@article{MunawarZhouPrommersbergeretal.2023,
  author    = {Munawar, Umair and Zhou, Xiang and Prommersberger, Sabrina and Nerreter, Silvia and Vogt, Cornelia and Steinhardt, Maximilian J. and Truger, Marietta and Mersi, Julia and Teufel, Eva and Han, Seungbin and Haertle, Larissa and Banholzer, Nicole and Eiring, Patrick and Danhof, Sophia and Navarro-Aguadero, Miguel Angel and Fernandez-Martin, Adrian and Ortiz-Ruiz, Alejandra and Barrio, Santiago and Gallardo, Miguel and Valeri, Antonio and Castellano, Eva and Raab, Peter and Rudert, Maximilian and Haferlach, Claudia and Sauer, Markus and Hudecek, Michael and Martinez-Lopez, J. and Waldschmidt, Johannes and Einsele, Hermann and Rasche, Leo and Kort{\"u}m, K. Martin},
  title     = {Impaired FADD/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma},
  series = {Communications Biology},
  volume    = {6},
  journal   = {Communications Biology},
  doi       = {10.1038/s42003-023-05683-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357609},
  year      = {2023},
  abstract  = {The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM.},
  language  = {en}
}
@article{RascheKumarGershneretal.2019,
  author    = {Rasche, Leo and Kumar, Manoj and Gershner, Grant and Samant, Rohan and Van Hemert, Rudy and Heidemeier, Anke and Lapa, Constantin and Bley, Thorsten and Buck, Andreas and McDonald, James and Hillengass, Jens and Epstein, Joshua and Thanendrarajan, Sharmilan and Schinke, Carolina and van Rhee, Frits and Zangari, Maurizio and Barlogie, Bart and Davies, Faith E. and Morgan, Gareth J. and Weinhold, Niels},
  title     = {Lack of Spleen Signal on Diffusion Weighted MRI is associated with High Tumor Burden and Poor Prognosis in Multiple Myeloma: A Link to Extramedullary Hematopoiesis?},
  series = {Theranostics},
  volume    = {9},
  journal   = {Theranostics},
  number    = {16},
  doi       = {10.7150/thno.33289},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224982},
  pages     = {4756-4763},
  year      = {2019},
  abstract  = {Due to the low frequency of abnormalities affecting the spleen, this organ is often overlooked during radiological examinations. Here, we report on the unexpected finding, that the spleen signal on diffusion-weighted MRI (DW-MRI) is associated with clinical parameters in patients with plasma cell dyscrasias. Methods: We investigated the spleen signal on DW-MRI together with clinical and molecular parameters in 295 transplant-eligible newly diagnosed Multiple Myeloma (NDMM) patients and in 72 cases with monoclonal gammopathy of undetermined significance (MGUS). Results: Usually, the spleen is the abdominal organ with the highest intensities on DW-MRI. Yet, significant signal loss on DW-MRI images was seen in 71 of 295 (24\%) NDMM patients. This phenomenon was associated with the level of bone marrow plasmacytosis (P=1x10(-10)) and International Staging System 3 (P=0.0001) but not with gain(1q), and del(17p) or plasma cell gene signatures. The signal was preserved in 72 individuals with monoclonal gammopathy of undetermined significance and generally re-appeared in MM patients responding to treatment, suggesting that lack of signal reflects increased tumor burden. While absence of spleen signal in MM patients with high risk disease defined a subgroup with very poor outcome, re-appearance of the spleen signal after autologous stem cell transplantation was seen in patients with improved outcome. Our preliminary observation suggests that extramedullary hematopoiesis in the spleen is a factor that modifies the DW-MRI signal of this organ. Conclusions: The DW-MRI spleen signal is a promising marker for tumor load and provides prognostic information in MM.},
  language  = {en}
}
@article{ZhouDierksKertelsetal.2020,
  author    = {Zhou, Xiang and Dierks, Alexander and Kertels, Olivia and Kircher, Malte and Schirbel, Andreas and Samnick, Samuel and Buck, Andreas K. and Knorz, Sebastian and B{\"o}ckle, David and Scheller, Lukas and Messerschmidt, Janin and Barakat, Mohammad and Kort{\"u}m, K. Martin and Rasche, Leo and Einsele, Hermann and Lapa, Constantin},
  title     = {18F-FDG, 11C-Methionine, and 68Ga-Pentixafor PET/CT in patients with smoldering multiple myeloma: imaging pattern and clinical features},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {8},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12082333},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211240},
  year      = {2020},
  abstract  = {This study aimed to explore the correlation between imaging patterns and clinical features in patients with smoldering multiple myeloma (SMM) who simultaneously underwent 18F-FDG, 11C-Methionine, and 68Ga-Pentixafor positron emission tomography/computed tomography (PET/CT). We retrieved and analyzed clinical characteristics and PET imaging data of 10 patients with SMM. We found a significant correlation between bone marrow (BM) plasma cell (PC) infiltration and mean standardized uptake values (SUV\(_{mean}\)) of lumbar vertebrae L2-L4 on 11C-Methionine PET/CT scans (r = 0.676, p = 0.031) and 68Ga-Pentixafor PET/CT scans (r = 0.839, p = 0.002). However, there was no significant correlation between BM involvement and SUV\(_{mean}\) of lumbar vertebrae L2-L4 on 18F-FDG PET/CT scans (r = 0.558, p = 0.093). Similarly, mean target-to-background ratios (TBR\(_{mean}\)) of lumbar vertebrae L2-L4 also correlated with bone marrow plasma cell (BMPC) infiltration in 11C-Methionine PET/CT (r = 0.789, p = 0.007) and 68Ga-Pentixafor PET/CT (r = 0.724, p = 0.018) PET/CT. In contrast, we did not observe a significant correlation between BMPC infiltration rate and TBR\(_{mean}\) in 18F-FDG PET/CT (r = 0.355, p = 0.313). Additionally, on 11C-Methionine PET/CT scans, we found a significant correlation between BMPC infiltration and TBR\(_{max}\) of lumbar vertebrae L2-L4 (r = 0.642, p = 0.045). In conclusion, 11C-Methionine and 68Ga-Pentixafor PET/CT demonstrate higher sensitivity than 18F-FDG PET/CT in detecting BM involvement in SMM.},
  language  = {en}
}
@article{RascheKortuemRaabetal.2019,
  author    = {Rasche, Leo and Kort{\"u}m, K. Martin and Raab, Marc S. and Weinhold, Niels},
  title     = {The impact of tumor heterogeneity on diagnostics and novel therapeutic strategies in multiple myeloma},
  series = {International Journal of Molecular Sciences},
  volume    = {20},
  journal   = {International Journal of Molecular Sciences},
  number    = {5},
  issn      = {1422-0067},
  doi       = {10.3390/ijms20051248},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285402},
  year      = {2019},
  abstract  = {Myeloma is characterized by extensive inter-patient genomic heterogeneity due to multiple different initiating events. A recent multi-region sequencing study demonstrated spatial differences, with progression events, such as TP53 mutations, frequently being restricted to focal lesions. In this review article, we describe the clinical impact of these two types of tumor heterogeneity. Target mutations are often dominant at one site but absent at other sites, which poses a significant challenge to personalized therapy in myeloma. The same holds true for high-risk subclones, which can be locally restricted, and as such not detectable at the iliac crest, which is the usual sampling site. Imaging can improve current risk classifiers and monitoring of residual disease, but does not allow for deciphering the molecular characteristics of tumor clones. In the era of novel immunotherapies, the clinical impact of heterogeneity certainly needs to be re-defined. Yet, preliminary observations indicate an ongoing impact of spatial heterogeneity on the efficacy of monoclonal antibodies. In conclusion, we recommend combining molecular tests with imaging to improve risk prediction and monitoring of residual disease. Overcoming intra-tumor heterogeneity is the prerequisite for curing myeloma. Novel immunotherapies are promising but research addressing their impact on the spatial clonal architecture is highly warranted.},
  language  = {en}
}
@article{JanjetovicLohneisNogaietal.2021,
  author    = {Janjetovic, Snjezana and Lohneis, Philipp and Nogai, Axel and Balci, Derya and Rasche, Leo and J{\"a}hne, Doris and Bokemeyer, Carsten and Schilling, Georgia and Blau, Igor Wolfgang and Schmidt-Hieber, Martin},
