Autologous Followed By Allogeneic Versus Tandem-Autologous Stem Cell Transplant in Newly Diagnosed FISH-del13q Myeloma

Stefan Knop, MD
Wuerzburg University Medical Center
Wuerzburg, Germany

Program: Oral and Poster Abstracts
Type: Oral
Session: 732. Clinical Allogeneic Transplantation: Results: Focus on Myeloma and Cord Blood 
Stefan Knop, MD1*, Peter Liebisch, MD2, Holger Hebart, MD3, Ernst Holler, MD4*, Monika Engelhardt, MD5, Bernd Metzner, MD6, Dietrich Peest, MD7*, Walter Aulitzky, MD8, Donald W. Bunjes, MD9*, Christian Straka, MD10, Thomas Fischer, MD11*, Hannes Wandt, MD12*, Orhan Sezer, MD13, Markus Hentrich, MD14*, Helmut Ostermann, MD15, Christian Peschel, MD16, Georg Hess, MD17*, Bernd Hertenstein, MD18*, Mathias Freund, MD19, Martin H Kropff, MD20, Hans-Heinrich Wolf, MD21*, Wolfram E Jung, MD22*, Norbert Frickhofen, MD23, Ralf C. Bargou24, Georg Maschmeyer, MD25, Else Heidemann, MD26*, Christian Langer, MD27, Lothar Kanz, MD28, Christoph Meisner, PhD29* and Hermann Einsele, MD1

1Department of Internal Medicine II, Division of Hematology and Medical Oncology, Wuerzburg University Medical Center, Wuerzburg, Germany
2Onkologische Praxis Moers, Moers, Germany
3Department of Internal Medicine, Stauferklinikum Schwäbisch Gmünd, Mutlangen, Germany
4Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany
5Dept. of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany
6Div. of Hematology and Oncology, Klinikum Oldenburg, Oldenburg, Germany
7Dept. of Hematology, Oncology and Hemostaseology, Hanover Medical School, Hanover, Germany
8Medical Center, Robert-Bosch-Hospital, Stuttgart, Germany
9Klinik für Innere Medzin III, Universitätsklinikum Ulm, Ulm, Germany
10Hematology and Oncology, Schön Klinik Starnberger See, Berg, Germany
11Department of Hematology and Oncology, Center of Internal Medicine, Otto-von-Guericke University Medical Center, Magdeburg, Germany
12Department of Hematology and Oncology, Klinikum Nuernberg, Nuernberg, Germany
13Dept. of Hematology/Oncology, Charite - Centrum für Tumormedizin, Berlin, Germany
14Hematology and Oncology, Klinikum Harlaching, Munich, Germany
15Dept. of Hematology, University Hospital Grosshadern, Munich, Germany
16III. Department of Internal Medicine, Hematology/Oncology, Technical University of Munich, Munich, Germany
17Department of Hematology, Oncology and Pneumology, Universitaetsmedizin Mainz, Mainz, Germany
18Department of Internal Medicine I, Klinikum Bremen Mitte, Bremen, Germany
19Hematology, Oncology, Palliative Medicine, University of Rostock, Rostock, Germany
20Hematology and Oncology, University of Munster, Munster, Germany
21Department of Hematology and Oncology, University Hospital, Halle, Germany
22Hematology and Oncology, Zentrum Innere Medizin, Gottingen, Germany
23Hematology / Oncology, HSK, Dr.-Horst-Schmidt-Klinik, Wiesbaden, Germany
24Comprehensive Cancer Center Mainfranken, Würzburg University Medical Center, Würzburg, Germany
25Department of Hematology, Oncology and Palliative Care, Ernst von Bergmann Hospital, Potsdam, Germany
26Hematology and Oncology, Diakonie-Klinikum Stuttgart, Stuttgart, Germany
27Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
28Department for Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University Hospital Tuebingen, Tuebingen, Germany
29Dept. of Biostatistics, Tuebingen University Medical School, Tuebingen, Germany

