Publications by authors named "Uta Bertsch"

53 Publications

MCT1 is a Predictive Marker for Lenalidomide Maintenance Therapy in Multiple Myeloma.

Blood Adv 2021 Nov 12. Epub 2021 Nov 12.

Technische Universitat Munchen, München, Germany.

Biomarkers that predict response to lenalidomide maintenance therapy in patients with multiple myeloma (MM) have remained elusive. We have shown that IMiDs exert anti-MM activity via destabilization of MCT1 and CD147. Here, samples of 654 patients receiving lenalidomide (n=455), thalidomide (n=98) or bortezomib (n=101) maintenance were assessed using gene expression profiling and RNA-sequencing, followed by correlation of MCT1 and CD147 expression with progression-free (PFS) and overall survival (OS) data. Patients with high gene expression levels of MCT1 showed significantly reduced PFS (31.9 vs. 48.2 months in MCT1high vs. MCT1low, P=.03) and OS (75.9 months vs. not reached (NR) months in MCT1high vs. MCT1low; P=.001) in case of lenalidomide maintenance, whereas MCT1 expression had no significant impact on PFS or OS in patients with bortezomib maintenance. We validated the predictive role of MCT1 for IMiD-based maintenance in an independent cohort of patients receiving thalidomide (OS 83.6 months vs. NR in MCT1high vs. MCT1low; P=.03). Functional validation showed that MCT1 overexpression in human MM cell lines significantly reduced efficacy of lenalidomide, while no change was observed upon bortezomib treatment, both in vitro and in an MM xenograft model. Together, we establish MCT1-expression as a predictive marker for response to lenalidomide-based maintenance treatment.
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http://dx.doi.org/10.1182/bloodadvances.2021005532DOI Listing
November 2021

Prognostic Impact of Serum Free Light Chain Ratio Normalization in Patients with Multiple Myeloma Treated within the GMMG-MM5 Trial.

Cancers (Basel) 2021 Sep 28;13(19). Epub 2021 Sep 28.

Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, 69120 Heidelberg, Germany.

We investigated the prognostic impact of time-dependent serum free light chain ratio (FLCr) normalization in 590 patients with secretory multiple myeloma (MM) during first-line treatment within the German-Speaking Myeloma Multicenter Group MM5 trial. Serum free light chains (sFLC) were assessed by the Freelite test at baseline, after induction, mobilization, autologous blood stem cell transplantation, consolidation and every three months during maintenance or follow up within two years after the start of maintenance. The proportion of patients with a normal or normalized FLCr increased from 3.6% at baseline to 23.2% after induction and 64.7% after consolidation. The achievement of FLCr normalization at any one time before the start of maintenance was associated with significantly prolonged progression-free survival (PFS) ( < 0.01, hazard ratio (HR) = 0.61, 95% confidence interval (95% CI) = 0.47-0.79) and overall survival (OS) ( = 0.02, HR = 0.67, 95% CI = 0.48-0.93) in multivariable time-dependent Cox regression analyses. Furthermore, reaching immune reconstitution, defined as the normalization of uninvolved immunoglobulins, before maintenance was associated with superior PFS ( = 0.04, HR = 0.77, 95% CI = 0.60-0.99) and OS ( = 0.01, HR = 0.59, 95% CI = 0.41-0.86). We conclude that FLCr normalization during therapy is an important favorable prognostic factor in MM. Therefore, we recommend serial measurements of sFLC during therapy until achieving FLCr normalization, even in patients with secretory MM.
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http://dx.doi.org/10.3390/cancers13194856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507729PMC
September 2021

The prognostic significance of [F]FDG PET/CT in multiple myeloma according to novel interpretation criteria (IMPeTUs).

EJNMMI Res 2021 Oct 9;11(1):100. Epub 2021 Oct 9.

Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69210, Heidelberg, Germany.

Purpose: [F]FDG PET/CT is the elective imaging modality for treatment monitoring in multiple myeloma (MM). However, MM is a heterogeneous disease from an imaging point of view, raising challenges in interpretation of PET/CT. We herein investigated the prognostic role of the novel Italian Myeloma criteria for PET Use (IMPeTUs) in MM patients undergoing high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT).

Methods: Forty-seven patients with newly diagnosed MM underwent [F]FDG PET/CT before commencement of treatment (baseline PET/CT). Thirty-four of them (72.3%) were also examined after completion of ASCT (follow-up PET/CT). PET/CT analysis was based on the IMPeTUs criteria, which take into consideration-among others-the metabolic state of the bone marrow based on the 5-point Deauville score (DS), the number and metabolic state of focal [F]FDG-avid lesions, as well as the presence of paramedullary disease (PMD) and extramedullary disease (EMD). We analyzed whether parameters from IMPeTUs correlate with clinically relevant parameters and patients' outcome, as assessed by progression-free survival (PFS).

Results: Median follow-up from baseline and follow-up PET/CT were 85.1 months and 76.7 months, respectively. The number of focal, [F]FDG-avid lesions significantly correlated with the bone marrow infiltration rate and the R-ISS stage, while the presence of PMD was associated with LDH. After univariate survival analysis, the number of focal, [F]FDG-avid lesions both before and after therapy as well as the presence of PMD and EMD before therapy adversely affected PFS. Multivariate survival analysis for baseline parameters confirmed that the number of focal, [F]FDG-avid lesions and the presence of EMD are associated with adverse prognosis, irrespective of the ISS stage and/or the presence of high-risk cytogenetic abnormalities. The 5-point DS of [F]FDG uptake in reference bone marrow and focal lesions showed a significant decrease as response to treatment, but it did not affect PFS.

Conclusion: Several parameters utilized in IMPeTUs predict PFS in MM patients, suggesting the potentially significant role of the new criteria in patient stratification and response assessment. Additional studies are warranted for the further evaluation of IMPeTUs in the direction of establishment of robust cut-off values with a prognostic significance in the disease.
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http://dx.doi.org/10.1186/s13550-021-00846-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502185PMC
October 2021

Antibiotic Prophylaxis or Granulocyte-Colony Stimulating Factor Support in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation.

Cancers (Basel) 2021 Jul 9;13(14). Epub 2021 Jul 9.

Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, 69120 Heidelberg, Germany.

We compare, in this manuscript, antibiotic prophylaxis versus granulocyte-colony stimulating factor (G-CSF) support as anti-infective strategies, in patients with multiple myeloma (MM), undergoing high-dose therapy followed by autologous stem cell transplantation (HDT/ASCT). At our institution, antibiotic prophylaxis after HDT/ASCT in MM was stopped in January 2017 and replaced by G-CSF support in March 2017. Consecutive MM patients who received HDT/ASCT between March 2016 and July 2018 were included in this single-center retrospective analysis. In total, 298 patients and 353 individual cases of HDT/ASCT were evaluated. In multivariate analyses, G-CSF support was associated with a significantly shortened duration of severe leukopenia < 1/nL ( < 0.001, hazard ratio (HR) = 16.22), and hospitalization (estimate = -0.19, < 0.001) compared to antibiotic prophylaxis. Rates of febrile neutropenia, need of antimicrobial therapy, transfer to intensive care unit, and death, were similar between the two groups. Furthermore, antibiotic prophylaxis was associated with a significantly increased risk for the development of multidrug resistant bacteria especially vancomycin-resistant Enterococcus faecium compared to G-CSF support (odds ratio (OR) = 17.38, = 0.01). Stop of antibiotic prophylaxis as an anti-infective strategy was associated with a reduction in overall resistance rates of bacterial isolates. These results indicate that G-CSF support should be the preferred option in MM patients undergoing HDT/ASCT.
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http://dx.doi.org/10.3390/cancers13143439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303829PMC
July 2021

Selective elimination of immunosuppressive T cells in patients with multiple myeloma.

Leukemia 2021 09 17;35(9):2602-2615. Epub 2021 Feb 17.

Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.

Elimination of suppressive T cells may enable and enhance cancer immunotherapy. Here, we demonstrate that the cell membrane protein SLAMF7 was highly expressed on immunosuppressive CD8CD28CD57 Tregs in multiple myeloma (MM). SLAMF7 expression associated with T cell exhaustion surface markers and exhaustion-related transcription factor signatures. T cells from patients with a high frequency of SLAMF7CD8 T cells exhibited decreased immunoreactivity towards the MART-1 antigen. A monoclonal anti-SLAMF7 antibody (elotuzumab) specifically depleted SLAMF7CD8 T cells in vitro and in vivo via macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). Anti-SLAMF7 treatment of MM patients depleted suppressive T cells in peripheral blood. These data highlight SLAMF7 as a marker for suppressive CD8 Treg and suggest that anti-SLAMF7 antibodies can be used to boost anti-tumoral immune responses in cancer patients.
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http://dx.doi.org/10.1038/s41375-021-01172-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410603PMC
September 2021

Lenalidomide versus bortezomib maintenance after frontline autologous stem cell transplantation for multiple myeloma.

