Kooperativer Bibliotheksverbund

In: The Lancet Oncology, Elsevier BV, Vol. 11, No. 11 ( 2010-11), p. 1057-1065

Type of Medium: Online Resource

ISSN: 1470-2045

URL: Article

DOI: 10.1016/S1470-2045(10)70206-0

Language: English

Publisher: Elsevier BV

Publication Date: 2010

detail.hit.zdb_id: 2049730-1

In: Blood Advances, American Society of Hematology, Vol. 2, No. 18 ( 2018-09-25), p. 2400-2411

Abstract: Despite the recent progress in treatment of multiple myeloma (MM), it is still an incurable malignant disease, and we are therefore in need of new risk stratification tools that can help us to understand the disease and optimize therapy. Here we propose a new subtyping of myeloma plasma cells (PCs) from diagnostic samples, assigned by normal B-cell subset associated gene signatures (BAGS). For this purpose, we combined fluorescence-activated cell sorting and gene expression profiles from normal bone marrow (BM) Pre-BI, Pre-BII, immature, naïve, memory, and PC subsets to generate BAGS for assignment of normal BM subtypes in diagnostic samples. The impact of the subtypes was analyzed in 8 available data sets from 1772 patients’ myeloma PC samples. The resulting tumor assignments in available clinical data sets exhibited similar BAGS subtype frequencies in 4 cohorts from de novo MM patients across 1296 individual cases. The BAGS subtypes were significantly associated with progression-free and overall survival in a meta-analysis of 916 patients from 3 prospective clinical trials. The major impact was observed within the Pre-BII and memory subtypes, which had a significantly inferior prognosis compared with other subtypes. A multiple Cox proportional hazard analysis documented that BAGS subtypes added significant, independent prognostic information to the translocations and cyclin D classification. BAGS subtype analysis of patient cases identified transcriptional differences, including a number of differentially spliced genes. We identified subtype differences in myeloma at diagnosis, with prognostic impact and predictive potential, supporting an acquired B-cell trait and phenotypic plasticity as a pathogenetic hallmark of MM.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2018018564

