Anemia and Erythropoeitic Growth Factors in Multiple Myeloma

  • Mark J Sloan
  • Noopur Raje
Part of the Contemporary Hematology book series (CH)


multiple myeloma (MM) is characterized by a clonal proliferation of plasma cells within the bone marrow compartment. Anemia is a common feature of MM and its presence often dictates the need for treatment. The proper management of anemia in MM can impact both the duration and the quality of life in myeloma patients. This chapter will focus on the prevalence, patho-physiology, and management of anemia associated with MM. Special attention will be paid to the use of erythropoietic growth factors in MM.

Prevalence and Severity of Anemia in Multiple Myeloma

Virtually no myeloma patient is exempt from the complication of anemia; of 1027 patients diagnosed with MM at the Mayo Clinic between 1985 and 1998, 73% were anemic at diagnosis and 97% had a hemoglobin (Hb) level of 12 g/dL or lower at some point in the course of their disease.1 A 7% minority of patients had an Hb level of < 8 g/dL at presentation. A similar prevalence was documented in the European Cancer Anaemia Survey.2...


Multiple Myeloma Darbepoetin Alfa Erythropoietin Level Malignant Plasma Cell Erythropoietin Deficiency 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Kyle, R.A., et al., Review of 1027 patients with newly diagnosed multiple myeloma Mayo Clin Proc, 2003. 78(1): p.21–33.PubMedCrossRefGoogle Scholar
  2. 2.
    Birgegard, G., P. Gascon, and H. Ludwig, Evaluation of anaemia in patients with multiple myeloma and lymphoma: findings of the European CANCER ANAEMIA SURVEY. Eur J Haematol, 2006. 77(5): p.378–86.PubMedCrossRefGoogle Scholar
  3. 3.
    Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol, 2003. 121(5): p.749–57.Google Scholar
  4. 4.
    Caro, J.J., et al. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer, 2001. 91(12): p.2214–21.PubMedCrossRefGoogle Scholar
  5. 5.
    Rosinol, L., et al., Smoldering multiple myeloma: natural history and recognition of an evolving type. Br J Haematol, 2003. 123(4): p.631–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Rajkumar, S.V., MGUS and smoldering multiple myeloma: update on pathogenesis, natural history, and management. Hematology Am Soc Hematol Educ Program, 2005: p.340–5.Google Scholar
  7. 7.
    Hirashima, K. and F. Takaku, Experimental studies on erythropoietin. II. The rela tionship between juxtaglomerular cells and erythropoietin. Blood, 1962. 20: p.1–8.PubMedGoogle Scholar
  8. 8.
    Astor, B.C., et al., Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey (1988–1994). Arch Intern Med, 2002. 162(12): p.1401–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Blade, J., et al., Renal failure in multiple myeloma: presenting features and predic tors of outcome in 94 patients from a single institution. Arch Intern Med, 1998. 158(17): p.1889–93.PubMedCrossRefGoogle Scholar
  10. 10.
    Pasqualetti, P., A. Collacciani, and R. Casale, Circadian rhythm of serum erythro-poietin in multiple myeloma. Am J Hematol, 1996. 53(1): p.40–2.PubMedCrossRefGoogle Scholar
  11. 11.
    Baer, A.N., et al., Blunted erythropoietin response to anaemia in rheumatoid arthritis. Br J Haematol, 1987. 66(4): p.559–64.PubMedCrossRefGoogle Scholar
  12. 12.
    Miller, C.B., et al., Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med, 1990. 322(24): p.1689–92.PubMedCrossRefGoogle Scholar
  13. 13.
    Beguin, Y., et al., Erythropoiesis in multiple myeloma: defective red cell production due to inappropriate erythropoietin production. Br J Haematol, 1992. 82(4): p.648–53.PubMedCrossRefGoogle Scholar
  14. 14.
    Majumdar, G., et al., Serum erythropoietin and circulating BFU-E in patients with multiple myeloma and anaemia but without renal failure. Leuk Lymphoma, 1993. 9(1–2): p.173–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Bondurant, M.C. and M.J. Koury, Anemia induces accumulation of erythropoietin mRNA in the kidney and liver. Mol Cell Biol, 1986. 6(7): p.2731–3.PubMedGoogle Scholar
  16. 16.
    Jelkmann,W., Proinflammatory cytokines lowering erythropoietin production J Interferon Cytokine Res, 1998. 18(8): p.555–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Pisa, P., et al., Tumor necrosis factor-alpha and interferon-gamma in serum of multiple myeloma patients. Anticancer Res, 1990. 10(3): p.817–20.PubMedGoogle Scholar
  18. 18.
    Barany, P., J.C. Divino Filho, and J. Bergstrom, High C-reactive protein is a strong predictor of resistance to erythropoietin in hemodialysis patients. Am J Kidney Dis, 1997. 29(4): p.565–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Aoki, I., et al., Responsiveness of bone marrow erythroid progenitors (CFU-E and BFU-E) to recombinant human erythropoietin (rh-Ep) in vitro in multiple myeloma Br J Haematol, 1992. 81(4): p.463–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Taniguchi, S., et al., Interferon gamma downregulates stem cell factor and erythro-poietin receptors but not insulin-like growth factor-I receptors in human erythroid colony-forming cells. Blood, 1997. 90(6): p.2244–52.PubMedGoogle Scholar
  21. 21.
    Maciejewski, J.P., et al., Nitric oxide suppression of human hematopoiesis in vitro. Contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha. J Clin Invest, 1995. 96(2): p.1085–92.PubMedCrossRefGoogle Scholar
  22. 22.
    Sato, T., et al., Hematopoietic inhibition by interferon-gamma is partially mediated through interferon regulatory factor-1. Blood, 1995. 86(9): p.3373–80.PubMedGoogle Scholar
  23. 23.
    Selleri, C.,et al., Interferon-gamma and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol, 1995. 165(3): p.538–46.PubMedCrossRefGoogle Scholar
  24. 24.
    Pigeon, C., et al., A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload J Biol Chem, 2001. 276(11): p.7811–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Nemeth, E., et al., Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science, 2004. 306(5704): p.2090–3.PubMedCrossRefGoogle Scholar
  26. 26.
    Truksa, J., et al., Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc Natl Acad Sci USA, 2006. 103(27): p.10289–93.PubMedCrossRefGoogle Scholar
  27. 27.
    Nicolas, G., et al., The gene encoding the iron regulatory peptide hepcidin is regu lated by anemia, hypoxia, and inflammation. J Clin Invest, 2002.110(7): p.1037–44.PubMedGoogle Scholar
  28. 28.
    Nemeth, E., et al., IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest, 2004. 113(9): p.1271–6.PubMedGoogle Scholar
  29. 29.
    Theurl, I., et al., Dysregulated monocyte iron homeostasis and erythropoietin forma tion in patients with anemia of chronic disease. Blood, 2006. 107(10): p.4142–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Cline, M.J. and N.I. Berlin, Studies of the anemia of multiple myeloma. Am J Med, 1962. 33: p.510–25.PubMedCrossRefGoogle Scholar
  31. 31.
    Cartwright, G.E., The anemia of chronic disorders. Semin Hematol, 1966. 3(4): p.351–75.PubMedGoogle Scholar
  32. 32.
    Larsson, S.O., Myeloma and pernicious anaemia. Acta Med Scand, 1962. 172: p.195–205.PubMedCrossRefGoogle Scholar
  33. 33.
    Hsing, A.W., et al., Pernicious anemia and subsequent cancer. A population-based cohort study. Cancer, 1993. 71 (3): p.745–50.PubMedCrossRefGoogle Scholar
  34. 34.
    Baz, R., et al., Prevalence of vitamin B12 deficiency in patients with plasma cell dyscrasias: a retrospective review. Cancer, 2004. 101(4): p.790–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Fossa, A., et al., Relation between S-phase fraction of myeloma cells and anemia in patients with multiple myeloma. Exp Hematol, 1999. 27(11): p.1621–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Silvestris, F., et al., Fas-L up-regulation by highly malignant myeloma plasma cells: role in the pathogenesis of anemia and disease progression. Blood, 2001. 97(5): p.1155–64.PubMedCrossRefGoogle Scholar
  37. 37.
    Silvestris, F., et al., Negative regulation of erythroblast maturation by Fas-L(+)/TRAIL(+) highly malignant plasma cells: a major pathogenetic mechanism of anemia in multiple myeloma. Blood, 2002. 99(4): p.1305–13.PubMedCrossRefGoogle Scholar
  38. 38.
    Richardson, P.G., et al., A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med, 2003. 348(26): p.2609–17.PubMedCrossRefGoogle Scholar
  39. 39.
    Rajkumar, S.V., et al., Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood, 2005. 106(13): p.4050–3.PubMedCrossRefGoogle Scholar
  40. 40.
    Cella, D., The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: a new tool for the assessment of outcomes in cancer anemia and fatigue Semin Hematol, 1997. 34(3 Suppl 2): p.13–9.PubMedGoogle Scholar
  41. 41.
    Littlewood, T.J., et al., Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol, 2001. 19(11): p.2865–74.PubMedGoogle Scholar
  42. 42.
    Osterborg, A., et al., Randomized, double-blind, placebo-controlled trial of recom binant human erythropoietin, epoetin Beta, in hematologic malignancies. J Clin Oncol, 2002. 20(10): p.2486–94.PubMedCrossRefGoogle Scholar
  43. 43.
    Hedenus, M., et al., Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol, 2003. 122(3): p.394–403.PubMedCrossRefGoogle Scholar
  44. 44.