Blood Cancer J 2021 01 7;11(1). Epub 2021 Jan 7.

Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany.

Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1-21 of 28 day cycles) followed by 10-15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with
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http://dx.doi.org/10.1038/s41408-020-00390-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791127PMC
January 2021

Front-line daratumumab-VTd versus standard-of-care in ASCT-eligible multiple myeloma: matching-adjusted indirect comparison.

Immunotherapy 2021 02 24;13(2):143-154. Epub 2020 Nov 24.

Erasmus University Medical Center Cancer Institute, Rotterdam 3015 GD, The Netherlands.

To compare daratumumab plus standard-of-care (SoC; bortezomib/thalidomide/dexamethasone [VTd]) and VTd alone with other SoC for transplant-eligible newly diagnosed multiple myeloma. We conducted an unanchored matching-adjusted indirect comparison of progression-free and overall survival (PFS/OS) with D-VTd/VTd versus bortezomib/lenalidomide/dexamethasone (VRd), bortezomib/cyclophosphamide/dexamethasone (VCd) and bortezomib/dexamethasone (Vd). After matching adjustment, significant improvements in PFS were estimated for D-VTd versus VRd (hazard ratio [HR]: 0.47 [95% CI: 0.33-0.69]), VCd (HR: 0.35 [95% CI: 0.21-0.58]) and Vd (HR: 0.42 [95% CI: 0.28-0.63]). OS was significantly longer with D-VTd versus VRd (HR: 0.31 [95% CI: 0.16-0.57]), VCd (HR: 0.35 [95% CI: 0.14-0.86]) and Vd (HR: 0.38 [95% CI: 0.18-0.77]). No significant PFS/OS differences were seen for VTd versus other SoC. This analysis supports front-line daratumumab for transplant-eligible newly diagnosed multiple myeloma.
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http://dx.doi.org/10.2217/imt-2020-0266DOI Listing
February 2021

Comparison of NGS and MFC Methods: Key Metrics in Multiple Myeloma MRD Assessment.

Cancers (Basel) 2020 Aug 18;12(8). Epub 2020 Aug 18.

Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, 69120 Heidelberg, Germany.

In order to meet the challenges in data evaluation and comparability between studies in multiple myeloma (MM) minimal residual disease (MRD) assessment, the goal of the current study was to provide a step-by-step evaluation of next-generation sequencing (NGS) and multicolor flow cytometry (MFC) data. Bone marrow (BM) sample pairs from 125 MM patients were analyzed by NGS and MFC MM MRD methods. Tumor load (TL) and limit of detection (LOD) and quantification (LOQ) were calculated. The best-fit MRD cut-off was chosen as 1 × 10, resulting in an overall 9.6% ( overall = 12 (NGS = 2, MFC = 10)) nonassessable cases. The overall concordance rate between NGS and MFC was 68.0% ( = 85); discordant results were found in 22.4% (11.2% ( = 14) of cases in each direction. Overall, 55.1% ( = 60/109) and 49.5% ( = 54/109) of patients with a serological response ≥ very good partial response (VGPR) showed BM MRD negativity by NGS and MFC, respectively. A good correlation in the TL assessed by both techniques was found (correlation coefficient = 0.8, = 40, < 0.001). Overall, our study shows good concordance between MM BM MRD status and TL when comparing NGS and MFC at a threshold of 10. However, a sufficient number of analyzed events and calculation of MRD key metrics are essential for the comparison of methods and evaluability of data at a specific MRD cut-off.
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http://dx.doi.org/10.3390/cancers12082322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464347PMC
August 2020

Bortezomib-based induction, high-dose melphalan and lenalidomide maintenance in myeloma up to 70 years of age.

Leukemia 2021 03 20;35(3):809-822. Epub 2020 Jul 20.

Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany.

