Annals of Hematology

, Volume 90, Issue 12, pp 1449–1456

Thalidomide, dexamethasone, Doxil and Velcade (ThaDD-V) followed by consolidation/maintenance therapy in patients with relapsed–refractory multiple myeloma

  • Massimo Offidani
  • Laura Corvatta
  • Claudia Polloni
  • Silvia Gentili
  • Anna Mele
  • Rita Rizzi
  • Massimo Catarini
  • Patrizia Caraffa
  • Arduino Samori
  • Nicola Blasi
  • Mario Ferranti
  • Lara Malerba
  • Marino Brunori
  • Pietro Leoni
Original Article

Abstract

In newly diagnosed multiple myeloma (MM), three/four-drug combinations as induction therapy seem to be more effective compared with two-drug associations in terms of response rate and duration of remission. Moreover, there is an emergent body of evidences that consolidation/maintenance therapy improves the quality of response and remission duration. However, the impact of these strategies in relapsed/refractory MM (r–rMM) is still unknown. This phase II study explored the four-drug combination of thalidomide, dexamethasone, pegylated liposomal doxorubicin (pLD), and bortezomib (ThaDD-V) as induction followed by consolidation therapy based on bortezomib–dexamethasone and thalidomide–dexamethasone and maintenance therapy with thalidomide in r–rMM patients. The primary end points of this study were best response and toxicity of the planned therapy. Forty-six patients were enrolled. At the end of therapy, the best response was as follows: 37% complete response (CR), 34.5% VGPR, and 4.5% PR with an ORR of 76%. Patients receiving ≤2 prior regimens had a CR rate significantly higher than those heavily treated (41% vs 0%; p = 0.010). With a median follow-up of 31 months, median time to progression (TTP) and OS were 18.5 months and 40 months, respectively. By a 6-month landmark analysis, patients who completed the protocol had a significantly longer TTP compared with those who did not because of toxicity (not reached vs 7 months; p < 0.0001). After the dose intensity of bortezomib was reduced due to an excess of peripheral neuropathy (PN), grade 3 PN occurred in 7.5% of patients. ThaDD-V followed by consolidation–maintenance therapy seems to be very effective in patients with r–rMM provided that this procedure is used early on relapse when very deep responses seem to be the rule.

Keywords

Bortezomib Multiple myeloma Pegylated liposomal doxorubicin Thalidomide 

References

  1. 1.
    Kumar SK, Rajkumar SV, Dispenzieri A et al (2008) Improved survival in multiple myeloma and the impact of novel therapies. Blood 111:2516–1520PubMedCrossRefGoogle Scholar
  2. 2.
    Richardson PG, Sonneveld P, Schuster MW et al (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487–2498PubMedCrossRefGoogle Scholar
  3. 3.
    Orlowski RZ, Nagler A, Sonneveld P et al (2007) Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 25:3892–3901PubMedCrossRefGoogle Scholar
  4. 4.
    Weber DM, Chen C, Niesvizky R et al (2007) Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357:2133–2142PubMedCrossRefGoogle Scholar
  5. 5.
    Dimopoulos M, Spencer A, Attal M et al (2007) Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357:2123–2132PubMedCrossRefGoogle Scholar
  6. 6.
    Stewart AK, Richardson PG, San-Miguel J (2009) How I treat multiple myeloma in younger patients. Blood 114:5436–5443PubMedCrossRefGoogle Scholar
  7. 7.
    Mitsiades N, Mitsiades CS, Poulaki V et al (2002) Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 99:4525–4530PubMedCrossRefGoogle Scholar
  8. 8.
    Hideshima T, Chauhan D, Shima Y et al (2000) Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96:2943–2950PubMedGoogle Scholar
  9. 9.
    Mitsiades N, Mitsiades CS, Richardson PG et al (2003) The proteasome inhibitor PS-341 potentiates sensitività of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101:2377–2380PubMedCrossRefGoogle Scholar
  10. 10.
    Small GW, Shi YY, Edmund NA, Somasundaram S, Moore DT, Orlowski RZ (2004) Evidence that mitogen-activated protein kinase phosphatase-1 induction by proteasome inhibitors plays an antiapoptotic role. Mol Pharmacol 66:1478–1490PubMedCrossRefGoogle Scholar
  11. 11.
    Hideshma T, Chauhan D, Ishitsuka K et al (2005) Molecular characterization of PS-341 (bortezomib) resistance: implications for overcoming resistance using lysophosphatidic acid acyltransferase (LPAAT)-beta inhibitors. Oncogene 24:3121–3129CrossRefGoogle Scholar
  12. 12.
    Offidani M, Corvatta L, Piersantelli MN et al (2006) Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma. Blood 108:2159–2164PubMedCrossRefGoogle Scholar
  13. 13.
    Offidani M, Corvatta L, Marconi M et al (2006) Low-dose thalidomide with pegylated liposomal doxorubicin and high-dose dexamethasone for relapsed/refractory multiple myeloma: a prospective, multicenter, phase II study. Haematologica 91:133–136PubMedGoogle Scholar
  14. 14.
    Orlowski RZ, Vooehees PM, Garcia RA et al (2005) Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 105:3058–3065PubMedCrossRefGoogle Scholar
  15. 15.
    Jakubowiak AJ, Brackett L, Kendall T, Friedman J, Kaminski MS (2005) Combination therapy with Velcade, Doxil, and dexamethasone (VDD) for patients with relapsed/refractory multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts) 106:5179Google Scholar
  16. 16.
    Durie BGM, Harousseau J-L, Miguel JS et al (2006) International uniform response criteria for multiple myeloma. Leukemia 20:1467–1473PubMedCrossRefGoogle Scholar
  17. 17.
    Ma MH, Yang HH, Parker K et al (2003) The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 9:1136–1144PubMedGoogle Scholar
  18. 18.
    Richardson PG, Jagannath S, Hussein M et al (2009) Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood 114:772–778PubMedCrossRefGoogle Scholar
  19. 19.
    Harrison SJ, Quach H, Dean J et al (2010) Bortezomib and dexamethasone from cycle 1 as treatment and maintenance for multiple myeloma relapse (The BoMeR trial): impact on response and time to progression. J Clin Oncol (ASCO Annual Meeting Abstracts) 28(15 suppl):8151Google Scholar
  20. 20.
    Gozzetti A, Fabbri A, Oliva S et al (2010) Weekly bortezomib, pegylated liposomal doxorubicin and dexamethasone is a safe and effective therapy for elderly patients with relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma 10:68–72CrossRefGoogle Scholar
  21. 21.
    Jakubowiak AJ, Brackett L, Kendall T, Friedman J, Kamiski MS (2005) Combination therapy with Velcade, Doxil, and dexamethasone (VDD) for patients with relapsed/refractory multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts) 106:5179Google Scholar
  22. 22.
    Reece DE, Rodriguez GP, Chen C et al (2008) Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J Clin Oncol 26:4777–4783PubMedCrossRefGoogle Scholar
  23. 23.
    Lee SS, Suh C, Kim B-S et al (2010) Bortezomib, doxorubicin, and dexamethasone combination therapy followed by thalidomide and dexamethasone consolidation as a salvage treatment for relapsed or refractory multiple myeloma: analysis of efficacy and safety. Ann Hematol 89:905–912PubMedCrossRefGoogle Scholar
  24. 24.
    Palumbo A, Gay F, Falco P et al (2010) Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation/maintenance in untreated multiple myeloma patients. J Clin Oncol 28:800–807PubMedCrossRefGoogle Scholar
  25. 25.
