Kai Neben

Publications of Kai Neben

• Report from the european myeloma network on interphase FISHin multiple myeloma and related disorders.

  Authors: Fiona Ross, Herve Avet-Loiseau, Genevieve Ameye, Norma C Gutierrez, Peter Liebisch, Sheila O' Connor, Klara Dalva, Sonia Fabris, Adele M Testi, Marie Jarosova [......] Kai Neben, Niels Emil U Hermansen, Katrina Rack, Alberto Rocci, Rebecca Protheroe, Laura Chiecchio, Helene A Poirel, Pieter Sonneveld, Mette Nyegaard, Hans E Johnsen

  Haematologica. 02/2012;

  The European Myeloma Network has organized two workshops on fluorescence in situ hybridization in multiple myeloma. The first aimed to identify specific indications and consensus technical approachesThe European Myeloma Network has organized two workshops on fluorescence in situ hybridization in multiple myeloma. The first aimed to identify specific indications and consensus technical approaches of current practice. A second workshop followed a quality control exercise in which 21 laboratories analysed diagnostic cases of purified plasma cells for recurrent abnormalities. The summary report was discussed at the EHA Myeloma Scientific Working Group Meeting 2010. During the quality control exercise there was acceptable agreement on more than 1000 tests. The conclusions from the collaboration were that the primary clinical applications for FISH analysis were for newly diagnosed cases of MM or frank relapse cases. A range of technical recommendations included: 1) Material should be part of the first draw of the aspirate; 2) Samples should be sent at suitable times that allow for the lengthy processing; 3) Most importantly PCs must be purified or specifically identified; 4) Positive cut-off levels should be the relatively conservative, 10% for fusion or break-apart probes and 20% for numerical abnormalities; 5) Informative probes should be combined to best effect; 6) In specialist laboratories a single experienced analyst is considered adequate; 7) At least 100 PC should be scored; 8) Essential abnormalities to test for are t(4;14), t(14;16) and 17p13 deletions; 9) Suitable commercial probes are available for clinically relevant abnormalities; 10) The clinical report should be expressed clearly and must state the percentage of PC involved and method used for identification; 11) A retrospective European based FISH data bank linked to clinical data should be generated and 12) Prospective analysis should be centralized for upcoming trials based on the recommendations. EMN aims to build on these recommendations to establish standards for a common European database to define subgroups with prognostic significance.

• Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p.

  Authors: Kai Neben, Henk M Lokhorst, Anna Jauch, Uta Bertsch, Thomas Hielscher, Bronno van der Holt, Hans Salwender, Igor W Blau, Katja Weisel, Michael Pfreundschuh [......] Christian Teschendorf, Hans Martin, Mathias Haenel, Hans G Derigs, Marc S Raab, Anthony D Ho, Helgi van de Velde, Dirk Hose, Pieter Sonneveld, Hartmut Goldschmidt

  Blood. 12/2011; 119(4):940-8.

  In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed theIn patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For allanalyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months (P = .024); the 3 year-OS for arm A was 17% and for arm B it was 69% (P = .028). After multivariate analysis, del(17p13) was an independent predictor for PFS (P < .0001) and OS (P < .0001) in arm A, whereas no statistically significant effect on PFS (P = .28) or OS (P = .12) was seen in arm B. In conclusion, the adverse impact of del(17p13) on PFS and OS could be significantly reduced by bortezomib-based treatment, suggesting that long-term administration of bortezomib should be recommended for patients carrying del(17p13). This trial is registered at the International Standard Randomised Controlled Trial Number Register as ISRCTN64455289.

• The role of fluorescence in situ hybridization and gene expression profiling in myeloma risk stratification.

  Authors: Dirk Hose, Anja Seckinger, Anna Jauch, Thierry Rème, Jérôme Moreaux, Uta Bertsch, Kai Neben, Bernard Klein, Hartmut Goldschmidt

  Srpski arhiv za celokupno lekarstvo. 12/2011; 139 Suppl 2:84-9.