Intensive upfront therapy in newly-diagnosed multiple myeloma (MM) including induction therapy (IT), high-dose melphalan (MEL200), and autologous blood stem cell transplantation (ASCT) followed by consolidation and/or maintenance is mostly restricted to patients up to 65 years of age. Prospective phase III trial data in the era of novel agents for patients up to 70 years of age are not available. The GMMG-MM5 trial included 601 patients between 18 and 70 years of age, divided in three groups for the present analysis: ≤60 years (S1, n = 353), 61-65 years (S2, n = 107) and 66-70 years (S3, n = 141). Treatment consisted of a bortezomib-containing IT, MEL200/ASCT, consolidation, and maintenance with lenalidomide. Adherence to treatment was similar among patients of the three age groups. Overall toxicity during all treatment phases was increased in S2 and S3 compared to S1 (any adverse event/any serious adverse event: S1:81.7/41.8% vs. S2:90.7/56.5% vs. S3:87.2/68.1%, p = 0.05/<0.001). With respect to progression-free survival (log-rank p = 0.73), overall survival (log-rank p = 0.54) as well as time-to-progression (Gray's p = 0.83) and non-relapse mortality (Gray's p = 0.25), no differences were found between the three age groups. Our results imply that an intensive upfront therapy with a bortezomib-containing IT, MEL200/ASCT, lenalidomide consolidation, and maintenance should be applied to transplant-eligible MM patients up to 70 years of age.
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http://dx.doi.org/10.1038/s41375-020-0976-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318883PMC
March 2021

Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial.

Leukemia 2020 07 7;34(7):1853-1865. Epub 2020 Feb 7.

Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany.

The MM5 trial aimed at demonstrating a progression-free survival (PFS) difference in continued vs. response-adapted (in case of complete response, CR) lenalidomide (LEN) maintenance therapy (MT) in newly diagnosed, transplant-eligible multiple myeloma (MM). Patients were equally randomized to receive induction therapy with PAd (bortezomib/doxorubicin/dexamethasone) or VCD (bortezomib/cyclophosphamide/dexamethasone), high-dose melphalan and autologous blood stem cell transplantation, and LEN consolidation, followed by either LEN MT for a fixed duration of 2 years (LEN-2Y) or until achievement of CR (LEN-CR, intention-to-treat population n = 502): arms A1:PAd + LEN-2Y (n = 125), B1:PAd + LEN-CR (n = 126), A2:VCD + LEN-2Y (n = 126), B2:VCD + LEN-CR (n = 125). In the LEN-CR group (B1 + B2), n = 88/17.5% patients did not start or discontinued LEN MT due to CR. There was no PFS (p = 0.60, primary endpoint) nor overall survival (OS) (p = 0.15) difference between the four study arms. On pooled LEN MT strategies, OS (hazard ratio, hazard ratio [HR] = 1.42, p = 0.03) but not PFS (HR = 1.15, p = 0.20) was shorter in LEN-CR (B1 + B2) vs. LEN-2Y (A1 + A2) groups. PFS was shortened on landmark analyses from the start of LEN MT in patients being in CR in the LEN-CR group (LEN-CR vs. LEN-2Y, HR = 1.84, p = 0.02). OS from first progression was shortened in the LEN-CR vs. LEN-2Y group (HR = 1.60, p = 0.01). LEN MT should be applied beyond CR for at least 2 years.
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http://dx.doi.org/10.1038/s41375-020-0724-1DOI Listing
July 2020

Prospective target assessment and multimodal prediction of survival for personalized and risk-adapted treatment strategies in multiple myeloma in the GMMG-MM5 multicenter trial.

J Hematol Oncol 2019 06 26;12(1):65. Epub 2019 Jun 26.

Labor für Myelomforschung, Universitätsklinikum Heidelberg, Heidelberg, Germany.

Background: Personalized and risk-adapted treatment strategies in multiple myeloma prerequisite feasibility of prospective assessment, reporting of targets, and prediction of survival probability in clinical routine. Our aim was first to set up and prospectively test our experimental and analysis strategy to perform advanced molecular diagnostics, i.e., interphase fluorescence in-situ hybridization (iFISH) in ≥ 90% and gene expression profiling (GEP) in ≥ 80% of patients within the first cycle of induction chemotherapy in a phase III trial, seen as prerequisite for target expression-based personalized treatment strategies. Secondly, whether the assessment of risk based on the integration of clinical, cytogenetic, and expression-based parameters ("metascoring") is possible in this setting and superior to the use of single prognostic factors.

Methods: We prospectively performed plasma cell purification, GEP using DNA-microarrays, and iFISH within our randomized multicenter GMMG-MM5-trial recruiting 604 patients between July 2010 and November 2013. Patient data were analyzed using our published gene expression report (GEP-R): after quality and identity control, integrated risk assessment (HM metascore) and targets were reported in clinical routine as pdf-document.

Results: Bone marrow aspirates were obtained from 573/604 patients (95%) and could be CD138-purified in 559/573 (97.6%). Of these, iFISH-analysis was possible in 556 (99.5%), GEP in 458 (82%). Identity control using predictors for sex, light and heavy chain type allowed the exclusion of potential sample interchanges (none occurred). All samples passed quality control. As exemplary targets, IGF1R-expression was reported expressed in 33.1%, AURKA in 43.2% of patients. Risk stratification using an integrated approach, i.e., HM metascore, delineated 10/77/13% of patients as high/medium/low risk, transmitting into significantly different median progression-free survival (PFS) of 15 vs. 39 months vs. not reached (NR; P < 0.001) and median overall survival (OS) of 41 months vs. NR vs. NR (P < 0.001). Five-year PFS and OS-rates were 5/31/54% and 25/68/98%, respectively. Survival prediction by HM metascore (Brier score 0.132, P < 0.001) is superior compared with the current gold standard, i.e., revised ISS score (0.137, P = 0.005).

Conclusions: Prospective assessment and reporting of targets and risk by GEP-R in clinical routine are feasible in ≥ 80% of patients within the first cycle of induction chemotherapy, simultaneously allowing superior survival prediction.
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http://dx.doi.org/10.1186/s13045-019-0750-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595705PMC
June 2019

Rationale and design of the German-speaking myeloma multicenter group (GMMG) trial HD6: a randomized phase III trial on the effect of elotuzumab in VRD induction/consolidation and lenalidomide maintenance in patients with newly diagnosed myeloma.

BMC Cancer 2019 May 28;19(1):504. Epub 2019 May 28.

University Hospital Heidelberg, Heidelberg, Germany.

Background: Despite major advances in therapy, multiple myeloma is still an incurable malignancy in the majority of patients. To increase survival, deeper remissions (i.e. CR) translating into longer PFS need to be achieved. Incorporation of new drugs (i.e. bortezomib and lenalidomide) as induction and maintenance treatment in an intensified treatment concept, including high dose melphalan (200 mg/m), has resulted in increased CR rates, and is considered the standard of care for younger patients. Elotuzumab in combination with lenalidomide and dexamethasone has given better results as lenalidomide and dexamethasone alone in a phase III trial. The GMMG-HD6 trial will be the first phase III trial investigating the role of elotuzumab in combination with bortezomib, lenalidomide and dexamethasone (VRD) induction/consolidation and lenalidomide maintenance within a high dose concept.

Methods: GMMG-HD6 is a randomized, open, multicenter phase III trial. The planned recruitment number is 564 NDMM patients. All patients will receive 4 VRD cycles as induction and undergo peripheral blood stem cell mobilization and harvesting. Thereafter they will be treated with high dose melphalan therapy plus autologous stem cell transplantation followed by 2 cycles of VRD consolidation and lenalidomide maintenance. Patients in arm B1 + B2 will additionally receive elotuzumab in the induction phase, whereas patients in A2 + B2 will be treated with elotuzumab added to consolidation and maintenance. The primary endpoint of the trial is PFS. Secondary objectives and endpoints are OS, CR rates after induction therapy comparing the two arms VRD (A1 + A2) vs VRD + elotuzumab (B1 + B2), CR rates after consolidation treatment, best response to treatment during the study, time to progression (TTP), duration of response (DOR), toxicity and quality of life.

Results: Since this is the publication of a study protocol of an ongoing study, no results can be presented.

Discussion: This phase III trial is designed to evaluate whether the addition of elotuzumab to an intensified treatment concept with high dose melphalan chemotherapy plus autologous stem cell transplantation and induction, consolidation and maintenance treatment with bortezomib and lenalidomide is able to improve PFS compared to the same concept without elotuzumab.

Trial Registration: NCT02495922 on June 24th, 2015.
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http://dx.doi.org/10.1186/s12885-019-5600-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537200PMC
May 2019

Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma.

Commun Biol 2019 4;2:89. Epub 2019 Mar 4.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.