    Mateos M-V, Oriol A, Martinez-Lopez J et al (2010) Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. doi:10.1016/S1470-2045810)70187-x PubMedGoogle Scholar
  26. 26.
    Ladetto M, Pagliano G, Ferrero S et al (2010) Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol 28:2077–2084PubMedCrossRefGoogle Scholar
  27. 27.
    Attal M, Harousseau JL, Leyvraz S et al (2006) Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 108:3289–3294PubMedCrossRefGoogle Scholar
  28. 28.
    Spencer A, Prince HM, Roberts AW et al (2009) Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol 27:1788–1793PubMedCrossRefGoogle Scholar
  29. 29.
    Niesvizky R, Richardson PG, Rajkumar SV et al (2008) The relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma. Br J Haematol 143:46–53PubMedCrossRefGoogle Scholar
  30. 30.
    Corso A, Zappasodi P, Barbarano L et al (2009) Long-term outcome in relapsed and refractory multiple myeloma treated with thalidomide. Balancing efficacy and side-effects. Leuk Res 33:e145–e149PubMedCrossRefGoogle Scholar
  31. 31.
    Harousseau JL, Dimopoulos MA, Wang M et al (2010) The quality of response to lenalidomide plus dexamethasone is associated with improved clinical outcomes in patients with relapsed or refractory multiple myeloma. Haematologica. doi:10.3324/haematol.2009.015917 Google Scholar
  32. 32.
    Baz R, Walzer E, Karan AM et al (2006) Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann Oncol 17:1766–1771PubMedCrossRefGoogle Scholar
  33. 33.
    Palumbo A, Ambrosiani MT, Benevolo G et al (2007) Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. Blood 109:2767–2772PubMedGoogle Scholar
  34. 34.
    Ciolli S, Leoni F, Casini C, Breschi C, Santini V, Bosi A (2008) The addition of liposomal doxorubicin to bortezomib, thalidomide and dexamethasone significantly improves clinical outcome of advanced multiple myeloma. Br J Haematol 141:814–819PubMedCrossRefGoogle Scholar
  35. 35.
    Terpos E, Kastritis E, Roussou M et al (2008) The combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide is an effective regimen for relapsed/refractory myeloma and is associated with improvement of abnormal bone metabolism and angiogenesis. Leukemia 22:2247–2256PubMedCrossRefGoogle Scholar
  36. 36.
    Palumbo A, Larocca A, Falco P et al (2010) Lenalidomide, melphalan, predispone and thalidomide (RMPT) for relapsed/refractory multiple myeloma. Leukemia 24:1037–1042PubMedCrossRefGoogle Scholar
  37. 37.
    Kim Y-K, Sohn S-K, Lee J-H et al (2010) Clinical efficacy of a bortezomib, cyclophosphamide, thalidomide and dexamethasone (Vel-CTD) regimen in patients with relapsed or refractory multiple myeloma: a phase II study. Ann Hematol 89:475–482PubMedCrossRefGoogle Scholar
  38. 38.
    Bringhen S, Larocca A, Rossi D et al (2010) Efficacy and safety of once weekly bortezomib in multiple myeloma patients. Blood 116:4745–4753PubMedCrossRefGoogle Scholar
  39. 39.
    Mateos M-V, Richardson PG, Schlag R et al (2010) Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA Trial. J Clin Oncol 28:2259–2266PubMedCrossRefGoogle Scholar
  40. 40.
    Reece DE, Masih-Khan E, Khan A et al (2009) Phase I-II trial of oral cyclophosphamide, prednisone and lenalidomide (CPR) for the treatment of patients with relapsed and refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts) 114:1874Google Scholar
  41. 41.
    Palumbo A, Avonto I, Bruno B et al (2006) Intravenous melphalan, thalidomide and prednisone in refractory and relapsed multiple myeloma. Eur J Haematol 76:273–277PubMedCrossRefGoogle Scholar
  42. 42.
    Knop S, Gerecke C, Liebisch P et al (2009) Lenalidomide, adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: a report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom). Blood 113:4137–4143PubMedCrossRefGoogle Scholar
  43. 43.
    Avet-Loiseau H, Soulier J, Fermand J-P et al (2010) Impact of high-risk cytogenetics and prior therapy on outcomes in patients with advanced relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone. Leukemia 24:623–628PubMedCrossRefGoogle Scholar
  44. 44.
    Chang H, Trieu Y, Qi X, Jiang NN, Xu W, Reece D (2011) Impact of cytogenetics in patients with relapsed or refractory multiple myeloma treated with bortezomib: adverse effect of 1q21 gains. Leuk Res 35:95–98PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Massimo Offidani
    • 1
  • Laura Corvatta
    • 2
  • Claudia Polloni
    • 1
  • Silvia Gentili
    • 1
  • Anna Mele
    • 2
  • Rita Rizzi
    • 3
  • Massimo Catarini
    • 2
  • Patrizia Caraffa
    • 1
  • Arduino Samori
    • 2
  • Nicola Blasi
    • 2
  • Mario Ferranti
    • 2
  • Lara Malerba
    • 2
  • Marino Brunori
    • 2
  • Pietro Leoni
    • 1
  1. 1.Clinica di Ematologia Azienda Ospedaliero-UniversitariaOspedali Riuniti di AnconaAnconaItaly
  2. 2.Marche Myeloma Network (GEMaMM)AnconaItaly
  3. 3.Sezione di Ematologia, Dipartimento di Patologia ed EmatologiaUniversità di BariBariItaly

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