  Multiple myeloma patients' survival under treatment varies from a few months to more than 15 years. Clinical prognostic factors, especially beta2-microglobulin (B2M) and the international stagingMultiple myeloma patients' survival under treatment varies from a few months to more than 15 years. Clinical prognostic factors, especially beta2-microglobulin (B2M) and the international staging system (ISS), allow risk assessment to a certain extent, but do not identify patients at very high risk. As malignant plasma cells are characterized by a variety of chromosomal aberrations and changes in gene expression, a molecular characterization ofCD138-purified myeloma cells by interphase fluorescence in situ hybridization (iFISH) and gene expression profiling (GEP) can be used for improved risk assessment, iFISH allows a risk stratification with presence of a translocation t(4;14) and/or deletion of 17p13 being the best documented adverse prognostic factors. A deletion of 13q14 is no longer considered to define adverse risk. Patients harbouring a t(4;14) seems to benefit from a bortezomib- or lenalidomide containing regimen, whereas patients with deletion 17p13 seem only to benefit from a high dose therapy approach using long term bortezomib (in induction and maintenance) and autologous tandem-transplantation as used in the GMMG-HD4 trial, or the total therapy 3 concept. Gene expression profiling allows the assessment of high risk scores (IFM, UAMS), remaining prognostic despite treatment with novel agents, and prognostic surrogates of biological factors (e.g. proliferation) and (prognostic) target gene expression (e.g. Aurora-kinase A). Thus, assessment of B2M and ISS-stage, iFISH, and GEP is considered extended routine diagnostics in therapy requiring multiple myeloma patients for risk assessment and, even now, to a certain extent selection of treatment.

• Gene expression profiling in multiple myeloma--reporting of entities, risk, and targets in clinical routine.

  Authors: Tobias Meissner, Anja Seckinger, Thierry Rème, Thomas Hielscher, Thomas Möhler, Kai Neben, Hartmut Goldschmidt, Bernard Klein, Dirk Hose

  Clinical cancer research : an official journal of the American Association for Cancer Research. 12/2011; 17(23):7240-7.

  Multiple myeloma is an incurable malignant plasma cell disease characterized by survival ranging from several months to more than 15 years. Assessment of risk and underlying molecular heterogeneityMultiple myeloma is an incurable malignant plasma cell disease characterized by survival ranging from several months to more than 15 years. Assessment of risk and underlying molecular heterogeneity can be excellently done by gene expression profiling (GEP), but its way into clinical routine is hampered by the lack of an appropriate reporting tool and the integration with other prognostic factors into a single "meta" risk stratification. The GEP-report (GEP-R) was built as an open-source software developed in R for gene expression reporting in clinical practice using Affymetrix microarrays. GEP-R processes new samples by applying a documentation-by-value strategy to the raw data to be able to assign thresholds and grouping algorithms defined on a reference cohort of 262 patients with multiple myeloma. Furthermore, we integrated expression-based and conventional prognostic factors within one risk stratification (HM-metascore). The GEP-R comprises (i) quality control, (ii) sample identity control, (iii) biologic classification, (iv) risk stratification, and (v) assessment of target genes. The resulting HM-metascore is defined as the sum over the weighted factors gene expression-based risk-assessment (UAMS-, IFM-score), proliferation, International Staging System (ISS) stage, t(4;14), and expression of prognostic target genes (AURKA, IGF1R) for which clinical grade inhibitors exist. The HM-score delineates three significantly different groups of 13.1%, 72.1%, and 14.7% of patients with a 6-year survival rate of 89.3%, 60.6%, and 18.6%, respectively. GEP reporting allows prospective assessment of risk and target gene expression and integration of current prognostic factors in clinical routine, being customizable about novel parameters or other cancer entities.

• Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk.

  Authors: Peter Broderick, Daniel Chubb, David C Johnson, Niels Weinhold, Asta Försti, Amy Lloyd, Bianca Olver, Yussanne P Ma, Sara E Dobbins, Brian A Walker [......] Anna Jauch, Per Hoffmann, Thomas W Mühleisen, Markus M Nöthen, Susanne Moebus, Ian P Tomlinson, Hartmut Goldschmidt, Kari Hemminki, Gareth J Morgan, Richard S Houlston

  Nature genetics. 11/2011; 44(1):58-61.

  To identify risk variants for multiple myeloma, we conducted a genome-wide association study of 1,675 individuals with multiple myeloma and 5,903 control subjects. We identified risk loci forTo identify risk variants for multiple myeloma, we conducted a genome-wide association study of 1,675 individuals with multiple myeloma and 5,903 control subjects. We identified risk loci for multiple myeloma at 3p22.1 (rs1052501 in ULK4; odds ratio (OR) = 1.32; P = 7.47 × 10(-9)) and 7p15.3 (rs4487645, OR = 1.38; P = 3.33 × 10(-15)). In addition, we observed a promising association at 2p23.3 (rs6746082, OR = 1.29; P = 1.22 × 10(-7)). Our study identifies new genomic regions associated with multiple myeloma risk that may lead to new etiological insights.

• Meeting report of the third Heidelberg myeloma workshop: current status and developments in diagnosis and therapy of multiple myeloma.

  Authors: Jens Hillengass, Kai Neben, Hartmut Goldschmidt

  Journal of cancer research and clinical oncology. 09/2011; 138(1):173-8.

• Kyphoplasty in patients with multiple myeloma a retrospective comparative pilot study.

