Novel Therapies in Multiple Myeloma

Abstract

The discovery of the activity of thalidomide in myeloma in the late 1990s transformed the therapy of myeloma dramatically. Apart from providing a useful treatment option for patients with myeloma, it has spurred clinical investigation of several other nonchemotherapeutic agents for this disease. These active, promising agents include CC-5013 (a thalidomide analog) and bortezomib (a proteasome inhibitor), as well as other agents, such as arsenic trioxide, ENMD 0995 and 2-methoxyestradiol. Preliminary data show that a number of these agents are active in treating disease that has relapsed after conventional chemotherapy as well as after high-dose therapy and transplantation, and some agents are active even after other novel agents have failed.The only novel drug that is commercially available currently is thalidomide, which has a therapeutically relevant benefit at all stages of the disease.A therapeutic trial of thalidomide is essential for all patients with myeloma. There are in vitro and in vivo data showing synergy between some of the novel agents. Although these novel drugs are typically used for treating disease that is refractory to or has relapsed after cytotoxic therapy, it is likely that they will start being used as part of frontline therapy, either by themselves or in combination with chemotherapy.

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References

  1. 1.

    Mehta J. Allogeneic hematopoietic stem cell transplantation in myeloma. In: Mehta J, Singhal S, eds. Myeloma. London, UK: Martin Dunitz; 2002:349–365.

    Google Scholar 

  2. 2.

    Singhal S. High-dose therapy and autologous transplantation. In: Mehta J, Singhal S, eds. Myeloma. London, UK: Martin Dunitz; 2002:327–347.

    Google Scholar 

  3. 3.

    Powles R, Singhal S, Sirohi B, Horton C, Treleaven J, Mehta J. “Discontinuous complete remission”: a new endpoint to evaluate the success of therapy in keeping myeloma patients disease-free for extended periods of time [abstract].Blood. 2001;98:166a.

    Google Scholar 

  4. 4.

    Powles R, Sirohi B, Treleaven J, et al. Continued first complete remission in multiple myeloma for over 10 years: a series of “operationally cured” patients [abstract].Blood. 2000;96(suppl 1):515a.

    Google Scholar 

  5. 5.

    Zwingenberger K, Wnendt, S. Immunomodulation by thalidomide: systematic review of the literature and of unpublished observations.J Inflamm. 1995;46:177–211.

    PubMed  CAS  Google Scholar 

  6. 6.

    Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma.N Engl J Med. 1999;341:1565–15711.

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    Vacca A, Singhal S, Ribatti D, Dammacco F. Angiogenesis in plasma cell disorders. In: Mehta J, Singhal S, eds. Myeloma. London, UK: Martin Dunitz; 2002:119–135.

    Google Scholar 

  8. 8.

    Singhal S, Mehta J. Thalidomide in cancer.Biomed Pharmacother. 2002;56:4–12.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes.J Exp Med. 1991;173:699–703.

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Rowland TL, McHugh SM, Deighton J, Ewan PW, Dearman RJ, Kimber I. Selective down-regulation of T cell- and non-T cellderived tumour necrosis factor alpha by thalidomide: comparisons with dexamethasone.Immunol Lett. 1999;68:325–332.

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Moller DR, Wysocka M, Greenlee BM, et al. Inhibition of IL-12 production by thalidomide.J Immunol. 1997;159:5157–5161.

    PubMed  CAS  Google Scholar 

  12. 12.

    Rowland TL, McHugh SM, Deighton J, Dearman RJ, Ewan PW, Kimber I. Differential regulation by thalidomide and dexamethasone of cytokine expression in human peripheral blood mononuclear cells.Immunopharmacology. 1998;40:11–20.

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Shannon EJ, Sandoval F. Thalidomide increases the synthesis of IL-2 in cultures of human mononuclear cells stimulated with concanavalin- A, staphylococcal enterotoxin A, and purified protein derivative.Immunopharmacology. 1995;31:109–116.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Moreira AL, Tsenova-Berkova L, Wang J, et al. Effect of cytokine modulation by thalidomide on the granulomatous response in murine tuberculosis.Tuber Lung Dis. 1997;78:47–55.

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    McHugh SM, Rifkin IR, Deighton J, et al. The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen- and antigenstimulated human peripheral blood mononuclear cell cultures.Clin Exp Immunol. 1995;99:160–167.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. 16.

    Haslett P, Hempstead M, Seidman C, et al. The metabolic and immunologic effects of short-term thalidomide treatment of patients infected with the human immunodeficiency virus.AIDS Res Hum Retroviruses. 1997;13:1047–1054.

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Walchner M, Meurer M, Plewig G, Messer G. Clinical and immunologic parameters during thalidomide treatment of lupus erythematosus.Int J Dermatol. 2000;39:383–388.

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Haslett PA, Corral LG, Albert M, Kaplan G. Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset.J Exp Med. 1998;187:1885–1892.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. 19.

    Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma.Blood. 2001;98:210–216.

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis.Proc Natl Acad Sci U S A. 1994;91:4082–40855.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Keifer JA, Guttridge DC, Ashburner BP, Baldwin AS Jr. Inhibition of NF-B activity by thalidomide through suppression of I-B kinase activity.J Biol Chem. 2001;276:22382–22387.

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Vacca A, Ribatti D, Roncali L, et al. Bone marrow angiogenesis and progression in multiple myeloma.Br J Haematol. 1994;87:503–5088.

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Barlogie B, Tricot G, Anaissie E, et al. Long-term follow-up (median of 4 yr) of 169 patients receiving thalidomide (THAL) for advanced and refractory multiple myeloma (MM): superior survival in the absence of cytogenetic abnormalities (CA) and low-2 microglobulin (B2M) [abstract]. Blood. 2002;100. Abstract 789.

  24. 24.

    Kneller A, Raanani P, Hardan I, et al. Therapy with thalidomide in refractory multiple myeloma patients: the revival of an old drug.Br J Haematol. 2000;108:391–393.

    Article  PubMed  CAS  Google Scholar 

  25. 25.

    Juliusson G, Celsing F, Turesson I, Lenhoff S, Adriansson M, Malm C. Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma.Br J Haematol. 2000;109:89–96.

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Yakoub-Agha I, Moreau P, Leyvraz S, et al. Thalidomide in patients with advanced multiple myeloma.Hematol J. 2000;1:186–189.

    Article  PubMed  CAS  Google Scholar 

  27. 27.

    Hus M, Dmoszynska A, Soroka-Wojtaszko M, et al. Thalidomide treatment of resistant or relapsed multiple myeloma patients.Haematologica. 2001;86:404–408.

    PubMed  CAS  Google Scholar 

  28. 28.

    Tosi P, Zamagni E, Cellini C, et al. Salvage therapy with thalidomide in patients with advanced relapsed/refractory multiple myeloma.Haematologica. 2002;87:408–414.

    PubMed  CAS  Google Scholar 

  29. 29.

    Blade J, Esteve J, Rosinol L, et al. Thalidomide in refractory and relapsing multiple myeloma.Semin Oncol. 2001;28:588–592.

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    Rajkumar SV, Gertz MA, Lacey MQ, et al. Single-agent thalidomide as initial therapy for asymptomatic (smoldering or indolent) myeloma [abstract]. Blood. 2002;100. Abstract 1567.

    Google Scholar 

  31. 31.

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

    PubMed  CAS  Google Scholar 

  32. 32.

    Palumbo A, Giaccone L, Bertola A, et al. Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma.Haematologica. 2001;86:399–403.

    PubMed  PubMed Central  CAS  Google Scholar 

  33. 33.

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

    Article  PubMed  CAS  Google Scholar 

  34. 34.

    Lee CK, Barlogie B, Zangari M, et al. D.T. PACE, a new effective angio-chemotherapy for patients with previously treated myeloma [abstract]. Blood. 2002;100. Abstract 3231.

    Google Scholar 

  35. 35.

    Hussein MA, Elson P, Tsoe EA, Karam M, Srkaloci G. Doxil (D), vincristine (V), decadron (d) and thalidomide (T) (DVd-T) for relapsed/refractory multiple myeloma (RMM) [abstract]. Blood. 2002;100. Abstract 1566.

  36. 36.

    Brinker B,Waller EK, Langston AA, et al. Therapy with thalidomide enhances overall survival after autologous PBSC transplant for multiple myeloma [abstract]. Blood. 2002;100. Abstract 667.

    Google Scholar 

  37. 37.

    Barlogie B, Desikan R, Eddlemon P, et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients.Blood. 2001;98:492–494.

    Article  PubMed  CAS  Google Scholar 

  38. 38.

    Zeldis JB, Williams BA, Thomas SD, Elsayed ME. S.T.E.P.S.: a comprehensive program for controlling and monitoring access to thalidomide.Clin Ther. 1999;21:319–330.

    Article  PubMed  CAS  Google Scholar 

  39. 39.

    Zangari M, Anaissie E, Barlogie B, et al. Increased risk of deepvein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy.Blood. 2001;98:1614–1615.

    Article  PubMed  CAS  Google Scholar 

  40. 40.

    Zangari M, Siegel E, Barlogie B, et al. Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy.Blood. 2002;100:1168–1171.

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    Marriott JB, Muller G, Stirling D, Dalgleish AG. Immunotherapeutic and antitumour potential of thalidomide analogues.Expert Opin Biol Ther. 2001;1:675–682.

    Article  PubMed  CAS  Google Scholar 

  42. 42.

    Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma.Blood. 2002;100:3063–30677.

    Article  PubMed  CAS  Google Scholar 

  43. 43.

    Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents.Cancer Res. 1999;59:2615–2622.

    PubMed  CAS  Google Scholar 

  44. 44.

    Richardson P, Barlogie B, Berenson J, et al. A phase II multicenter study of the proteasome inhibitor bortezomib (Velcade’, formerly PS-341) in multiple myeloma patients (pts) with relapsed/refractory disease [abstract]. Blood. 2002;100. Abstract 385.

  45. 45.

    Zangari M, Barlogie B, Prather J, et al. Marked activity also in del 13 multiple myeloma (MM) of PS 341 (PS) and subsequent thalidomide (THAL) in a setting of resistance to post-autotransplant salvage therapies [abstract]. Blood. 2002;100. Abstract 387.

  46. 46.

    Mitsiades CS, Mitsiades N, Bailey C, et al. Gene expression and proteomic profiling of drug-treated multiple myeloma (MM) cells: mechanisms of drug-responsiveness vs. resistance and rationale for design of novel combination therapies for MM [abstract]. Blood. 2002;100. Abstract 1509.

  47. 47.

    Shaughnessy J, Zhan F, McCastlain K, Tian E, Tricot G. Gene expression profiling in the prediction of response of multiple myeloma to the proteasome inhibitor PS-341 [abstract]. Blood. 2002;100. Abstract 1512.

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Correspondence to Seema Singhal or Jayesh Mehta.

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Singhal, S., Mehta, J. Novel Therapies in Multiple Myeloma. Int J Hematol 77, 226–231 (2003). https://doi.org/10.1007/BF02983778

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Key words

  • Bortezomib
  • Thalidomide
  • Angiogenesis
  • CC-5013
  • Angiochemotherapy