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  • American Society of Hematology  (5)
  • Engelhardt, Monika  (5)
  • 1
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    The Efficacy and Safety of RAD (Lenalidomide, Adriamycin and Dexamethasone) In Newly Diagnosed Multiple Myeloma – First Results of a Phase II Trial by the German DSMM Group
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 1945-1945
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1945-1945
    Abstract: Abstract 1945 Background Prognosis of patients with multiple myeloma (MM) has significantly improved by the introduction of autologous (auto) stem cell transplantation (SCT). The “novel drugs” which have shown activity in relapsed MM are increasingly used in first-line therapy aiming at maximized response prior to SCT. Whether allogeneic (allo) SCT adds to further disease control remains a matter of debate. Our group has shown the RAD regimen (lenalidomide, adriamycin and dexamethasone) to be highly effective and relatively well tolerated in relapsed and refractory MM. Therefore, we decided to explore RAD in the up-front management. Patients and Methods The current phase-II trial (DSMM XII) was designed to include patients (pts) up to the age of 65 years with newly diagnosed MM requiring treatment. We chose four cycles of RAD (lenalidomide 25 mg d-21; infusional adriamycin 9 mg/m2 per day d1-4; dexamethasone 40 mg d1-4 and 17–20; pegfilgrastim 6 mg d 6) every 4 weeks for induction followed by chemomobilization of peripheral blood stem cells. Low molecular weight heparin is mandatory during RAD treatment for thromboprophylaxis. All pts are to undergo one cycle of melphalan 200 mg/m2 followed by auto SCT. A subsequent allo SCT after reduced intensity conditioning (treosulfan/fludarabin) is scheduled for pts featuring at least one previously identified (cytogenetic or serologic) risk factor. Those with very favourable risk are to proceed to a second auto SCT. All patients will receive 12 months of lenalidomide maintenance (10 mg per day) on a continuous basis. Here, we present results of a planned safety analysis. Results 75 pts with a median age of 57 (range, 35–66) years have been enrolled by 11 German centers between 9/2009 and 7/2010. Currently, 51 pts are evaluable for toxicity during RAD induction: In all, 25 severe adverse events (SAEs) were reported for 16 subjects (31%). 68% of SAEs were assessed to be drug-related. Most frequent events were venous thrombosis (VTE; n=4), pyrexia (n=3) and syncope (n=2). Neutropenia, extravasation, pleural effusion, and allergic dermatitis accounted for one SAE each. 17 patients, 10 of whom (59%) had ISS stage II/III disease, are evaluable for post-induction response. Ten subjects (59%) achieved VGPR or better: 6 pts had VGPR and 2 patients each CR and stringent CR as assessed by the investigator. Conclusions Our preliminary results suggest RAD to be a well tolerated and effective novel induction protocol in up-front treatment of MM. Notably, incidence of severe hematotoxicity observed so far is significantly lower than was in our previous study in relapsed/refractory pts. Incidence of VTE was acceptable while no neurotoxicity occurred. Updated results will be presented. Disclosures: Knop: Celgene Germany: Consultancy, Honoraria. Off Label Use: Lenalidomide in combination with doxorubicin in myeloma first-line therapy. Reichle:Celgene Germany: Research Funding. Einsele:Celgene Germany: Consultancy, Honoraria. Bargou:Celgene Germany: Consultancy, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.1945.1945
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 2
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    Allogeneic Stem Cell Transplant Versus Tandem High-Dose Melphalan for Front-Line Treatment of Deletion 13q14 Myeloma – An Interim Analysis of the German DSMM V Trial.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 51-51
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 51-51
    Abstract: Abstract 51 Background Allogeneic stem cell transplantation (allo SCT), a treatment modality based on transfer of immunocompetent donor lymphocytes offers curative potential to subjects with a variety of hematological cancers. In multiple myeloma (MM), high-dose melphalan followed by autologous stem cell transplantation (auto SCT) is adopted as a standard of care. However, it remains palliative since virtually all patients (pts) relapse and renders allo SCT an option of interest. Deletion of chromosome 13q14 (13q-) in MM has been shown to negatively impact prognosis. Therefore, improvement of therapy for 13q- pts is highly desirable. Patients and methods A prospective two-arm multi-center trial (DSMM V) was set up by our group to compare tandem high-dose melphalan 200 mg/m2 (HD Mel) with a reduced intensity conditioning allo-SCT after one cycle of HD Mel for 13q- MM. Eligibility criteria were 13q- on bone marrow FISH analysis; age up to 60 years; newly diagnosed MM in Salmon and Durie stages II and III; and measurable disease. Allocation to either treatment arm was by availability of an HLA-matched (one mismatch allowed) volunteer related (VRD) or unrelated donor (VUD). Initially, all pts