  Authors: Christian Kasperk, Andreas Haas, Jens Hillengass, Christel Weiss, Kai Neben, Hartmut Goldschmidt, Ulrike Sommer, Peter Nawroth, Peter-Jürgen Meeder, Bernd Wiedenhöfer, Gerhard Schmidmaier, Michael Tanner, Dirk Neuhof, Gerd Nöldge, Ingo A Grafe

  Journal of surgical oncology. 09/2011;

  BACKGROUND: This retrospective study of 73 myeloma patients with painful vertebral lesions compares clinical and radiomorphological outcomes up to 2 years after additional kyphoplasty, radiationBACKGROUND: This retrospective study of 73 myeloma patients with painful vertebral lesions compares clinical and radiomorphological outcomes up to 2 years after additional kyphoplasty, radiation therapy or systemic treatment only. METHODS: We assessed pain, disability and radiomorphological parameters by visual analogue scale (VAS 0-100), Oswestry Disability Index and by re-evaluating available follow-up X-rays, respectively, in patients that were treated according to a clinical pathway. RESULTS: After 2 years the VAS score was reduced in all groups by 66 ± 8.2 (kyphoplasty), 35 ± 10.5 (radiation therapy) and 38 ± 20.5 (systemic therapy only). Only after kyphoplasty we observed a significantly reduced Oswestry Disability Index after 1 year (P < 0.001). Vertebral height remained stable after kyphoplasty (P = 0.283), in contrast to a progressive height loss in the other groups (P = 0.013 and P = 0.015 for radiation and systemic therapy only, respectively). Two years after kyphoplasty and radiotherapy the overall vertebral fracture incidence was significantly decreased as compared to the group after systemic therapy only (9.7% of all thoracic and lumbar vertebrae had new vertebral fractures after systemic therapy only, 2% after kyphoplasty (P < 0.001), 4.8% after radiation (P = 0.032)). CONCLUSION: Additional kyphoplasty was more effective than additional radiation or systemic therapy in terms of pain relief, reduction of pain associated disability and reduction of fracture incidence of the entire lumbar and thoracic spine. J. Surg. Oncol © 2011 Wiley Periodicals, Inc.

• Diffusion-weighted imaging for non-invasive and quantitative monitoring of bone marrow infiltration in patients with monoclonal plasma cell disease: a comparative study with histology.

  Authors: Jens Hillengass, Tobias Bäuerle, Reiner Bartl, Mindaugas Andrulis, Fabienne McClanahan, Frederik B Laun, Christian Martin Zechmann, Rajiv Shah, Barbara Wagner-Gund, Dirk Simon, Christiane Heiss, Kai Neben, Anthony D Ho, Heinz-Peter Schlemmer, Hartmut Goldschmidt, Stefan Delorme, Bram Stieltjes

  British journal of haematology. 06/2011; 153(6):721-8.

  Bone marrow plasma cell infiltration is a crucial parameter of disease activity in monoclonal plasma cell disorders. Until now, the only way to quantify such infiltration was bone marrow biopsy orBone marrow plasma cell infiltration is a crucial parameter of disease activity in monoclonal plasma cell disorders. Until now, the only way to quantify such infiltration was bone marrow biopsy or aspiration. Diffusion-weighted imaging (DWI) is a magnetic resonance imaging-technique that may mirror tissue cellularity by measuring random movements of water molecules. To investigate if DWI is capable of assessing bone marrow cellularity in monoclonal plasma cell disease, we investigated 56 patients with multiple myeloma or monoclonal gammopathy of undetermined significance, and 30 healthy controls using DWI of the pelvis and/or the lumbar spine. In 25 of 30 patients who underwent biopsy, bone marrow trephine and DWI could be compared. Of the patients with symptomatic disease 15 could be evaluated after systemic treatment. There was a positive correlation between the DWI-parameter apparent diffusion coefficient (ADC) and bone marrow cellularity as well as micro-vessel density (P<0·001 respectively). ADC was significantly different between patients and controls (P<0·01) and before and after systemic therapy (P<0·001). In conclusion, DWI enabled bone marrow infiltration to be monitored in a non-invasive, quantitative way, suggesting that after further investigations on larger patient groups this might become an useful tool in the clinical work-up to assess tumour burden.

• Chromosomal aberrations +1q21 and del(17p13) predict survival in patients with recurrent multiple myeloma treated with lenalidomide and dexamethasone.

  Authors: Ulrike Klein, Anna Jauch, Thomas Hielscher, Jens Hillengass, Marc S Raab, Anja Seckinger, Dirk Hose, Anthony D Ho, Hartmut Goldschmidt, Kai Neben

  Cancer. 05/2011; 117(10):2136-44.

  In the era of novel agents such as lenalidomide and bortezomib, risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches in patients withIn the era of novel agents such as lenalidomide and bortezomib, risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches in patients with multiple myeloma (MM). The authors analyzed the prognostic value of deletion del(13q14), del(17p13), +1q21, translocation t(4;14), t(11;14), and t(14;16) by fluorescence in situ hybridization (FISH) in a series of 92 patients with recurrent MM who were treated with lenalidomide and dexamethasone (len/dex) at the study center. Patients carrying del(13q14) or t(14;16) were found to have a shorter median time to disease progression (TTP) of 5.1 months (vs 14.4 months; P = .009) and 2.0 months (vs 10.5 months; P <.001), respectively. However, no effect on TTP was observed in patients harboring del(13q14) as an exclusive chromosomal aberration without the concomitant presence of t(4;14) or del(17p13). The median overall survival (OS) for patients with del(17p13) or +1q21 was 6.7 months (P = .002) and 8.3 months (P < .001), respectively, whereas the median OS for patients carrying none of these abnormalities was not reached. Multivariate analysis revealed that the effects of del(17p13) and +1q21 on OS were independent of patient age as well as the type and number of regimens administered before len/dex. The results of the current study suggest that the prognostic significance of t(4;14) may be ameliorated or eliminated in patients treated with len/dex, whereas the presence of del(17p13) or +1q21 is still associated with a dismal OS. The presence of t(11;14) and del(13q14) as exclusive chromosomal aberrations indicates no impact on outcome. Because of its rarity in MM, a confirmation of the prognostic role of the t(14;16) aberration is still pending.

• Lenalidomide in combination with dexamethasone: effective regimen in patients with relapsed or refractory multiple myeloma complicated by renal impairment.

  Authors: Ulrike Klein, Kai Neben, Thomas Hielscher, Christiane Heiss, Anthony D Ho, Hartmut Goldschmidt

  Annals of hematology. 04/2011; 90(4):429-39.

  Over the past decade, treatment options for patients with multiple myeloma (MM) have improved substantially, resulting in better response rates and prolonged overall survival (OS). Nevertheless, MMOver the past decade, treatment options for patients with multiple myeloma (MM) have improved substantially, resulting in better response rates and prolonged overall survival (OS). Nevertheless, MM remains a challenging disease, especially if renal insufficiency (RI) or extensive pre-treatment aggravates the assignment of the optimal treatment schedule. In this retrospective study, we analyzed the outcome of lenalidomide plus dexamethasone in 167 patients with relapsed or refractory MM with focus on RI. The baseline creatinine clearance (CLCr) was normal in 94 patients (CLCr≥80 ml/min), while RI was observed in 73 patients, including 40 patients with mild RI (50≤CLCr<80 ml/min) and 33 patients with moderate or severe RI (CLCr<50 ml/min). Response rates declined depending on the severity of RI, being 67% among patients with normal kidney function, 60% among patients with mild RI and 49% among patients with moderate or severe RI. Time to progression (TTP) was significantly reduced in patients with severe RI and in case of >2 previous treatment lines. OS was not significantly different between patients with normal and impaired renal function. In contrast, the number of previous treatment lines (2 vs. <2) and the use of novel agents like bortezomib or thalidomide prior to lenalidomide plus dexamethasone therapy had a more adverse effect on OS. In conclusion, lenalidomide plus dexamethasone is an effective regimen for relapsed or refractory patients with MM complicated by RI with manageable toxicity.

• Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14).

  Authors: Tilmann Bochtler, Ute Hegenbart, Christiane Heiss, Axel Benner, Marion Moos, Anja Seckinger, Stephanie Pschowski-Zuck, Désirée Kirn, Kai Neben, Claus R Bartram, Anthony D Ho, Hartmut Goldschmidt, Dirk Hose, Anna Jauch, Stefan O Schonland

  Blood. 02/2011; 117(14):3809-15.

  In multiple myeloma (MM) pathogenesis, hyperdiploidy and nonhyperdiploidy are recognized as 2 major cytogenetic pathways. Here, we assessed the role of hyperdiploidy in 426 patients with monoclonalIn multiple myeloma (MM) pathogenesis, hyperdiploidy and nonhyperdiploidy are recognized as 2 major cytogenetic pathways. Here, we assessed the role of hyperdiploidy in 426 patients with monoclonal plasma cell disorders, among them 246 patients with AL amyloidosis (AL), by interphase fluorescence in situ hybridization. Hyperdiploidy was defined by a well-established score requiring trisomies for at least 2 of the 3 chromosomes 5, 9, and 15. The hyperdiploidy frequency in AL was a mere 11% compared with 30% in monoclonal gammopathy of undetermined significance (P < .001) and 46% in AL with concomitant MM I (P < .001). Overall, hyperdiploidy was associated with an intact immunoglobulin, κ light chain restriction, higher age, and bone marrow plasmacytosis, but was unrelated to the organ involvement pattern in AL. Clustering of 6 major cytogenetic aberrations in AL by an oncogenetic tree model showed that hyperdiploidy and t(11;14) were almost mutually exclusive, whereas gain of 1q21 favored hyperdiploidy. Deletion 13q14 and secondary IgH translocations were equally distributed between ploidy groups. We conclude that the interphase fluorescence in situ hybridization-based hyperdiploidy score is also a feasible tool to delineate hyperdiploid patients in early-stage monoclonal gammopathies and that the cytogenetic pathogenetic concepts developed in MM are transferable to AL.