  title     = {Clinical and biological characteristics of medullary and extramedullary plasma cell dyscrasias},
  series = {Biology},
  volume    = {10},
  journal   = {Biology},
  number    = {7},
  issn      = {2079-7737},
  doi       = {10.3390/biology10070629},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242592},
  year      = {2021},
  abstract  = {Background: Extramedullary plasma cell (PC) disorders may occur as extramedullary disease in multiple myeloma (MM-EMD) or as primary extramedullary plasmocytoma (pEMP)/solitary osseous plasmocytoma (SOP). In this study, we aimed to obtain insights into the molecular mechanisms of extramedullary spread of clonal PC. Methods: Clinical and biological characteristics of 87 patients with MM-EMD (n = 49), pEMP/SOP (n = 20) and classical MM (n = 18) were analyzed by using immunohistochemistry (CXCR4, CD31, CD44 and CD81 staining) and cytoplasmic immunoglobulin staining combined with fluorescence in situ hybridization (cIg-FISH). Results: High expression of CD44, a cell-surface glycoprotein involved in cell-cell interactions, was significantly enriched in MM-EMD (90\%) vs. pEMP/SOP (27\%) or classical MM (33\%) (p < 0.001). In addition, 1q21 amplification by clonal PC occurred at a similar frequency of MM-EMD (33\%), pEMP/SOP (57\%) and classical MM (44\%). Conversely, del(17p13), t(4;14) and t(14;16) were completely absent in pEMP/SOP. Besides this, 1q21 amplification was identified in 64\% of not paraskeletal samples from MM-EMD or pEMP compared to 9\% of SOP or paraskeletal MM-EMD/pEMP and 44\% of classical MM samples, respectively (p = 0.02). Conclusion: Expression of molecules involved in homing and cytogenetic aberrations differ between MM with or without EMD and pEMP/SOP.},
  language  = {en}
}
@article{DahlhoffManzSteinfattetal.2022,
  author    = {Dahlhoff, Julia and Manz, Hannah and Steinfatt, Tim and Delgado-Tascon, Julia and Seebacher, Elena and Schneider, Theresa and Wilnit, Amy and Mokhtari, Zeinab and Tabares, Paula and B{\"o}ckle, David and Rasche, Leo and Martin Kort{\"u}m, K. and Lutz, Manfred B. and Einsele, Hermann and Brandl, Andreas and Beilhack, Andreas},
  title     = {Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression},
  series = {Leukemia},
  volume    = {36},
  journal   = {Leukemia},
  number    = {3},
  issn      = {1476-5551},
  doi       = {10.1038/s41375-021-01422-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271787},
  pages     = {790-800},
  year      = {2022},
  abstract  = {Multiple myeloma remains a largely incurable disease of clonally expanding malignant plasma cells. The bone marrow microenvironment harbors treatment-resistant myeloma cells, which eventually lead to disease relapse in patients. In the bone marrow, CD4\(^{+}\)FoxP3\(^{+}\) regulatory T cells (Tregs) are highly abundant amongst CD4\(^{+}\) T cells providing an immune protective niche for different long-living cell populations, e.g., hematopoietic stem cells. Here, we addressed the functional role of Tregs in multiple myeloma dissemination to bone marrow compartments and disease progression. To investigate the immune regulation of multiple myeloma, we utilized syngeneic immunocompetent murine multiple myeloma models in two different genetic backgrounds. Analyzing the spatial immune architecture of multiple myeloma revealed that the bone marrow Tregs accumulated in the vicinity of malignant plasma cells and displayed an activated phenotype. In vivo Treg depletion prevented multiple myeloma dissemination in both models. Importantly, short-term in vivo depletion of Tregs in mice with established multiple myeloma evoked a potent CD8 T cell- and NK cell-mediated immune response resulting in complete and stable remission. Conclusively, this preclinical in-vivo study suggests that Tregs are an attractive target for the treatment of multiple myeloma.},
  language  = {en}
}
@article{ZhouRuckdeschelPeteretal.2022,
  author    = {Zhou, Xiang and Ruckdeschel, Anna and Peter, Jessica and B{\"o}ckle, David and Hornburger, Hannah and Danhof, Sophia and Steinhardt, Maximilian Johannes and Heimeshoff, Larissa and Einsele, Hermann and Kort{\"u}m, Klaus Martin and Rasche, Leo},
