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Myeloma

The role of novel agents on the reversibility of renal impairment in newly diagnosed symptomatic patients with multiple myeloma

Abstract

The role of thalidomide, bortezomib and lenalidomide in multiple myeloma patients presenting with renal impairment was evaluated in 133 consecutive newly diagnosed patients who were treated with a novel agent-based regimen. A significant improvement of renal function (renalPR (renal partial response)) was observed in 77% of patients treated with bortezomib, in 55% with thalidomide and in 43% with lenalidomide (P=0.011). In multivariate analysis, bortezomib-based therapy was independently associated with a higher probability of renal response compared with thalidomide- or lenalidomide-based therapy. Other important variables included eGFR (estimated glomerular filtration rate) 30 ml/min, age 65 years and myeloma response. Patients treated with bortezomib achieved at least renalPR in a median of 1.34 months vs 2.7 months for thalidomide and >6 months for lenalidomide-treated patients (P=0.028). In multivariate analysis bortezomib-based therapy, higher doses of dexamethasone (160 mg during the first month of treatment), an eGFR 30 ml/min and age 65 years were independently associated with shorter time to renal response. In conclusion, bortezomib-based therapies may be more appropriate for the initial management of patients with myeloma-related renal failure; however, thalidomide and lenalidomide are also associated with significant probability of improvement of their renal function.

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References

  1. Alexanian R, Barlogie B, Dixon D . Renal failure in multiple myeloma. Pathogenesis and prognostic implications. Arch Intern Med 1990; 150: 1693–1695.

    Article  CAS  Google Scholar 

  2. Knudsen LM, Hippe E, Hjorth M, Holmberg E, Westin J . Renal function in newly diagnosed multiple myeloma--a demographic study of 1353 patients. The Nordic Myeloma Study Group. Eur J Haematol 1994; 53: 207–212.

    Article  CAS  Google Scholar 

  3. Eleutherakis-Papaiakovou V, Bamias A, Gika D, Simeonidis A, Pouli A, Anagnostopoulos A et al. Renal failure in multiple myeloma: incidence, correlations, and prognostic significance. Leuk Lymphoma. 2007; 48: 337–341.

    Article  CAS  Google Scholar 

  4. Augustson BM, Begum G, Dunn JA, Barth NJ, Davies F, Morgan G et al. Early mortality after diagnosis of multiple myeloma: analysis of patients entered onto the United kingdom Medical Research Council trials between 1980 and 2002-Medical Research Council Adult Leukaemia Working Party. J Clin Oncol 2005; 23: 9219–9226.

    Article  Google Scholar 

  5. Dimopoulos MA, Terpos E, Chanan-Khan A, Leung N, Ludwig H, Jagannath S et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol 2010; 28: 4976–4984.

    Article  Google Scholar 

  6. Tosi P, Zamagni E, Cellini C, Cangini D, Tacchetti P, Tura S et al. Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure. Eur J Haematol 2004; 73: 98–103.

    Article  CAS  Google Scholar 

  7. Kastritis E, Anagnostopoulos A, Roussou M, Gika D, Matsouka C, Barmparousi D et al. Reversibility of renal failure in newly diagnosed multiple myeloma patients treated with high dose dexamethasone-containing regimens and the impact of novel agents. Haematologica 2007; 92: 546–549.

    Article  CAS  Google Scholar 

  8. Tosi P, Zamagni E, Tacchetti P, Ceccolini M, Perrone G, Brioli A et al. Thalidomide-dexamethasone as induction therapy before autologous stem cell transplantation in patients with newly diagnosed multiple myeloma and renal insufficiency. Biol Blood Marrow Transplant 2010; 16: 1115–1121.

    Article  CAS  Google Scholar 

  9. Reece DE, Masih-Khan E, Chen C, Wang L, Dean S, Kukreti V et al. Use of Lenalidomide (Revlimid(R) +/- Corticosteroids in Relapsed/Refractory Multiple Myeloma Patients with Elevated Baseline Serum Creatinine Levels. ASH Annu Meet Abstr 2006; 108: 3548.

    Google Scholar 

  10. Niesvizky R, Naib T, Christos PJ, Jayabalan D, Furst JR, Jalbrzikowski J et al. Lenalidomide-induced myelosuppression is associated with renal dysfunction: adverse events evaluation of treatment-naive patients undergoing front-line lenalidomide and dexamethasone therapy. Br J Haematol 2007; 138: 640–643.

