NCT Research

CCRP Multiple Myeloma

Summary

The Heidelberg Myeloma Program is internationally renowned for the diagnosis and treatment of patients with monoclonal plasma cell diseases. In 2016 more than 7500 outpatient contacts, about 360 new patient admissions and 197 autologous hematopoietic stem cell transplantations were coordinated and supervised by the “Section Multiple Myeloma” of the Department of Hematology and Oncology, University Hospital Heidelberg and National Center for Tumor Diseases (NCT) Heidelberg.

CCRP Multiple Myeloma
 

The German-speaking Myeloma Multicenter Group (GMMG) headed by Hartmut Goldschmidt is the largest study group focusing on MM in Germany. Its Headquarter is based in Heidelberg. Within the last 20 years, the GMMG study group has performed numerous trials including five randomized, multicenter Phase III clinical trials with about 3000 patients enrolled from 74 centers throughout Germany, Austria and Switzerland.
Translational research projects of the group focus on systems medicine using “omics”- and imaging data in clinical routine and their integration with conventional clinical data in personalizing myeloma treatment. Overall goal of the Heidelberg Myeloma group is to generate improved therapies for myeloma patients through the development and testing of novel and personalized, genome- and signaling-driven treatment strategies.

Members designated as Contact Persons

Dr. U. Bertsch
Section Multiple Myeloma, Dept. of Hematology, Oncology and Rheumatology, Heidelberg University Hospital

Prof. Dr. H. Brenner
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center  

Dr. J. Burhenne, Dr. J. Weiß
Dept. of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital    

Prof. Dr. S. Delorme, Prof. Dr. H.P. Schlemmer, Dr. J. Mosebach
Division of Radiology, German Cancer Research Center        

Prof. Dr. A. Dimitrakopoulou-Strauss
Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center

Prof. Dr. V. Ewerbeck, Dr. S. Hemmer
Dept. of Orthopedics, Heidelberg University Hospital    

Prof. Dr. H. Goldschmidt
Section Multiple Myeloma, Dept. of Hematology, Oncology and Rheumatology/NCT, Heidelberg University Hospital    

Prof. Dr. W. E. Haefeli
Dept. of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital

PD Dr. U. Hegenbart, PD Dr. S. Schönland
Dept. of Internal Medicine V: Hematology, Oncology and Rheumatology, Heidelberg University Hospital

Prof. Dr. K. Hemminki, Dr. A. Försti
Division of Molecular Genetic Epidemiology, German Cancer Research Center

Prof. Dr. J. Hillengaß
Section Multiple Myeloma, Dept. of Hematology, Oncology and Rheumatology, Heidelberg University Hospital

PD Dr. Dr. D. Hose
Section Multiple Myeloma, Dept. of Hematology, Oncology and Rheumatology, Heidelberg University Hospital

Dr. S. Huhn
Section Multiple Myeloma, Dept. of Hematology, Oncology and Rheumatology, Heidelberg University Hospital    

PD Dr. M. Hundemer

Dept. of Internal Medicine V: Hematology, Oncology and Rheumatology, Heidelberg University Hospital 

Prof. Dr. D. Jäger
Dept. of Medical Oncology, NCT/Heidelberg University Hospital    

Prof. Dr. A. Jauch
Institute of Human Genetics, Heidelberg University Hospital

Prof. Dr. P. Knaup-Gregori, Dr. M. Ganzinger
Dept. of Medical Biometry, Institute of Medical Biometry and Informatics, Heidelberg University Hospital

Dr. D. Komljenovic
Division of Medical Physics in Radiology, German Cancer Research Center

Prof. Dr. A. Kopp-Schneider, A. Benner, Th. Hielscher
Division of Biostatistics, German Cancer Research Center

Prof. A. Krämer

Clinical Cooperation Unit Molecular Hematology, DKFZ/ Internal Medicine V, Heidelberg University Hospital

Dr. S. Luntz
Coordinating Centre for Clinical Trials Heidelberg, Medical Faculty of the Ruprecht Karls University Heidelberg

Prof. Dr. C. Müller-Tidow
Dept. of Internal Medicine V: Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg University Hospital    

PD Dr. M. Raab
Section Multiple Myeloma, Dept. of Hematology, Oncology and Rheumatology, Heidelberg University Hospital
Max-Eder-Junior Research Group Experimental therapies for hematologic malignancies, German Cancer Research Center

Prof. Dr. K. Rippe
Research Group Genome Organization and Function, German Cancer Research Center  

Prof. Dr. P. Schirmacher

Dept. of Pathology, Heidelberg University Hospital

Prof. Dr. C. von Kalle, Prof. Dr. H. Glimm, Dr. Heining

Dept. of Translational Oncology, NCT/German Cancer Research Center

Prof. Dr. M-A Weber, PD Dr. D. Spira, Dr. J. Nattenmüller

Dept. of Radiology, Heidelberg University Hospital

Scientific Aims

  • Generating improved therapies for relapsed and refractory multiple myeloma patients through the development and testing of novel personalized, genome- and signaling-driven treatment strategies.
  • Systems medicine: prediction of survival, response to treatment or therapy-limiting side effects and assessment of targets by interrelation between different “omics”, molecular and conventional clinical and imaging data. Development of prognostic markers to define and monitor high-risk smoldering myeloma.
  • Personalizing myeloma treatment by translating experimental findings directly into clinical testing.
  • Using novel imaging techniques (DWI, PET-CT/MRI) to monitor bone marrow involvement and biology of the disease.
  • Assessment of molecular disease heterogeneity in patients with multiple myeloma by imaging guided biopsy
  • Improving results of high-dose therapy followed by autologous hematopoietic stem cell transplantation and including new compounds in myeloma treatment.


Clinical Aims

  • To further improve the comprehensive patient care for Myeloma patients in terms of quality of life and overall survival.
  • Enrollment of many patients in innovative diagnostic and treatment programs / trials for both newly diagnosed and relapsed / refractory multiple myeloma patients.
  • Cure of Multiple Myeloma
  • Systems medicine by combining and integrating GEP-, RNA-sequencing- and GWAS data with conventional clinical, imaging and molecular data (e.g. iFISH) to provide a more complete characterization of the individual patient.
  1. Neben, K., Lokhorst, H.M., Jauch, A., Bertsch, U., Hielscher, T., van der Holt, B., Salwender, H., Blau, I.W., Weisel, K., Pfreundschuh, M., Scheid, C., Dührsen, U., Lindemann, W., Schmidt-Wolf, I.G., Peter, N., Teschendorf, C., Martin, H., Haenel, M., Derigs, H.G., Raab, M.S., Ho, A.D., van de Velde, H., Hose, D., Sonneveld, P., Goldschmidt, H. Administration of bortezomib before and after autologous stem-cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 119(4), 940-8 (2012) 10,498, Impact factor: 10,452
  2. Sonneveld, P., Schmidt-Wolf, I., van der Holt, B., el Jarari, L., Bertsch, U., Salwender, H., Zweegman, S., Vellenga, E., Broyl, A., Blau, I.W., Weisel, K.C., Wittebol, S., Bos, G., Stevens-Kroef, M., Scheid, C., Pfeundschuh, M., Hose, D., Jauch, A., van der Velde, H., Raymakers, R., Schaafsma, M.R., Kersten, M.J., van Marwijk Kooy, M., Duehrsen, U., Lindemann, W., Wijermans, P.W., Lokhorst, H., Goldschmidt, H. (2012) Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase 3 HOVON-65/GMMG-HD4 trial.  J Clin Oncol 30(24):2946-55 10,498, Impact factor: 18,443
  3. Chubb, D., Weinhold, N., Broderick, P., Chen, B., Johnson, D.C., Försti, A., Vijayakrishnan, J., Migliorini, G., Dobbins, S.E., Holroyd, A., Hose, D., Walker, B.A., Davies, F.E., Gregory, W.A., Jackson, G.H., Irving, J.A., Pratt, G., Fegan, C., Fenton, J.A., Neben, K., Hoffmann, P., Nöthen, M.M., Mühleisen, T.W., Eisele, L., Ross, F.M., Straka, C., Einsele, H., Langer, C., Dörner, E., Allan, J.M., Jauch, A., Morgan, G.J., Hemminki, K., Houlston, R.S., Goldschmidt, H. (2013) Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk. Nat Genet. 45(10):1221-5 28,419, Impact factor: 29,351
  4. Hillengass, J., Weber, M.A., Kilk, K., Listl, K., Wagner-Gund, B., Hillengass, M., Hielscher, T., Farid, A., Neben, K., Delorme, S., Landgren, O., Goldschmidt, H. (2013) Prognostic significance of whole-body MRI in patients with monoclonal gammopathy of undetermined significance. Leukemia. 28(1):174-8. 9,379, Impact factor: 10,431
  5. Mai, E.K., Bertsch, U., Dürig, J., Kunz, C., Haenel, M., Blau, I.W., Munder, M., Jauch, A., Schurich, B., Hielscher, T., Merz, M., Huegle-Doerr, B., Seckinger, A., Hose, D, Hillengass, J., Raab, M.S., Neben, K, Lindemann, H.W., Zeis, M., Gerecke, C., Schmidt-Wolf, I.G., Weisel, K., Scheid, C., Salwender, H., Goldschmidt H. (2015) Phase III trial of bortezomib, cyclophosphamide, dexamethasone (VCD) versus bortezomib, doxorubicin, dexamethasone (PAd) in newly-diagnosed myeloma. Leukemia. 29(8):1721-9 10,431, Impact factor: 10,431
  6. Merz, M., Salwender, H., Haenel, M., Mai, E.K., Bertsch, U., Kunz, C., Hielscher, T., Blau, I.W., Scheid, C., Hose, D., Seckinger, A., Jauch, A., Hillengass, J., Raab, M.S., Schurich, B, Munder, M., Schmidt-Wolf, IG, Gerecke, C., Lindemann, H.W., Zeis, M., Weisel, K., Duerig, J., Goldschmidt, H. (2015) Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: Interim analysis from the prospective GMMG-MM5 trial. Haematologica. 100(7):964-9, Impact factor: 5,814
  7. Raab, M.S., Lehners, N., Xu, J., Ho, A.D., Schirmacher, P., Goldschmidt, H., Andrulis, M. (2016) Spatially divergent clonal evolution in multiple myeloma: overcoming resistance to BRAF inhibition. Blood. 127(17):2155-7
  8. Mai, E.K., Benner, A., Bertsch, U., Brossart, P., Hänel, A., Kunzmann, V., Naumann, R., Neben, K., Egerer, G., Ho, A.D., Hillengass, J., Raab, M.S., Neubauer, A., Peyn, A., Ko, Y.D., Peter, N., Scheid, C., Goldschmidt, H. (2016) Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial. Br J Haematol. 173(5):731-41
  9. Mitchell, J.S., Li, N., Weinhold, N., Försti, A., Ali, M., van Duin, M., Thorleifsson, G., Johnson, D.C., Chen, B., Halvarsson, B.M., Gudbjartsson, D.F., Kuiper, R., Stephens, O.W., Bertsch, U., Broderick, P., Campo, C., Einsele, H., Gregory, W.A., Gullberg, U., Henrion, M., Hillengass, J., Hoffmann, P., Jackson, G.H., Johnsson, E, Jöud, M, Kristinsson, SY, Lenhoff, S, Lenive, O, Mellqvist, UH, Migliorini, G., Nahi, H., Nelander, S., Nickel, J., Nöthen, M.M., Rafnar, T., Ross, F.M., da Silva Filho, M.I., Swaminathan, B., Thomsen, H., Turesson, I., Vangsted, A., Vogel, U., Waage, A., Walker, B.A., Wihlborg, A.K., Broyl, A., Davies, F.E., Thorsteinsdottir, U., Langer, C., Hansson, M., Kaiser, M., Sonneveld, P., Stefansson, K., Morgan, G.J., Goldschmidt, H., Hemminki, K., Nilsson, B., Houlston, R.S. (2016) Genome-wide association study identifies multiple susceptibility loci for multiple myeloma Nat Commun. 7:12050
  10. Kortüm, K.M., Mai, E.K., Hanafiah, N.H., Shi, C.X., Zhu, Y.X., Bruins, L., Barrio, S., Jedlowski, P., Merz, M., Xu, .J, Stewart, R.A., Andrulis, M., Jauch, A., Hillengass, J., Goldschmidt, H., Bergsagel, P.L., Braggio, E., Stewart, A.K., Raab, M.S. (2016) Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes. Blood. 128(9):1226-33

Clinical Activities

Multidisciplinary patient management
Myeloma Patients are treated by a multidisciplinary Treatment Team. Individual treatment plans are developed within interdisciplinary tumour boards (Internal Medicine, Radio Therapy, Orthopedics, Nephrology, Neurology)

Specific treatment options

  • Phase I to IV trials for both newly diagnosed and relapsed/refractory multiple myeloma patients
  • High dose therapy, autologous stem cell transplantation, new substances
  • Personalized treatment
  • Supervising and treating of myeloma precursor diseases (MGUS, Smoldering Myeloma)

The Heidelberg Multiple Myeloma Section was founded in 2005 and is shared between the Heidelberg University Hospital and National Center for Tumor diseases (NCT) Heidelberg.

  • Within a Germany-wide network, the German-Speaking Myeloma Multicentre Group (GMMG) headed by Hartmut Goldschmidt carries out phase III clinical studies improving high dose therapy as well as phase I/II clinical trials evaluating new compounds for multiple myeloma treatment. The results of the GMMG- trials are continuously changing standards of myeloma treatment. Results of the study group contributed to a change of the standard induction treatment in Germany (to a Bortezomib based induction).
  • The adverse impact of deletion (17p13) on PFS and OS of Myeloma patients could be significantly reduced by Bortezomib based treatment (Neben et al. Blood 2012) and Bortezomib treatment of Multiple Myeloma patients during induction and maintenance improves complete response and achieves superior PFS und OS (Sonneveld et al. J Clin Oncol. 2012). The GMMG study group further investigated the impact of subcutaneous versus intravenous bortezomib in the MM5 trial. In conclusion, compared to IV bortezomib, SC bortezomib in PAd and VCD induction therapy reduced toxicity and achieved similar overall response rates, regardless of whether adverse prognostic factors such as ISS stage III disease, renal impairment or cytogenetic abnormalities were present at initial diagnosis (Merz et al. Haematologica 2015). The GMMG-MM5 trial also demonstrated non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/ dexamethasone (PAd) induction therapy with respect to response.  Despite higher rates of leukocytopenia/neutropenia, which did not translate into increased infection rates, VCD has a favorable toxicity profile in terms of the total numbers of SAEs during IT, neuropathy rates and thromboembolic events. VCD is therefore an established standard IT in newly diagnosed transplanteligible MM and is recommended to be preferred over Pad (Mai et al. Leukemia 2015).
  • Long term results from the phase III GMMG-HD2 trial supports the hypothesis that upfront single high-dose melphalan followed by autologous stem cell transplantation (HDM/ASCT) in newly diagnosed multiple myeloma is non-inferior to tandem HDM/ASCT. (Mai et al. Br J Haematol. 2016).
  • When using targeted biomarker based therapies in a patient with refractory myeloma the development of resistance can be overcome or even prevented. We showed for the first time that combining of compounds with complementary mechanisms of action is very successful. This represents a significant step toward the goal of personalizing treatment for this genetically complex malignancy (Raab et al. Blood 2016).
  • Imaging methods like whole-body MRI serve as an excellent tool to non-invasively display bone marrow infiltration patterns, especially in patients with early stages of monoclonal plasma cell disease. The presence of focal lesions detected by whole-body MRI in a well-documented group of individuals with MGUS is prognostically significant (Hillengaß et al. Leukemia 2013).

Preclinical Activities

Established Technologies

  • Gene expression profiling
  • RNA sequencing
  • FISH
  • Genome wide association studies GWAS
  • DNA Sequencing
  • Minimal Residual Disease MRD FACS
  • Minimal Residual Disease ASO PCR
  • Modelling
  • Epigenetics


Technologies to be established

  • Proteomics
  • Metabolomics
  • Targeted sequencing of refractory myeloma revealed a high incidence of mutations in CRBN and Ras pathway genes. In a cohort of 50 heavily pretreated refractory myeloma patients 88 frequently mutated or drug resistance pathway myeloma genes with a focus on genes relevant to IMiD and PI interactions were investigated. Compared with newly diagnosed myeloma, an increased prevalence of mutations in the Ras pathway genes, as well as TP53, CRNB and CRBN pathway genes was observed. These data indicate a differential genetic landscape in refractory myeloma associated with drug response. (Kortüm et al. Blood 2016).
  • Together with other groups we identified genetic risk factors for Multiple Myeloma by developing the largest Genome wide association studies (GWAS) of Multiple Myeloma to date. We identified eight novel MM risk loci taking the total count to 17. Our findings provide further evidence for an inherited genetic susceptibility to MM and provide the first steps in identifying the genetic causes of Myeloma. (Chubb et al. Nat Genet. 2013, Mitchell et al. Nat. Commun. 2016).