Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Effect of thalidomide therapy on bone marrow angiogenesis in multiple myeloma

Abstract

Bone marrow (BM) angiogenesis is increased in multiple myeloma and is an important prognostic factor for survival. Previous studies have shown that BM angiogenesis does not change following chemotherapy or stem cell transplant. Given its potential antiangiogenic effect, we evaluated if thalidomide therapy would affect the BM microvessel density (MVD). We studied BM angiogenesis in 81 patients with various disease stages treated with thalidomide with or without dexamethasone. MVD was determined as previously described. MVD was compared between pretreatment marrows and those obtained 4–6 months following therapy. The median (range) MVD pretherapy was 28 (2–116) and post-therapy was 15 (3–97). A partial or complete response was seen in 58% of patients, stable disease in 41% and progressive disease in one patient. MVD decreased significantly in responders (median decrease of 12, P<0.001). In contrast, no significant change in MVD was seen in those failing to respond to thalidomide. Unlike the lack of resolution of angiogenesis reported with other therapies, we demonstrate for the first time a significant decrease in microvessels with thalidomide therapy. Although not conclusive, this result lends further support to the hypothesis that angiogenesis is a relevant therapeutic target in myeloma.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Kyle RA . Long-term survival in multiple myeloma. N Engl J Med 1983; 308: 314–316.

    Article  CAS  PubMed  Google Scholar 

  2. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 348: 1875–1883.

    Article  CAS  PubMed  Google Scholar 

  3. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996; 335: 91–97.

    Article  CAS  PubMed  Google Scholar 

  4. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–1571.

    Article  CAS  PubMed  Google Scholar 

  5. Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002; 20: 4319–4323.

    Article  CAS  PubMed  Google Scholar 

  6. Rajkumar SV, Gertz MA, Lacy MQ, Dispenzieri A, Fonseca R, Geyer SM et al. Thalidomide as initial therapy for early-stage myeloma. Leukemia 2003; 17: 775–779.

    Article  CAS  PubMed  Google Scholar 

  7. Kumar S, Gertz MA, Dispenzieri A, Lacy MQ, Geyer SM, Iturria NL et al. Response rate, durability of response, and survival after thalidomide therapy for relapsed multiple myeloma. Mayo Clin Proc 2003; 78: 34–39.

    Article  PubMed  Google Scholar 

  8. Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R . Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003; 21: 16–19.

    Article  CAS  PubMed  Google Scholar 

  9. D'Amato RJ, Loughnan MS, Flynn E, Folkman J . Thalidomide is an inhibitor of angiogenesis. Proc Natn Acad Sci USA 1994; 91: 4082–4085.

    Article  CAS  Google Scholar 

  10. Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000; 96: 2943–2950.

    CAS  PubMed  Google Scholar 

  11. Folkman J . Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med 1995; 333: 1757–1763.

    Article  CAS  PubMed  Google Scholar 

  12. Folkman J . New perspectives in clinical oncology from angiogenesis research. Eur J Cancer 1996; 32A: 2534–2539.

    Article  CAS  PubMed  Google Scholar 

  13. Folkman J . Angiogenesis-dependent diseases. Semin Oncol 2001; 28: 536–542.

    Article  CAS  PubMed  Google Scholar 

  14. Rajkumar SV, Leong T, Roche PC, Fonseca R, Dispenzieri A, Lacy MQ et al. Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res 2000; 6: 3111–3116.

    CAS  PubMed  Google Scholar 

  15. Rajkumar SV, Greipp PR . Prognostic factors in multiple myeloma. Hematol Oncol Clin N Am 1999; 13: 1295–1314, xi.

    Article  CAS  Google Scholar 

  16. Vacca A, Ribatti D, Roncali L, Ranieri G, Serio G, Silvestris F et al. Bone marrow angiogenesis and progression in multiple myeloma. Br J Haematol 1994; 87: 503–508.

    Article  CAS  PubMed  Google Scholar 

  17. Sezer O, Niemoller K, Eucker J, Jakob C, Kaufmann O, Zavrski I et al. Bone marrow microvessel density is a prognostic factor for survival in patients with multiple myeloma. Ann Hematol 2000; 79: 574–577.

    Article  CAS  PubMed  Google Scholar 

  18. Aguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D et al. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 2000; 96: 2240–2245.

    CAS  PubMed  Google Scholar 

  19. Hussong JW, Rodgers GM, Shami PJ . Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 2000; 95: 309–313.

    CAS  PubMed  Google Scholar 

  20. Schneider P, Jerome MV, Paysant J, Soria PC, Vannier JP . The role of angiogenesis in leukemia proliferation. Am J Pathol 1999; 155: 1007–1008.

    CAS  PubMed  Google Scholar 

  21. Perez-Atayde AR, Sallan SE, Tedrow U, Connors S, Allred E, Folkman J . Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol 1997; 150: 815–821.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kini AR, Kay NE, Peterson LC . Increased bone marrow angiogenesis in B cell chronic lymphocytic leukemia. Leukemia 2000; 14: 1414–1418.