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 2876449-3

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 728-728

Abstract: Introduction: Daratumumab (DARA)-based regimens are effective and well tolerated in both newly diagnosed and relapsed/refractory multiple myeloma (RRMM) patients. However, the prognosis for patients who have become refractory to proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and DARA is poor. A better understanding of determinants of response and mechanisms of resistance to DARA may lead to new rationally designed treatment strategies. We therefore characterized the effect of DARA on the immune system in MM patients treated with DARA monotherapy in part A of the DARA-ATRA study (ClinicalTrials.gov NCT02751255). Methods: In part A of this prospective multicenter phase 2 trial, 63 DARA-naïve patients were treated with DARA monotherapy (16 mg/kg; approved schedule). Median number of prior lines of treatment was 4 (range 2-11), all patients were previously exposed to lenalidomide and a PI; 89% was refractory to an IMiD, 71% to a PI and 67% to both IMiD and PI. Bone marrow (BM) aspirates obtained at baseline (BL) and at progression (PD; primary refractory, or acquired resistance after prior response) were subjected to deep immune profiling using 28 surface- and intracellular proteins measured by flow cytometry (BL n=51, PD n=47). In a subset of these patients (BL n=39, PD n=33) mass cytometry (CyTOF) was also performed profiling 39 proteins. In addition, peripheral blood (PB) samples obtained at BL (n=44) and PD (n=37) were analyzed using CyTOF. Computational analyses of flow data were performed using UMAP and FlowSOM; CyTOF data were analyzed using SPADE and Freeviz. Statistical analyses included Wilcoxon rank-sum and signed-rank tests, Generalized Linear Mixed Models and ANOVA. Results: A partial response or better was achieved in 41% of patients treated with DARA monotherapy. We compared immune profiles of responding and non-responding (primary-refractory) patients. At BL, the percentages of MM-, T-, B- and NK cells in BM were similar between both groups. However, NK cells of non-responding patients had a lower proportion of CD16 + (P=0.029), and a higher proportion of TIM-3 + (P=0.010) and HLA-DR + (P=0.043) NK cells, suggesting an exhausted phenotype. Non-responders also had a higher proportion of TIM-3 + CD4 + (P=0.022) and TIM-3 + CD8 + T-cells (P=0.004), and a higher proportion of TIM-3 + regulatory T-cells (Tregs) (P=0.042). A higher proportion of TIM-3 + -NK cells, -T-cells, or -Tregs in BM was also associated with poor progression-free and overall survival (PFS; OS). In addition, clinical characteristics associated with poor PFS such as LDH (P=0.016), extramedullary disease (P=0.001) and (R-)ISS stage III (P=0.015) were associated with an increased number of phenotypically exhausted NK- and T-cells. Similar to prior studies, DARA treatment resulted in reduced levels of CD38 on all immune cell subsets and a marked decrease in Tregs, regulatory B cells (Bregs) and NK cells in both BM and PB. Upon acquired resistance, remaining NK cells displayed higher proportions of TIM-3 + (P=0.022), HLA-DR + (P=0.0007) and LAG-3 + (P=0.011), and lower proportions of CD16 + (P=0.002) (Figure 1), compatible with an exhausted phenotype. Furthermore, disease progression was associated with an increase in CD4 + and CD8 + terminally differentiated effector memory T-cells and a decrease in CD4 + and CD8 + central memory T-cells in BM. There was no significant change in the proportion of T-cells expressing immune checkpoint molecules. CyTOF analysis of BM and PB samples confirmed flow cytometric findings. Furthermore, data-driven analysis identified immune profiles specific to progression, including a significant decrease in the fraction of Granzyme B + NK cells, and increase in the fraction of Granzyme B + Bregs at the time of progression. Based on NK cell depletion and -exhaustion observed at PD, we hypothesized that NK cell repletion may restore DARA sensitivity. Indeed, in ex vivo experiments we show that DARA-resistance can be overcome by addition of healthy donor derived NK cells to MM cells obtained from DARA-refractory patients. Conclusion: Here we show that an increased proportion of NK cells with an exhausted phenotype is associated with primary and acquired DARA-resistance, which is in line with the important role of NK cells in DARA-mediated tumor cell elimination ex vivo. Future DARA-based treatment strategies may benefit from reinvigorating NK cells and restoring their cytotoxic capacities. Figure 1 Figure 1. Disclosures Zweegman: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Minnema: Celgene: Other: Travel expenses; Alnylam: Consultancy; Cilag: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; BMS: Consultancy. Broyl: Celgene/BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Kersten: Kite/Gilead: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Roche: Honoraria; Takeda: Consultancy; BMS/Celgene: Consultancy; Miltenyi Biotech: Consultancy. Krevvata: Janssen: Current Employment. Casneuf: Janssen: Current Employment. Abraham: Janssen: Current Employment. Verona: Janssen: Current Employment. Smets: Janssen: Current Employment. Vanhoof: Janssen: Current Employment. Cortes-Selva: Janssen: Current Employment. van Steenbergen: Biolizard working for Janssen: Current Employment. Vieyra: Janssen: Current Employment. Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Mutis: Janssen: Honoraria; Genmab: Research Funding; Takeda: Research Funding; Novartis: Research Funding; ONK Therapeutics: Research Funding. van de Donk: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-150913

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 690-690

Abstract: Background: In multiple myeloma, tumor cell survival, disease progression and therapy response are influenced by signals derived from the non-malignant bone marrow niche. This notwithstanding, a detailed in-vivo definition of the cells that define the multiple myeloma niche is lacking. Mesenchymal stromal cells are important niche constituents. Recent progress made with single cell transciptomics suggests that mesenchymal stromal cells are a dynamic population of cells that can exist as several subsets with functionally distinct activation and differentiation profiles. Aim: To identify mesenchymal stromal cell subsets specific for the multiple myeloma bone marrow niche, by comparing stromal cells from myeloma patients to non-cancer controls. Methods: The non-hematopoietic bone marrow niche was isolated from viably frozen bone marrow aspirates from 10 newly diagnosed multiple myeloma patients (6 hyperdiploid, 3 t(11;14) and 1 with deletion of 17p) and 2 non-cancer controls using high speed cell sorting. The purified cells were analyzed by 10X Genomics single cell sequencing directly post-thawing, without prior cell culture. From 10 multiple myeloma patients we generated single cell transcriptomes with an average read-depth of 20,000 reads per cell of in total 12,000 niche cells and from the 2 non-cancer controls a total of 3,500 niche cells. Transcriptomes were pooled and subjected to clustering analyses using the Seurat package for R to identify genetically distinct clusters of niche cells and changes in these clusters associated specifically with multiple myeloma. Results: The bioinformatical analyses generated 10 distinct clusters of niche cells, all of which were present in both non-cancer and multiple myeloma bone marrow. One of these clusters contained CDH5+ endothelial cells while the remaining 9 clusters were subsets of CXCL12+LEPR+ mesenchymal stromal cells. Because samples were taken from the central marrow by aspiration, peripheral endosteal or neuronal lineage cells were not represented in these clusters. Gene Set Enrichment Analysis (GSEA) of the stromal cell clusters from myeloma versus non-cancer controls revealed two significantly altered pathways: TNF signaling via NF-kB and Inflammatory response. Detailed analyses of the individual stromal cell clusters identified two clusters that were responsible for the inflammatory changes identified by GSEA. Both clusters were present in all myeloma patients, constituted on average 20% of total stromal cells and were defined by transcription of the inflammatory chemokines CXCL2, CXCL3 and CXCL8 the cytokine IL6. All these transcripts were absent from the equivalent clusters in control bone marrow. The presence of inflammatory stroma in the multiple myeloma niche indicates either the appearance of a novel stromal cell subset, or activation of pre-existing stromal cells. GSEA analyses suggested inflammatory signaling, and to functionally confirm this, we tested whether activation of stromal cells would induce the inflammatory stromal phenotype. Stimulation of primary human stromal cells in vitro with recombinant TNF was sufficient to induce transcription of CXCL2, CXCL3 and CXCL8, recapitulating the inflammatory transcriptome. Moreover, manual removal of these TNF target genes from the in-silico clustering analyses led to a merging of the inflammatory clusters with non-inflammatory clusters. This indicates that the major distinguishing feature of the myeloma-specific stromal cells are genes induced upon stromal cell activation. Conclusion: Through single cell transcriptomic analyses we have identified the presence of activated inflammatory stromal cells associated with TNF signaling in the multiple myeloma stromal niche. These inflammatory stromal cells are reminiscent of pathogenic cancer-associated fibroblasts found in solid tumors, where these cells create a pro-tumorigenic niche that favors tumor survival and proliferation while simultaneously inhibiting anti-cancer immunity. These findings represent the first description of myeloma-specific stromal cell subsets, and provide novel cellular targets for interventions aimed at disrupting the pro-tumorigenic microenvironment in multiple myeloma. Disclosures Broyl: Celgene, amgen, Janssen,Takeda: Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123012

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 392-392

Abstract: Introduction: Clinical development of bortezomib in multiple myeloma (MM) included pharmacogenomic gene expression profiling (GEP) of pre-treatment tumor biopsies in order to evaluate the feasibility of developing predictive classifiers in prospective clinical trials and to better define the biological pathways related to drug sensitivity. By partitioning the samples into train (n=101) and test (n=80) datasets, statistically significant classifiers of response and survival were identified and then validated [Mulligan G, et al: Blood. 2007; 109:3177–88]. Here we describe specific genes and biological pathways associated with bortezomib efficacy in relapsed MM. Methods: Using tumor GEP data from 188 patients treated with single-agent bortezomib we identified genes associated with overall survival (OS), as well as genes associated with response (R) or progressive disease (PD) after bortezomib therapy. These clinical endpoints were also analyzed with biological pathway algorithms including GSEA [Subramanian A, et al: Proc Natl Acad Sci2005; 102:15545–50] Ingenuity Pathway Analysis and Gene Ontology/GATHER. These results were then compared to GEP data from a patient subset (n=76) treated with single-agent dexamethasone and also cell lines selected for differential sensitivity to bortezomib. Results: A comparison of R and PD highlighted numerous differentially expressed genes; approximately 200 were over-expressed in R and 500 were over-expressed in PD (t-test & lt;0.01). R-associated genes include signaling molecules like TRADD, CFLAR and TANK, while PD-associated genes included oncogenes (NRAS), apoptotic regulators (DAP3) and cancer antigens (CTAG). Pathway tools helped to integrate and extend these observations, consistently identifying NFkB activation and overexpression of adhesion pathways as R-associated. Overexpression of protein synthesis and mitochondrial pathways were PD-associated. The overexpression of pathways such as NFkB, adhesion and cytokines appear linked specifically with bortezomib and not dexamethasone sensitivity. These approaches were also applied to patient survival. In contrast to analyses of single genes, the pathway tools highlighted links between response and survival, including adhesion and inflammatory cytokine pathway expression. Conclusions: This study highlights the diversity of biological pathways expressed in MM and the utility of clinical genomics to associate pathways with activity of single-agent bortezomib.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.392.392

