Annals of Hematology

, Volume 86, Issue 3, pp 211–216 | Cite as

Extended follow-up of outcome measures in multiple myeloma patients treated on a phase I study with bortezomib and pegylated liposomal doxorubicin

  • Suzanne E. Biehn
  • Dominic T. Moore
  • Peter M. Voorhees
  • Reynaldo A. Garcia
  • Mary Jo Lehman
  • E. Claire Dees
  • Robert Z. Orlowski
Original Article
First Online:
Received:
Accepted:

Abstract

A phase I study of a combination of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin showed significant anti-tumor activity against advanced multiple myeloma, with 36% of patients achieving a complete or near-complete response and 73% having a partial response or better. Given this encouraging efficacy, it was therefore of interest to update the prior experience and define parameters such as time to progression, time to retreatment, and overall survival. Additional follow-up was collected on all evaluable multiple myeloma patients and revealed a median time to progression of 9.3 months versus 3.8 months on whatever had been the patient’s prior therapy. Time to retreatment was prolonged from 5.9 months after the patient’s prior therapy to 24.2 months after bortezomib with pegylated liposomal doxorubicin. The median overall survival after therapy with bortezomib and pegylated liposomal doxorubicin was 38.3 months. These findings compare favorably with results reported for bortezomib alone and support the possibility that the bortezomib/pegylated liposomal doxorubicin regimen may provide superior efficacy against relapsed/refractory multiple myeloma.

Keywords

Bortezomib Liposomal doxorubicin Multiple myeloma Phase I trial Proteasome inhibitor 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgment

The authors would like to thank and dedicate this paper to all the patients whose participation in the phase I study made this research possible.

S.E.B. was supported in part by the Doris Duke Charitable Foundation (Clinical Research Fellows) and the General Clinical Research Centers program of the Division of Research Resources, National Institutes of Health (RR-000046). R.Z.O., a Leukemia and Lymphoma Society Mansbach Foundation Scholar in Clinical Research, would like to acknowledge support from the Leukemia and Lymphoma Society (6096-07), the Multiple Myeloma Research Foundation, and the National Cancer Institute (RO1 CA102278).

References

  1. 1.
    Barlogie B, Shaughnessy JD, Tricot G, Jacobson J, Zangari M, Anaissie E, Walker R, Crowley J (2004) Treatment of multiple myeloma. Blood 103:20–32PubMedCrossRefGoogle Scholar
  2. 2.
    Berenson JR, Yang HH, Sadler K, Jarutirasarn SG, Vescio RA, Mapes R, Purner M, Lee SP, Wilson J, Morrison B, Adams J, Schenkein D, Swift R (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 24:937–944PubMedCrossRefGoogle Scholar
  3. 3.
    Bladé J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, Gertz M, Giralt S, Jagannath S, Vesole D (1998) 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 102:1115–1123PubMedCrossRefGoogle Scholar
  4. 4.
    Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, Anderson KC (2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61:3071–3076PubMedGoogle Scholar
  5. 5.
    Ma MH, Yang HH, Parker K, Manyak S, Friedman JM, Altamirano C, Wu ZQ, Borad MJ, Frantzen M, Roussos E, Neeser J, Mikail A, Adams J, Sjak-Shie N, Vescio RA, Berenson JR (2003) The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 9:1136–1144PubMedGoogle Scholar
  6. 6.
    Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Schlossman R, Munshi NC, Hideshima T, Anderson KC (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101:2377–2380PubMedCrossRefGoogle Scholar
  7. 7.
    Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, Adams J, Esseltine DL, Elliott PJ, Pien CS, Guerciolini R, Anderson JK, Depcik-Smith ND, Bhagat R, Lehman MJ, Novick SC, O’Connor OA, Soignet SL (2002) Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 20:4420–4427PubMedCrossRefGoogle Scholar
  8. 8.
    Orlowski RZ, Voorhees PM, Garcia RA, Hall MD, Kudrik FJ, Allred T, Johri AR, Jones PE, Ivanova A, Van Deventer HW, Gabriel DA, Shea TC, Mitchell BS, Adams J, Esseltine DL, Trehu EG, Green M, Lehman MJ, Natoli S, Collins JM, Lindley CM, Dees EC (2005) Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 105:3058–3065PubMedCrossRefGoogle Scholar
  9. 9.
    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 348:2609–2617PubMedCrossRefGoogle Scholar
  10. 10.
    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, Bladé 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 352:2487–2498PubMedCrossRefGoogle Scholar
  11. 11.
    Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Hideshima T, Xiao H, Esseltine D, Schenkein D, Anderson KC (2005) Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma. Blood 106:2977–2981PubMedCrossRefGoogle Scholar
  12. 12.
    Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin DH, Rajkumar SV, Srkalovic G, Alsina M, Anderson KC (2006) Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma: final time-to-event results from the SUMMIT trial. Cancer 106:1316–1319PubMedCrossRefGoogle Scholar
  13. 13.
    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
  14. 14.
    Zangari M, Barlogie B, Burns MJ, Bolejack V, Hollmig KA, van Rhee F, Pineda-Roman M, Elice F, Tricot GJ (2005) VELCADE-Thalidomide (T)-Dexamethasone for advanced and refractory multiple myeloma: long-term follow-up of phase I-II trial UARK 2001-37: superior outcome in patients with normal cytogenetics and no prior T. Blood 106:Abstract 2552Google Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Suzanne E. Biehn
    • 1
  • Dominic T. Moore
    • 2
    • 3
  • Peter M. Voorhees
    • 3
    • 4
  • Reynaldo A. Garcia
    • 3
  • Mary Jo Lehman
    • 3
  • E. Claire Dees
    • 1
    • 3
    • 4
  • Robert Z. Orlowski
    • 1
    • 3
    • 4
    • 5
  1. 1.University of North Carolina at Chapel Hill School of MedicineChapel HillUSA
  2. 2.Department of BiostatisticsUniversity of North Carolina at Chapel HillChapel HillUSA
  3. 3.Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillChapel HillUSA
  4. 4.Division of Hematology/Oncology, Department of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  5. 5.Department of PharmacologyUniversity of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations