The comparison of serum levels of selected biomarkers in monoclonal gammopathy of undetermined significance and multiple myeloma

Authors: V. Ščudla 1;  M. Budíková 2;  T. Pika 1;  J. Bačovský 1;  J. Minařík 1;  V. Heinzová 3;  K. Langová 4;  Česká Myelomová Skupina
Authors‘ workplace: Lékařská fakulta Univerzity Palackého v Olomouci, 3. interní klinika FN 1;  Lékařská fakulta Univerzity Palackého v Olomouci, Oddělení klinické biochemie FN 2;  Slezská nemocnice Opava, Hematologické a transfuzní oddělení 3;  Lékařská fakulta Univerzity Palackého v Olomouci, Ústav lékařské biofyziky 4
Published in: Čas. Lék. čes. 2009; 148: 315-322
Category: Original Article


The aim of the study was the evaluation of serum levels of 12 selected biomarkers in monoclonal gammopathy of undetermined significance (MGUS) and in initial, asyptomatic phase of multiple myeloma, especially from the view of potential differentiation of these conditions in clinical practice.

Methods and results.
Analyzed group of 268 individuals consisted of 89 individuals with MGUS and 179 patients with MM examined in time of diagnosis before treatment initiation. For evaluation of serum levels were used following methods: radioenzymatic method (thymidinekinase), enzymatic immunoassay (β2-M, IL-6R, ICAM-1, VCAM-1, ICTP, PINP and OPG) and quantitative sandwich enzymatic immunoassay (HGF, VEGF, syndecan-1/CD138 and Fas). Pearson’s χ2-test and test according to Mann-Whitney were used for statistical evaluation (p < 0.05). Wide statistic differences in serum levels of analyzed markers in MGUS vs. MM were detected in case of β2-M, TK, ICTP, OPG, HGF and syndecan-1 (p < 0.0001), lower differences in case of VCAM-1, PINP and VEGF (p = 0.003, 0.001 and 0.04), and without difference in case of Fas. Except for thymidinekinase (p = 0.014) and syndecan-1 (p = 0.001) was not detected statistically important contrast of measured values in MGUS individuals and in patients with initial, asymptomatic phase of MM (stage 1), but these markers cannot be used in clinical practice due to significant overlap of serum values. Continuous downgrade of serum values of VEGF due to degree of MM progression (stages 1–3 according to Durie-Salmon) was unexpected.

Although the significant differences in 9 of 12 evaluated serum levels of selected biomarkers in groups of MGUS and MM were seen, the results revealed that these markers are unprofitable to bring discriminatory potential capable of being used to distinguish between MGUS and initial, asymptomatic phase of MM.

Key words:
monoclonal gammopathy of undetermined significance, multiple myeloma, thymidinekinase, angiogenic cytokines, parameters of bone metabolism.


1. Hideshima T, Bergsagel PL, Kuehl MW, et al. Advances in biology of multiple myeloma: Clinical applications. Blood 2004; 104: 607–618.

2. Urashima M, Chen BP, Chen S, et al. The development of a model for the homing of multiple myeloma cells to human bone marrow. Blood 1997; 90: 754–765.

3. International Myeloma Working Group. Criteria for the clasification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Brit J Haematol 2003; 121: 749–757.

4. Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Cancer 1975; 36: 842–854.

5. Greipp PR, San Miguel J, Durie BGM, et al. International Staging System for multiple myeloma. J Clin Oncol 2005; 23: 3412–3420.

6. Adam Z, Česká myelomová skupina a Myelomová sekce ČHS pro diagnostiku a léčbu mnohočetného myelomu: Diagnostika a léčba mnohočetného myelomu. Transf Hematol dnes 2005; 11(Suppl 1): 3–51.

7. Kyle RA, Rajkumar V. Monoclonal gammopathies of undetermined significance: a review. Immunol Rev 2003; 194: 112–139.

8. Greipp PR. Prognosis in myeloma. Mayo Clin Proc 1994; 69: 895–2000.

9. Yacoby S, Pearse RN, Johnson CL, et al. Myeloma interacts with the bone marrow microenvironmentes induce osteoclastogenesis and is dependent on osteoclast activity. Br J Haematol 2002; 116: 278–290.

10. Chauhan D, Uchiyama H, Akbarali Y, et al. Multiple myeloma cell adhesion – induced interleukin-6 expression in bone marrow stromal cells involves activation of NF- B. Blood 1996; 87: 1104–1112.

11. Vacca A, Ria R, Ribatti D, et al. A paracrine loop in the vascular endothelial growth factor pathway triggers tumor angiogenesis and growth in multiple myeloma. Haematologica 2003; 88: 176–185.

12. Holt RV, Fagerli VM, Baykov V, et al. Hepatocyte growth factor promotes migration of human myeloma cells. Haematologica 2008; 93: 619–622.

13. Seidel C, BŅrset M, Hjertner S, et al. High levels of soluble syndecan-1 in myeloma-derived bone marrow: modulation of hepatocyte growth factor activity. Blood 2000; 96: 3139–3146.

14. Silvestris F, Tucci M, Cafforio P, et al. Fas-L-upregulatio by highly malignant myeloma plasma cells: role in the pathogenesis of anemia and disease progression. Blood 2001; 97: 1155–1164.

15. Fonseca R, Trendle MC, Leong T, et al. Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients. Brit J Haematol 2000; 109: 24–29.

16. Alexandrakis MG, Passam FH, Boula A, et al. Relationship between circulating serum soluble interleukin-6 receptor and the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in multiple myeloma. Ann Hematol 2003; 82: 19–23.

17. Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res 2004; 64: 1546–1558.

18. Kyrtsonis MC, Dedoussis G, Zervas C, et al. Soluble interleukin-6 receptor (sIL-6R), a new prognostic factor in multiple myeloma. Brit J Haematol 1966; 93: 398–400.

19. Cook G, Dunbar M, Franklin IM. The role of adhesion molecules in multiple myeloma. Acta Haematol 1997; 97: 81–89.

20. Giuliani N, Calla S, Rizzoli V. New insight in the mechanism of osteoclast activation and formation in multiple myeloma: Focus on the receptor activator of NF-kB ligand (RANKL). Exp Hematol 2004; 32: 685–691.

21. Roux S, Meignin V, Quillard J, et al. RANK and RANKL expression in multiple myeloma. Brit J Haematol 2002; 117: 86–92.

22. Abildgaard N, Bentzen SM, Nielsen JL, for the Nordic Myeloma Study Group (NMSG). Serum markers of bone metabolism in multiple myeloma: Prognostic value of the carboxy-terminal telopeptide of type I collagen (ICTP). Brit J Haematol 1997; 96: 103–110.

23. Špička I, Cieslar P, Procházka B, et al. Prognostické faktory a markery aktivity u mnohočetného myelomu. Čas Lék čes 2001; 139: 208–212.

24. Seidel C, Hjertner O, Abildgaard N, et al. Nordic Myeloma Study Group serum osteoprotegerin levels are reduced in patients with multiple myeloma with lytic bone disease. Blood 2001; 98: 2269–2271.

25. Terpos E, Szydlo R, Apperley JF, et al. Soluble receptor activator of nuclear factor B ligand – osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood 2003; 102: 1064–1069.

26. Corso A, Dovio A, Rusconi C, et al. Osteoprotegerin serum levels in multiple myeloma and MGUS patients compared with age and sex-matched healthy controls. Leukemia 2004; 18: 1555–1557.

27. Rajkumar SV. Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis. Clin Cancer Res 2002; 8: 2210–2216.

28. Pour L, Hájek R, Buchler T, et al. Angiogeneze a antiangiogenní terapie u nádorů. Vnitř Lék 2004; 50: 930–938.

29. Sezer O, Jakob C, Eucker J, et al. Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma. Eur J Haematol 2001; 66: 83–88.

30. Di Raimondo F, Azzaro MP, Palumbo GA, et al. Angiogenic factors in multiple myeloma: higher levels in bone marrow than in peripheral blood. Haematologica 2000; 85: 800–805.

31. Seidel C, Borset M, Turesson I, et al., for the Nordic Myeloma Study Group. Elevated serum concentrations of hepatocyte growth factor in patients with multiple myeloma. Blood 1998; 91: 806–812.

32. Banks RE, Forbes MA, Kinsey SE, et al. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer 1998; 77: 956–964.

33. Dhodapkar MV, Kelly T, Theus A, et al. Elevated levels of shed syndecan-1 correlated with tumour mass and decreased matrix metalloproteinase-9 activity in the serum of patients with multiple myeloma. Br J Haematol 1997; 99: 368–371.

34. Maisnar V, Toušková M, Malý J, et al. Význam laboratorních ukazatelů v diferenciální diagnóze a monitorování mnohočetného myelomu. Vnitř Lék 2002; 48: 290–297.

35. Seidel C, Sundan A, Hjorth M, et al. Serum syndecan-1: a new independent prognostic marker in multiple myeloma. Blood 2000; 95: 388–392.

36. Kyrtsonis MC, Vassilakopoulos TP, Siakantaris MP. et al. Serum syndecan-1, basic fibroblast growth factor and osteoprotegerin in multiple myeloma patients at diagnosis and during the course of the disease. Eur J Haematol 2004; 72: 252–258.

37. Janosi J, Sebestydu A, Mikala G. et al. Soluble syndecan-1 levels in different plasma cell dyscrasias and in different stages of multiple myeloma. Haematologica 2004; 89: 370–371.

38. Schaar CG, Vermeer HJ, Wijermans PW, et al. Serum syndecan-1 in patients with newly diagnosed monoclonal proteinaemia. Haematologica 2005; 90: 1437–1438.

39. Witzig TE, Kimlinger T, Stenson M, et al. Syndecan-1 expression on malignant cells from the blood and marrow of patients with plasma cell proliferative disorders and B-cell chronic lymphocytic leukemia. Leuk Lymphoma 1998; 31: 167–175.

40. Landowski TH, Qu N, Buyuksal I, et al. Mutations in the Fas antigen in patients with multiple myeloma. Blood 1997; 90: 4266–4270.

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