Advertisement

Journal of Cancer Research and Clinical Oncology

, Volume 143, Issue 12, pp 2545–2553 | Cite as

Lenalidomide in combination with bendamustine and prednisolone in relapsed/refractory multiple myeloma: results of a phase 2 clinical trial (OSHO-#077)

  • Juliane Beck
  • Andreas Schwarzer
  • Dietrich Gläser
  • Lars-Olof Mügge
  • Jens Uhlig
  • Simone Heyn
  • Brigitte Kragl
  • Martin Mohren
  • Franz Albert Hoffmann
  • Thoralf Lange
  • Thomas Schliwa
  • Thomas Zehrfeld
  • Cornelia Becker
  • Ute Kreibich
  • Cornelia Winkelmann
  • Thomas Edelmann
  • Marc Andrea
  • Marius Bill
  • Madlen Jentzsch
  • Sebastian Schwind
  • Dietger Niederwieser
  • Wolfram PönischEmail author
Original Article – Clinical Oncology

Abstract

Introduction

While lenalidomide monotherapy is established for relapsed and/or refractory multiple myeloma (MM) treatment, combination therapies including lenalidomide are still under investigation in a number of phase 2/3 studies. In the current study, a treatment regime of lenalidomide (Revlimid®), bendamustine and prednisolone (RBP) was tested in patients with relapsed/refractory MM.

Methods

In the previously completed phase 1 study RBP with a dose of 75 mg/m2 bendamustine days 1–2, prednisolone 100 mg days 1–4 and 25 mg lenalidomide days 1–21 was well tolerated.

Results

Between July 2011 and September 2013, 25 patients were included in this analysis. The median number of previous treatments was 1 (range 1–2). Twenty-two patients (88%) responded after at least two cycles of RBP (one sCR, five nCR, eight VGPR and eight PR). The median time to first haematological response was 28 days, and median time to best response was 56 days. Due to increased haematological toxicity a dose reduction in most patients required in subsequent cycles of therapy. The median progression-free and overall survival was 22 and 38 months, respectively.

Summary

In conclusion RBP is a highly effective therapy for patients with relapsed/refractory MM. In contrast to our phase 1 study, dose reduction was necessary in many patients because of haematological toxicity.

Keywords

Relapsed/refractory multiple myeloma Lenalidomide Bendamustine Prednisolone Phase 2 study 

Notes

Author contributions

WP and SH designed the study. JB, WP, TS and SH collected the data, analysed and interpreted the data, performed statistical analysis and wrote the manuscript. MM, FAH and TL were members of independent data-monitoring committee. JB, AS, DG, LOM, JU, SH, BK, TZ, CB, UK, CW, TE, MA, MB, MJ, SS, DN and WP enrolled patients and collected the data. All authors reviewed and revised the manuscript.

Compliance with ethical standards

Conflict of interest

This study was supported in part by research funding from Celgene, Mundipharma and Amgen. We want to thank our contract research organisation ClinAssess for performing data management and site management for all study centres. No authors declare competing financial interests.

