Balancing the Efficacy and Tolerability of First-line Treatment in Elderly Myeloma Patients

European Haematology, 2010;4:85-93

Abstract:

Multiple myeloma (MM) is the second most frequent malignancy of the blood. It is more common among the elderly population, with <28% of patients 65–74 years of age and 37% >75 years of age. Before the introduction of novel agents, melphalan and prednisone (MP) was the best treatment for patients not eligible for autologous stem cell transplantation (ASCT). Steroids provide other options but with a higher toxicity, especially in elderly patients. Currently, the association of thalidomide with MP (MPT) represents the gold standard of treatment for patients ineligible for ASCT. Bortezomib and lenalidomide associated with MP provided effective and safe alternatives. High-dose dexamethasone combined with the new drugs is effective, but very toxic for elderly patients. Trials that combine low-dose dexamethasone with thalidomide, lenalidomide and bortezomib plus other agents such as doxorubicin and cyclophosphamide are ongoing. The role of transplantation is controversial in myeloma patients >65 years of age because elderly patients are fragile and the choice of therapy must take into account the likelihood of co-morbidities. Reducing the dose of the standard drug – eventually prolonging the duration of the treatment and administering prophylaxis – allows effective treatment of MM, without important or life-threatening toxicities.
Keywords: Multiple myeloma, thalidomide, lenalidomide, bortezomib, toxicities, elderly patients
Disclosure: Valeria Magarotto has no conflicts of interest to declare. Antonio Palumbo has received honoraria from Johnson & Johnson and Celgene.
Received: September 18, 2009 Accepted February 23, 2010 Citation European Haematology, 2010;4:85-93
Correspondence: Valeria Magorotto, Divisione Universitaria di Ematologia, Az Ospedaliera S Giovanni Battista, via Genova 3 10126 Torino, Italy. E: vmagarotto@yahoo.it

Multiple myeloma (MM) accounts for 10% of haematological malignancies.1,2 Its frequency is constantly increasing with the age of the general population. Currently, <40% of myeloma patients are <65 years of age, while the incidence of elderly MM patients (>65 years of age) will increase in the near future, in part due to the increased lifespan of the population and also because of the progress made in the field of myeloma treatments.
In newly diagnosed young MM patients (<65 years of age), the standard treatment is autologous stem cell transplantation (ASCT). For elderly (>65 years of age) or unfit patients, conventional chemotherapy (CC) is the best choice. The adverse prognostic effects of age in myeloma predominantly relate to co-morbidity, performance status, lowered physiological reserve, social support and undertreatment of the tumour. Novel, more effective treatment approaches are now available to improve outcome and extend survival.
Recently, agents with a specific and innovative mechanism of action, such as the immunomodulant drugs (IMiDs) thalidomide and lenalidomide, and bortezomib, the first proteasome inhibitor, have been shown to be safe and effective in both newly diagnosed and relapsed/refractory settings.
Thalidomide and lenalidomide inhibit angiogenesis, stimulate T and natural killer (NK) cells and interfere with cytokines that play a role in the growth and the acquisition of chemoresistance of MM cells.3 Bortezomib is the first in the class of proteasome inhibitors and inhibits the 26S proteasome subunit that is responsible for transcription and degradation of the protein involved in cell proliferation and metabolism.4
Until the 2000s, the association of melphalan and prednisone (MP) represented the gold standard treatment for patients >65 years of age or not eligible for ASCT.5 Another option was a high dose of glucocorticoids alone or in combination with other agents, such as alkylators.6 In the last 10 years, the association of the new agents with these older drugs has been shown to increase response rates (RR), in particular the complete remission (CR) rate, and to improve outcomes.
In this article, we will focus on the most recent treatments for elderly myeloma patients, with particular attention paid to the balance between efficacy and safety.
References:
  1. Ries LAG, Eisner MP, Kosary CL et al. (eds), SEER cancer statistics review, 1975–2000. National Cancer Institute. Available at: seer.cancer.gov//csr/1975_2001 (accessed 7 September 2004).
  2. Kyle RA, Rajkumar SV, Leukemia, 2009;23(1):3–9.
  3. Vallet S, Palumbo A, Raje N, et al., Leuk Lymphoma, 2008;49(7):1238–45.
  4. Orlowski RZ, Kuhn D, Clin Cancer Res, 2008;14(6):1649–57.
  5. Myeloma Trialists’ Collaborative Group. J Clin Oncol, 1998;16: 3832–42.
  6. Alexanian R, Dimopoulos MA, Delasalle K, et al., Blood, 1992;80:887–90.
  7. Rajkumar SV, Blood E, Vesole D, et al., J Clin Oncol, 2006;24:431–6.
  8. Rajkumar SV, Rosinol L, Hussein M, et al., J Clin Oncol, 2008;26:2171–7.
  9. Ludwig H, Hajek R, Tothova E, et al., Blood, 2009;113:3435–42.
  10. Morgan GJ, Davies FE, Owen RG, et al., Blood (ASH Annual Meeting Abstracts), 2007; 110: abstract 3593.
  11. Offidani M, Corvatta L, Piersantelli MN, et al., Blood, 2006;108: 2159–64.
  12. Offidani M, Corvatta L, Polloni C, Br J Haematol, 2009;144(5):653–9.
  13. Lacy MQ, Gertz MA, Dispenzieri A, et al., Mayo Clin Proc, 2007;82:1179–84.
  14. Zonder JA, Crowley J, Hussein MA, et al., Blood (ASH Annual Meeting Abstracts), 2007;110: abstract 77.
  15. Rajkumar SV, Jacobus S, Callander N, et al., ASCO Annual Meeting Proceedings, 2007;25(18S): abstract LBA8025.
  16. Durie BG, Villarete L, Farvard A, et al., Blood, 1997;10(Suppl. 1):579a.
  17. Niesvizky R, Bergsagel PL, Pearse RN, et al., Blood, 2002;100:389b.
  18. Niesvizky R, Jayabalan DS, Christos PJ, et al., Blood, 2008;111:1101–9.
  19. Kumar S, Haymann S, Buadi F, et al., Blood (ASH Annual Meeting Abstracts), 2008;112: abstract 91.
  20. Harousseau JL, Attal M, Lelu X, et al., Haematologica, 2006;91:1498–1505.
  21. Harousseau JL, Mathiot C, Attal M, et al., Blood (ASH Annual Meeting Abstracts), 2007;110: abstract 139.
  22. Corso A, Barbarano L, Mangiacavalli S, et al., Blood (ASH Annual Meeting Abstracts), 2006;110: abstract 1051.
  23. Jagannath S, Durie BGM, Lee Wolf J, et al., Br J Haematol, 2009;146:619–6.
  24. Palumbo A, Bringhen S, Caravita T, et al., Lancet, 2006;367:825–31.
  25. Palumbo A, Bringhen S, Liberati AM et al. Blood, 2008;12:3107–14.
  26. Facon T, Mary J, Hulin C, et al., Lancet, 2007;370:1209–18.
  27. Hulin C, Facon T, Rodon P, et al., J Clin Oncol, 2009;27:3664–70.
  28. Waage A, Gimsing P, Juliusson G, et al., Blood, 2007;110:75.
  29. Wijermans P, Schaafsma M, van Norden Y, et al., Blood, 2008;112: abstract 649.
  30. Palumbo A, Falco P, Corradini P, et al., J Clin Oncol, 2007;25:4459–65.
  31. Mateos MV, Hernandez JM, Hernandez MT, et al., Blood, 2006;108:2165–72.
  32. Mateos MV, Hernandez JM, Hernandez MT, et al., Haematologica, 2008;93(4):560–65.
  33. San Miguel JF, Schlag R, Khuageva NK, et al., N Engl J Med, 2008;359:906–17.
  34. Palumbo A, Bringhen S, Rossi D, et al., 2008 ASH annual meeting abstract, 2008;112(11): abstract 652.
  35. Kumar S, Flinn IW, Noga SJ, et al., Blood (ASH Annual Meeting Abstracts), 2008;112: abstract 93.
  36. Palumbo A, Bringhen S, Petrucci MT, et al., Blood, 2004;104:3052–7.
  37. Palumbo A, Falco P, Gay F, et al., Blood (ASH Annual Meeting Abstracts), 2008;112: abstract 159.
  38. Gay F, Palumbo A, et al., Med Oncol, 2009 (Epub ahead of print).
Keywords: Multiple myeloma, thalidomide, lenalidomide, bortezomib, toxicities, elderly patients