Clinical trial NCT02288741: Tandem Melphalan and Autolog. SCT in MM Patients 60 to 70 Years of Age With and Without Induction Chemotherapy
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Myeloma
Keywords: high-dose chemotherapy
autologous blood stem-cell transplantation
induction chemotherapy
elderly patients
Lead sponsor: WiSP Wissenschaftlicher Service Pharma GmbH
Sponsor class: OTHER
First posted: 2014-11-11
Enrollment: 549
Sex: ALL
Minimum age (years): 60
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Event free survival
timeFrame: From randomization to 10 years follow up
Secondary outcomes:
measure: Overall survival
timeFrame: From randomization to 10 years follow up
measure: Rate of remission (Evaluation of the overall response rate)
timeFrame: After last therapy to at least 6 weeks thereafter
measure: Quality of remission (Evaluation of the best response)
timeFrame: After last therapy to at least 6 weeks thereafter
measure: Short and long time toxicity according to NCI Common Terminology Criteria for Adverse Events (CTCAE)
timeFrame: From randomization until 2 years after last therapy
measure: 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.)
timeFrame: From randomization to 10 years follow up
Other outcomes:
Locations:
Study officials:
affiliation: Schön Klink Starnberger See
name: Christian Straka, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
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. doi: 10.1046/j.1365-2141.2002.03519.x.
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. doi: 10.1159/000073368.
citation: 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.
citation: 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.