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Dr. Einsele - An Overview of Two Studies Conducted at the University Clinic of Würzburg
Hermann Einsele, MD
University Clinic of Würzburg
Würzburg, Germany
Member, IMF Board of Scientific Advisors

"A Randomized Comparison of Total-Marrow Irradiation, Busulfan and Cyclophosphamide with Tandem High-Dose Melphalan inPatients with Multiple Myeloma" and "The Efficacy and Toxicity of the RAD Regimen (Revlimid, Adriamycin, Dexamethasone) in Relapsed and Refractory Multiple: Myeloma A Phase I/II Trial of Deutsche Studiengruppe Multiples Myelom"

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[728] A Randomized Comparison of Total-Marrow Irradiation, Busulfan and Cyclophosphamide with Tandem High-Dose Melphalan in Patients with Multiple Myeloma. Session Type: Oral Session

Stefan Knop, Katja Bauer, Holger Hebart, Hannes Wandt, Lorenz Trumper, Peter Liebisch, Georg Maschmeyer, Dietrich Peest, Hans H. Wolf, Nikolaus Kroger, Christian Straka, Michael Pfreundschuh, Paolo Coser, Christoph Meisner, Lothar Kanz, Hermann Einsele Hematology/Oncology, University Hospital, Wurzburg, Germany; Hematology/Oncology, University Hospital, Tubingen, Germany; Hematology, Klinikum Nord, Nuremberg, Germany; Hematology, University Hospital, Gottingen, Germany; Hematology, University Hospital, Ulm, Germany; Hematology, Klinikum, Potsdam, Germany; Hematology, Medical School, Hannover, Germany; Hematology, University Hospital, Halle, Germany; Stem Cell Transplantation, University Hospital, Hamburg, Germany; Hematology, University Hospital, Munich, Germany; Hematology, University Hospital, Homburg, Germany; Hematology, Regional Hospital, Bolzano, Italy; Statistics, University Hospital, Tubingen, Germany

Background Myeloablative chemotherapy with support of autologous peripheral blood stem cells (APBSC) has widely been accepted as a standard of care in patients (pts) with newly diagnosed multiple myeloma (MM). High-dose (HD) melphalan (Mel) 200 mg/m was considered superior to total-body irradiaton (TBI) plus Mel 140 mg/m for toxicity reasons. Since MM plasma cells are inherently responsive to irradiation, our group evaluated TBI aimed at reduced organ toxicity by shielding lungs and liver (total-marrow irradiation [TMI], 9 Gy) combined with busulfan (Bu, 12 mg/kg) and cyclophosphamide (Cy, 120 mg/kg) in a previous phase I/II trial (Einsele et al, Bone Marrow Transplant, 2003). Patients and methods In the current study (DSMM I), subjects with previously untreated MM in Durie-Salmon stages II/III were randomly assigned to either receive one course of TMI/Bu/Cy versus two cycles of HD Mel 200 mg/m each with APBSC transplantation if having had an adequate number of stem cells collected and at least stable disease. Primary end point was event-free survival (EFS), secondary end points overall (OS) and disease-free survival (DFS). Results A total of 294 pts (median age, 54 years), 246 of whom completed stem cell harvest were enrolled between 8/1998 and 1/2002 by 46 centres. Eventually, 198 (n=100 TMI/Bu/Cy and n=98 HD Mel) pts were randomized and included into the ITT population. The safety population (n=80 TMI and n=118 HD Mel, due to 18 pts switching to Mel) was analyzed for toxicity and response. CR rate before HD therapy was 7.0% (7/100) in the TMI and 6.1% (6/98) in the Mel arm respectively. Significantly more pts receiving TMI/Bu/Cy experienced WHO grades 3 and 4 pulmonary and gastrointestinal toxicity and pain. Following HDT, CR rate increased to 17.5% (14/80, TMI) and 32.2% (38/118, HD Mel; p=.022) respectively. After a median follow-up of 1447 days, median EFS in the TMI group was 1161 days versus 1090 days for HD Mel (p=.812). Probability of 4-year OS was 72.7% (95%-CI: 62.1-80.7) with TMI and also 72.7% (95%-CI: 61.7-81.1) after HD Mel (p=.754). For pts in CR following HD therapy, probability of 4 year DFS was 62.4% (95%-CI: 33.6-81.6) for TMI vs. 50.4% (95%-CI: 30.6-67.3) for HD-Mel (p=.138). Conclusion In this randomized trial on pts with newly diagnosed MM, the irradiation-based regimen was associated with more pulmonary and GI toxicity when compared to HD Mel. Incidences of other toxicities including hepatotoxicity, however, were not different between the two treatment arms. CR rate was superior for HD-Mel, while there was no difference in OS and EFS between the two treatment arms. Subjects achieving CR may be more likely to enjoy prolonged DFS after TMI/Bu/Cy.

Abstract #728 appears in Blood, Volume 110, issue 11, November 16, 2007

Keywords: High Dose Therapy|Total Body Irradiation|Toxicity

Disclosure: No relevant conflicts of interest to declare.

