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Modified Bortezomib, Adriamycin and Dexamethasone (PAD) Regimen in Advanced Multiple Myeloma

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Pathology & Oncology Research

Abstract

The PAD regime, composed of bortezomib, adriamycin and dexamethasone, improves the outcomes of patients with advanced multiple myeloma (MM), but at the same time produces high frequency of serious toxic side effects. For the first time, we evaluated the efficacy and safety of a bortezomib-dose-reduced PAD regime in the treatment of relapsed/refractory MM in this clinical study. Forty-five patients were treated with two to six 21-day cycles of PAD, comprising bortezomib at 1.3 mg/m2 (P1AD, n = 21) or 1.0 mg/m2 (P2AD, n = 24) (days 1, 4, 8, 11), adriamycin at 9 mg/m2 (days 1–4) and dexamethasone at 40 mg/day (days 1–4). Overall, 36 patients (80 %) showed at least partial remission (PR), in which 9 cases (20 %) showed complete remission (CR) and 10 cases (22 %) showed very good partial remission (VGPR). The efficacy of PAD regimen in advanced MM patients was not related to the traditional prognostic factors. There was no significant difference between P1AD and P2AD in the rates of PR, CR or VGPR, 1.5-year progression-free survival (PFS), and overall survival (OS) (81 % vs. 79 %, 48 % vs. 38 %, 64 % vs. 59 %, and 85 % vs. 73 %, respectively). However, the grade 3–4 toxic effects, including thrombocytopenia (13 % vs. 38 %), peripheral neuropathy (8 % vs. 33 %) and 3–4 grade gastrointestinal reaction (13 % vs. 43 %), were markedly inhibited after P2AD compared to P1AD (P < 0.05). The bortezomib-dose-reduced PAD regime reduced the incidence of adverse reactions without affecting the treatment efficacy in patients with advanced MM.

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References

  1. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR (2006) Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 24(3):431–436

    Article  PubMed  CAS  Google Scholar 

  2. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348(26):2609–2617

    Article  PubMed  CAS  Google Scholar 

  3. Mohty B, El-Cheikh J, Yakoub-Agha I, Avet-Loiseau H, Moreau P, Mohty M (2012) Treatment strategies in relapsed and refractory multiple myeloma: a focus on drug sequencing and ‘retreatment’ approaches in the era of novel agents. Leukemia 26(1):73–85

    Article  PubMed  CAS  Google Scholar 

  4. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Blade J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352(24):2487–2498

    Article  PubMed  CAS  Google Scholar 

  5. Chanan-Khan A, Miller KC, Musial L, Padmanabhan S, Yu J, Ailawadhi S, Sher T, Mohr A, Bernstein ZP, Barcos M, Patel M, Iancu D, Lee K, Czuczman MS (2009) Bortezomib in combination with pegylated liposomal doxorubicin and thalidomide is an effective steroid independent salvage regimen for patients with relapsed or refractory multiple myeloma: results of a phase II clinical trial. Leuk Lymphoma 50(7):1096–1101

    Article  PubMed  CAS  Google Scholar 

  6. Popat R, Oakervee H, Williams C, Cook M, Craddock C, Basu S, Singer C, Harding S, Foot N, Hallam S, Odeh L, Joel S, Cavenagh J (2009) Bortezomib, low-dose intravenous melphalan, and dexamethasone for patients with relapsed multiple myeloma. Br J Haematol 144(6):887–894

    Article  PubMed  CAS  Google Scholar 

  7. Benevolo G, Larocca A, Gentile M, Pregno P, Gay F, Botto B, Frairia C, Evangelista A, Morabito F, Boccadoro M (2011) The efficacy and safety of bortezomib and dexamethasone as a maintenance therapy in patients with advanced multiple myeloma who are responsive to salvage bortezomib‐containing regimens. Cancer 117(9):1884–1890

    Article  PubMed  CAS  Google Scholar 

  8. Waterman GN, Yellin O, Swift RA, Mapes R, Eades B, Ackerman E, Berenson JR (2011) A modified regimen of pegylated liposomal doxorubicin, bortezomib, and dexamethasone is effective and well tolerated in the treatment of relapsed or refractory multiple myeloma. Ann Hematol 90(2):193–200

    Article  PubMed  CAS  Google Scholar 

  9. Romano A, Chiarenza A, Consoli U, Conticello C, Forte S, Uccello G, Vetro C, Cavalli M, Coppolino F, Palumbo GA, Di Raimondo F (2013) Intravenous injection of bortezomib, melphalan and dexamethasone in refractory and relapsed multiple myeloma. Ann Oncol 24(4):1038–1044

    Article  PubMed  CAS  Google Scholar 

  10. Pantani L, Zamagni E, Zannetti BA, Pezzi A, Tacchetti P, Brioli A, Mancuso K, Perrone G, Rocchi S, Tosi P, Cavo M (2013) Bortezomib and dexamethasone as salvage therapy in patients with relapsed/refractory multiple myeloma: analysis of long-term clinical outcomes. Annals of Hematology: Epub ahead of print. http://www.bioportfolio.com/resources/pmarticle/464488/Bortezomib-and-dexamethasone-as-salvage-therapy-in-patients-with-relapsed-refractory-multiple.html

  11. Richardson P, Jagannath S, Colson K (2006) Optimizing the efficacy and safety of bortezomib in relapsed multiple myeloma. Clin Adv Hematol Oncol 4(5):1

    PubMed  Google Scholar 

  12. Palumbo A, Gay F, Bringhen S, Falcone A, Pescosta N, Callea V, Caravita T, Morabito F, Magarotto V, Ruggeri M, Avonto I, Musto P, Cascavilla N, Bruno B, Boccadoro M (2008) Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma. Ann Oncol 19(6):1160–1165

    Article  PubMed  CAS  Google Scholar 

  13. Telek B, Mehes L, Batar P, Kiss A, Udvardy M (2008) Effective PAD (bortezomib, doxorubicin, dexamethasone) treatment of a patient with plasma cell leukaemia that has developed after autologous stem cell transplantation. Orv Hetil 149(41):1957–1959

    Article  PubMed  Google Scholar 

  14. Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M, Agrawal S, Stec J, Schenkein D, Esseltine DL, Cavenagh JD (2005) PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol 129(6):755–762

    Article  PubMed  CAS  Google Scholar 

  15. Popat R, Oakervee HE, Hallam S, Curry N, Odeh L, Foot N, Esseltine DL, Drake M, Morris C, Cavenagh JD (2008) Bortezomib, doxorubicin and dexamethasone (PAD) front-line treatment of multiple myeloma: updated results after long-term follow-up. Br J Haematol 141(4):512–516

    Article  PubMed  CAS  Google Scholar 

  16. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J (2005) International staging system for multiple myeloma. J Clin Oncol 23(15):3412–3420

    Article  PubMed  Google Scholar 

  17. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV (2006) International uniform response criteria for multiple myeloma. Leukemia 20(9):1467–1473

    Article  PubMed  CAS  Google Scholar 

  18. Min H, Hui W, Ji P (2006) Genetic Polymorphism of humanCYP3A4gene in population of Han nationality in China. Chin J Clin Pharmacol Ther 11(3):300–304

    Google Scholar 

  19. Hsieh KP, Lin YY, Cheng CL, Lai ML, Lin MS, Siest JP, Huang JD (2001) Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos 29(3):268–273

    PubMed  CAS  Google Scholar 

  20. Wei JY, Tong HY, Zhu WF, Liu H, Zhang FJ, Yu WJ, Jin J (2009) Bortezomib in treatment of extramedullary plasmacytoma of the pancreas. Hepatobiliary Pancreat Dis Int 8(3):329–331

    PubMed  Google Scholar 

  21. Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH (2006) Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 107(12):4907–4916

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Meister S, Schubert U, Neubert K, Herrmann K, Burger R, Gramatzki M, Hahn S, Schreiber S, Wilhelm S, Herrmann M, Jack HM, Voll RE (2007) Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res 67(4):1783–1792

    Article  PubMed  CAS  Google Scholar 

  23. Gotoh A, Ohyashiki K, Oshimi K, Usui N, Hotta T, Dan K, Ikeda Y (2006) Lung injury associated with bortezomib therapy in relapsed/refractory multiple myeloma in Japan: a questionnaire-based report from the “lung injury by bortezomib” joint committee of the Japanese society of hematology and the Japanese society of clinical hematology. Int J Hematol 84(5):406–412

    Article  PubMed  CAS  Google Scholar 

  24. Miyakoshi S, Kami M, Yuji K, Matsumura T, Takatoku M, Sasaki M, Narimatsu H, Fujii T, Kawabata M, Taniguchi S, Ozawa K, Oshimi K (2006) Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myeloma. Blood 107(9):3492–3494

    Article  PubMed  CAS  Google Scholar 

  25. Tong Y, Qian J, Li Y, Meng H, Jin J (2007) The high incidence of varicella herpes zoster with the use of bortezomib in 10 patients. Am J Hematol 82(5):403–404

    Article  PubMed  CAS  Google Scholar 

  26. Reece DE, Sullivan D, Lonial S, Mohrbacher AF, Chatta G, Shustik C, Burris H 3rd, Venkatakrishnan K, Neuwirth R, Riordan WJ, Karol M, von Moltke LL, Acharya M, Zannikos P, Keith Stewart A (2011) Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma. Cancer Chemother Pharmacol 67(1):57–67

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Yuan ZG, Jin J, Huang XJ, Li Y, Chen WM, Liu ZG, Chen XQ, Shen ZX, Hou J (2011) Different dose combinations of bortezomib and dexamethasone in the treatment of relapsed or refractory myeloma: an open-label, observational, multi-center study in China. Chin Med J 124(19):2969–2974

    PubMed  CAS  Google Scholar 

  28. Petrucci M, Blau I, Corradini P, Dimopoulos M, Drach J, Giraldo P, Teixeira A, Blade J (2010) Efficacy and safety of retreatment with bortezomib in patients with multiple myeloma: interim results from RETRIEVE, a prospective international phase 2 study. Haematologica 95(s2):152

    Google Scholar 

  29. Lonial S, Waller EK, Richardson PG, Jagannath S, Orlowski RZ, Giver CR, Jaye DL, Francis D, Giusti S, Torre C, Barlogie B, Berenson JR, Singhal S, Schenkein DP, Esseltine DL, Anderson J, Xiao H, Heffner LT, Anderson KC (2005) Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 106(12):3777–3784

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Berges C, Haberstock H, Fuchs D, Miltz M, Sadeghi M, Opelz G, Daniel V, Naujokat C (2008) Proteasome inhibition suppresses essential immune functions of human CD4+ T cells. Immunology 124(2):234–246

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgments

We wish to express our warm thanks to Fenghe (shanghai) Information Technology Co. Ltd. Their ideas and help gave a valuable added dimension to our research. This work was supported by the National Natural Science Foundation of China (No. 30871089 and No.81071951).

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All authors have no conflicts of interest.

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Authors and Affiliations

  1. Department of Hematology, the 309th Hospital of Chinese People’s Liberation Army, 17 Heishanhu Road, Beijing, 100091, China

    Yongqing Zhang, Bing Shi, Lihui Liu, DengMei Tian & Mingjuan Liu

  2. Department of Geriatrics, the 309th Hospital of Chinese People’s Liberation Army, Beijing, 100091, China

    Hongjuan Liu

  3. Department of Hematology, Xijing Hospital, the Fourth Military Medical University, Xi’an, 710032, China

    Xiequn Chen, Qingxian Bai & Rong Liang

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  1. Yongqing Zhang
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Correspondence to Yongqing Zhang or Xiequn Chen.

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Yongqing Zhang and Hongjuan Liu contributed equally to this work.

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Zhang, Y., Liu, H., Chen, X. et al. Modified Bortezomib, Adriamycin and Dexamethasone (PAD) Regimen in Advanced Multiple Myeloma. Pathol. Oncol. Res. 20, 987–995 (2014). https://doi.org/10.1007/s12253-014-9785-7

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