INTRODUCTION: Multiple myeloma (MM) is still incurable due to resistance against various therapies. Thus, the identification of biomarkers predicting progression is urgently needed. Here, we evaluated four biomarkers in bone marrow and peripheral blood of MM patients for their prognostic significance. MATERIALS & METHODS: Bone marrow- and peripheral blood plasma levels of FLT3-L, soluble TIE2, endostatin, and osteoactivin were determined in patients with monoclonal gammopathy of undetermined significance (MGUS, n = 14/n = 4), patients with newly diagnosed MM (NDMM, n = 42/n = 31) and patients with relapsed/refractory MM (RRMM, n = 27/n = 16) by sandwich ELISA. RESULTS: Median FLT3-L expression increased from MGUS (58.77 pg/ml in bone marrow; 80.40 pg/ml in peripheral blood) to NDMM (63.15 pg/ml in bone marrow; 85.05 pg/ml in peripheral blood) and was maximal in RRMM (122 pg/ml in bone marrow; 160.47 pg/ml in peripheral blood; NDMM vs. RRMM p<0.001). A cut-off value of FLT3-L >92 pg/ml in bone marrow and >121 pg/ml in peripheral blood was associated with relapse or refractoriness in MM patients. FLT3-L was found to be a high predictive marker for discrimination between NDMM and RRMM as well in bone marrow as in peripheral blood (AUC 0.75 in bone marrow; vs 0.84 in peripheral blood). CONCLUSION: High levels of FLT3-L in bone marrow and peripheral blood of MM patients identify patients with progressive disease and are associated with relapse or refractoriness in MM patients. FLT3-L could be useful as a marker to identify RRMM patients and should be evaluated as target for future therapies.

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

Department of Clinical Hematology University Hospital Brno Czech Republic

Department of Hematology Oncology University Hospital Ostrava Ostrava Czech Republic

Department of Internal Medicine 5 Innsbruck Medical University Anichstr 35 Innsbruck Austria

Department of Medical Statistics Informatics and Health Economics Innsbruck Medical University Schöpfstr 41 Innsbruck Austria

Faculty of Medicine University of Ostrava Ostrava Czech Republic

Laboratory for Tumor Biology and Angiogenesis Innsbruck Medical University Innrain 66 Innsbruck Austria

Tyrolean Cancer Research Institute Innrain 66 Innsbruck Austria

Zobrazit více v PubMed

Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28(5):1122–8. Epub 2013/10/26. doi: 10.1038/leu.2013.313 ; PubMed Central PMCID: PMCPmc4000285. PubMed DOI PMC

Gentile M, Recchia AG, Mazzone C, Lucia E, Vigna E, Morabito F. Perspectives in the treatment of multiple myeloma. Expert Opin Biol Ther. 2013;13 Suppl 1:S1–22. Epub 2013/05/23. doi: 10.1517/14712598.2013.799132 . PubMed DOI

Moreau P, Touzeau C. Multiple myeloma: from front-line to relapsed therapies. Am Soc Clin Oncol Educ Book. 2015:e504–11. Epub 2015/05/21. doi: 10.14694/EdBook_AM.2015.35.e504 . PubMed DOI

Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nature reviews Cancer. 2007;7(8):585–98. Epub 2007/07/25. doi: 10.1038/nrc2189 . PubMed DOI

Vacca A, Ribatti D. Bone marrow angiogenesis in multiple myeloma. Leukemia. 2006;20(2):193–9. Epub 2005/12/17. doi: 10.1038/sj.leu.2404067 . PubMed DOI

Fowler JA, Mundy GR, Lwin ST, Edwards CM. Bone Marrow Stromal Cells Create a Permissive Microenvironment for Myeloma Development: A New Stromal Role for Wnt Inhibitor Dkk1. Cancer research. 2012;72(9):2183–9. doi: 10.1158/0008-5472.CAN-11-2067 PubMed DOI PMC

Ribatti D, Vacca A. Role of Endothelial Cells and Fibroblasts in Multiple Myeloma Angiogenic Switch. Cancer treatment and research. 2016;169:51–61. Epub 2016/10/04. doi: 10.1007/978-3-319-40320-5_5 . PubMed DOI

Belloni D, Marcatti M, Ponzoni M, Ciceri F, Veschini L, Corti A, et al. Angiopoietin-2 in Bone Marrow milieu promotes Multiple Myeloma-associated angiogenesis. Experimental cell research. 2015;330(1):1–12. Epub 2014/12/03. doi: 10.1016/j.yexcr.2014.10.017 . PubMed DOI

Pappa CA, Tsirakis G, Samiotakis P, Tsigaridaki M, Alegakis A, Goulidaki N, et al. Serum levels of angiopoietin-2 are associated with the growth of multiple myeloma. Cancer investigation. 2013;31(6):385–9. Epub 2013/06/14. doi: 10.3109/07357907.2013.800093 . PubMed DOI

Pappa CA, Alexandrakis MG, Boula A, Thanasia A, Konsolas I, Alegakis A, et al. Prognostic impact of angiopoietin-2 in multiple myeloma. Journal of cancer research and clinical oncology. 2014;140(10):1801–5. Epub 2014/06/08. doi: 10.1007/s00432-014-1731-2 . PubMed DOI PMC

Jones N, Iljin K, Dumont DJ, Alitalo K. Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nature reviews Molecular cell biology. 2001;2(4):257–67. Epub 2001/04/03. doi: 10.1038/35067005 . PubMed DOI

Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118(2):149–61. Epub 2004/07/21. doi: 10.1016/j.cell.2004.07.004 . PubMed DOI

Martin V, Liu D, Fueyo J, Gomez-Manzano C. Tie2: a journey from normal angiogenesis to cancer and beyond. Histology and histopathology. 2008;23(6):773–80. Epub 2008/03/28. doi: 10.14670/HH-23.773 . PubMed DOI

Findley CM, Cudmore MJ, Ahmed A, Kontos CD. VEGF induces Tie2 shedding via a phosphoinositide 3-kinase/Akt dependent pathway to modulate Tie2 signaling. Arteriosclerosis, thrombosis, and vascular biology. 2007;27(12):2619–26. Epub 2007/09/29. doi: 10.1161/ATVBAHA.107.150482 . PubMed DOI

McClanahan T, Culpepper J, Campbell D, Wagner J, Franz-Bacon K, Mattson J, et al. Biochemical and genetic characterization of multiple splice variants of the Flt3 ligand. Blood. 1996;88(9):3371–82. Epub 1996/11/01. . PubMed

Antonysamy MA, Thomson AW. Flt3 ligand (FL) and its influence on immune reactivity. Cytokine. 2000;12(2):87–100. Epub 2000/02/15. doi: 10.1006/cyto.1999.0540 . PubMed DOI

Buza-Vidas N, Cheng M, Duarte S, Nozad H, Jacobsen SE, Sitnicka E. Crucial role of FLT3 ligand in immune reconstitution after bone marrow transplantation and high-dose chemotherapy. Blood. 2007;110(1):424–32. Epub 2007/03/24. doi: 10.1182/blood-2006-09-047480 . PubMed DOI

Kokonozaki M, Tsirakis G, Devetzoglou M, Kyriakaki S, Antonakis A, Vyzoukaki R, et al. Potential role of FLT3-ligand in the angiogenic process of multiple myeloma. Leukemia research. 2015;39(12):1467–72. Epub 2015/11/03. doi: 10.1016/j.leukres.2015.10.009 . PubMed DOI

Felbor U, Dreier L, Bryant RA, Ploegh HL, Olsen BR, Mothes W. Secreted cathepsin L generates endostatin from collagen XVIII. The EMBO journal. 2000;19(6):1187–94. Epub 2000/03/16. doi: 10.1093/emboj/19.6.1187 ; PubMed Central PMCID: PMCPMC305660. PubMed DOI PMC

O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88(2):277–85. Epub 1997/01/24. . PubMed

Wen W, Moses MA, Wiederschain D, Arbiser JL, Folkman J. The generation of endostatin is mediated by elastase. Cancer research. 1999;59(24):6052–6. Epub 2000/01/08. . PubMed

Ergun S, Kilic N, Wurmbach JH, Ebrahimnejad A, Fernando M, Sevinc S, et al. Endostatin inhibits angiogenesis by stabilization of newly formed endothelial tubes. Angiogenesis. 2001;4(3):193–206. Epub 2002/03/26. . PubMed

Safadi FF, Xu J, Smock SL, Rico MC, Owen TA, Popoff SN. Cloning and characterization of osteoactivin, a novel cDNA expressed in osteoblasts. Journal of cellular biochemistry. 2001;84(1):12–26. Epub 2001/12/18. . PubMed

Abdelmagid SM, Barbe MF, Rico MC, Salihoglu S, Arango-Hisijara I, Selim AH, et al. Osteoactivin, an anabolic factor that regulates osteoblast differentiation and function. Experimental cell research. 2008;314(13):2334–51. Epub 2008/06/17. doi: 10.1016/j.yexcr.2008.02.006 . PubMed DOI

Sondag GR, Mbimba TS, Moussa FM, Novak K, Yu B, Jaber FA, et al. Osteoactivin inhibition of osteoclastogenesis is mediated through CD44-ERK signaling. Experimental & molecular medicine. 2016;48(9):e257 Epub 2016/09/03. doi: 10.1038/emm.2016.78 ; PubMed Central PMCID: PMCPMC5050297. PubMed DOI PMC

Rose AA, Annis MG, Dong Z, Pepin F, Hallett M, Park M, et al. ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties. PloS one. 2010;5(8):e12093 Epub 2010/08/17. doi: 10.1371/journal.pone.0012093 ; PubMed Central PMCID: PMCPMC2919417. PubMed DOI PMC

Hu X, Zhang P, Xu Z, Chen H, Xie X. GPNMB enhances bone regeneration by promoting angiogenesis and osteogenesis: potential role for tissue engineering bone. Journal of cellular biochemistry. 2013;114(12):2729–37. Epub 2013/06/25. doi: 10.1002/jcb.24621 . PubMed DOI

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

Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3(1):32–5. Epub 1950/01/01. . PubMed

Pour L, Svachova H, Adam Z, Almasi M, Buresova L, Buchler T, et al. Levels of angiogenic factors in patients with multiple myeloma correlate with treatment response. Annals of hematology. 2010;89(4):385–9. Epub 2009/09/29. doi: 10.1007/s00277-009-0834-3 . PubMed DOI

Solanilla A, Grosset C, Lemercier C, Dupouy M, Mahon FX, Schweitzer K, et al. Expression of Flt3-ligand by the endothelial cell. Leukemia. 2000;14(1):153–62. Epub 2000/01/19. . PubMed

Greystoke A, O'Connor JP, Linton K, Taylor MB, Cummings J, Ward T, et al. Assessment of circulating biomarkers for potential pharmacodynamic utility in patients with lymphoma. British journal of cancer. 2011;104(4):719–25. Epub 2011/01/20. doi: 10.1038/sj.bjc.6606082 ; PubMed Central PMCID: PMCPMC3049589. PubMed DOI PMC

Ribatti D, Nico B, Vacca A. Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma. Oncogene. 2006;25(31):4257–66. Epub 2006/03/07. doi: 10.1038/sj.onc.1209456 . PubMed DOI

Ribatti D, Mangialardi G, Vacca A. Antiangiogenic therapeutic approaches in multiple myeloma. Current cancer drug targets. 2012;12(7):768–75. Epub 2012/07/12. . PubMed

Ferrarini M, Ferrero E. Proteasome inhibitors and modulators of angiogenesis in multiple myeloma. Current medicinal chemistry. 2011;18(34):5185–95. Epub 2011/11/18. . PubMed

Campochiaro PA, Peters KG. Targeting Tie2 for Treatment of Diabetic Retinopathy and Diabetic Macular Edema. Current diabetes reports. 2016;16(12):126 Epub 2016/10/26. doi: 10.1007/s11892-016-0816-5 . PubMed DOI

Rajkumar SV, Mesa RA, Fonseca R, Schroeder G, Plevak MF, Dispenzieri A, et al. Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis. Clinical cancer research: an official journal of the American Association for Cancer Research. 2002;8(7):2210–6. Epub 2002/07/13. . PubMed

Vacca A, Ria R, Ribatti D, Semeraro F, Djonov V, Di Raimondo F, et al. A paracrine loop in the vascular endothelial growth factor pathway triggers tumor angiogenesis and growth in multiple myeloma. Haematologica. 2003;88(2):176–85. Epub 2003/02/27. . PubMed

Babarovic E, Valkovic T, Budisavljevic I, Balen I, Stifter S, Duletic-Nacinovic A, et al. The expression of osteopontin and vascular endothelial growth factor in correlation with angiogenesis in monoclonal gammopathy of undetermined significance and multiple myeloma. Pathology, research and practice. 2016;212(6):509–16. Epub 2016/03/22. doi: 10.1016/j.prp.2015.11.021 . PubMed DOI

Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science (New York, NY). 1997;277(5322):55–60. Epub 1997/07/04. . PubMed

Pour L, Svachova H, Adam Z, Mikulkova Z, Buresova L, Kovarova L, et al. Pretreatment hepatocyte growth factor and thrombospondin-1 levels predict response to high-dose chemotherapy for multiple myeloma. Neoplasma. 2010;57(1):29–34. Epub 2009/11/10. . PubMed

Urbanska-Rys H, Robak T. High serum level of endostatin in multiple myeloma at diagnosis but not in the plateau phase after treatment. Mediators of inflammation. 2003;12(4):229–35. Epub 2003/09/30. doi: 10.1080/09629350310001599675 ; PubMed Central PMCID: PMCPMC1781619. PubMed DOI PMC

Silvestris F, Ciavarella S, Strippoli S, Dammacco F. Cell fusion and hyperactive osteoclastogenesis in multiple myeloma. Advances in experimental medicine and biology. 2011;714:113–28. Epub 2011/04/21. doi: 10.1007/978-94-007-0782-5_5 . PubMed DOI

Vacca A, Ribatti D, Roncali L, Ranieri G, Serio G, Silvestris F, et al. Bone marrow angiogenesis and progression in multiple myeloma. British journal of haematology. 1994;87(3):503–8. Epub 1994/07/01. . PubMed

Levels of CEACAM6 in Peripheral Blood Are Elevated in Patients with Plasma Cell Disorders: A Potential New Diagnostic Marker and a New Therapeutic Target?