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1879-1879

Abstract: Introduction: Daratumumab (DARA) monotherapy is effective and well tolerated in heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients. However, approximately 70% of patients do not respond and eventually all patients will develop progressive disease. DARA treatment results in depletion of CD38+ immune suppressor cells and thereby increased T cell frequencies. A partner drug with immune stimulating activity through a different mechanism of action could further improve the efficacy of DARA. As a single agent, the Programmed Death (PD)-1 checkpoint inhibitor nivolumab induced only stable disease in 67% of RRMM. Immune modulation through targeting CD38 combined with blocking the PD-1/PD-L1 axis may lead to improved T and NK cell activity and therefore better anti-MM efficacy. Preclinical studies showed that cyclophosphamide has synergistic activity with both DARA and PD-1 inhibitors. In this study, we investigate the efficacy and safety of DARA combined with nivolumab, with or without low-dose cyclophosphamide, in RRMM. This trial is registered at ClinicalTrials.gov as NCT03184194. Methods: In part A of this prospective multicenter phase 2 trial, we treated 6 patients with nivolumab-daratumumab (ND), and subsequently 6 patients with nivolumab-daratumumab-cyclophosphamide (NDc) as safety run-in. Next, 28 patients were randomized between both treatment arms at a 1:1 ratio. Twenty additional patients will be treated with either ND or NDc in part B, based on safety and efficacy data as derived in part A. Patients were treated with 28-day cycles until progressive disease. Daratumumab 16 mg/kg i.v. was administered weekly in cycles 1-2, biweekly in cycles 3-6 and every 4 weeks from cycle 7. Nivolumab was administered biweekly (240mg i.v) in cycles 1-6 (in cycle 1 on day 2 and 16) and every 4 weeks (480mg i.v ) thereafter. In the NDc arm, low-dose oral cyclophosphamide (50mg once daily) was given continuously. Inclusion criteria were age ≥18 years, WHO performance score of 0-2, ≥2 prior therapies, lenalidomide-refractory disease, and prior treatment with a proteasome-inhibitor-containing regimen for ≥2 consecutive cycles. Main exclusion criteria were platelet count 〈 75x109/L, absolute neutrophil count 〈 1.0x109/L, FEV1 〈 50%, significant hepatic or renal dysfunction (CrCl 〈 30 mL/min), or active autoimmune disease or inflammatory disorder. All patients gave written informed consent. The study was conducted in accordance with the principles of the Declaration of Helsinki. In this first planned interim analysis we report on efficacy (overall response rate (ORR)) and safety of part A of the study. Results: Between February 2018 and January 2019, 40 patients were enrolled in part A of this study. The demographics are described in Table 1. At data cut-off (July 1st 2019), 13 patients were still on treatment. Median follow-up of surviving patients is 8.6 months (range 5.0-16.1). The ORR was 50% in both treatment groups (Figure 1); the disease control rate (≥ stable disease) was 85% for ND and 80% for NDc. Ten patients (25%) died due to progressive disease, which was equally distributed over treatment arms. Two patients died during NDc treatment: one (2.5%) due to a cardiac arrest and one (2.5%) due to an Aspergillus fumigatus infection. Non-hematologic toxicity was manageable: daratumumab-associated infusion related reactions (IRRs) occurred in 8 (20%) patients, all during the first administration and all grade ≤3. No IRRs related to nivolumab were reported. Two immune-mediated adverse events occurred: both concerned grade 2 hypothyroidism. The infection rate was higher in patients treated with NDc (24 infections in 12 patients; CTC grade ≥3 in 25% of infections), compared to ND treatment (13 infections in 9 patients; CTC grade ≥3 in 8%). A higher need for supportive care in the form of granulocyte-colony stimulating factor, erythrocyte- and/or platelet transfusion was found in the NDc arm (n=10; 50%), compared to ND treatment (n=6; 30%). Conclusion: Here we show for the first time that, although follow-up is still short, the combination of daratumumab and nivolumab may be a new therapeutic regimen with an acceptable safety profile in RRMM. Addition of low-dose cyclophosphamide did not improve ORR, but increased the frequency of infections and hematologic toxicity, when compared to ND alone. Therefore, the nivolumab-daratumumab regimen was selected for further evaluation in part B. Disclosures Minnema: Gilead: Honoraria; Amgen: Honoraria; Jansen Cilag: Honoraria; Servier: Honoraria; Celgene Corporation: Honoraria, Research Funding. Bos:Celgene: Research Funding; Kiadis Pharma: Other: Shareholder (of Cytosen, acquired by Kiadis). Mutis:Genmab: Research Funding; Janssen Research and Development: Research Funding; Celgene: Research Funding; Onkimmune: Research Funding. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Levin:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Van De Donk:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Nivolumab: off-label treatment for Multiple Myeloma