received four cycles of anthracycline/dexamethasone-based induction followed by chemomobilization of peripheral blood stem cells (PBSCT) and one cycle of HD Mel. Allogeneic SCT was performed after preparation with fludarabine (30 mg/m2 for 3 consecutive days) and melphalan 140 mg/m2. ATG was administered for VUD transplants. Results 199 pts with a median age of 53 (range, 30 – 60) years were enrolled between October 2002 and March 2007 and included in this interim analysis. Sixty-seven percent had stage III disease. Allo SCT was performed in 126 of 199 pts (63%), 76 of whom (60%) received VUD allografts. The remaining 73 subjects uniformely received tandem HD Mel. Pts following allo SCT were more likely to achieve CR (59%) when compared to tandem HD Mel (32%; p=.003) within one year after end of therapy. Similarly, overall response rate was significantly higher with allo SCT (91% versus 86%; p=.003). Of note, depth of response to allo SCT was not associated with presence of acute graft-versus-host disease (GVHD): 62% CR with grades II to IV GVHD vs 58% CR with grades 0 and I (p=.75). Treatment-related mortality (TRM) at 2 years from allo SCT was 16/126 (12.7%). At a median follow up of 25 months for tandem HD Mel and 34 months for allo SCT, projected 3-year overall survival is 72% (auto) and 60% (auto/allo SCT; p=0.22), respectively. Conclusions This is the largest trial on first-line allogeneic stem cell transplant in MM so far. Our interim results show a higher CR rate in FISH 13q- subjects undergoing allo SCT when compared to tandem HD Mel. Despite a majority of allografts in our study being delivered from unrelated donors, TRM was comparable to trials confined to sibling transplants. At a relatively short follow-up, there is not yet a difference between both arms regarding OS, albeit longer follow-up may be important as previously described. This as well as analysis of the impact of donor type and chronic GVHD on outcome will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.51.51
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
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  • 3
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    Autologous Followed By Allogeneic Versus Tandem-Autologous Stem Cell Transplant in Newly Diagnosed FISH-del13q Myeloma
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 43-43
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 43-43
    Abstract: 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. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.43.43
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 4
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    Lenalidomide, Adriamycin and Dexamethasone (RAD) As An Induction Regimen In Newly Diagnosed Multiple Myeloma – Interim Results From a German Multicenter Phase II Trial
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 1987-1987
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1987-1987
    Abstract: Induction triplets utilizing at least one of the “novel drugs” and steroids with or without chemotherapy are considered current standard of care in newly diagnosed, symptomatic multiple myeloma (MM). Medically fit patients (pts) remain candidates for subsequent autologous (auto) stem cell transplant (SCT) while use of allogeneic (allo) SCT remains a matter of debate. As we had previously shown the RAD regimen to be well tolerated and highly effective in relapsed and relapsed/refractory MM, we evaluated this combination in first-line treatment. Methods The current phase II trial (DSMM XII) was designed to include a total of 190 pts up to 65 years of age with symptomatic MM. Four 4-week cycles of RAD (lenalidomide 25 mg/day, d 1-21; adriamycin 9 mg/m² as 24-hour infusion, d1-4; oral dexamethasone 40 mg, d1-4 and 17-20; pegfilgrastim 6 mg, d 6) preceded stem cell chemomobilization. Low-molecular weight heparin for prophylaxis of venous thromboembolic events (VTE) was mandatory. Pts received either tandem auto SCT (melphalan 200 mg/m²; Mel200) or auto followed by allo SCT. Allo SCT (preparative regimen: treosulfan/fludarabine) was reserved for pts featuring at least one cytogenetic or serologic risk factor who had a matched sibling or unrelated donor available. Lenalidomide maintenance was administered for one year following both tandem auto and auto/allo SCT. This is the second pre-planned interim safety and efficacy analysis. Results Eighty-nine pts with a median age of 54 (range, 30-65) years, who were recruited between August 2009 and October 2010, are evaluable. Fifty pts (56.2%) had ISS stage II/III disease and in all except three, molecular cytogenetic analysis was performed. Incidences of chromosomal abnormalities were as follows: deletion of (del) 13q, 24.7%; translocation t(4;14), 12.4%; t(14;16), 3.4%; and del 17p, 5.6%. Treatment-related mortality with RAD induction was 0% while 61.8% of pts had treatment-emergent SAEs. Seventeen pts (19%) experienced neutropenia of grades 1 to 4. Incidences of severe (grades 3/4) and febrile neutropenia were 5.6 and 1%, respectively. Seven pts each (8%) had pneumonia and VTE, respectively. Post-RAD-induction CR/sCR and at least VGPR rates were 9% and 