  title     = {Salvage therapy with "Dara-KDT-P(A)CE" in heavily pretreated, high-risk, proliferative, relapsed/refractory multiple myeloma},
  series = {Hematological Oncology},
  volume    = {40},
  journal   = {Hematological Oncology},
  number    = {2},
  doi       = {10.1002/hon.2949},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257495},
  pages     = {202-211},
  year      = {2022},
  abstract  = {The multi-agent therapy "VDT-PACE" represents an established regimen in relapsed/refractory multiple myeloma (RRMM). Here, we report on our experience with a "modified VDT-PACE" incorporating new generation anti-MM agents daratumumab and carfilzomib ("Dara-KDT-P(A)CE"). We retrospectively analyzed 38 patients with RRMM treated with "Dara-KDT-P(A)CE". The median age was 62 (range 45-82) years, and the patients were heavily pretreated with a median of 5 (range 2-12) prior lines of therapy. Twenty-one (55\%) patients suffered from penta-refractory MM. High-risk cytogenetics was present in 31 (81\%) patients. The patients received a median of 2 (range 1-10) cycles of this therapy, and the overall response rate (ORR) was 70\%. Patients with penta-refractory MM and high-risk cytogenetics showed similar ORR of 65\% and 79\%, respectively. The median progression-free survival (PFS) and overall survival were 4.1 (95\% CI 2.7-5.4) and 8.4 (95\% CI 6.7-10.0) months, respectively. Patients with lactate dehydrogenase >250 IU/L showed significantly shorter PFS in comparison with others patients (p = 0.006). We used this regimen as bridging therapy prior to chimeric antigen receptor T-cell infusion in four patients. In conclusion, "Dara-KDT-P(A)CE" is an effective salvage therapy for patients with heavily pretreated, multi-refractory, high-risk RRMM lacking alternative options.},
  language  = {en}
}
@article{DanhofRascheMottoketal.2021,
  author    = {Danhof, Sophia and Rasche, Leo and Mottok, Anja and Steinm{\"u}ller, Tabea and Zhou, Xiang and Schreder, Martin and Kilian, Teresa and Strifler, Susanne and Rosenwald, Andreas and Hudecek, Michael and Einsele, Hermann and Gerhard-Hartmann, Elena},
  title     = {Elotuzumab for the treatment of extramedullary myeloma: a retrospective analysis of clinical efficacy and SLAMF7 expression patterns},
  series = {Annals of Hematology},
  volume    = {100},
  journal   = {Annals of Hematology},
  number    = {6},
  issn      = {1432-0584},
  doi       = {10.1007/s00277-021-04447-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266468},
  pages     = {1537-1546},
  year      = {2021},
  abstract  = {Extramedullary disease (EMD) represents a high-risk state of multiple myeloma (MM) associated with poor prognosis. While most anti-myeloma therapeutics demonstrate limited efficacy in this setting, some studies exploring the utility of chimeric antigen receptor (CAR)-modified T cells reported promising results. We have recently designed SLAMF7-directed CAR T cells for the treatment of MM. SLAMF7 is a transmembrane receptor expressed on myeloma cells that plays a role in myeloma cell homing to the bone marrow. Currently, the only approved anti-SLAMF7 therapeutic is the monoclonal antibody elotuzumab, but its efficacy in EMD has not been investigated thoroughly. Thus, we retrospectively analyzed the efficacy of elotuzumab-based combination therapy in a cohort of 15 patients with EMD. Moreover, since the presence of the target antigen is an indispensable prerequisite for effective targeted therapy, we investigated the SLAMF7 expression on extramedullary located tumor cells before and after treatment. We observed limited efficacy of elotuzumab-based combination therapies, with an overall response rate of 40\% and a progression-free and overall survival of 3.8 and 12.9 months, respectively. Before treatment initiation, all available EMD tissue specimens (n = 3) demonstrated a strong and consistent SLAMF7 surface expression by immunohistochemistry. Furthermore, to investigate a potential antigen reduction under therapeutic selection pressure, we analyzed samples of de novo EMD (n = 3) outgrown during elotuzumab treatment. Again, immunohistochemistry documented strong and consistent SLAMF7 expression in all samples. In aggregate, our data point towards a retained expression of SLAMF7 in EMD and encourage the development of more potent SLAMF7-directed immunotherapies, such as CAR T cells.},