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-124339

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4763-4763

Abstract: Multiple myeloma is a disease of the antibody producing plasma cells in the bone marrow. It has been characterized by frequent genomic alterations including gains and losses of chromosomes. Some of these alterations result in poor clinical prognosis. Bortezomib, a first in class proteasome inhibitor, is approved for the treatment of relapsed multiple myeloma. To better understand how the genome wide changes observed in myeloma relate to prognosis and treatment response, we have used single nucleotide polymorphism (SNP) array technology to assess genotypes and DNA copy number at up to 100,000 genomic loci. DNA from 147 bone marrow tumor biopsies collected in multi-center phase II and III clinical trials of relapsed multiple myeloma patients prior to treatment with Bortezomib were hybridized on SNP arrays to assess genomic aberrations. Commonly seen genomic alterations in myeloma were observed, including deletions of chromosome 13 (37%), 1p (25%), 6q (23%), and amplifications on 1q (35%). We found that 35% of this relapsed myeloma population exhibited a hyperdiploid genome characterized by gains of chromosomes 3, 5, 7, 9, 11, 15, and 19. Other notable genomic deletions included 17p (22%), 8p (27%) and 10p (16%). A correlation of response to bortezomib therapy in patients with differential gains and losses at the chromosomal level is ongoing. Consistent with previous reports, response to bortezomib was observed in patients with poor prognostic chr 13 deletions. A more in-depth analysis of specific loci associated with clinical outcome will be discussed. In summary, this data will help further define genomic aberrations in multiple myeloma and their association with treatment outcome.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.4763.4763