• Quality of life of long-term survivors with Hodgkin lymphoma after high-dose chemotherapy, autologous stem cell transplantation, and conventional chemotherapy.

  Authors: Juliane Brandt, Sascha Dietrich, Julia Meissner, Kai Neben, Anthony D Ho, Mathias Witzens-Harig

  Leukemia & lymphoma. 11/2010; 51(11):2012-20.

  In this study, we investigated the quality of life (QoL) of long-term survivors with Hodgkin lymphoma who received high-dose chemotherapy (HDCT) followed by peripheral blood stem cell transplantationIn this study, we investigated the quality of life (QoL) of long-term survivors with Hodgkin lymphoma who received high-dose chemotherapy (HDCT) followed by peripheral blood stem cell transplantation (PBSCT). QoL of this group was compared with QoL of patients who were treated with conventional chemotherapy and with QoL of the healthy German population. Two standardized questionnaires, the EORTC QLQ-C30 and the EQ-5D, including the visual analogue scale (VAS) were applied. A total of 98 patients were included in the study, all of them treated in our institution. Thirty-seven patients who received HDCT with PBSCT between 1986 and 2007 were compared with 61 patients treated with conventional chemotherapy and supplementary radiation between 1998 and 2009. The median follow-up for the HDCT group was 11 years. Statistical analysis with the one-sample t-test shows a reduced QoL of both groups of patients compared to the healthy population. Compared to the group of patients who received conventional chemotherapy, there is a tendency towards reduced QoL in patients with HDCT in all of the three main categories of the EORTC-QLQ-C30. However, these differences were not statistically significant, with the exception of the subcategory of dyspnoea, which was worse in the group that was treated with BCNU containing high-dose protocols. We conclude that the negative impact of both HDCT and conventional therapy on the QoL of long-term survivors with Hodgkin lymphoma should not be underestimated and should lead to the development of less toxic therapy strategies.

• Staging monoclonal plasma cell disease: comparison of the Durie-Salmon and the Durie-Salmon PLUS staging systems.

  Authors: Kerstin Fechtner, Jens Hillengass, Stefan Delorme, Christiane Heiss, Kai Neben, Hartmut Goldschmidt, Hans-Ulrich Kauczor, Marc-André Weber

  Radiology. 10/2010; 257(1):195-204.

  To investigate the concordance of the Durie-Salmon staging system with the Durie-Salmon PLUS staging system in monoclonal plasma cell disease. Institutional review board approval was obtained, withTo investigate the concordance of the Durie-Salmon staging system with the Durie-Salmon PLUS staging system in monoclonal plasma cell disease. Institutional review board approval was obtained, with waiver of informed consent. Lesions in 403 untreated patients (age range, 21-83 years) with monoclonal gammopathy of undetermined significance (MGUS) (n = 84), solitary plasmacytoma (n = 17), amyloid light-chain amyloidosis (n = 12), and multiple myeloma (MM) (n = 290) were first staged on the basis of the classic Durie-Salmon staging system, which included conventional radiography. After examination with whole-body (WB) magnetic resonance (MR) imaging, lesions in these patients were, in addition, staged by using the Durie-Salmon PLUS staging system. Bone marrow infiltration pattern and focal lesions described as intramedullary, transcortical, and soft-tissue lesions, were assessed. The staging levels of both systems were compared. Of 84 patients with MGUS, lesions in 33 (39%) would have been staged differently with Durie-Salmon PLUS staging system when compared with Durie-Salmon staging system (stage I MM [37%], stage II MM [0%], and stage III MM [2%]). All 17 patients with plasmacytoma showed additional focal lesions or a diffuse infiltration leading to a classification as stage I MM (76%), stage II MM (12%), or stage III MM (12%) with Durie-Salmon PLUS. Of the 149 patients with stage I MM, lesions in 81 (54%) would have been staged differently with the Durie-Salmon PLUS staging system. Of the 21 patients with stage II MM, lesions in 19 (91%) would have been staged differently with Durie-Salmon PLUS staging system when compared with the Durie-Salmon staging system. Of the 120 patients with stage III MM, lesions in 72 (60%) would have been staged differently with the Durie-Salmon PLUS staging system. Given the fact that the Durie-Salmon and Durie-Salmon PLUS staging systems were concordant in only 45% of all examined patients with monoclonal plasma cell disease, in most cases, treatment decisions depend on the staging system used and, thus, remain a matter of debate.

• Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma.

  Authors: Dirk Hose, Thierry Rème, Thomas Hielscher, Jérôme Moreaux, Tobias Messner, Anja Seckinger, Axel Benner, John D Shaughnessy, Bart Barlogie, Yiming Zhou, Jens Hillengass, Uta Bertsch, Kai Neben, Thomas Möhler, Jean François Rossi, Anna Jauch, Bernard Klein, Hartmut Goldschmidt

  Haematologica. 09/2010; 96(1):87-95.

  Proliferation of malignant plasma cells is a strong adverse prognostic factor in multiple myeloma and simultaneously targetable by available (e.g. tubulin polymerase inhibitors) and upcoming (e.g.Proliferation of malignant plasma cells is a strong adverse prognostic factor in multiple myeloma and simultaneously targetable by available (e.g. tubulin polymerase inhibitors) and upcoming (e.g. aurora kinase inhibitors) compounds. We assessed proliferation using gene expression-based indices in 757 samples including independent cohorts of 298 and 345 samples of CD138-purified myeloma cells from previously untreated patients undergoing high-dose chemotherapy, together with clinical prognostic factors, chromosomal aberrations, and gene expression-based high-risk scores. In the two cohorts, 43.3% and 39.4% of the myeloma cell samples showed a proliferation index above the median plus three standard deviations of normal bone marrow plasma cells. Malignant plasma cells of patients in advanced stages or those harboring disease progression-associated gain of 1q21 or deletion of 13q14.3 showed significantly higher proliferation indices; patients with gain of chromosome 9, 15 or 19 (hyperdiploid samples) had significantly lower proliferation indices. Proliferation correlated with the presence of chromosomal aberrations in metaphase cytogenetics. It was significantly predictive for event-free and overall survival in both cohorts, allowed highly predictive risk stratification (e.g. event-free survival 12.7 versus 26.2 versus 40.6 months, P < 0.001) of patients, and was largely independent of clinical prognostic factors, e.g. serum β₂-microglobulin, International Staging System stage, associated high-risk chromosomal aberrations, e.g. translocation t(4;14), and gene expression-based high-risk scores. Proliferation assessed by gene expression profiling, being independent of serum-β₂-microglobulin, International Staging System stage, t(4;14), and gene expression-based risk scores, is a central prognostic factor in multiple myeloma. Surrogating a biological targetable variable, gene expression-based assessment of proliferation allows selection of patients for risk-adapted anti-proliferative treatment on the background of conventional and gene expression-based risk factors.

• Combining information regarding chromosomal aberrations t(4;14) and del(17p13) with the International Staging System classification allows stratification of myeloma patients undergoing autologous stem cell transplantation.

  Authors: Kai Neben, Anna Jauch, Uta Bertsch, Christiane Heiss, Thomas Hielscher, Anja Seckinger, Tina Mors, Nadine Zoe Müller, Jens Hillengass, Marc S Raab, Anthony D Ho, Dirk Hose, Hartmut Goldschmidt

  Haematologica. 03/2010; 95(7):1150-7.

  Chromosomal abnormalities have been shown to play a major role in disease evolution of multiple myeloma. Specific changes in interphase cells can be detected by fluorescent in situ hybridization,Chromosomal abnormalities have been shown to play a major role in disease evolution of multiple myeloma. Specific changes in interphase cells can be detected by fluorescent in situ hybridization, which overcomes the problem of the lack of dividing cells required for conventional cytogenetics. We analyzed the prognostic value of 12 frequent chromosomal abnormalities detected by fluorescent in situ hybridization in a series of patients (n=315) with newly diagnosed, symptomatic multiple myeloma. All patients underwent frontline autologous stem cell transplantation according to the GMMG-HD3- or GMMG-HD4-trial protocols or analogous protocols. Univariate statistical analyses revealed that the presence of del(13q14), del(17p13), t(4;14), +1q21 and non-hyperdiploidy was associated with adverse progression-free and overall survival rates independently of the International Staging System (ISS) classification. Multivariate analyses showed that only t(4;14) and del(17p13) retained prognostic value for both progression-free and overall survival. According to the presence or absence of t(4;14) and del(17p13) and the patients' International Staging System classification, the cohort could be stratified into three distinct groups: a group with a favorable prognosis [absence of t(4;14)/del(17p13) and ISS I], a group with a poor prognosis [presence of t(4;14)/del(17p13) and ISS II/III] and a group with an intermediate prognosis (all remaining patients). The probabilities of overall survival at 5 years decreased from 72% in the favorable prognostic group to 62% (hazard ratio 2.4; P=0.01) in the intermediate and 41% (hazard ratio 5.6; P<0.001) in the poor prognostic groups. These results have implications for risk-adapted management for patients with multiple myeloma undergoing high-dose chemotherapy followed by autologous stem cell transplantation and suggest that new treatment concepts are urgently needed for patients who belong to the poor prognosis group. As targeted therapies evolve, different treatment options might have variable success, depending on the underlying genetic nature of the clone.

• Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma.

  Authors: Jens Hillengass, Kerstin Fechtner, Marc-André Weber, Tobias Bäuerle, Sofia Ayyaz, Christiane Heiss, Thomas Hielscher, Thomas M Moehler, Gerlinde Egerer, Kai Neben, Anthony D Ho, Hans-Ulrich Kauczor, Stefan Delorme, Hartmut Goldschmidt

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 02/2010; 28(9):1606-10.

  With whole-body magnetic resonance imaging (wb-MRI), almost the whole bone marrow compartment can be examined in patients with monoclonal plasma cell disease. Focal lesions (FLs) detected by spinalWith whole-body magnetic resonance imaging (wb-MRI), almost the whole bone marrow compartment can be examined in patients with monoclonal plasma cell disease. Focal lesions (FLs) detected by spinal MRI have been of prognostic significance in symptomatic multiple myeloma (sMM). In this study, we investigated the prognostic significance of FLs in wb-MRI in patients with asymptomatic multiple myeloma (aMM). Wb-MRI was performed in 149 patients with aMM. The prognostic significance of the presence and absence, as well as the number, of FLs for progression into sMM was analyzed. FLs were present in 28% of patients. The presence per se of FLs and a number of greater than one FL were the strongest adverse prognostic factors for progression into sMM (P < .001) in multivariate analysis. A diffuse infiltration pattern in MRI, a monoclonal protein of 40 g/L or greater, and a plasma cell infiltration in bone marrow of 20% or greater were other adverse prognostic factors for progression-free survival in univariate analysis. We recommend use of wb-MRI for risk stratification of patients with asymptomatic multiple myeloma.

• Poor Mobilization of Hematopoietic Stem Cells - Definitions, Incidence, Risk Factors and Impact on Outcome of Autologous Transplantation.

  Authors: Patrick Wuchter, Dan Ran, Thomas Bruckner, Thomas Schmitt, Mathias Witzens-Harig, Kai Neben, Hartmut Goldschmidt, Anthony D Ho

  Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 11/2009;

  As more efficient agents for stem cell mobilization are being developed, there is an urgent need to define which patient population might benefit from these novel drugs. For a precise and prospectiveAs more efficient agents for stem cell mobilization are being developed, there is an urgent need to define which patient population might benefit from these novel drugs. For a precise and prospective definition of "poor mobilization", we have analyzed the efficiency of mobilization in patients intended to receive autologous transplantation at our center in the past 6 years. Between January 2003 to December 2008, 840 patients with the following diagnoses were scheduled to undergo leukapheresis: multiple myeloma (MM, n=602) and non-Hodgkin's lymphoma (NHL, n=238). Most patients mobilized readily: close to 85% of the patients had a level of 20/muL to >500/muL of CD34+ cells at the peak of stimulation. Of the 840 patients, 129 (15.3%) were considered to be "poor mobilizers" (PM), defined as patients who had a peak concentration of <20/muL of CD34+ cells upon stimulation with G-CSF subsequent to induction chemotherapy appropriate for the respective disease. Among them, 38 (4.5%) patients had CD34+ levels between 11-19/muL at maximum stimulation, defined as "borderline" PM, 49 (5.8%) patients had CD34+ levels between 6-10/muL, defined as "relative" PM and 42 patients (5%) with levels of <5/muL, defined as "absolute" PM. There was no difference in the incidence of PM between patients with MM versus those with NHL. Sex, age, body weight (bw) and previous irradiation therapy did not make any significant difference. Only the total number of cycles of previous chemotherapy (p=0.0034), and previous treatment with melphalan (p=0.0078) had a significant impact on the ability to mobilize. For the good mobilizers, the median time to recovery of the WBC to 1.0/nL or more was 13 days with a range of 7 to 22 days, whereas for the PM group it was 14 days with a range of 8 to 37 days. This difference was statistically not significant. The median time to recovery of the platelets counts to an unmaintained level of >20/nL was 11 days with a range of 6 to 17 days for the good mobilizers, whereas for the PM it was 11 days with a range of 7 to 32 days. Again this difference was not significant. The majority of the patients nowadays intended for autologous transplantations were able to mobilize readily. As long as >/=2.0 x10(6) of CD34+ cells per kg body weight have been collected, poor mobilization was not associated with inferior engraftment.

• Multiple myeloma and monoclonal gammopathy of undetermined significance: importance of whole-body versus spinal MR imaging.

  Authors: Tobias Bäuerle, Jens Hillengass, Kerstin Fechtner, Christian M Zechmann, Lars Grenacher, Thomas M Moehler, Heiss Christiane, Barbara Wagner-Gund, Kai Neben, Hans-Ulrich Kauczor, Hartmut Goldschmidt, Stefan Delorme

  Radiology. 09/2009; 252(2):477-85.

  PURPOSE: To examine if standard magnetic resonance (MR) imaging of the axial skeleton is sufficient for evaluation of patients with multiple myeloma (MM) or monoclonal gammopathy of undeterminedPURPOSE: To examine if standard magnetic resonance (MR) imaging of the axial skeleton is sufficient for evaluation of patients with multiple myeloma (MM) or monoclonal gammopathy of undetermined significance (MGUS) or if whole-body MR is necessary. MATERIALS AND METHODS: A total of 100 untreated patients with MGUS (n = 27) or any stages of MM (n = 73) were examined with whole-body MR imaging and MR imaging of the axial skeleton. The study was approved by the institutional ethics committee, and written informed consent was given. Spinal pattern ("no diffuse involvement" or "diffuse involvement" as assessed from the signal intensity of the spinal bone marrow), serum parameters, and stage of disease were correlated with the probability of detecting extra-axial lesions with and without destruction of cortical bone by using a multiple logistic regression model. RESULTS: Of 100 patients, 39 had lesions in the axial skeleton and 37 had lesions in the extra-axial skeleton. Of the latter group, nine patients had no axial lesions and 13 patients had lesions that violated cortical bone, which implied an increased fracture risk. Because of the extraaxial location, lesions in these patients could be diagnosed with whole-body MR only. In addition, no single or combination of clinical factors observed (stage of disease, serum parameters, and spinal pattern) allowed investigators to identify patients with a significantly increased probability of having extra-axial lesions or lesions violating cortical bone. CONCLUSION: Whole-body MR imaging has potential for use in the initial work-up of patients with MGUS or MM, since almost one-half of all observed lesions would have been missed by using spinal MR imaging only and clinical parameters could not exclude the presence of extra-axial lesions.

• Current status and developments in diagnosis and therapy of multiple myeloma.

  Authors: Jens Hillengass, Kai Neben, Hartmut Goldschmidt

  Journal of cancer research and clinical oncology. 09/2009;

• Dynamic Contrast-Enhanced Magnetic Resonance Imaging Identifies a Subgroup of Patients with Asymptomatic Monoclonal Plasma Cell Disease and Pathologic Microcirculation.

  Authors: Jens Hillengass, Christian Zechmann, Tobias Bäuerle, Barbara Wagner-Gund, Christiane Heiss, Axel Benner, Anthony Ho, Kai Neben, Dirk Hose, Hans-Ulrich Kauczor, Hartmut Goldschmidt, Stefan Delorme, Thomas Moehler

  Clinical cancer research : an official journal of the American Association for Cancer Research. 04/2009;

  PURPOSE: The aim of our study was to investigate whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows visualization of changes in microcirculation between healthy controls onPURPOSE: The aim of our study was to investigate whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows visualization of changes in microcirculation between healthy controls on the one side and early/advanced stages of plasma cell disease on the other.EXPERIMENTAL DESIGN: We examined a group of 222 individuals consisting of 60 patients with monoclonal gammopathy of undetermined significance (MGUS), 65 patients with asymptomatic multiple myeloma (aMM), 75 patients with newly diagnosed symptomatic MM (sMM), and 22 healthy controls with DCE-MRI of the lumbar spine.RESULTS: A continuous increase in microcirculation parameters amplitude A and exchange rate constant kep reflecting vascular volume and permeability, respectively, was detected from normal controls over MGUS and aMM to sMM. For A and kep, significant differences were found between controls and aMM (P = 0.03 and P = 0.004, respectively) as well as controls and sMM (P = 0.001 and P < 0.001, respectively). Although diffuse microcirculation patterns were found in healthy controls as well as MGUS and MM, a pattern with focal hotspots was exclusively detected in 42.6% of sMM and in 3 MGUS and 3 aMM patients. MGUS and aMM patients with increased microcirculation patterns showed significantly higher bone marrow plasmocytosis compared with patients with a low microcirculation pattern.CONCLUSIONS: Our investigations substantiate the concept of an angiogenic switch from early plasma cell disorders to sMM. Pathologic DCE-MRI findings correlate with adverse prognostic factors and DCE-MRI identifies a distinct group of patients with increased microcirculation parameters in aMM and MGUS patients.