according to the method of Kaplan and Meier	From randomization to 10 years follow up	No
Secondary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	No