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 2873-2873

Abstract: Consolidation treatment with high dose chemotherapy in combination with an autologous peripheral blood stem celll transplant. is widely used in patients with high risk non-Hodgkin lymphoma (NHL). Also this treatment has its place in patients with relapsed intermediate lymphoma. Earlier studies in patients with breast cancer or multiple myeloma showed evidence for (minimal) tumour contamination in the graft that might lead to the occurence of relapse. For patients with NHL this is less clear. For the present analysis 60 patients (pts) were included: 18 pts with primary high risk NHL, 6 patients with mantle cell lymphoma, and 36 pts with primary refractory or relapsed intermediate NHL. Patients with high risk NHL were treated with induction chemotherapy according to the Hovon-27 or Hovon-40 protocol(www.hovon.nl). Two patients (1 pt with T-Lymphoblastair lymphoma, 1 pt with Burkitt Lymphoma ) received intensive induction chemotherapy according to our leukemia protocols. Stem cells were collected as early as possible, provided the peripheral blood and bone marrow showed no histological evidence of NHL and 〈 20% lymfocytes. In the patients with mantle cell lymphoma stem cells were collected during the induction chemotherapy (Hovon-45 protocol:www.hovon.nl), irrespective of their presence in the bone marrow. The patients with primary refractory or relapsed intermediate NHL received reinduction chemotherapy with DHAP (Dexamethason, Cytarabin, Cisplatin) or EMP (Etopside, Mitoxantrone, Prednisone). After two or three courses peripheral blood stem cells were mobilised with G-CSF (Neupogen, Amgen) 10 μg/kg sc daily starting day 5 and harvested for autologous stem cell transplant. Before the start of mobilisation patients were required to be responsive to the induction chemotherapy and to have a bone marrow without histological and immunological detectable tumour cells. In all patients a sample of the first day stem cell collection was analyzed with the use of three or four colour Flowcytometry. The sensitivity of the assay was 1/ 104–105 lymphoma cells. Only in 3 pts tumour cells were found at a level 〉 0.05 %. Interestingly two patients had a primary diagnosis of diffuse large B-cell lymphoma T-cell/ histiocyte rich variant. Both pts relapsed: one within 6 months and the other one within 12 months.The third patient suffered from a anaplastic large cell T-cell lymphoma and relapsed after 15 months. In all other patients no lymphoma cells were detectable in the stemcell harvest at a minimum level of 〈 0.02%. Follow up showed a relapse within 12 months in 16 of 36 patients with relapse or primary refractory NHL (44%) and 6 of 24 patients with high risk NHL (25%). In conclusion, in the vast majority of the above patients, no circulating lymphoma cells were detectable with the use of flowcytometry in the stemcell harvest. Therefore we conclude that with the present techniques and sensitivity immunological analysis of the graft does not give additional information and therefore is not necessary in this patient group. Provided the bone marrow before collection is free of lymphoma cells, we feel that the currently used mobilisation regimen is safe in these patients and does not lead to the presence of detectable tumour cells in the collected stemcells.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V104.11.2873.2873

Language: English

Publisher: American Society of Hematology

Publication Date: 2004

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 125, No. 3 ( 2015-01-15), p. 449-456

Abstract: KTd is an effective induction and consolidation regimen for transplant-eligible MM patients. The KTd regimen is safe and well tolerated with a notable lack of peripheral neuropathy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2014-05-576256