Background: In multiple myeloma (MM), the introduction of novel compounds into first-line intensive treatment pathways has clearly improved patients’ prognosis. Very recently however, specific molecular cytogenetic abnormalities, lactate dehydrogenase elevation and International Staging System 3 disease were identified to be associated with dismal prognosis despite upfront autologous (auto) stem cell transplant (SCT). Consolidative allogeneic (allo) following initial auto SCT was shown to extend progression-free survival (PFS) as well as overall survival (OS) in some prospective studies on newly diagnosed MM patients (pts). Relatively little is known on the impact of cytogenetic features other than chromosome 13q deletion (del13q) on the outcomes of pts undergoing upfront auto followed by allo (auto/allo) SCT.

Patients and methods: When the DSMM V treatment program was designed del13q detected by fluorescence in situ hybridisation (FISH) was accepted as one of the distinct risk factors in MM. We therefore used FISH del13q to define the study’s “high-risk” group and aimed to compare tandem high-dose melphalan 200 mg/m² (Mel) with one cycle of Mel followed by reduced-intensity conditioning (RIC) allo SCT. Allocation to either transplant regimen was by availability of an HLA-matched (at least 9/10 matches) related (MRD) or unrelated donor (MUD). Initially, all pts underwent non-novel compound cytoreduction and chemomobilization of peripheral blood stem cells (PBSC). RIC allo SCT was prepared by fludarabine and melphalan (plus ATG in MUD cases). PFS was the primary endpoint. The study was powered to detect an improvement of 2-year PFS from 20% (tandem Mel) to 40.3% (HR, 1.769).

Results: 199 out of 225 del13q pts with a median age of 53 (range, 30 – 60) yrs who had been enrolled between 10/2001 and 03/2007, were included in the intent-to treat population. Allo SCT was performed in 126/199 pts (63%), 74 of whom (59%) received MUD allografts. At a median follow-up of 49.2 months (mo), 2-year PFS (calculated from day 1 of second SCT) was 59% with auto/allo SCT versus 47% with tandem Mel. Median PFS with auto/allo SCT was 34.5 mo versus 21.8 mo, respectively (p=.005). Two-year non-relapse mortality (NRM) associated with auto/allo SCT was 11.9%. As of yet, there is no difference in OS between the groups, with the median not yet reached for either transplant modality. PFS/OS in auto/allo SCT were independent of donor source (MRD vs MUD). As definitions of cytogenetic risk have evolved over time, we analyzed further FISH abnormalities in pts’ baseline samples: in addition to uniform del13q, 13.6% of pts displayed del17p. Median PFS for del13q/del17p pts after HD Mel was 6 mo versus not reached with auto/allo SCT, respectively (p=.0002). Median OS in del13q/del17p after HD Mel was 23.4 mo versus not reached, respectively (p=.011). In translocation (4;14)/del13q pts (20.7%), median PFS with tandem Mel was 19.3 mo versus 19.1 with auto/allo SCT, respectively (p=.251).

Conclusions: This prospective trial shows auto/allo SCT to significantly extend PFS when compared to tandem HD Mel in a large cohort of del13q MM pts. It is the first study to demonstrate allo SCT in MM can be safely performed from matched unrelated donors at a reasonable rate of NRM. Utilizing a comprehensive set of FISH cytogenetics, our data for the first time demonstrate allo SCT to specifically benefit patients with high-risk features (del13q/del17p). Incremental gain of PFS when compared to tandem Mel was more than 20 months. Extended OS data on the whole study will be presented.


Dr. Stefan Knop is a Hematologist and Oncologist and a Professor at the Julius-Maximilians-Universitat Wurzburg, in Germany. Dr. Knop is Head of the Wilhelm Sander Therapy Unit Multiple Myeloma at the University Hospital Wurzburg. Dr. Knop is the author of several peer-reviewed publications on clinical trials and on treatment recommendations in multiple myeloma and other hematological malignancies.

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