Inherited genetic susceptibility to multiple myeloma has been investigated in a number of studies. Although 23 individual risk loci have been identified, much of the genetic heritability remains unknown. Here we carried out genome-wide interaction analyses on two European cohorts accounting for 3,999 cases and 7,266 controls and characterized genetic susceptibility to multiple myeloma with subsequent meta-analysis that discovered 16 unique interacting loci. These risk loci along with previously known variants explain 17% of the heritability in liability scale. The genes associated with the interacting loci were found to be enriched in transforming growth factor beta signaling and circadian rhythm regulation pathways suggesting immunoglobulin trait modulation, T17 cell differentiation and bone morphogenesis as mechanistic links between the predisposition markers and intrinsic multiple myeloma biology. Further tissue/cell-type enrichment analysis associated the discovered genes with hemic-immune system tissue types and immune-related cell types indicating overall involvement in immune response.
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http://dx.doi.org/10.1038/s42003-019-0329-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399257PMC
April 2020

Cereblon-binding proteins expression levels correlate with hyperdiploidy in newly diagnosed multiple myeloma patients.

Blood Cancer J 2019 01 29;9(2):13. Epub 2019 Jan 29.

Department of Hematology, Oncology and Rheumatology, Heidelberg University, Heidelberg, Germany.

Immunomodulatory drugs (IMIDs) are very effective in the treatment of multiple myeloma (MM). The description of their cereblon-mediated mechanism of action was a hallmark in MM research. Although the importance of IMID-induced degradation of cereblon-binding proteins is well described in vitro, the prognostic value of their expression levels in MM cells is less clear. Based on recently published data showing somewhat conflicting RNA levels, we analyzed the association between the levels of the Ikaros family zinc finger protein 1 (IKZF1), IKZF3, and karyopherin subunit alpha 2 (KPNA2) proteins measured by flow cytometry and prognostic parameters in 214 newly diagnosed MM patients who were randomized in the GMMG HD6 trial. No statistically significant associations between the expression levels and age, gender, light chain type, International Staging System (ISS) stage or cytogenetic high- and normal risk groups could be identified. Hyperdiploid MM cells expressed significantly higher levels of IKZF1, IKZF3 and KPNA2 than nonhyperdiploid cells. In contrast, translocation t(11;14) was associated with significantly lower expression levels. In conclusion, the observed overexpression of cereblon-binding proteins in MM cells with gain of chromosomes 5, 9, 11, 15, and 19 is consistent with the previously proposed positive regulation of MYC by IKZF1 and IKZF3, as well as MYC activation in hyperdiploid MM cells.
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http://dx.doi.org/10.1038/s41408-019-0174-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351644PMC
January 2019

Author Correction: Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma.

Nat Commun 2019 01 10;10(1):213. Epub 2019 Jan 10.

Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, D-45147, Germany.

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.
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http://dx.doi.org/10.1038/s41467-018-08107-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328616PMC
January 2019

Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.

Blood Cancer J 2018 12 21;9(1). Epub 2018 Dec 21.

German Cancer Research Center, 69120, Heidelberg, Germany.

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.
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http://dx.doi.org/10.1038/s41408-018-0162-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315026PMC
December 2018

The prognostic and predictive value of IKZF1 and IKZF3 expression in T-cells in patients with multiple myeloma.

Oncoimmunology 2018;7(10):e1486356. Epub 2018 Aug 1.

Department of Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany.

: While recent studies described the role of IKZF1/3 proteins in multiple myeloma (MM) cells, few have highlighted the significance of IKZF1/3 expression in T-cells. In this study we examine the prognostic and predictive value of IKZF1/3 expression in T-cells in patients with MM stage III. : We analysed the IKZF1/3 expression levels in T-cells from 45 MM stage I (MMI) and 50 newly diagnosed MM stage III (MMIII) patients, according to Durie-Salmon staging system, by flow cytometry to examine their prognostic and predictive value. We also combined observations with assays to determine the effect of IKZF1/3 expression on the T-cell immunophenotype and anti-tumour T-cell response in 162 MMIII patients. : We found that high IKZF3, but not IKZF1, expression in T-cells correlates with superior overall survival in MMIII patients treated with immunomodulatory drugs (thalidomide, lenalidomide and pomalidomide). Moreover, we show that higher IKZF3 expression in T-cells inhibits myeloma-specific T-cell response and that the immunophenotype of patients with high IKZF3 expression shows features that are contrary to the changes induced by immunomodulatory drugs. Although we observed higher IKZF3 expression levels in T-cells from patients with MMIII compared to MMI, IKZF3 expression was unaffected by the tumour microenvironment. : In conclusion, IKZF3 expression in T-cells is a predictive value for clinical outcome in MMIII patients treated with immunomodulatory drugs due to its profound modulation of T-cell functionality.
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http://dx.doi.org/10.1080/2162402X.2018.1486356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169592PMC
August 2018

A multiple myeloma classification system that associates normal B-cell subset phenotypes with prognosis.

Blood Adv 2018 09;2(18):2400-2411

Department of Haematology, Aalborg University Hospital, Aalborg, Denmark.

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 ene 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.
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http://dx.doi.org/10.1182/bloodadvances.2018018564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156884PMC
September 2018

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma.

Nat Commun 2018 09 13;9(1):3707. Epub 2018 Sep 13.

Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, D-45147, Germany.

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.
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http://dx.doi.org/10.1038/s41467-018-04989-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137048PMC
September 2018

Prognostic significance of cytogenetic heterogeneity in patients with newly diagnosed multiple myeloma.

Blood Adv 2018 01 27;2(1):1-9. Epub 2017 Dec 27.

Medizinische Klinik V and.

We investigated subclonal cytogenetic aberrations (CA) detected by interphase fluorescence in situ hybridization (iFISH) in patients with newly diagnosed multiple myeloma (MM) enrolled in the Haemato Oncology Foundation for Adults in the Netherlands (HOVON)-65/German-Speaking MM Group (GMMG)-HD4 phase 3 trial. Patients were either treated with 3 cycles of vincristine, Adriamycin, and dexamethasone or bortezomib, Adriamycin, and dexamethasone and then thalidomide or bortezomib maintenance after tandem autologous transplantation. Subclones were defined either by presence of different copy numbers of the same chromosome loci and/or CA present in at least 30% less and maximally 2/3 of cells compared with the main clone CA. Patients with subclones harbored more frequently high risk (31.0%) or hyperdiploid main clone aberrations (24.8%) than patients with t(11;14) in the main clone (10.1%). Gains and deletions of c-MYC were the only CA that occurred more frequently as subclone (8.1%/20.5%) than main clone (6.2%/3.9%, respectively). Treatment with bortezomib completely overcame the negative prognosis of high-risk CA in patients without subclones, but not in patients with additional subclonal CA. High-risk patients treated without bortezomib showed dismal outcome whether subclones were present or not. Cytogenetic heterogeneity defined by subclonal CA is of major prognostic significance in newly diagnosed MM patients treated with bortezomib within the HOVON-65/GMMG-HD4 trial.
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http://dx.doi.org/10.1182/bloodadvances.2017013334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761630PMC
January 2018

Body fat composition as predictive factor for treatment response in patients with newly diagnosed multiple myeloma - subgroup analysis of the prospective GMMG MM5 trial.

Oncotarget 2017 Sep 25;8(40):68460-68471. Epub 2017 Jul 25.

University of Heidelberg, Department of Internal Medicine V, Heidelberg, Germany.

Introduction/background: Obesity is a well-known risk factor for malignant tumors and increased body mass index (BMI) is correlated to the risk of developing multiple myeloma (MM). The correlation of body fat composition with disease activity, adverse events and treatment response of MM patients has not been investigated yet.

Patients And Methods: A subgroup of 108 patients from a single institution enrolled in the prospective GMMG-MM5 trial, who received a whole-body low-dose computed tomography (WBLDCT) before induction therapy, were included in this study. Body fat composition was measured in WBLDCT for each patient, divided in the compartments abdomen, pelvis, thigh and further categorized in subcutaneous (SAT) and visceral adipose tissue (VAT). The correlation of these parameters with disease activity (M protein, plasma cell count, LDH, CRAB-criteria), adverse cytogenetics, adverse events and treatment response were evaluated.

Results: Significant reciprocal correlation was found between adverse cytogenetics and VAT of the abdomen and pelvis, respectively (gain 1q21: p=0.009 and p=0.021; t(4;14): p=0.038 and p=0.042). No correlation of VAT or SAT with adverse events was observed. Significant reciprocal correlation was observed between abdominal (p=0.03) and pelvic (p=0.035) VAT and treatment response. Abdominal VAT remains significant (p=0.034) independently of revised ISS stage and treatment. The BMI did not show a significant correlation with treatment response or investigated cytogenetics.

Conclusion: Based on the clinically relevant difference in treatment outcome depending on VAT and SAT, excessive body fat of abdomen and pelvis might be a predictive factor for poor treatment response. Further influences in this context should be considered as well, e.g. chemotherapy dosing and body fat metabolism. Further studies are necessary to investigate this hypothesis.
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http://dx.doi.org/10.18632/oncotarget.19536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620270PMC
September 2017

Longitudinal fluorescence hybridization reveals cytogenetic evolution in myeloma relapsing after autologous transplantation.

Haematologica 2017 08 11;102(8):1432-1438. Epub 2017 May 11.

Medizinische Klinik V, University Hospital Heidelberg, Heidelberg, Germany.

To investigate cytogenetic evolution after upfront autologous stem cell transplantation for newly diagnosed myeloma we retrospectively analyzed fluorescence hybridization results of 128 patients with paired bone marrow samples from the time of primary diagnosis and at relapse. High-risk cytogenetic abnormalities (deletion 17p and/or gain 1q21) occurred more frequently after relapse (odds ratio: 6.33; 95% confidence interval: 1.86-33.42; <0.001). No significant changes were observed for defined translocations [t(4;14); t(11;14); t(14;16)] or hyperdiploid karyotypes between primary diagnosis and relapse. translocations with unknown partners occurred more frequently at relapse. New deletion 17p and/or gain 1q21 were associated with cytogenetic heterogeneity, since some lesions with different copy numbers were present only in subclones. No distinct baseline characteristics were associated with the occurrence of new high-risk cytogenetic abnormalities after progression. Patients who relapsed after novel agent-based induction therapy had an increased risk of developing high-risk aberrations (odds ratio 10.82; 95% confidence interval: 1.65-127.66; =0.03) compared to those who were treated with conventional chemotherapy. Survival analysis revealed dismal outcomes regardless of whether high-risk aberrations were present at baseline (hazard ratio, 3.53; 95% confidence interval: 1.53-8.14; =0.003) or developed at relapse only (hazard ratio, 3.06; 95% confidence interval: 1.09-8.59; =0.03). Our results demonstrate cytogenetic evolution towards high-risk disease after autologous transplantation and underline the importance of repeated genetic testing in relapsed myeloma (EudraCT number of the HD4 trial: 2004-000944-26).
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http://dx.doi.org/10.3324/haematol.2017.168005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541876PMC
August 2017

Frequency of expression and generation of T-cell responses against antigens on multiple myeloma cells in patients included in the GMMG-MM5 trial.

Oncotarget 2017 Oct 11;8(49):84847-84862. Epub 2016 Aug 11.

Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany.

Background: Raising T-cell response against antigens either expressed on normal and malignant plasma cells (e.g. HM1.24) or aberrantly on myeloma cells only (e.g. cancer testis antigens, CTA) by vaccination is a potential treatment approach for multiple myeloma.

Results: Expression by GEP is found for in all, in 318/458 (69.4%), in 209/458 (45.6%), in 40/458 (8.7%), and in 4/458 (0.8%) of samples with the pattern being confirmed by RNA-sequencing. T-cell-activation is found in 9/26 (34.6%) of patient samples, i.e. against HM1.24 (4/24), RHAMM-R3 (3/26), RHAMM1-8 (2/14), WT-1 (1/11), NY-ESO-1/2 (1/9), and MAGE-A3 (2/8). In 7/19 T-cell activation responses, myeloma cells lack respective antigen-expression. Expression of , and is associated with adverse survival.

Experimental Design: We assessed expression of and the CTAs , , and in CD138-purified myeloma cell samples of previously untreated myeloma patients in the GMMG-MM5 multicenter-trial by gene expression profiling (GEP; = 458) and RNA-sequencing ( = 152) as potential population regarding vaccination trials. We then validated the feasibility to generate T-cell responses ( = 72) against these antigens by IFN-γ EliSpot-assay ( = 26) related to antigen expression ( = 22). Lastly, we assessed survival impact of antigen expression in an independent cohort of 247 patients treated by high-dose therapy and autologous stem cell transplantation.

Conclusions: As T-cell responses can only be raised in a subfraction of patients despite antigen expression, and the number of responses increases with more antigens used, vaccination strategies should assess patients' antigen expression and use a "cocktail" of peptide vaccines.
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http://dx.doi.org/10.18632/oncotarget.11215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689578PMC
October 2017
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