References

  1. Berdeja JG, Savona MR, Chu L, Essell J, Murphy P, Bauer T, Raefsky E, Boccia RV, Flinn IW (2013) Bendamustine, bortezomib and dexamethasone (BBD) as first-line treatment of patients (pts) with Multiple Myeloma who are not candidates for high dose chemotherapy: toxicity comparison of two dose schedules. Blood (Abstract) 122:3193Google Scholar
  2. Berenson JR, Yellin O, Bessudo A, Boccia RV, Noga SJ, Gravenor DS, Patel-Donnelly D, Siegel RS, Kewalramani T, Gorak EJ, Nassir Y, Swift RA, Mayo D (2013) Phase I/II trial assessing bendamustine plus bortezomib combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. Br J Haematol 160:321–330CrossRefPubMedGoogle Scholar
  3. 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 36:842–854CrossRefPubMedGoogle Scholar
  4. Durie BG, Harousseau JL, Miguel JS, Bladé 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, International Myeloma Working Group (2006) International uniform response criteria for multiple myeloma. Leukemia 20:1467–1473CrossRefPubMedGoogle Scholar
  5. Grey-Davies E, Bosworth JL, Boyd KD, Ebdon C, Saso R, Chitnavis D, Mercieca JE, Morgan GJ, Davies FE (2012) Bendamustine, thalidomide and dexamethasone is an effective salvage regimen for advanced stage multiple myeloma. Br J Haematol 156:552–555CrossRefPubMedGoogle Scholar
  6. Kastritis E, Zervas K, Symeonidis A, Terpos E, Anagnostopoulos N, Michali E, Zomas A, Katodritou E, Gika D, Pouli A, Christoulas D, Roussou M, Kartasis Z, Economopoulos T, Dimopoulos MA (2009) Improved survival of patients with multiple myeloma after the introduction of novel agents and the applicability of the international staging system (ISS): an analysis of the Greek Myeloma Study Group (GMSG). Leukemia 23:1152–1157CrossRefPubMedGoogle Scholar
  7. Knop S, Straka C, Haen M, Schwedes R, Hebart H, Einsele H (2005) The efficacy and toxicity of bendamustine in recurrent multiple myeloma after high-dose chemotherapy. Haematologica 90:1287–1288PubMedGoogle Scholar
  8. Knop S, Gerecke C, Liebisch P, Topp MS, Platzbecker U, Sezer O, Vollmuth C, Falk K, Glasmacher A, Maeder U, Einsele H, Bargou RC (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 Myeloma). Blood 113:4137–4143CrossRefPubMedGoogle Scholar
  9. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, Dingli D, Russell SJ, Lust JA, Greipp PR, Kyle RA, Gertz MA (2008) Improved survival in multiple myeloma and the impact of novel therapies. Blood 111:2516–2520CrossRefPubMedPubMedCentralGoogle Scholar
  10. Kumar SK, Krishnan A, LaPlant B, Laumann K, Roy V, Zimmerman T, Gertz MA, Buadi FK, Stockerl-Goldstein K, Birgin A, Fiala M, Duarte L, Maharaj M, Levy J, Vij R (2015) Bendamustine, lenalidomide, and dexamethasone (BRD) is highly effective with durable responses in relapsed multiple myeloma. Am J Hematol 90:1106–1110CrossRefPubMedGoogle Scholar
  11. Lau I-J, Smith D, Aitchison R, Blesing N, Roberts P, Peniket A, Yong K, Rabin N, Ramasamy K (2015) Bendamustine in combination with thalidomide and dexamethasone is a viable salvage option in myeloma relapsed and/or refractory to bortezomib and lenalidomide. Ann Hematol 94:643–649CrossRefPubMedGoogle Scholar
  12. Lentzsch S, O’Sullivan A, Kennedy RC, Abbas M, Dai L, Pregja SL, Burt S, Boyiadzis M, Roodman GD, Mapara MY, Agha M, Waas J, Shuai Y, Normolle D, Zonder JA (2012) Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase I/II open-label, dose escalation study. Blood 119:4608–4613CrossRefPubMedPubMedCentralGoogle Scholar
  13. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461–470CrossRefPubMedGoogle Scholar