Tuesday, December 11, 2007 7:45 AM

Session Info: Simultaneous Session: Autologous Transplantation for Plasma Cell Disorders: Transplant Regimens (7:30 a.m.-9:00 a.m.)

[2716] The Efficacy and Toxicity of the RAD Regimen (Revlimid, Adriamycin, Dexamethasone) in Relapsed and Refractory Multiple Myeloma A Phase I/II Trial of Deutsche Studiengruppe Multiples Myelom. Session Type: Poster Session, Board #906-II

Stefan Knop, Christian Gerecke, Peter Liebisch, Max S. Topp, Georg Hess, Uwe Platzbecker, Sandra Frohnert, Hermann Einsele, Ralf Bargou Wrzburg University Hospital, Wrzburg, Germany; Charit Campus Buch, Berlin, Germany; University Hospital, Ulm, Germany; University Hospital, Mainz, Germany; University Hospital, Dresden, Germany

Background: Lenalidomide (Revlimid; Len) has important efficacy in relapsed/refractory multiple myeloma (MM), with or without dexamethasone (Dex). Addition of Adriamycin might further enhance antimyeloma activity of Len and Dex in patients (pts) with relapsed/refractory MM. We report data from a multicentre dose-finding phase I/II trial involving the RAD regimen (Revlimid, Adriamycin, Dex). Methods: A modified Fibonacci design was chosen to enroll MM pts with measurable disease and <3 prior treatment lines. Pts were required to have adequate hematopoietic and organ function; prior Len treatment was an exclusion criterion. RAD was administered for 6 28-day cycles along with either aspirin 100 mg/day or low-molecular-weight heparin for prophylaxis of venous thromboembolism (VTE). Phase I was a dose-escalating study with increasing doses of either Len (10-25 mg/day) or Adriamycin (4-9 mg/m/day). Using pegfilgrastim support (G; 6 mg, day (d) 6), the maximum tolerated dose was not reached, even at the 5th dose level (DL; 5+G: Len 25 mg d1-21; Adriamycin 9 mg/m as a 24h infusion d1-4; and Dex 40 mg d1-4 and 17-20 of each 28-day cycle). This dose was next used in phase II. Results: 69 pts with a median age of 65 (range, 46-77) years were included in the study and received at least 3 cycles. Prior anti-myeloma treatments included prior autologous stem cell transplantation (72%), prior allogeneic SCT (12%), bortezomib (57%), and thalidomide (20%). Grades 3/4 neutropenia and thrombocytopenia occurred in 44% and 32% of pts, respectively. Incidence of VTE was 7.5%. No neuropathy was diagnosed de novo. Three patients prematurely discontinued the trial due to catheter-related septicemia, thrombosis of basilar artery, and prolonged pneumonia. Fifty pts evaluable for response assessment were divided into 2 groups: 20 pts from phase I, who received doses up to DL 5+G and 30 pts on DL 5+G from both phase I and II. Using the European Group for Blood and Marrow Transplantation criteria, overall response rate (ORR) for DL 1-4 was 60% including 5 pts (25%) with near complete response (nCR). ORR for 30 pts on DL 5+G was 87%, including 7 pts (23%) with immunofixation-negative CR and an additional 18 pts (60%) with nCR. Median overall time to progression was 40 (4 to 75+) weeks with a very short median time to response of 4 (3-28) weeks. Several pts were evaluable for cytogenetic analysis performed by FISH: 17/37 (46%) had 13 q deletion (del[13q]). Partial response (PR) or better was seen in 12/17 pts (71%) with del(13q). Chromosomal translocation (4;14) was present in 4/25 (16%) evaluable pts with 1 having progressive disease (PD) and 3 PR. Del(17p) involving the tumor suppressor gene p53 and being associated with a particular adverse prognosis was found in 6/31 pts (19%): PR was noted in 2 pts, while 2 pts each had stable disease and PD. Conclusion: RAD incorporating 25 mg of Len for 21 of 28 days demonstrated potential utility as a new combination regimen for heavily pre-treated myeloma pts. Toxicity was moderate and predictable. The efficacy of this regimen is considerable as a CR plus nCR rate of 83% was observed with DL 5+G. In addition, high responses were observed even in patients displaying high-risk cytogenetic abnormalities.

Abstract #2716 appears in Blood, Volume 110, issue 11, November 16, 2007

Keywords: Dose Escalation|Cytogenetics|Immunomodulatory Thalidomide Analog

Disclosure: Research Funding: Stephan Knop, Hermann Einsele, Uwe Platzbecker, Ralf Bargou (Celgene). Honoraria Information: Stephan Knop, Hermann Einsele, Uwe Platzbecker, Ralf Bargou (speakers honoraria; Celgene).

Sunday, December 9, 2007 6:00 PM

Session Info: Poster Session: Myeloma: Relapsed and Refractory Multiple Myeloma (6:00 p.m.-8:00 p.m.)

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