Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma
Paul G. Richardson, M.D., Pieter Sonneveld, M.D., Michael W. Schuster, M.D., David Irwin, M.D., Edward A. Stadtmauer, M.D., Thierry Facon, M.D., Jean-Luc Harousseau, M.D., Dina Ben-Yehuda, M.D., Sagar Lonial, M.D., Hartmut Goldschmidt, M.D., Donna Reece, M.D., Jesus F. San-Miguel, M.D., Joan Bladé, M.D., Mario Boccadoro, M.D., Jamie Cavenagh, M.D., William S. Dalton, M.D., Anthony L. Boral, M.D., Ph.D., Dixie L. Esseltine, M.D., Jane B. Porter, M.S., David Schenkein, M.D., Kenneth C. Anderson, M.D., for the Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators
Background This study compared bortezomib with high-dose dexamethasonein patients with relapsed multiple myeloma who had receivedone to three previous therapies.
Methods We randomly assigned 669 patients with relapsed myelomato receive either an intravenous bolus of bortezomib (1.3 mgper square meter of body-surface area) on days 1, 4, 8, and11 for eight three-week cycles, followed by treatment on days1, 8, 15, and 22 for three five-week cycles, or high-dose dexamethasone(40 mg orally) on days 1 through 4, 9 through 12, and 17 through20 for four five-week cycles, followed by treatment on days1 through 4 for five four-week cycles. Patients who were assignedto receive dexamethasone were permitted to cross over to receivebortezomib in a companion study after disease progression.
Results Patients treated with bortezomib had higher responserates, a longer time to progression (the primary end point),and a longer survival than patients treated with dexamethasone.The combined complete and partial response rates were 38 percentfor bortezomib and 18 percent for dexamethasone (P<0.001),and the complete response rates were 6 percent and less than1 percent, respectively (P<0.001). Median times to progressionin the bortezomib and dexamethasone groups were 6.22 months(189 days) and 3.49 months (106 days), respectively (hazardratio, 0.55; P<0.001). The one-year survival rate was 80percent among patients taking bortezomib and 66 percent amongpatients taking dexamethasone (P=0.003), and the hazard ratiofor overall survival with bortezomib was 0.57 (P=0.001). Grade3 or 4 adverse events were reported in 75 percent of patientstreated with bortezomib and in 60 percent of those treated withdexamethasone.
Conclusions Bortezomib is superior to high-dose dexamethasonefor the treatment of patients with multiple myeloma who havehad a relapse after one to three previous therapies.
Source Information
From the Dana–Farber Cancer Institute, Boston (P.G.R., K.C.A.); University Hospital Rotterdam, Rotterdam, the Netherlands (P.S.); New York–Presbyterian Hospital, New York (M.W.S.); Alta Bates Cancer Center, Berkeley, Calif. (D.I.); University of Pennsylvania Cancer Center, Philadelphia (E.A.S.); Hospital Claude Huriez, Lille, France (T.F.); Hotel Dieu Hospital, Nantes, France (J.-L.H.); Hadassah University Hospital, Jerusalem (D.B.-Y.); Emory University, Atlanta (S.L.); Universitaetsklinikum Heidelberg, Heidelberg, Germany (H.G.); Princess Margaret Hospital, Toronto (D.R.); Hospital Universitario de Salamanca, Salamanca, Spain (J.F.S.-M.); Institut d'Investigacions Biomèdiques Agusti Pi i Sunyer, Barcelona (J.B.); Università di Torino, Torino, Italy (M.B.); St. Bartholomew's Hospital, London (J.C.); H. Lee Moffitt Cancer Center, Tampa, Fla. (W.S.D.); and Millennium Pharmaceuticals, Cambridge, Mass. (A.L.B., D.L.E., J.B.P., D.S.).
Address reprint requests to Dr. Richardson at the Dana–Farber Cancer Institute, 44 Binney St., Boston, MA 02115, or at paul_richardson{at}dfci.harvard.edu.
Bortezomib in Multiple Myeloma
Cecchi M., Caccese E., Messori A., Vandenbroucke J. P., Kroep J. R., Richardson P. G., Boral A. L., Anderson K. C.
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N Engl J Med 2005;
353:1297-1298, Sep 22, 2005.
Correspondence
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Brenner, H., Gondos, A., Pulte, D.
(2008). Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood
111: 2521-2526
[Abstract][Full Text]
Kumar, S. K., Rajkumar, S. V., Dispenzieri, A., Lacy, M. Q., Hayman, S. R., Buadi, F. K., Zeldenrust, S. R., Dingli, D., Russell, S. J., Lust, J. A., Greipp, P. R., Kyle, R. A., Gertz, M. A.
(2008). Improved survival in multiple myeloma and the impact of novel therapies. Blood
111: 2516-2520
[Abstract][Full Text]
Piva, R., Ruggeri, B., Williams, M., Costa, G., Tamagno, I., Ferrero, D., Giai, V., Coscia, M., Peola, S., Massaia, M., Pezzoni, G., Allievi, C., Pescalli, N., Cassin, M., di Giovine, S., Nicoli, P., de Feudis, P., Strepponi, I., Roato, I., Ferracini, R., Bussolati, B., Camussi, G., Jones-Bolin, S., Hunter, K., Zhao, H., Neri, A., Palumbo, A., Berkers, C., Ovaa, H., Bernareggi, A., Inghirami, G.
(2008). CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood
111: 2765-2775
[Abstract][Full Text]
Wechalekar, A. D., Lachmann, H. J., Offer, M., Hawkins, P. N., Gillmore, J. D.
(2008). Efficacy of bortezomib in systemic AL amyloidosis with relapsed/refractory clonal disease. haematol
93: 295-298
[Abstract][Full Text]
Shi, J., Tricot, G. J., Garg, T. K., Malaviarachchi, P. A., Szmania, S. M., Kellum, R. E., Storrie, B., Mulder, A., Shaughnessy, J. D. Jr, Barlogie, B., van Rhee, F.
(2008). Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma. Blood
111: 1309-1317
[Abstract][Full Text]
Schmitt, M., Schmitt, A., Rojewski, M. T., Chen, J., Giannopoulos, K., Fei, F., Yu, Y., Gotz, M., Heyduk, M., Ritter, G., Speiser, D. E., Gnjatic, S., Guillaume, P., Ringhoffer, M., Schlenk, R. F., Liebisch, P., Bunjes, D., Shiku, H., Dohner, H., Greiner, J.
(2008). RHAMM-R3 peptide vaccination in patients with acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma elicits immunologic and clinical responses. Blood
111: 1357-1365
[Abstract][Full Text]
Chng, W. J., Braggio, E., Mulligan, G., Bryant, B., Remstein, E., Valdez, R., Dogan, A., Fonseca, R.
(2008). The centrosome index is a powerful prognostic marker in myeloma and identifies a cohort of patients that might benefit from aurora kinase inhibition. Blood
111: 1603-1609
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Chauhan, D., Singh, A., Brahmandam, M., Podar, K., Hideshima, T., Richardson, P., Munshi, N., Palladino, M. A., Anderson, K. C.
(2008). Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood
111: 1654-1664
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Bensinger, W.
(2008). Stem-Cell Transplantation for Multiple Myeloma in the Era of Novel Drugs. JCO
26: 480-492
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Zhan, F., Barlogie, B., Mulligan, G., Shaughnessy, J. D. Jr, Bryant, B.
(2008). High-risk myeloma: a gene expression based risk-stratification model for newly diagnosed multiple myeloma treated with high-dose therapy is predictive of outcome in relapsed disease treated with single-agent bortezomib or high-dose dexamethasone. Blood
111: 968-969
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Colado, E., Alvarez-Fernandez, S., Maiso, P., Martin-Sanchez, J., Vidriales, M. B., Garayoa, M., Ocio, E. M., Montero, J. C., Pandiella, A., San Miguel, J. F.
(2008). The effect of the proteasome inhibitor bortezomib on acute myeloid leukemia cells and drug resistance associated with the CD34+ immature phenotype. haematol
93: 57-66
[Abstract][Full Text]
Min, C.-K., Lee, M.-J., Eom, K.-S., Lee, S., Lee, J.-W., Min, W.-S., Kim, C.-C., Kim, M., Lim, J., Kim, Y., Han, K.
(2007). Bortezomib in Combination with Conventional Chemotherapeutic Agents for Multiple Myeloma Compared with Bortezomib Alone. Jpn J Clin Oncol
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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., the Multiple Myeloma (009) Study Investigators,
(2007). Lenalidomide plus Dexamethasone for Relapsed Multiple Myeloma in North America. NEJM
357: 2133-2142
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Richardson, P. G., Sonneveld, P., Schuster, M., Irwin, D., Stadtmauer, E., Facon, T., Harousseau, J.-L., Ben-Yehuda, D., Lonial, S., Goldschmidt, H., Reece, D., Miguel, J. S., Blade, J., Boccadoro, M., Cavenagh, J., Alsina, M., Rajkumar, S. V., Lacy, M., Jakubowiak, A., Dalton, W., Boral, A., Esseltine, D.-L., Schenkein, D., Anderson, K. C.
(2007). Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood
110: 3557-3560
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Voorhees, P. M., Chen, Q., Kuhn, D. J., Small, G. W., Hunsucker, S. A., Strader, J. S., Corringham, R. E., Zaki, M. H., Nemeth, J. A., Orlowski, R. Z.
(2007). Inhibition of Interleukin-6 Signaling with CNTO 328 Enhances the Activity of Bortezomib in Preclinical Models of Multiple Myeloma. Clin. Cancer Res.
13: 6469-6478
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Kuhn, D. J., Chen, Q., Voorhees, P. M., Strader, J. S., Shenk, K. D., Sun, C. M., Demo, S. D., