INTRODUCTION: Multiple myeloma (MM), a malignant plasma cell disorder, is still an incurable disease. Thus, the identification of novel therapeutic targets is of utmost importance. Here, we evaluated the peripheral blood-based metabolic profile of patients with MM. MATERIAL & METHODS: Peripheral blood plasma levels of 188 endogenous metabolites, including amino acids, biogenic amines, acylcarnitines, glycerophospholipids, sphingomyelins, and hexoses were determined in patients with plasma cell dyscrasias: monoclonal gammopathy of undetermined significance, a precursor stage of MM (MGUS, n = 15), newly diagnosed MM, (NDMM, n = 32), relapsed/refractory MM (RRMM, n = 19) and in 25 healthy controls by mass spectrometry. RESULTS: Patients with NDMM, RRMM and MGUS have a substantially different metabolomic profile than healthy controls. The amount of eight plasma metabolites significantly differs between the NDMM and MGUS group: free carnitine, acetylcarnitine, glutamate, asymmetric dimethylarginine (ADMA) and four phosphatidylcholine (PC) species. In addition, the levels of octadecanoylcarnitine, ADMA and six PCs were significantly different between RRMM and MGUS patients. 13 different concentrations of metabolites were found between RRMM and NDMM patients (free carnitine, acetylcarnitine, creatinine, five LysoPCs and PCs). Pathway analyses revealed a distinct metabolic profile with significant alterations in amino acid, lipid, and energy metabolism in healthy volunteers compared to MGUS/MM patients. CONCLUSION: We identified different metabolic profiles in MGUS und MM patients in comparison to healthy controls. Thus, different metabolic processes, potentially the immunoregulation by indoleamine 2,3 dioxygenase-1 (IDO), which is involved in cancer development and progression supporting inflammatory processes in the tumor microenvironment and glutaminolysis, can serve as novel promising therapeutic targets in MM.

Babak Myeloma Group Department of Pathological Physiology Faculty of Medicine Masaryk University Brno Czech Republic

Biocrates Life Sciences AG Innsbruck Austria

Department of Clinical Hematology University Hospital Brno Brno Czech Republic

Department of Hematooncology University Hospital Ostrava Ostrava Czech Republic

Department of Medical Statistics Informatics and Health Economics Medical University of Innsbruck Innsbruck Austria

Faculty of Medicine University of Ostrava Ostrava Czech Republic

Laboratory for Tumor Biology and Angiogenesis Department of Internal Medicine 5 Medical University of Innsbruck Innsbruck Austria

Salzburg Cancer Research Institute Laboratory for Immunological and Molecular Cancer Research Salzburg Austria

Tyrolean Cancer Research Institute Innsbruck Austria

Zobrazit více v PubMed

Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. Blood. 2015;125(20):3069–75. Epub 2015/04/04. 10.1182/blood-2014-09-568899 . PubMed DOI PMC

Rollig C, Knop S, Bornhauser M. Multiple myeloma. Lancet (London, England). 2015;385(9983):2197–208. Epub 2014/12/30. 10.1016/s0140-6736(14)60493-1 . PubMed DOI

Nooka AK, Kastritis E, Dimopoulos MA, Lonial S. Treatment options for relapsed and refractory multiple myeloma. Blood. 2015;125(20):3085–99. Epub 2015/04/04. 10.1182/blood-2014-11-568923 . PubMed DOI

Pavlova NN, Thompson CB. The Emerging Hallmarks of Cancer Metabolism. Cell metabolism. 2016;23(1):27–47. Epub 2016/01/16. 10.1016/j.cmet.2015.12.006 . PubMed DOI PMC

Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (New York, NY). 2009;324(5930):1029–33. Epub 2009/05/23. 10.1126/science.1160809 . PubMed DOI PMC

Beger RD. A review of applications of metabolomics in cancer. Metabolites. 2013;3(3):552–74. Epub 2013/01/01. 10.3390/metabo3030552 . PubMed DOI PMC

Goveia J, Pircher A, Conradi LC, Kalucka J, Lagani V, Dewerchin M, et al. Meta-analysis of clinical metabolic profiling studies in cancer: challenges and opportunities. EMBO molecular medicine. 2016;8(10):1134–42. Epub 2016/09/08. 10.15252/emmm.201606798 . PubMed DOI PMC

