Bendamustine, thalidomide and dexamethasone combination therapy for relapsed/refractory myeloma patients: results of the MUKone randomized dose selection trial

British Journal of Haematology

Volumn 170, Issue 3, 2015, Pages 336-348

  Schey, Steve ^a   Brown, Sarah R ^b   Tillotson, Avie Lee ^b   Yong, Kwee ^c   Williams, Cathy ^d   Davies, Faith ^e   Morgan, Gareth ^e   Cavenagh, Jamie ^f   Cook, Gordon ^g   Cook, Mark ^h   Orti, Guillermo ^a   Morris, Curly ⁱ   Sherratt, Debbie ^b   Flanagan, Louise ^b   Gregory, Walter ^b   Cavet, James ^j  

^a KING S COLLEGE HOSPITAL   (United Kingdom)

^b UNIVERSITY OF LEEDS   (United Kingdom)

^c UNIVERSITY COLLEGE LONDON   (United Kingdom)

^d NOTTINGHAM UNIVERSITY HOSPITALS NHS TRUST   (United Kingdom)

^e INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^f ST BARTHOLOMEW S HOSPITAL   (United Kingdom)

^g ST JAMES S UNIVERSITY HOSPITAL   (United Kingdom)

^h QUEEN ELIZABETH HOSPITAL   (United Kingdom)

ⁱ QUEEN'S UNIVERSITY BELFAST   (United Kingdom)

^j CHRISTIE HOSPITAL   (United Kingdom)

more..

Author keywords

bendamustine; dosing; myeloma; phase 2; relapsed refractory

Indexed keywords

BENDAMUSTINE; DEXAMETHASONE; THALIDOMIDE; ANTINEOPLASTIC AGENT; CHLORMETHINE DERIVATIVE;

ADULT; AGED; ANEMIA; ARTICLE; CANCER COMBINATION CHEMOTHERAPY; CANCER RECURRENCE; CANCER SURVIVAL; CLINICAL EFFECTIVENESS; CONSTIPATION; CONTROLLED STUDY; DIARRHEA; DOSE RESPONSE; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; FATIGUE; HUMAN; LOW DRUG DOSE; MAJOR CLINICAL STUDY; MOTOR NEUROPATHY; MULTICENTER STUDY; MULTIPLE CYCLE TREATMENT; MYELOMA; NAUSEA; NEUROTOXICITY; NEUTROPENIA; PERIPHERAL MOTOR NEUROPATHY; PERIPHERAL SENSORY NEUROPATHY; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; RANDOMIZED CONTROLLED TRIAL; SENSORY NEUROPATHY; SURVIVAL TIME; THROMBOCYTOPENIA; TREATMENT DURATION; VOMITING; CLINICAL TRIAL; DISEASE FREE SURVIVAL; FEMALE; MALE; MIDDLE AGED; MORTALITY; MULTIPLE MYELOMA; SURVIVAL RATE; VERY ELDERLY;

ADULT; AGED; AGED, 80 AND OVER; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; DEXAMETHASONE; DISEASE-FREE SURVIVAL; FEMALE; HUMANS; MALE; MIDDLE AGED; MULTIPLE MYELOMA; NITROGEN MUSTARD COMPOUNDS; SURVIVAL RATE; THALIDOMIDE;

EID: 84942097336     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/bjh.13435     Document Type: Article

References (43)

1. Attal, M., Lauwers-Cances, V., Marit, G., Caillot, D., Moreau, P., Facon, T., Stoppa, A.M., Hulin, C., Benboubker, L., Garderet, L., Decaux, O., Leyvraz, S., Vekemans, M.C., Voillat, L., Michallet, M., Pegourie, B., Dumontet, C., Roussel, M., Leleu, X., Mathiot, C., Payen, C., Avet-Loiseau, H., Harousseau, J.L. & IFM Investigators. (2012) Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. New England Journal of Medicine, 366, 1782–1791.
2. Berenson, J.R., Yellin, O., Bessudo, A., Boccia, R.V., Noga, S.J., Gravenor, D.S., Patel-Donnelly, D., Siegel, R.S., Kewalramani, T., Gorak, E.J., Nassir, Y., Swift, R.A. & Mayo, D. (2013) Phase I/II trial assessing bendamustine plus bortezomib combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. British Journal of Haematology, 160, 321–330.
3. Bryant, J. & Day, R. (1995) Incorporating toxicity considerations into the design of two-stage phase II clinical trials. Biometrics, 51, 1372–1383.
4. Damaj, G., Malard, F., Hulin, C., Caillot, D., Garidi, R., Royer, B., Marit, G., Stoppa, A.M., Banos, A., Morineau, N., Moreau, P., Fitoussi, O., Tiab, M. & Moreau, P. (2012) Efficacy of bendamustine in relapsed/refractory myeloma patients: results from the French compassionate use program. Leukaemia & Lymphoma, 53, 632–634.
5. Dimopoulos, M.A., Hamilos, G., Zomas, A., Gika, D., Efstathiou, E., Grigoraki, V., Poziopoulos, C., Xilouri, I., Zorzou, M.P., Anagnostopoulos, N. & Anagnostopoulos, A. (2004) Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regimen for previously treated patients with multiple myeloma. Hematology Journal, 5, 112–117.
6. Dimopoulos, M., Spencer, A., Attal, M., Prince, H.M., Harousseau, J., Dmoszynska, A., San Miguel, J., Hellmann, A., Facon, T., Foa, R., Corso, A., Masliak, Z., Olesnyckyj, M., Yu, Z.N., Patin, J., Zeldis, J.B. & Knight, R.D. (2007) Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. New England Journal of Medicine, 357, 2123–2132.
7. Durie, B.G., Harousseau, J.L., Miguel, J.S., 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, S.V. (2006) International uniform response criteria for multiple myeloma. Leukemia, 20, 1467–1473.
8. Eriksson, T., Hoglund, P., Turesson, I., Waage, A., Don, B.R., Vu, J., Scheffler, M. & Kaysen, G.A. (2003) Pharmacokinetics of thalidomide in patients with impaired renal function and while on and off dialysis. Journal of Pharmacy and Pharmacology, 55, 1701–1706.
9. Facon, T., Mary, J.Y., Hulin, C., Benboubker, L., Attal, M., Pegourie, B., Renaud, M., Harousseau, J.L., Guillerm, G., Chaleteix, C., Dib, M., Voillat, L., Maisonneuve, H., Troncy, J., Dorvaux, V., Monconduit, M., Martin, C., Casassus, P., Jaubert, J., Jardel, H., Doyen, C., Kolb, B., Anglaret, B., Grosbois, B., Yakoub-Agha, I., Mathiot, C., Avet-Loiseau, H. & Intergroupe Francophone du Myélome. (2007) Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet, 370, 1209–1218.
10. Garcia-Sanz, R., Gonzalez-Porras, J.R., Hernandez, J.M., Polo-Zarzuela, M., Sureda, A., Barrenetxea, C., Palomera, L., Lopez, R., Grande-Garcia, C., Alegre, A., Vargas-Pabon, M., Gutierrez, O.N., Rodriguez, J.A. & San Miguel, J.F. (2004) The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma. Leukemia, 18, 856–863.
11. Grey-Davies, E., Bosworth, J.L., Boyd, K.D., Ebdon, C., Saso, R., Chitnavis, D., Mercieca, J.E., Morgan, G.J. & Davies, F.E. (2012) Bendamustine, thalidomide and dexamethasone is an effective salvage regimen for advanced stage multiple myeloma. British Journal of Haematology, 156, 552–555; author reply 555.
12. Hulin, C., Facon, T., Rodon, P., Pegourie, B., Benboubker, L., Doyen, C., Dib, M., Guillerm, G., Salles, B., Eschard, J.P., Lenain, P., Casassus, P., Azais, I., Decaux, O., Garderet, L., Mathiot, C., Fontan, J., Lafon, I., Virion, J.M. & Moreau, P. (2009) Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. Journal of Clinical Oncology, 27, 3664–3670.
13. 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, 1287–1288.
14. Kortuem, K.M. & Stewart, A.K. (2013) Carfilzomib. Blood, 121, 893–897.
15. Kropff, M.H., Lang, N., Bisping, G., Domine, N., Innig, G., Hentrich, M., Mitterer, M., Sudhoff, T., Fenk, R., Straka, C., Heinecke, A., Koch, O.M., Ostermann, H., Berdel, W.E. & Kienast, J. (2003) Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma. British Journal of Haematology, 122, 607–616.
16. Kumar, S.K., Lee, J.H., Lahuerta, J.J., Morgan, G., Richardson, P.G., Crowley, J., Haessler, J., Feather, J., Hoering, A., Moreau, P., LeLeu, X., Hulin, C., Klein, S.K., Sonneveld, P., Siegel, D., Blade, J., Goldschmidt, H., Jagannath, S., Miguel, J.S., Orlowski, R., Palumbo, A., Sezer, O., Rajkumar, S.V., Durie, B.G. & International Myeloma Working Group. (2012) Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia, 26, 149–157.
17. Leleu, X., Attal, M., Arnulf, B., Moreau, P., Traulle, C., Marit, G., Mathiot, C., Petillon, M.O., Macro, M., Roussel, M., Pegourie, B., Kolb, B., Stoppa, A.M., Hennache, B., Brechignac, S., Meuleman, N., Thielemans, B., Garderet, L., Royer, B., Hulin, C., Benboubker, L., Decaux, O., Escoffre-Barbe, M., Michallet, M., Caillot, D., Fermand, J.P., Avet-Loiseau, H., Facon, T. & Intergroupe Francophone du Myélome. (2013) Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myelome 2009–02. Blood, 121, 1968–1975.
18. Lentzsch, S., O'Sullivan, A., Kennedy, R.C., Abbas, M., Dai, L., Pregja, S.L., Burt, S., Boyiadzis, M., Roodman, G.D., Mapara, M.Y., Agha, M., Waas, J., Shuai, Y., Normolle, D. & Zonder, J.A. (2012) Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood, 119, 4608–4613.
19. Lonial, S., Mitsiades, C.S. & Richardson, P.G. (2011) Treatment options for relapsed and refractory multiple myeloma. Clinical Cancer Research, 17, 1264–1277.
20. 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 is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood, 123, 985–991.
21. McCarthy, P.L., Owzar, K., Hofmeister, C.C., Hurd, D.D., Hassoun, H., Richardson, P.G., Giralt, S., Stadtmauer, E.A., Weisdorf, D.J., Vij, R., Moreb, J.S., Callander, N.S., Van Besien, K., Gentile, T., Isola, L., Maziarz, R.T., Gabriel, D.A., Bashey, A., Landau, H., Martin, T., Qazilbash, M.H., Levitan, D., McClune, B., Schlossman, R., Hars, V., Postiglione, J., Jiang, C., Bennett, E., Barry, S., Bressler, L., Kelly, M., Seiler, M., Rosenbaum, C., Hari, P., Pasquini, M.C., Horowitz, M.M., Shea, T.C., Devine, S.M., Anderson, K.C. & Linker, C. (2012) Lenalidomide after stem-cell transplantation for multiple myeloma. New England Journal of Medicine, 366, 1770–1781.
22. Mele, G., Spina, A., Guaragna, G., Giannotta, A., Melpignano, A. & Quarta, G. (2013) Activity and toxicity profiles of the combinations bendamustine-lenalidomide-dexamethasone and bendamustine-bortezomib-dexamethasone for advanced stage multiple myeloma. Leukaemia & Lymphoma, 55, 1191–1193.
23. Michael, M., Bruns, I., Bolke, E., Zohren, F., Czibere, A., Safaian, N.N., Neumann, F., Haas, R., Kobbe, G. & Fenk, R. (2010) Bendamustine in patients with relapsed or refractory multiple myeloma. European Journal of Medical Research, 15, 13–19.
24. Morgan, G.J., Davies, F.E., Gregory, W.M., Russell, N.H., Bell, S.E., Szubert, A.J., Navarro Coy, N., Cook, G., Feyler, S., Byrne, J.L., Roddie, H., Rudin, C., Drayson, M.T., Owen, R.G., Ross, F.M., Jackson, G.H., Child, J.A. & NCRI Haematological Oncology Study Group. (2011) Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood, 118, 1231–1238.
25. Morgan, G.J., Davies, F.E., Gregory, W.M., Bell, S.E., Szubert, A.J., Navarro Coy, N., Cook, G., Feyler, S., Johnson, P.R., Rudin, C., Drayson, M.T., Owen, R.G., Ross, F.M., Russell, N.H., Jackson, G.H., Child, J.A. & National Cancer Research Institute Haematological Oncology Clinical Studies Group. (2012) Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica, 97, 442–450.
26. Offidani, M., Corvatta, L., Maracci, L., Liberati, A.M., 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., Olivieri, 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 Journal, 3, e162.
27. Palumbo, A., Hajek, R., Delforge, M., Kropff, M., Petrucci, M.T., Catalano, J., Gisslinger, H., Wiktor-Jedrzejczak, W., Zodelava, M., Weisel, K., Cascavilla, N., Iosava, G., Cavo, M., Kloczko, J., Blade, J., Beksac, M., Spicka, I., Plesner, T., Radke, J., Langer, C., Ben Yehuda, D., Corso, A., Herbein, L., Yu, Z., Mei, J., Jacques, C., Dimopoulos, M.A. & Investigators, M.M. (2012) Continuous lenalidomide treatment for newly diagnosed multiple myeloma. New England Journal of Medicine, 366, 1759–1769.
28. Paull, K.D., Shoemaker, R.H., Hodes, L., Monks, A., Scudiero, D.A., Rubinstein, L., Plowman, J. & Boyd, M.R. (1989) Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm. Journal of the National Cancer Institute, 81, 1088–1092.
29. Ponisch, W., Mitrou, P.S., 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 & East German Study Group of Hematology and Oncology (OSHO). (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 Hematology and Oncology (OSHO). Journal of Cancer Research & Clinical Oncology, 132, 205–212.
30. Ponisch, W., Rozanski, M., Goldschmidt, H., Hoffmann, F.A., 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 Hematology and Oncology (OSHO). (2008) Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell transplantation or conventional chemotherapy: results of a Phase I clinical trial. British Journal of Haematology, 143, 191–200.
31. Ponisch, W., Bourgeois, M., Moll, B., Heyn, S., Jakel, N., Wagner, I., Rohrberg, R., Hurtz, H.J., Schmalfeld, M., Assmann, M., Edelmann, T., Mohren, M., Hoffmann, F.A., Becker, C., Schwarzer, A., Schonfelder, U., Zehrfeld, T., Hensel, G., Loschcke, K., Krahl, R., Ali, H.A. & Niederwieser, D. (2013a) Combined bendamustine, prednisone and bortezomib (BPV) in patients with relapsed or refractory multiple myeloma. Journal of Cancer Research and Clinical Oncology, 139, 499–508.
32. Ponisch, W., Heyn, S., Beck, J., Wagner, I., Mohren, M., Hoffmann, F.A., Lange, T., Schmalfeld, M., Zehrfeld, T., Schwarzer, A., Winkelmann, C., Edelmann, T., Rohrborn, R., Hebenstreit, K., Al-Ali, H.K., Jakel, N. & Niederwieser, D. (2013b) 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. British Journal of Haematology, 162, 202–209.
33. Ramasamy, K., Hazel, B., Mahmood, S., Corderoy, S. & Schey, S. (2011) Bendamustine in combination with thalidomide and dexamethasone is an effective therapy for myeloma patients with end stage renal disease. British Journal of Haematology, 155, 632–634.
34. Richardson, P.G., Hofmeister, C., Raje, N.S., Siegel, D.S.D., Lonial, S., Laubach, J., Efebera, Y.A., Vesole, D.H., Nook, A.K., Rosenblatt, J., Zaki, M.H., Hua, Y., Li, Y., Shah, S., Wang, J. & Anderson, K.C. (2014a) MM-005: phase 1 trial of pomalidomide (POM), bortezomib (BORT), and low-dose dexamethasone (LoDEX [PVD]) in lenalidomide (LEN)-refractory and proteasome inhibitor (PI)-exposed myeloma. Journal of Clinical Oncology, 32, 8589.
35. Richardson, P.G., Siegel, D.S., Vij, R., Hofmeister, C.C., Baz, R., Jagannath, S., Chen, C., Lonial, S., Jakubowiak, A., Bahlis, N., Song, K., Belch, A., Raje, N., Shustik, C., Lentzsch, S., Lacy, M., Mikhael, J., Matous, J., Vesole, D., Chen, M., Zaki, M.H., Jacques, C., Yu, Z. & Anderson, K.C. (2014b) Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood, 123, 1826–1832.
36. San Miguel, J., Weisel, K., Moreau, P., Lacy, M., Song, K., Delforge, M., Karlin, L., Goldschmidt, H., Banos, A., Oriol, A., Alegre, A., Chen, C., Cavo, M., Garderet, L., Ivanova, V., Martinez-Lopez, J., Belch, A., Palumbo, A., Schey, S., Sonneveld, P., Yu, X., Sternas, L., Jacques, C., Zaki, M. & Dimopoulos, M. (2013) Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncology, 14, 1055–1066.
37. Sargent, D.J. & Goldberg, R.M. (2001) A flexible design for multiple armed screening trials. Statistics in Medicine, 20, 1051–1060.
38. Schey, S., Yong, K., Marcus, R. & Anderson, K. (2013) Myeloma Pathology, Diagnosis and Treatment. Cambridge University Press, New York.
39. Shah, J.J., Stadtmauer, E.A., Abonour, R., Cohen, A.D., Bensinger, W.I., Gasparetto, C., Kaufman, J.L., Lentzsch, S., Vogl, D.T., Orlowski, R.Z., Kim, E.L., McKinley, M.B. & Durie, B.G.M. (2012) A multi-center phase I/II trial of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts), 120, 74.
40. Siegel, D. (2013) From clinical trials to clinical practice: single-agent carfilzomib adverse events and their management in patients with relapsed and/or refractory multiple myeloma. Therapeutic Advances in Hematology, 4, 354–365.
41. Stewart, A.K., Rajkumar, S.V., Dimopoulos, M.A., Masszi, T., Spicka, I., Oriol, A., Hajek, R., Rosinol, L., Siegel, D.S., Mihaylov, G.G., Goranova-Marinova, V., Rajnics, P., Suvorov, A., Niesvizky, R., Jakubowiak, A.J., San-Miguel, J.F., Ludwig, H., Wang, M., Maisnar, V., Minarik, J., Bensinger, W.I., Mateos, M.V., Ben-Yehuda, D., Kukreti, V., Zojwalla, N., Tonda, M.E., Yang, X., Xing, B., Moreau, P., Palumbo, A. & ASPIRE Investigators. (2015) Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. New England Journal of Medicine, 372, 142–152.
42. Strumberg, D., Harstrick, A., Doll, K., Hoffmann, B. & Seeber, S. (1996) Bendamustine hydrochloride activity against doxorubicin-resistant human breast carcinoma cell lines. Anti-Cancer Drugs, 7, 415–421.
43. Weber, D.M., Chen, C., Niesvizky, R., Wang, M., Belch, A., Stadtmauer, E.A., Siegel, D., Borrello, I., Rajkumar, S.V., Chanan-Khan, A.A., Lonial, S., Yu, Z., Patin, J., Olesnyckyj, M., Zeldis, J.B. & Knight, R.D. (2007) Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. New England Journal of Medicine, 357, 2133–2142.