    Article  CAS  Google Scholar 

  11. Chen N, Lau H, Kong L, Kumar G, Zeldis JB, Knight R et al. Pharmacokinetics of lenalidomide in subjects with various degrees of renal impairment and in subjects on hemodialysis. J Clin Pharmacol 2007; 47: 1466–1475.

    Article  CAS  Google Scholar 

  12. Dimopoulos M, Alegre A, Stadtmauer EA, Goldschmidt H, Zonder JA, de Castro CM et al. The efficacy and safety of lenalidomide plus dexamethasone in relapsed and/or refractory multiple myeloma patients with impaired renal function. Cancer 2010; 116: 3807–3814.

    Article  CAS  PubMed Central  Google Scholar 

  13. Dimopoulos MA, Christoulas D, Roussou M, Kastritis E, Migkou M, Gavriatopoulou M et al. Lenalidomide and dexamethasone for the treatment of refractory/relapsed multiple myeloma: dosing of lenalidomide according to renal function and effect on renal impairment. Eur J Haematol 2010; 85: 1–5.

    Article  CAS  Google Scholar 

  14. Klein U, Neben K, Hielscher T, Heiss C, Ho AD, Goldschmidt H . Lenalidomide in combination with dexamethasone: effective regimen in patients with relapsed or refractory multiple myeloma complicated by renal impairment. Ann Hematol 2011; 90: 429–439.

    Article  CAS  Google Scholar 

  15. de la Rubia J, Roig M, Ibanez A, Garcia I, Vera JA, Aguilar C et al. Activity and safety of lenalidomide and dexamethasone in patients with multiple myeloma requiring dialysis: a Spanish multicenter retrospective study. Eur J Haematol 2010; 85: 363–365.

    Article  Google Scholar 

  16. Jagannath S, Barlogie B, Berenson JR, Singhal S, Alexanian R, Srkalovic G et al. Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impared renal function. Cancer 2005; 103: 1195–1200.

    Article  CAS  Google Scholar 

  17. Mulkerin D, Remick S, Ramanathan R, Hamilton A, Takimoto C, Davies A et al. A dose-escalating and pharmacologic study of bortezomib in adult cancer patients with impaired renal function. J Clin Oncol (Meeting Abstracts) 2006; 24 (18_suppl): 2032.

    Google Scholar 

  18. Chanan-Khan AA, Kaufman JL, Mehta J, Richardson PG, Miller KC, Lonial S et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood 2007; 109: 2604–2606.

    Article  CAS  PubMed Central  Google Scholar 

  19. Mulkerin D, Remick S, Takimoto C, Ivy P, Karol M, Eton O et al. Safety, tolerability, and pharmacology of bortezomib in cancer patients with renal failure requiring dialysis: results from a prospective phase 1 study. ASH Annu Meet Abstr 2007; 110: 3477.

    Google Scholar 

  20. Ludwig H, Drach J, Graf H, Lang A, Meran JG . Reversal of acute renal failure by bortezomib-based chemotherapy in patients with multiple myeloma. Haematologica 2007; 92: 1411–1414.

    Article  CAS  Google Scholar 

  21. San-Miguel JF, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA et al. Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study. Leukemia 2008; 22: 842–849.

    Article  CAS  Google Scholar 

  22. Roussou M, Kastritis E, Migkou M, Psimenou E, Grapsa I, Matsouka C et al. Treatment of patients with multiple myeloma complicated by renal failure with bortezomib-based regimens. Leuk Lymphoma 2008; 49: 890–895.

    Article  CAS  Google Scholar 

  23. Roussou M, Kastritis E, Migkou M, Psimenou E, Grapsa I, Matsouka C et al. Treatment of patients with multiple myeloma complicated by renal failure with bortezomib-based regimens. Leuk Lymphoma 2008; 49: 890–895.

    Article  CAS  Google Scholar 

  24. Blade J, Sonneveld P, San Miguel JF, Sutherland HJ, Hajek R, Nagler A et al. Pegylated liposomal doxorubicin plus bortezomib in relapsed or refractory multiple myeloma: efficacy and safety in patients with renal function impairment. Clin Lymphoma Myeloma 2008; 8: 352–355.

    Article  CAS  Google Scholar 

  25. Dimopoulos MA, Richardson PG, Schlag R, Khuageva NK, Shpilberg O, Kastritis E et al. VMP (Bortezomib, Melphalan, and Prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: cohort analysis of the phase III VISTA study. J Clin Oncol 2009; 27: 6086–6093.

    Article  CAS  Google Scholar 

  26. Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J et al. Definition and classification of chronic kidney disease: a position statement from kidney disease: improving global outcomes (KDIGO). Kidney Int 2005; 67: 2089–2100.

    Article  Google Scholar 

  27. National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39: S1–S266.

    Google Scholar 

  28. Dimopoulos M, Kyle R, Fermand JP, Rajkumar SV, San Miguel J, Chanan-Khan A et al. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood 2011; 117: 4701–4705.

    Article  CAS  Google Scholar 

  29. Ludwig H, Adam Z, Hajek R, Greil R, Tothova E, Keil F et al. Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: results of a phase II study. J Clin Oncol 2010; 28: 4635–4641.

    Article  CAS  Google Scholar 

  30. Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998; 102: 1115–1123.

    Article  CAS  PubMed Central  Google Scholar 

  31. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467–1473.

    Article  CAS  PubMed Central  Google Scholar 

  32. Hutchison CA, Cockwell P, Stringer S, Bradwell A, Cook M, Gertz MA et al. Early reduction of serum-free light chains associates with renal recovery in myeloma kidney. J Am Soc Nephrol 2011; 22: 1129–1136.

    Article  CAS  PubMed Central  Google Scholar 

  33. Dimopoulos MA, Richardson PG, Schlag R, Khuageva NK, Shpilberg O, Kastritis E et al. VMP (bortezomib, melphalan, and prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: cohort analysis of the phase III VISTA study. J Clin Oncol 2009; 27: 6086–6093.

    Article  CAS  Google Scholar 

  34. Dimopoulos MA, Roussou M, Gavriatopoulou M, Zagouri F, Migkou M, Matsouka C et al. Reversibility of renal impairment in patients with multiple myeloma treated with bortezomib-based regimens: identification of predictive factors. Clin Lymphoma Myeloma 2009; 9: 302–306.

    Article  CAS  Google Scholar 

  35. Burnette BL, Leung N, Rajkumar SV . Renal improvement in myeloma with bortezomib plus plasma exchange. N Engl J Med 2011; 364: 2365–2366.

    Article  CAS  Google Scholar 

  36. Hutchison CA, Cook M, Basu S, Cockwell P, Basnayake K, Bradwell A . Combined chemotherapy and high cut-off hemodialysis improve outcomes in multiple myeloma patients with severe renal failure. ASH Annu Meet Abstr 2007; 110: 3610.

    Google Scholar 

  37. Uttamsingh V, Lu C, Miwa G, Gan LS . Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab Dispos 2005; 33: 1723–1728.

    Article  CAS  Google Scholar 

  38. Pekol T, Daniels JS, Labutti J, Parsons I, Nix D, Baronas E et al. Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites. Drug Metab Dispos 2005; 33: 771–777.

    Article  CAS  Google Scholar 

  39. Labutti J, Parsons I, Huang R, Miwa G, Gan LS, Daniels JS . Oxidative deboronation of the peptide boronic acid proteasome inhibitor bortezomib: contributions from reactive oxygen species in this novel cytochrome P450 reaction. Chem Res Toxicol 2006; 19: 539–546.

    Article  CAS  Google Scholar 

  40. Sarkozi R, Perco P, Hochegger K, Enrich J, Wiesinger M, Pirklbauer M et al. Bortezomib-induced survival signals and genes in human proximal tubular cells. J Pharmacol Exp Ther 2008; 327: 645–656.

    Article  Google Scholar 

  41. Ying WZ, Wang PX, Aaron KJ, Basnayake K, Sanders PW . Immunoglobulin light chains activate nuclear factor-{kappa}B in renal epithelial cells through a Src-dependent mechanism. Blood 2011; 117: 1301–1307.

    Article  CAS  PubMed Central  Google Scholar 

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Correspondence to M A Dimopoulos.

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Prof Dimopoulos has received honoraria from Celgene, Orthobiotech and Janssen-Cilag. Dr Terpos has received honoraria from Celgene. The other authors declare no conflict of interest.

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Dimopoulos, M., Roussou, M., Gkotzamanidou, M. et al. The role of novel agents on the reversibility of renal impairment in newly diagnosed symptomatic patients with multiple myeloma. Leukemia 27, 423–429 (2013). https://doi.org/10.1038/leu.2012.182

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