    Glaspy, J., et al., Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol, 1997. 15(3): p.1218–34.PubMedGoogle Scholar
  45. 45.
    Demetri, G.D., et al., Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. Procrit Study Group. J Clin Oncol, 1998. 16(10): p.3412–25.PubMedGoogle Scholar
  46. 46.
    Gabrilove, J.L., et al., Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol, 2001. 19(11): p.2875–82.PubMedGoogle Scholar
  47. 47.
    Boccia, R., et al., The effectiveness of darbepoetin alfa administered every 3 weeks on hematologic outcomes and quality of life in older patients with chemotherapy-induced anemia. Oncologist, 2007. 12(5): p.584–93.PubMedCrossRefGoogle Scholar
  48. 48.
    Straus, D.J., et al., Quality-of-life and health benefits of early treatment of mild anemia: a randomized trial of epoetin alfa in patients receiving chemotherapy for hematologic malignancies. Cancer, 2006. 107(8): p.1909–17.PubMedCrossRefGoogle Scholar
  49. 49.
    Crawford, J., et al., Relationship between changes in hemoglobin level and qual ity of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer, 2002. 95(4): p.888–95.PubMedCrossRefGoogle Scholar
  50. 50.
    Wisloff, F., et al., Quality of life may be affected more by disease parameters and response to therapy than by haemoglobin changes. Eur J Haematol, 2005. 75(4): p.293–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Bergsagel, D.E., et al. Treatment of anemia associated with multiple myeloma N Engl J Med, 1991. 324(1): p.59–60.PubMedCrossRefGoogle Scholar
  52. 52.
    Hebert, P.C., et al., A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med, 1999. 340(6): p.409–17.PubMedCrossRefGoogle Scholar
  53. 53.
    Lacroix, J., et al., Transfusion strategies for patients in pediatric intensive care units. N Engl J Med, 2007. 356(16): p.1609–19.PubMedCrossRefGoogle Scholar
  54. 54.
    Khuri, F., Weighing the hazards of erythropoiesis stimulation in patients with can cer. N Engl J Med, 2007. 356(24): p.2445–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Elliott, S., et al., Control of rHuEPO biological activity: the role of carbohydrate Exp Hematol, 2004. 32(12): p.1146–55.PubMedCrossRefGoogle Scholar
  56. 56.
    Bohlius, J., et al., Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev, 2006. 3: p.CD003407.PubMedGoogle Scholar
  57. 57.
    Mittelman, M., et al., Erythropoietin induces tumor regression and antitumor immune responses in murine myeloma models. Proc Natl Acad Sci USA, 2001. 98(9): p.5181–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Prutchi-Sagiv, S., et al., Erythropoietin treatment in advanced multiple myeloma is associated with improved immunological functions: could it be beneficial in early disease? Br J Haematol, 2006. 135(5): p.660–72.PubMedCrossRefGoogle Scholar
  59. 59.
    Silvestris, F., et al., Long-term therapy with recombinant human erythropoietin (rHu-EPO) in progressing multiple myeloma. Ann Hematol, 1995. 70(6): p.313–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Barrios, M. and C. Alliot, IgA multiple myeloma responding to erythropoietin monotherapy. Am J Hematol, 2005. 80 (2): p.165–6.PubMedCrossRefGoogle Scholar
  61. 61.
    Mittelman, M., et al., Erythropoietin has an anti-myeloma effect — a hypothesis based on a clinical observation supported by animal studies. Eur J Haematol, 2004. 72(3): p.155–65.PubMedCrossRefGoogle Scholar
  62. 62.
    Baz, R., et al., Recombinant human erythropoietin is associated with increased overall survival in patients with multiple myeloma. Acta Haematol, 2007. 117(3): p.162–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Bohlius, J., et al., Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst, 2006. 98(10): p.708–14.PubMedCrossRefGoogle Scholar
  64. 64.
    Lee, M.S., J.S. Lee, and J.Y. Lee, Prevention of erythropoietin-associated hyperten sion. Hypertension, 2007.Google Scholar
  65. 65.
    Gleason, K., et al., Recombinant erythropoietin (Epo)darbepoetin (Darb) associated venous thromboembolism (VTE) in the oncology setting: findings from the Research on Adverse Drug Events and Reports (RADAR) project. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I., 2007. 25(18S): p.2552.Google Scholar
  66. 66.
    Steurer, M., et al., Thromboembolic events in patients with myelodysplastic syndrome receiving thalidomide in combination with darbepoietin-alpha. Br J Haematol, 2003. 121(1): p.101–3.PubMedCrossRefGoogle Scholar
  67. 67.
    Knight, R., R.J. DeLap, and J.B. Zeldis, Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med, 2006. 354(19): p.2079–80.PubMedCrossRefGoogle Scholar
  68. 68.
    Galli, M., et al., Recombinant human erythropoietin and the risk of thrombosis in patients receiving thalidomide for multiple myeloma. Haematologica, 2004. 89(9): p.1141–2.PubMedGoogle Scholar
  69. 69.
    Baz, R., et al., An analysis of erythropoietin (Epo) and venous thromboembolic events (VTE) in multiple myeloma (MM) patients (pts) treated with anthracycline-based chemotherapy and the immunomodulator agent thalidomide. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I., 2007. 25(18S): p.8107.Google Scholar
  70. 70.
    Singh, A.K., et al. Correction of anemia with epoetin alfa in chronic kidney disease N Engl J Med, 2006. 355(20): p.2085–98.PubMedCrossRefGoogle Scholar
  71. 71.
    Seidenfeld, J., et al., Comparative effectiveness of epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment. Comparative effectiveness review no. 3. (Prepared by Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practive Center under Contract No. 290-02-0026). Agency for Healthcare Research and Quality, 2006 (available at:
  72. 72.
    Henke, M., et al., Erythropoietin to treat head and neck cancer patients with anae mia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet, 2003. 362(9392): p.1255–60.PubMedCrossRefGoogle Scholar
  73. 73.
    Leyland-Jones, B., et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol, 2005. 23(25): p.5960–72.PubMedCrossRefGoogle Scholar
  74. 74.
    Olujohungbe, A.,S. Handa, and J. Holmes, Does erythropoietin accelerate malignant transformation in multiple myeloma? Postgrad Med J, 1997. 73(857): p.163–4.PubMedCrossRefGoogle Scholar
  75. 75.
    Okuno, Y., et al., Establishment and characterization of four myeloma cell lines which are responsive to interleukin-6 for their growth. Leukemia, 1991. 5(7): p.585–91.PubMedGoogle Scholar
  76. 76.
    Glaspy, J., Results from a Phase III, randomized, double-blind, placebo-controlled study of darbepoetin alfa (DA) for th treatment of anemia in patients not receiv ing chemotherapy or radiotherapy. Presented April 16, 2007 at the American Association for Cancer Research Meeting, 2007.Google Scholar
  77. 77.
    Longmore, G.D., Do cancer cells express functional erythropoietin receptors? N Engl J Med, 2007. 356(24): p.2447.PubMedCrossRefGoogle Scholar
  78. 78.
    Kaufman, J.S., et al., Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. Department of Veterans Affairs Cooperative Study Group on Erythropoietin in Hemodialysis Patients. N Engl J Med, 1998. 339(9): p.578–83.PubMedCrossRefGoogle Scholar
  79. 79.
    Justice, G., et al., A randomized, multicenter study of subcutaneous and intravenous darbepoetin alfa for the treatment of chemotherapy-induced anemia. Ann Oncol, 2005. 16(7): p.1192–8.PubMedCrossRefGoogle Scholar
  80. 80.
    Granetto, C., et al. Comparing the efficacy and safety of fixed versus weight-based dosing of epoetin alpha in anemic cancer patients receiving platinum-based chemotherapy. Oncol Rep, 2003. 10(5): p.1289–96.PubMedGoogle Scholar
  81. 81.
    Hesketh, P.J., et al., A randomized controlled trial of darbepoetin alfa administered as a fixed or weight-based dose using a front-loading schedule in patients with anemia who have nonmyeloid malignancies. Cancer, 2004. 100(4): p.859–68.PubMedCrossRefGoogle Scholar
  82. 82.
    Cheung, W., N. Minton, and K. Gunawardena, Pharmacokinetics and pharmacody-namics of epoetin alfa once weekly and three times weekly. Eur J Clin Pharmacol, 2001. 57(5): p.411–8.PubMedCrossRefGoogle Scholar
  83. 83.
    Canon, J.L., et al., Randomized, double-blind, active-controlled trial of every-3-week darbepoetin alfa for the treatment of chemotherapy-induced anemia. J Natl Cancer Inst, 2006. 98(4): p.273–84.PubMedCrossRefGoogle Scholar
  84. 84.
    Rivera, S., et al., Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia. Blood, 2005. 105(4): p.1797–802.PubMedCrossRefGoogle Scholar
  85. 85.
    Auerbach, M., et al., Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. J Clin Oncol, 2004. 22(7): p.1301–7.PubMedCrossRefGoogle Scholar
  86. 86.
    Henry, D.H., et al., Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist, 2007. 12(2): p.231–42.PubMedCrossRefGoogle Scholar
  87. 87.
    Hedenus, M., et al., Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoprolifer ative malignancies: a randomized multicenter study. Leukemia, 2007. 21(4): p.627–32.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Mark J Sloan
  • Noopur Raje
    • 1
  1. 1.Dana-Farber Cancer InstituteBostonUSA

Personalised recommendations