  language  = {en}
}
@article{BachmannSchrederEngelhardtetal.2021,
  author    = {Bachmann, Friederike and Schreder, Martin and Engelhardt, Monika and Langer, Christian and Wolleschak, Denise and M{\"u}gge, Lars Olof and D{\"u}rk, Heinz and Sch{\"a}fer-Eckart, Kerstin and Blau, Igor Wolfgang and Gramatzki, Martin and Liebisch, Peter and Grube, Matthias and Metzler, Ivana v. and Bassermann, Florian and Metzner, Bernd and R{\"o}llig, Christoph and Hertenstein, Bernd and Khandanpour, Cyrus and Dechow, Tobias and Hebart, Holger and Jung, Wolfram and Theurich, Sebastian and Maschmeyer, Georg and Salwender, Hans and Hess, Georg and Bittrich, Max and Rasche, Leo and Brioli, Annamaria and Eckardt, Kai-Uwe and Straka, Christian and Held, Swantje and Einsele, Hermann and Knop, Stefan},
  title     = {Kinetics of renal function during induction in newly diagnosed multiple myeloma: results of two prospective studies by the German Myeloma Study Group DSMM},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {6},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13061322},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234139},
  year      = {2021},
  abstract  = {Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. Results: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3\% at baseline to 1.9\% PInd (p < 0.0001). Thirty-seven point one percent of VCD versus 49\% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined "renal complete response (CRrenal)" was achieved in 17/25 (68\%) pts after VCD, 12/19 (63\%) after RAD, and 14/27 (52\%) after VRd (p = 0.4747). Conclusions: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment "renal fitness" in the latter group.},
  language  = {en}
}
@article{ZhouFluechterNickeletal.2020,
  author    = {Zhou, Xiang and Fl{\"u}chter, Patricia and Nickel, Katharina and Meckel, Katharina and Messerschmidt, Janin and B{\"o}ckle, David and Knorz, Sebastian and Steinhardt, Maximilian Johannes and Krummenast, Franziska and Danhof, Sophia and Einsele, Hermann and Kort{\"u}m, K. Martin and Rasche, Leo},
  title     = {Carfilzomib based treatment strategies in the management of relapsed/refractory multiple myeloma with extramedullary disease},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {4},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12041035},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203704},
  year      = {2020},
  abstract  = {Published experience with carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) and extramedullary disease (EMD) is still limited. The current study aimed to assess the efficacy and safety of carfilzomib containing therapy regimens in EMD. We retrospectively analyzed 45 patients with extramedullary RRMM treated with carfilzomib from June 2013 to September 2019. The median age at the start of carfilzomib was 64 (range 40-80) years. Twenty (44\%) and 25 (56\%) patients had paraosseous manifestation and EMD without adjacency to bone, respectively. The serological overall response rate (ORR) was 59\%. Extramedullary response was evaluable in 33 patients, nine (27\%) of them achieved partial remission (PR) (ORR = 27\%). In 15 (33\%) patients, we observed no extramedullary response despite serological response. The median progression-free survival (PFS) and overall survival (OS) were five (95\% CI, 3.5-6.5) and ten (95\% CI, 7.5-12.5) months, respectively. EMD without adjacency to bone was associated with a significantly inferior PFS (p = 0.004) and OS (p = 0.04) compared to paraosseous lesions. Carfilzomib based treatment strategies showed some efficacy in heavily pretreated patients with extramedullary RRMM but could not overcome the negative prognostic value of EMD. Due to the discrepancy between serological and extramedullary response, evaluation of extramedullary response using imaging is mandatory in these patients.},
  language  = {en}
}