47.2%, respectively. All 78 pts with at least stable disease successfully mobilized stem cells. Overall response rate (at least partial response, PR) following first SCT on an intention-to-treat basis was 83%. Twelve pts each (13.5%) achieved centrally confirmed complete response (CR) or stringent (s)CR, respectively, and 54 pts (60.7%) had at least very good PR (VGPR). Conclusions This interim analysis shows RAD to be very well tolerated and effective in first line treatment of symptomatic MM. Mel200 further increased rates of deep response (at least VGPR) achieved by RAD induction. We are currently comparing this regimen to bortezomib, lenalidomide and dexamethasone (VRd) in a phase III trial. Disclosures: Knop: Celgene GmbH: Honoraria. Off Label Use: Lenalidomide and doxorubicin in newly diagnosed multiple myeloma. Engelhardt:MSD, Janssen-Cilag: Research Funding. Einsele:Celgene GmbH: Consultancy, Honoraria, Research Funding. Bargou:Celgene GmbH: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.1987.1987
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 5
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    Online Resource
    RAD (Lenalidomide, Adriamycin and Dexamethasone) Is a Novel and Very Effective Induction Regimen in Newly Diagnosed Multiple Myeloma Preceding a Risk-Adjusted Transplant Strategy,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3967-3967
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3967-3967
    Abstract: Abstract 3967 Background Triple combinations utilizing dexamethasone, at least one of the “novel drugs” and either an alkylating agent or an anthracycline are currently considered standard induction regimens in newly diagnosed multiple myeloma (MM). In patients (pts) deemed medically fit, subsequent autologous (auto) stem cell transplantation (SCT) yet is a mainstay of care. Whether allogeneic (allo) SCT in first line treatment of MM further improves prognosis remains, however, a matter of debate. We have shown the RAD regimen to be highly effective and well tolerated in relapsed and refractory MM. Therefore, we decided to integrate this combination as a means of induction into the up-front management. Patients and methods The current phase-II trial (DSMM XII) was designed to include pts up to the age of 65 years with newly diagnosed, symptomatic MM. We chose four cycles of RAD induction (lenalidomide 25 mg/day d 1–21; infusional adriamycin 9 mg/m2 and day d1-4; dex 40 mg d1-4 and 17–20; pegfilgrastim 6 mg d 6) every 4 weeks followed by chemomobilization (cyclophosphamide, etoposide) of peripheral blood stem cells. Thromboprophylaxis by low molecular weight heparin is mandatory. All pts are scheduled to receive two transplants, the first of which being an auto SCT following standard high-dose melphalan (200 mg/m2). A subsequent allo SCT after preparation with treosulfan/fludarabin is scheduled for pts featuring at least one cytogenetic or serologic risk factor (RF). Those without any RF (“very favourable risk”) are to proceed to a second auto SCT. All patients will receive 12 months of lenalidomide maintenance. The primary end point of this trial is response to risk-adapted transplant as assessed after second SCT. This is the first planned efficacy interim analysis after 50 pts having terminated induction treatment. Results 148 pts with a median age of 55.5 (range, 30–66) years have been enrolled by 16 German centers between 9/2009 and 7/2011. In addition to the intended sample size, 2 pts had progressive disease for a total of 52 pts being evaluable for post-induction response according to the IMWG criteria. 32 pts (62%) had ISS stage II and III disease and all except three were evaluable for cytogenetic analysis based on fluorescence in situ hybridization (FISH). Incidences of chromosomal abnormalities were as follows: deletion of 13q, 31%; translocation (4;14), 15%; and deletion of 17p, 12%. Overall response rate was 79% including a 52% rate of at least very good partial response (VGPR). Seven pts (13%) achieved confirmed complete response (CR) and stringent CR. 18/52 pts (35%) experienced severe treatment-emergent adverse events (t-SAEs) with an incidence of hematologic events of 4%. Incidences of infections and venous thromboembolism were 8% and 6%, respectively. Conclusions Results from this interim analysis indicate RAD to be a very effective and well tolerated induction protocol in newly diagnosed MM. High-quality response (VGPR or better) to induction is known to be a major prognosticator for long-term prognosis in a given patient. Thus, combination of RAD with risk-adjusted SCT may contribute to enhanced disease control in a substantial proportion of pts. Disclosures: Knop: Celgene Germany GmbH: Consultancy. Off Label Use: Lenalidomide in combination with dexamethasone and adriamycine in first line treatment of multiple myeloma. Langer:Celgene Germany GmbH: Consultancy. Gramatzki:Novartis, Celgene: Consultancy, Research Funding. Einsele:Celgene Germany GmbH: Consultancy, Honoraria. Bargou:Celgene Germany GmbH: Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3967.3967
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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