Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial

C B Reeder, D E Reece, V Kukreti, C Chen, S Trudel, J Hentz, B Noble, N A Pirooz, J E Spong, J G Piza, V H J Zepeda, J R Mikhael, J F Leis, P L Bergsagel, R Fonseca, A K Stewart, C B Reeder, D E Reece, V Kukreti, C Chen, S Trudel, J Hentz, B Noble, N A Pirooz, J E Spong, J G Piza, V H J Zepeda, J R Mikhael, J F Leis, P L Bergsagel, R Fonseca, A K Stewart

Abstract

We have studied a three-drug combination with cyclophosphamide, bortezomib and dexamethasone (CyBorD) on a 28-day cycle in the treatment of newly diagnosed multiple myeloma (MM) patients to assess response and toxicity. The primary endpoint of response was evaluated after four cycles. Thirty-three newly diagnosed, symptomatic patients with MM received bortezomib 1.3 mg/m(2) intravenously on days 1, 4, 8 and 11, cyclophosphamide 300 mg/m(2) orally on days 1, 8, 15 and 22 and dexamethasone 40 mg orally on days 1-4, 9-12 and 17-20 on a 28-day cycle for four cycles. Responses were rapid with a mean 80% decline in the sentinel monoclonal protein at the end of two cycles. The overall intent to treat response rate (>or= partial response) was 88%, with 61% of very good partial response or better (>or=VGPR) and 39% of complete/near complete response (CR/nCR). For the 28 patients who completed all four cycles of therapy, the CR/nCR rate was 46% and VGPR rate was 71%. All patients undergoing stem cell harvest had a successful collection. Twenty-three patients underwent stem cell transplantation (SCT) and are evaluable through day 100 with CR/nCR documented in 70% and >or=VGPR in 74%. In conclusion, CyBorD produces a rapid and profound response in patients with newly diagnosed MM with manageable toxicity.

Figures

Figure 1
Figure 1
Response per cycle as measured by the mean percentage monoclonal protein reduction from baseline per cycle (standard error margins shown in dotted lines). For this analysis the dominant monoclonal protein for each patient was evaluated. Abbreviations: SEM, standard error margin
Figure 2
Figure 2
Response rates by ITT (column 1), for those completing 4 cycles (column 2) and for those completing SCT (column 3) Abbreviations: SD/PD, stable/progressive disease; PR, partial response; VGPR, very good partial response; CR/nCR, complete/near complete response; SCT, stem cell transplant

References

    1. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy M, Hayman S, Buadi F, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516–2520.
    1. Barlogie B, Tricot GJ, van Rhee F, Angtuaco E, Walker R, Epstein J, et al. Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol. 2006;135:158–164.
    1. Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood. 2008;111:2521–2526.
    1. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer E, Facon T, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487–2498.
    1. Weber D. Thalidomide and its derivatives: new promise for multiple myeloma. Cancer Control. 2003;10:375–383.
    1. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341:1565–1571.
    1. Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer S, Kabat B, et al. Combination therapy with lenalidomide plus dexamethasone (REV/DEX) for newly diagnosed myeloma. Blood. 2005;106:4050–4053.
    1. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. 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. 2006;24:431–436.
    1. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos M, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906–917.
    1. Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomized controlled trial. Lancet. 2006;367:825–831.
    1. Wang M, Weber DM, Delasalle K, Alexanian R. Thalidomide-dexamethasone as primary therapy for advanced multiple myeloma. Am J Hematol. 2005;79:194–197.
    1. Barlogie B, Pineda Roman M, van Rhee F, Haessler J, Anaissie E, Hollmig K, et al. Thalidomide arm of total therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood. 2008;112:3115–3121.
    1. Lacy MQ, Gertz MA, Dispenzieri A, Hayman S, Geyer S, Kabat B, et al. Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc. 2007;82:1179–1184.
    1. Jagannath S, Durie BG, Wolf J, Camacho E, Irwin D, Lutzky J, et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol. 2005;129:776–783.
    1. Richardson PG, Hideshima T, Anderson KC. Bortezomib (PS-341): a novel, first-in-class proteasome inhibitor for the treatment of multiple myeloma and other cancers. Cancer Control. 2003;10:361–369.
    1. Wang M, Giralt S, Delasalle K, Handy B, Alexanian R. Bortezomib in combination with thalidomide-dexamethasone for previously untreated multiple myeloma. Hematology. 2007;12:235–239.
    1. Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol. 2007;138:176–185.
    1. Trieu Y, Trudel S, Pond GR, Mikhael J, Jaksic W, Reece D, et al. Weekly cyclophosphamide and alternate-day prednisone: an effective, convenient, and well-tolerated oral treatment for relapsed multiple myeloma after autologous stem cell transplantation. Mayo Clin Proc. 2005;80:1578–1582.
    1. Reece DE, Piza Rodriguez G, Chen C, Trudel S, Kukreti V, Mikhael J, et al. Phase I-II Trial of Bortezomib Plus Oral Cyclophosphamide and Prednisone in Relapsed and Refractory Multiple Myeloma. J Clin Oncol. 2008;26:4777–4783.
    1. Blade J, Sampson D, Reece D, Apperley J, BJOrkstrand B, Gahrton G, et al. Criteria For Evaluating Disease Response and Progression in Patients with Multiple Myeloma Treated by High-Dose Therapy and Haematopoietic Stem Cell Transplantation. Br J Haematol. 1998;102:1115–23.
    1. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467–1473.
    1. Rajkumar SV, Durie BG. Eliminating the complete response penalty from myeloma response criteria. Blood. 2008;111:5759–5760.
    1. Greipp PR, San Miguel J, Durie BG, Crowley J, Barlogie B, Blade J, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412–3420.
    1. Prince HM, Imrie K, Sutherland DR, Keating A, Meharchand J, Crump RM, et al. Peripheral blood progenitor cell collections in multiple myeloma: predictors and management of inadequate collections. Br J Haematol. 1996;93:142–145.
    1. Gertz MA, Lacy MQ, Inwards DJ, Pineda A, Chen M, Gastineau D, et al. Factors influencing platelet recovery after blood cell transplantation in multiple myeloma. Bone Marrow Transplant. 1997;20:375–380.
    1. Kumar S, Dispenzieri A, Lacy MQ, Hayman S, Buadi F, Gastineau D, et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia. 2007;21:2035–2042.
    1. Paripati H, Stewart AK, Cabou S, Dueck A, Zepeda V, Pirooz N, et al. Compromised stem cell mobilization following induction therapy with lenalidomide in myeloma. Leukemia. 2008;22:1282–1284.
    1. Attal M, Harousseau JL. Standard therapy versus autologous transplantation in multiple myeloma. Hematol Oncol Clin North Am. 1997;11:133–146.
    1. Child JA, Morgan GJ, Davies FE, Owen R, Bell S, Hawkins K, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875–1883.
    1. Attal M, Harousseau JL, Facon T, Guilhot F, Doyen F, Fuzibet J-G, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349:2495–2502.
    1. Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289–3294.
    1. Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007;25:2434–2441.
    1. Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V, et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized, controlled trial. Blood. 2008;112:3107–3114.

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