  14. Ludwig H, Kasparu H, Leitgeb C, Rauch E, Linkesch W, Zojer N, Greil R, Seebacher A, Pour L, Weissmann A, Adam Z (2014) Bendamustine-bortezomib-dexamethasone (BBD) ia an active and well tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood 123:985–991CrossRefPubMedPubMedCentralGoogle Scholar
  15. Mateos MV, Oriol A, Rosinol L, de Arriba F, Puig N, Martin J, Martinez-Lopez J, Echeveste MA, Sarra J, Ocio EM, Ramirez G, Martinez R, Palomera L, Payer A, Iglesias R, de la Rubia J, Alegre A, Chinea AI, Blade J, Lahuerta JJ, San Miguel JF (2015) Bendamustine, bortezomib and prednisone for the treatment of newly diagnosed multiple myeloma patients: results of a prospective phase 2 Spanish/Pethesma trial. Haematologica 100(8):1096–1102PubMedPubMedCentralGoogle Scholar
  16. Mey UJ, Brugger W, Schwarb H, Pederiva S, Schwarzer A, Dechow T, Jehner P, Rauh J, Taverna CJ, Schmid M, Schmidt-Hieber M, Doerfel S, Fischer N, Ruefer A, Ziske C, Knauf W, Cathomas R, von Moos R, Hitz F, Sauter R, Hiendlmeyer E, Cantoni N, Bargetzi M, Driessen C (2017) Bendamustine, lenalidomide and dexamethasone (BRd) has high activity as 2nd—line therapy for relapsed and refractory multiple myeloma—a phase II trial. Br J Haematol 176:770–782CrossRefPubMedGoogle Scholar
  17. Offidani M, Corvatta L, Maracci L, Liberati AM, Ballanti S, Attolico I, Caraffa P, Alesiani F, Caravita di Toritto T, Gentili S, Tosi P, Brunori M, Derudas D, Ledda A, Gozzetti A, Cellini C, Malerba L, Mele A, Andriani A, Galimberti S, Mondello P, Pulini S, Coppetelli U, Fraticelli P, Oliveri A, Leoni P (2013) Efficacy and tolerability of bendamustine, bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma: a phase II study. Blood Cancer J 3:e162. doi: 10.1038/bcj.2013.58 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Poenisch W, Plötze M, Holzvogt B, Andrea M, Schliwa T, Zehrfeld T, Hammerschmidt D, Schwarz M, Edelmann T, Becker C, Hoffmann FA, Schwarzer A, Kreibich U, Gutsche K, Reifenrath K, Schwarzbach H, Heyn S, Franke GN, Jentzsch M, Leiblein S, Schwind S, Lange T, Vucinic V, AlAli HK, Niederwieser D (2015) Stem cell mobilization and autologous stem cell transplantation after pretreatment with bendamustine, prednisone and bortezomib (BPV) in newly diagnosed multiple myeloma. J Cancer Res Clin Oncol 141:2013–2022CrossRefPubMedGoogle Scholar
  19. Pönisch W, Mitrou PS, Merkle K, Herold M, Assmann M, Wilhelm G, Dachselt K, Richter P, Schirmer V, Schulze A, Subert R, Harksel B, Grobe N, Stelzer E, Schulze M, Bittrich A, Freund M, Pasold R, Friedrich T, Helbig W, Niederwieser D (2006) Treatment of bendamustine and prednisone in patients with newly diagnosed multiple myeloma results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with melphalan and prednisone—a randomized phase III study of the East German Study Group of Haematology and Oncology (OSHO). J Cancer Res Clin Oncol 132:205–212CrossRefPubMedGoogle Scholar
  20. Pönisch W, Rozanski M, Goldschmidt H, Hoffmann FA, Boldt T, Schwarzer A, Ritter U, Rohrberg R, Schwalbe E, Uhlig J, Zehrfeld T, Schirmer V, Haas A, Kreibich U, Niederwieser D, East German Study Group of Haematology and Oncology (OSHO) (2008) Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell transplantation or conventional chemo-therapy: results of a Phase I clinical trial. Br J Haematol 143:191–200CrossRefPubMedGoogle Scholar
  21. Pönisch W, Heyn S, Beck J, Wagner I, Mohren M, Hoffmann FA, Lange T, Schmalfeld M, Zehrfeld T, Schwarzer A, Winkelmann C, Edelmann T, Röhrborn R, Hebenstreit K, Al-Ali HK, Jäckel N, Niederwieser D (2013a) Lenalidomide, bendamustine and prednisolone exhibits a favourable safety and efficacy profile in relapsed or refractory multiple myeloma: final results of a phase 1 clinical trial OSHO-#077. Br J Haematol 162:202–209CrossRefPubMedGoogle Scholar
  22. Pönisch W, Bourgeois M, Moll B, Heyn S, Jäkel N, Wagner I, Rohrberg R, Hurtz HJ, Schmalfeld M, Aßmann M, Edelmann T, Mohren M, Hoffmann FA, Becker C, Schwarzer A, Schönfelder U, Zehrfeld T, Hensel G, Löschcke K, Krahl R, AlAli HK, Niederwieser D (2013b) Combined Bendamustine, prednisone and bortezomib (BPV) in patients with relapsed or refractory multiple myeloma. J Cancer Res Clin Oncol 139:499–508CrossRefPubMedGoogle Scholar
  23. Pozzi S, Gentile M, Sacchi S, Marcheselli R, Corso A, Cocito F, Musto P, Guarini A, Minoia C, Vincelli I, Ria R, Rivolti E, Mele G, Bari A, Mazzone C, Badiali S, Marcheselli L, Palumbo A, Morabito F (2017) Bendamustine, low-dose dexamethasone, and lenalidomide (BdL) for the treatment of patients with relapsed/refractory multiple myeloma confirms very promising results in a phase I/II study. Leuk Lymphoma 58:552–559CrossRefPubMedGoogle Scholar
  24. Richardson P, Jagannath S, Hussein M, Berenson J, Singhal S, Irwin D, Williams SF, Bensinger W, Badros AZ, Vescio R, Kenvin L, Yu Z, Olesnyckyj M, Zeldis J, Knight R, Anderson KC (2009) Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood 114:772–778CrossRefPubMedGoogle Scholar
  25. Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, Alsina M, Ghobrial M, Schlossman RL, Munshi NC, Mazumder A, Vesole DH, Kaufman JL, Colson K, McKenney M, Lunde LE, Feather J, Maglio ME, Warren D, Francis D, Hideshima T, Knight R, Esseltine DL, Mitsiades CS, Weller E, Anderson KC (2014) A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood 123:1462–1469Google Scholar
  26. Schey SA, Morgan GJ, Ramasamy K, Hazel B, Ladon D, Corderoy S, Jenner M, Phekoo K, Boyd K, Davies FE (2010) The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study. Br J Haematol 150:326–333CrossRefPubMedGoogle Scholar
  27. Schey S, Brown SR, Tillotson A-L, Williams C, Davies F, Morgan G, Cavenagh J, Cook G, Cook M, Orti G, Morris C, Sherratt D, Flanagan L, Gregory W, Cavet J (2015) Bendamustine, thalidomide and dexamethasone combination therapy for relapsed/refractory myeloma patients: results of the MUKone randomized dose selection trial. Br J Haematol 170:336–348CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Juliane Beck
    • 1
  • Andreas Schwarzer
    • 2
  • Dietrich Gläser
    • 3
  • Lars-Olof Mügge
    • 4
  • Jens Uhlig
    • 5
  • Simone Heyn
    • 1
  • Brigitte Kragl
    • 6
  • Martin Mohren
    • 7
  • Franz Albert Hoffmann
    • 8
  • Thoralf Lange
    • 9
  • Thomas Schliwa
    • 1
  • Thomas Zehrfeld
    • 10
  • Cornelia Becker
    • 8
  • Ute Kreibich
    • 11
  • Cornelia Winkelmann
    • 12
  • Thomas Edelmann
    • 13
  • Marc Andrea
    • 1
  • Marius Bill
    • 1
  • Madlen Jentzsch
    • 1
  • Sebastian Schwind
    • 1
  • Dietger Niederwieser
    • 1
  • Wolfram Pönisch
    • 1
    Email author
  1. 1.Department of Haematology and OncologyUniversity of LeipzigLeipzigGermany
  2. 2.Haematology PracticeLeipzigGermany
  3. 3.Department of Haematology and OncologyKlinikum Südstadt RostockRostockGermany
  4. 4.Department of Haematology and OncologyUniversity of JenaJenaGermany
  5. 5.Haematology PracticeNaunhofGermany
  6. 6.Department of Haematology and OncologyUniversity of RostockRostockGermany
  7. 7.Department of Haematology and OncologyJohanniter KrankenhausStendalGermany
  8. 8.Haematology PracticeLeipzigGermany
  9. 9.Department of Haematology and OncologyAsklepios HospitalWeissenfelsGermany
  10. 10.Department of Haematology and OncologyHospital Johann KentmannTorgauGermany
  11. 11.Department of Haematology and OncologyHeinrich-Braun-HospitalZwickauGermany
  12. 12.Department of Haematology and OncologyPaul Gerhardt StiftWittenbergGermany
  13. 13.Haematology PracticeSchkeuditzGermany

Personalised recommendations