Bajpai R, Matulis SM, Wei C, Nooka AK, Von Hollen HE, Lonial S, et al. Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax. Oncogene. 2016;35(30):3955–64. Epub 2015/12/08. 10.1038/onc.2015.464 . PubMed DOI PMC

Puchades-Carrasco L, Lecumberri R, Martinez-Lopez J, Lahuerta JJ, Mateos MV, Prosper F, et al. Multiple myeloma patients have a specific serum metabolomic profile that changes after achieving complete remission. Clinical cancer research: an official journal of the American Association for Cancer Research. 2013;19(17):4770–9. Epub 2013/07/23. 10.1158/1078-0432.ccr-12-2917 . PubMed DOI

Maiso P, Huynh D, Moschetta M, Sacco A, Aljawai Y, Mishima Y, et al. Metabolic signature identifies novel targets for drug resistance in multiple myeloma. Cancer research. 2015;75(10):2071–82. Epub 2015/03/15. 10.1158/0008-5472.CAN-14-3400 . PubMed DOI PMC

Ludwig C, Williams DS, Bartlett DB, Essex SJ, McNee G, Allwood JW, et al. Alterations in bone marrow metabolism are an early and consistent feature during the development of MGUS and multiple myeloma. Blood cancer journal. 2015;5:e359 Epub 2015/10/17. 10.1038/bcj.2015.85 . PubMed DOI PMC

Group IMW. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. British journal of haematology. 2003;121(5):749–57. Epub 2003/06/05. . PubMed

Armitage EG, Godzien J, Alonso-Herranz V, Lopez-Gonzalvez A, Barbas C. Missing value imputation strategies for metabolomics data. Electrophoresis. 2015;36(24):3050–60. Epub 2015/09/17. 10.1002/elps.201500352 . PubMed DOI

Suzuki Y, Suda T, Furuhashi K, Suzuki M, Fujie M, Hahimoto D, et al. Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer. Lung cancer (Amsterdam, Netherlands). 2010;67(3):361–5. Epub 2009/06/03. 10.1016/j.lungcan.2009.05.001 . PubMed DOI

Curti A, Trabanelli S, Salvestrini V, Baccarani M, Lemoli RM. The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology. Blood. 2009;113(11):2394–401. Epub 2008/11/22. 10.1182/blood-2008-07-144485 . PubMed DOI

Glavey SV, Naba A, Manier S, Clauser K, Tahri S, Park J, et al. Proteomic characterization of human multiple myeloma bone marrow extracellular matrix. Leukemia. 2017;31(11):2426–34. Epub 2017/03/28. 10.1038/leu.2017.102 . PubMed DOI

Ramsay RR, Gandour RD, van der Leij FR. Molecular enzymology of carnitine transfer and transport. Biochimica et biophysica acta. 2001;1546(1):21–43. Epub 2001/03/21. . PubMed

Hattori A, Tsunoda M, Konuma T, Kobayashi M, Nagy T, Glushka J, et al. Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia. Nature. 2017;545(7655):500–4. Epub 2017/05/18. 10.1038/nature22314 . PubMed DOI PMC

Mayers JR, Vander Heiden MG. Nature and Nurture: What Determines Tumor Metabolic Phenotypes? Cancer research. 2017;77(12):3131–4. Epub 2017/06/07. 10.1158/0008-5472.CAN-17-0165 . PubMed DOI

Tonjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nature medicine. 2013;19(7):901–8. Epub 2013/06/25. 10.1038/nm.3217 . PubMed DOI PMC

Dey P, Baddour J, Muller F, Wu CC, Wang H, Liao WT, et al. Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer. Nature. 2017;542(7639):119–23. Epub 2017/01/19. 10.1038/nature21052 . PubMed DOI PMC

Zheng YH, Hu WJ, Chen BC, Grahn TH, Zhao YR, Bao HL, et al. BCAT1, a key prognostic predictor of hepatocellular carcinoma, promotes cell proliferation and induces chemoresistance to cisplatin. Liver international: official journal of the International Association for the Study of the Liver. 2016;36(12):1836–47. Epub 2016/06/02. 10.1111/liv.13178 . PubMed DOI

Wang ZQ, Faddaoui A, Bachvarova M, Plante M, Gregoire J, Renaud MC, et al. BCAT1 expression associates with ovarian cancer progression: possible implications in altered disease metabolism. Oncotarget. 2015;6(31):31522–43. Epub 2015/09/16. 10.18632/oncotarget.5159 . PubMed DOI PMC

Zhang L, Han J. Branched-chain amino acid transaminase 1 (BCAT1) promotes the growth of breast cancer cells through improving mTOR-mediated mitochondrial biogenesis and function. Biochemical and biophysical research communications. 2017;486(2):224–31. Epub 2017/02/27. 10.1016/j.bbrc.2017.02.101 . PubMed DOI

Zaal EA, Wu W, Jansen G, Zweegman S, Cloos J, Berkers CR. Bortezomib resistance in multiple myeloma is associated with increased serine synthesis. Cancer & metabolism. 2017;5:7 Epub 2017/09/01. 10.1186/s40170-017-0169-9 . PubMed DOI PMC

Moon YW, Hajjar J, Hwu P, Naing A. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. Journal for immunotherapy of cancer. 2015;3:51 Epub 2015/12/18. 10.1186/s40425-015-0094-9 . PubMed DOI PMC

Johnson TS, Munn DH. Host indoleamine 2,3-dioxygenase: contribution to systemic acquired tumor tolerance. Immunological investigations. 2012;41(6–7):765–97. Epub 2012/09/29. 10.3109/08820139.2012.689405 . PubMed DOI

Heng B, Lim CK, Lovejoy DB, Bessede A, Gluch L, Guillemin GJ. Understanding the role of the kynurenine pathway in human breast cancer immunobiology. Oncotarget. 2016;7(6):6506–20. Epub 2015/12/10. 10.18632/oncotarget.6467 . PubMed DOI PMC

Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011;478(7368):197–203. Epub 2011/10/07. 10.1038/nature10491 . PubMed DOI

Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, et al. Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer immunology, immunotherapy: CII. 2014;63(7):721–35. Epub 2014/04/09. 10.1007/s00262-014-1549-4 . PubMed DOI PMC

Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature medicine. 2003;9(10):1269–74. Epub 2003/09/23. 10.1038/nm934 . PubMed DOI

Willard SS, Koochekpour S. Glutamate, glutamate receptors, and downstream signaling pathways. International journal of biological sciences. 2013;9(9):948–59. Epub 2013/10/25. 10.7150/ijbs.6426 . PubMed DOI PMC

Jin L, Alesi GN, Kang S. Glutaminolysis as a target for cancer therapy. Oncogene. 2016;35(28):3619–25. Epub 2015/11/26. 10.1038/onc.2015.447 . PubMed DOI PMC

Yang L, Venneti S, Nagrath D. Glutaminolysis: A Hallmark of Cancer Metabolism. Annual review of biomedical engineering. 2017;19:163–94. Epub 2017/03/17. 10.1146/annurev-bioeng-071516-044546 . PubMed DOI

El Arfani C, De Veirman K, Maes K, De Bruyne E, Menu E. Metabolic Features of Multiple Myeloma. International journal of molecular sciences. 2018;19(4). Epub 2018/04/18. 10.3390/ijms19041200 . PubMed DOI PMC

Wilcken DE, Sim AS, Wang J, Wang XL. Asymmetric dimethylarginine (ADMA) in vascular, renal and hepatic disease and the regulatory role of L-arginine on its metabolism. Molecular genetics and metabolism. 2007;91(4):309–17; discussion 8. Epub 2007/06/15. 10.1016/j.ymgme.2007.04.017 . PubMed DOI

Zairis MN, Patsourakos NG, Tsiaousis GZ, Theodossis Georgilas A, Melidonis A, Makrygiannis SS, et al. Plasma asymmetric dimethylarginine and mortality in patients with acute decompensation of chronic heart failure. Heart (British Cardiac Society). 2012;98(11):860–4. Epub 2012/03/17. 10.1136/heartjnl-2011-301372 . PubMed DOI

Raynor A, Jantscheff P, Ross T, Schlesinger M, Wilde M, Haasis S, et al. Saturated and mono-unsaturated lysophosphatidylcholine metabolism in tumour cells: a potential therapeutic target for preventing metastases. Lipids in health and disease. 2015;14:69 Epub 2015/07/15. 10.1186/s12944-015-0070-x . PubMed DOI PMC

Rapid discrimination of multiple myeloma patients by artificial neural networks coupled with mass spectrometry of peripheral blood plasma