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A modified regimen of pegylated liposomal doxorubicin, bortezomib, and dexamethasone is effective and well tolerated in the treatment of relapsed or refractory multiple myeloma

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Abstract

Preclinical and clinical studies have demonstrated synergy between bortezomib and pegylated liposomal doxorubicin (PLD) for relapsed/refractory (R/R) multiple myeloma (MM) patients compared to bortezomib as a single agent. This retrospective study evaluated the efficacy and safety of a more frequent low-dose schedule of PLD, bortezomib, and intravenous dexamethasone (DVD) for patients with R/R MM, many of whom were previously treated with bortezomib. Twenty-eight patients with R/R MM were treated, and 23 (83%) had been previously treated with ≥1 bortezomib-containing regimen. Treatment consisted of dexamethasone 40 mg intravenously, bortezomib 1.0 mg/m2, and PLD 5.0 mg/m2 on days 1, 4, 8, and 11 of a 28-day cycle for a maximum of eight cycles. Patients ranged from 33 to 81 years of age (median, 67) and had received 1–14 prior therapies (median, 5). At baseline, ten, nine, and nine patients were in stages I, II, and III, respectively, as defined by the International Staging System, and eight (29%) patients had elevated serum creatinine levels. The overall response rate was 61%, which included one (4%) complete response, three (11%) very good partial responses, eight (29%) partial responses, and five (18%) minimal responses. Of the 23 patients who had previously received bortezomib, 12 (52%) responded. The regimen was well tolerated with only six patients (21%) who showed worsening of their baseline peripheral neuropathy (PN). One patient discontinued this regimen due to an adverse event (grade II PN). DVD appears to represent a well-tolerated regimen with a high response rate for the treatment of R/R MM patients.

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References

  1. Jemal A, Siegel R, Em W et al (2008) Cancer statistics, 2009. CA Cancer J Clin 59(4):225–249

    Article  Google Scholar 

  2. Berenson JR, Matous J, Swift RA et al (2007) A phase I/II study of arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of relapsed or refractory multiple myeloma. Clin Cancer Res 13(6):1762–1768

    Article  CAS  PubMed  Google Scholar 

  3. Berenson et al. (2006) Survival in patients with multiple myeloma receiving zoledronic acid: stratification by baseline bone alkaline phosphatase levels. J Clin Oncol ASCO Annual Meeting Proceedings Part I 24(18S):7505

  4. Alexanian R, Dimopoulos M (1994) The treatment of multiple myeloma. N Engl J Med 330:484–489

    Article  CAS  PubMed  Google Scholar 

  5. Anderson KC, Alsina M, Bensinger W, Biermann JS, Chanan-Khan A, Comenzo RL, de Castro CM, Djulbegovic B et al (2007) Multiple myeloma. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 5:118–147

    CAS  PubMed  Google Scholar 

  6. Barlogie B, Smith L, Alexanian R (1984) Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med 310(21):1353–1356

    Article  CAS  PubMed  Google Scholar 

  7. Rifkin RM, Gregory SA, Mohrbacher A, Hussein MA (2006) Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma. A Phase III multicenter randomized trial. Cancer 106(4):848–858

    Article  CAS  PubMed  Google Scholar 

  8. Ma MH, Yang HH, Parker K, Manyak S et al (2003) The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 9:1136–1144

    CAS  PubMed  Google Scholar 

  9. Mitsiades N, Mitsiades CS, Richardson PG et al (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101:2377–2380

    Article  CAS  PubMed  Google Scholar 

  10. Orlowski RZ, Stinchcombe TE, Mitchell BS et al (2002) Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 20:4420–4427

    Article  CAS  PubMed  Google Scholar 

  11. 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 25:3892–3901

    Article  CAS  PubMed  Google Scholar 

  12. Berenson JR, Yang HH, Sadler K et al (2006) Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. J Clin Oncol 24(6):937–944

    Article  CAS  PubMed  Google Scholar 

  13. San Miguel JF, Schlag R, Khuageva NK et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359(9):906–917

    Article  CAS  PubMed  Google Scholar 

  14. Reeder CB, Reece DE, Kukreti V et al (2009) Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia 23(7):1337–1341

    Article  CAS  PubMed  Google Scholar 

  15. Li J, Gorospe M, Hutter D et al (2001) Transcriptional induction of MKP-1 in response to stress is associated with histone H3 phosphorylation-acetylation. Mol Cell Biol 21:8213–8224

    Article  CAS  PubMed  Google Scholar 

  16. Small GW, Shi YY, Edmund NA et al (2004) Evidence that mitogen-activated protein kinase phosphatase-1 induction by proteasome inhibitors plays an antiapoptotic role. Mol Pharmacol 66:1478–1490

    Article  CAS  PubMed  Google Scholar 

  17. Jakubowiak AJ, Brackett L, Kendall T et al (2005) Combination therapy with Velcade, Doxil, and dexamethasone (VDD) for patients with relapsed/refractory multiple myeloma (MM). Blood 106:378b, Abstract #5179

    Google Scholar 

  18. Oakervee HE, Popat R, Curry N et al (2005) PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol 129:755–762

    Article  CAS  PubMed  Google Scholar 

  19. Popat R, Oakervee HE, Curry N et al (2005) Reduced dose PAD combination therapy (PS-341/bortezomib, adriamycin and dexamethasone) for previously untreated patients with multiple myeloma. Blood 106:717a, Abstract #2554

    Article  Google Scholar 

  20. Orlowski RZ, Peterson B, Sanford B et al (2006) Bortezomib and pegylated liposomal doxorubicin as induction therapy for adult patients with symptomatic multiple myeloma: Cancer and Leukemia Group B study 10301. Blood 108:239a, Abstract #797

    Google Scholar 

  21. Jakubowiak AJ, Kendall T, Al-Zoubi A et al (2009) Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol 27(30):5015–5022

    Article  CAS  PubMed  Google Scholar 

  22. Campbell RA, Manyak SJ, Honghao HY et al (2006) LAGλ-1: a clinically relevant drug resistant human multiple myeloma tumor murine model that enables rapid evaluation of treatments for multiple myeloma. Int J Oncol 28:1409–1417

    CAS  PubMed  Google Scholar 

  23. Millennium Pharmaceuticals (92006) Velcade (bortezomib) for Injection [package insert]. Millennium Pharmaceuticals, Cambridge, MA

  24. Durie BG, Salmon SE (1975) A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 36(3):842–854

    Article  CAS  PubMed  Google Scholar 

  25. Blade J et al (1998) Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and hemopoietic stem cell transplantation. Br J Haematol 102:1115–1123

    Article  CAS  PubMed  Google Scholar 

  26. Durie BG, Harousseau JL, Miguel JS et al (2006) International uniform response criteria for multiple myeloma. Leukemia 20:1467–1473

    Article  CAS  PubMed  Google Scholar 

  27. Palumbo A, Gay F, Bringhen S et al (2008) Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma. Ann Oncol 19(6):1160–1165

    Article  CAS  PubMed  Google Scholar 

  28. San Miguel JF, Richardson P, Sonneveld P et al (2005) Frequency, characteristics, and reversibility of peripheral neuropathy (PN) in the APEX trial. ASH Annual Meeting Abstracts 106:366

    Google Scholar 

  29. Richardson PG, Briemberg H, Jagannath S et al (2006) Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24(19):3113–3120

    Article  CAS  PubMed  Google Scholar 

  30. Wolf J, Richardson PG, Schuster M et al (2008) Utility of bortezomib retreatment in relapsed or refractory multiple myeloma patients: a multicenter case series. Clin Adv Hematol Oncol 6(10):755–760

    PubMed  Google Scholar 

  31. Sood R, Carloss H, Kerr R et al (2009) Retreatment with bortezomib alone or in combination for patients with multiple myeloma following an initial response to bortezomib. Am J Hematol 84(10):657–60

    Article  CAS  PubMed  Google Scholar 

  32. Berenson JR, Yellin O, Patel R et al (2009) A phase II study of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) for patients with previously untreated multiple myeloma (MM). ASH Annual Meeting Abstracts 114:4936

    Google Scholar 

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Acknowledgments

This study was supported by grants from Millennium Pharmaceuticals, Inc. and Centocor Ortho Biotech Services, LLC.

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Authors and Affiliations

  1. James R. Berenson, M.D., Inc, West Hollywood, CA, USA

    Gabriel N. Waterman, Regina A. Swift, Russell Mapes, Benjamin Eades, Emily Ackerman & James R. Berenson

  2. Oncotherapeutics, West Hollywood, CA, USA

    Ori Yellin & James R. Berenson

  3. Institute for Myeloma and Bone Cancer Research, 9201 W. Sunset Blvd., Suite 300, West Hollywood, CA, 90069, USA

    James R. Berenson

Authors
  1. Gabriel N. Waterman
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  2. Ori Yellin
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  3. Regina A. Swift
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  4. Russell Mapes
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  5. Benjamin Eades
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  6. Emily Ackerman
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  7. James R. Berenson
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Correspondence to James R. Berenson.

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Waterman, G.N., Yellin, O., Swift, R.A. et al. 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, 193–200 (2011). https://doi.org/10.1007/s00277-010-1052-8

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  • DOI: https://doi.org/10.1007/s00277-010-1052-8

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