    Article  CAS  PubMed  Google Scholar 

  23. Munshi NC, Wilson C . Increased bone marrow microvessel density in newly diagnosed multiple myeloma carries a poor prognosis. Semin Oncol 2001; 28: 565–569.

    Article  CAS  PubMed  Google Scholar 

  24. 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. Clin Cancer Res 2002; 8: 2210–2216.

    PubMed  Google Scholar 

  25. Rajkumar SV, Fonseca R, Witzig TE, Gertz MA, Greipp PR . Bone marrow angiogenesis in patients achieving complete response after stem cell transplantation for multiple myeloma. Leukemia 1999; 13: 469–472.

    Article  CAS  PubMed  Google Scholar 

  26. Kumar S, Fonseca R, Dispenzieri A, Lacy MQ, Lust JA, Witzig TE et al. Bone marrow angiogenesis in multiple myeloma: effect of therapy. Br J Haematol 2002; 119: 665–671.

    Article  CAS  PubMed  Google Scholar 

  27. Laroche M, Brousset P, Ludot I, Mazieres B, Thiechart M, Attal M . Increased vascularization in myeloma. Eur J Haematol 2001; 66: 89–93.

    Article  CAS  PubMed  Google Scholar 

  28. Rajkumar SV, Witzig TE . A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma. Cancer Treat Rev 2000; 26: 351–362.

    Article  CAS  PubMed  Google Scholar 

  29. Vacca A, Ribatti D, Presta M, Minischetti M, Iurlaro M, Ria R et al. Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 1999; 93: 3064–3073.

    CAS  PubMed  Google Scholar 

  30. 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: 176–185.

    CAS  PubMed  Google Scholar 

  31. Vacca A, Ria R, Semeraro F, Merchionne F, Coluccia M, Boccarelli A et al. Endothelial cells in the bone marrow of patients with multiple myeloma. Blood 2003; 102: 3340–3348.

    Article  CAS  PubMed  Google Scholar 

  32. Dankbar B, Padro T, Leo R, Feldmann B, Kropff M, Mesters RM et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood 2000; 95: 2630–2636.

    CAS  PubMed  Google Scholar 

  33. Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 2001; 15: 1950–1961.

    Article  CAS  PubMed  Google Scholar 

  34. Kumar S, Witzig TE, Thompson MA, Haug J, Timm MM, Fonseca R et al. Expression of angiogenic cytokines by plasma cells. A comparison of MGUS, smoldering myeloma and newly diagnosed symptomatic myeloma. Blood 2002; 100: 807a.

    Google Scholar 

  35. Kumar S, Witzig TE, Timm M, Haug J, Wellik L, Fonseca R et al. Expression of VEGF and its receptors by myeloma cells. Leukemia 2003; 17: 2025–2031.

    Article  CAS  PubMed  Google Scholar 

  36. Bellamy WT . Expression of vascular endothelial growth factor and its receptors in multiple myeloma and other hematopoietic malignancies. Semin Oncol 2001; 28: 551–559.

    Article  CAS  PubMed  Google Scholar 

  37. Podar K, Tai YT, Davies FE, Lentzsch S, Sattler M, Hideshima T et al. Vascular endothelial growth factor triggers signalling cascades mediating multiple myeloma cell growth and migration. Blood 2001; 98: 428–435.

    Article  CAS  PubMed  Google Scholar 

  38. Thompson MA, Witzig TE, Kumar S, Timm MM, Haug J, Fonseca R et al. Plasma levels of tumour necrosis factor alpha and interleukin-6 predict progression-free survival following thalidomide therapy in patients with previously untreated multiple myeloma. Br J Haematol 2003; 123: 305–308.

    Article  CAS  PubMed  Google Scholar 

  39. Lentzsch S, LeBlanc R, Podar K, Davies F, Lin B, Hideshima T et al. Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo. Leukemia 2003; 17: 41–44.

    Article  CAS  PubMed  Google Scholar 

  40. Yaccoby S, Johnson CL, Mahaffey SC, Wezeman MJ, Barlogie B, Epstein J . Antimyeloma efficacy of thalidomide in the SCID-hu model. Blood 2002; 100: 4162–4168.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by Grants CA 100080, CA 93842, CA85818 and CA62242 from the National Cancer Institute, MD, USA. Dr Rajkumar is a Leukemia and Lymphoma Society of America Translational Research Awardee and is also supported by the Goldman Philanthropic Partnerships, IL, USA, and the Multiple Myeloma Research Foundation, CT, USA.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S V Rajkumar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kumar, S., Witzig, T., Dispenzieri, A. et al. Effect of thalidomide therapy on bone marrow angiogenesis in multiple myeloma. Leukemia 18, 624–627 (2004). https://doi.org/10.1038/sj.leu.2403285

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403285

Keywords

This article is cited by

Search

Quick links