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3308-3308

Abstract: Background: Novel agents such as IMIDs and proteasome inhibitors have substantially changed the therapeutic landscape in the first line treatment of multiple myeloma (MM). Better response rates and prolonged progression-free survival have lead to an improvement in overall survival (OS) with median values well beyond 5 years. Therefore to assess whether first line therapy strategies have an impact on the prognosis for patients with MM, long-term results of clinical trials with follow up covering 〉 10 years are necessary. Methods: The HOVON-65/GMMG-HD4 study is a prospective randomized trial testing bortezomib+adriamycin+dexamethasone (PAD) for 3 cycles as induction prior to high-dose chemotherapy (HDT) and autologous stem cell transplantation compared to vincristine+adriamycin+dexamethasone (VAD) in the control arm. After one (HOVON) or two (GMMG) HDT maintenance was given for 2 years consisting of bortezomib every 2 weeks in the PAD arm and thalidomide 50 mg daily in the VAD arm. The study results were initially reported in 2012 (1) and with a median follow up of 91 months in 2018 (2). In this analysis we present OS results after a median follow up of 137 months. All hazard ratios (HR) are given with 95% confidence intervals (CI). Results: Overall survival at 12 years was 32% (CI 27-37%) in the VAD arm versus 36% (CI 31-41%) in the PAD arm without significant difference in the univariate Cox model (HR 0.87, CI 0.73 - 1.03, p=0. 11 or in multivariate Cox model including ISS stage and treatment arm (HR 0.87, CI 0.73 - 1.04, p=0.12; the primary analysis) as specified in the study protocol. When other factors including age, sex, ISS stage, WHO performance status, Immunoglobulin-type, Durie and Salmon-stage, LDH, del 13q, study group and renal impairment (RI, defined as serum creatinine ≥ 2 mg/dl) were added to the Cox model, treatment in the PAD arm was a significant factor for improved OS (HR 0.84, CI 0.7 - 1.0, p=0.048). Of the remaining factors age (HR 1.02, CI 1.01 - 1.03, p=0.002), female sex (HR 0.83, CI 0.69 - 0.99, p=0.044), ISS stage (HR 1.19, CI 1.04 - 1.35, p=0.01), WHO performance status (HR 1.32, CI 1.17 - 1.48, p 〈 0.001), IgA (HR 1.56, CI 1.18 - 2.06, p=0.002), LDH 〉 ULN (HR 1.44, CI 1.14 - 1.82, p=0.002), del 13q (HR 1.42, CI 1.17 - 1.73, p 〈 0.001) and RI (HR 1.42, CI 1.04 - 1.95, p=0.026) were significantly associated with OS. Tests for heterogeneity revealed two factors as significant: RI and del17p (only fully evaluated for the GMMG cohort). For patients with RI the OS probability at 12 years was 39% in the PAD arm versus 5% in the VAD arm (HR 0.34, CI 0.20 - 0.59, p 〈 0.0001, Fig. 1). 12 year OS in patients without RI was 36% in the PAD arm and 35% in the VAD arm without significant difference (HR 0.97, CI 0.81 - 1.17, p=0.77, Fig,1). In the GMMG cohort (receiving tandem-HDT) del17p results were available and patients with del17p had a significantly better OS in the PAD arm than in the VAD arm (HR 0.36, CI 0.17 - 0.77, p=0.006), while no significant difference between treatment arms was found in patients without del17p (HR 1.01, CI 0.75 - 1.37, p=0.92). Discussion: Long-term results of the HOVON-65/GMMG-HD4 trial show that one third of patients receiving HDT with either thalidomide-based or bortezomib-based maintenance are still alive at 12 years. In contrast to earlier analyses with shorter follow up (1,2) the use of bortezomib in the induction and maintenance treatment provided a significant OS benefit when adjusting for other risk in a multivariate Cox model, although not in the primary analysis. A particular OS benefit was found in patients with RI receiving bortezomib before and after HDT and this could completely abolish the negative prognostic impact of RI. Similarly bortezomib used in combination with tandem-HDT improved OS in patients with del17p so that more than a third of these patients with high-risk MM survived more than 10 years. Our results underline that despite the growing options for treatment at relapse the choice of an optimal first-line therapy is of critical prognostic importance, in particular for patients with high-risk myeloma. References: 1) Sonneveld et al., J Clin Oncol, 2012; 30:2946-2955 2) Goldschmidt et al., Leukemia 2018; 32: 383-390 Figure 1 Disclosures Scheid: Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Bertsch:Celgene: Other: travel support; Sanofi: Other: travel support. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisel:Celgene: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Adaptive Biotech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Kersten:Gilead: Honoraria; Kite Pharma: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Miltenyi: Honoraria; Roche: Honoraria, Research Funding; Takeda Oncology: Research Funding; Celgene: Honoraria, Research Funding. Mai:Mundipharma: Other: travel support; Takeda: Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support; Celgene: Consultancy, Honoraria, Other: travel support. Hillengass:Amgen: Consultancy, Honoraria; Janssen: Honoraria. Stilgenbauer:AbbVie, AstraZeneca, Celgene, Gilead Sciences, Inc., GSK, Hoffmann La-Roche, Janssen, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Bos:Kiadis Pharma: Other: Shareholder (of Cytosen, acquired by Kiadis); Celgene: Research Funding. Dührsen:Amgen: Consultancy, Honoraria, Research Funding; CPT: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Teva: Honoraria; Novartis: Consultancy, Honoraria; Alexion: Honoraria; Gilead: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Honoraria; Celgene: Research Funding. Salwender:Celgene: Honoraria, Other: Travel or accommodations; Sanofi: Honoraria, Other: Travel or accommodations; Takeda: Honoraria, Other: Travel or accommodations; Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Amgen: Honoraria, Other: Travel or accommodations; Janssen Cilag: Honoraria, Other: Travel or accommodations. Goldschmidt:Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Mundipharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; John-Hopkins University: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; John-Hopkins University: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Research Funding; Janssen: Consultancy, Research Funding. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SkylineDx: Research Funding. OffLabel Disclosure: bortezomib maintenance thalidomide maintenance

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-129684

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7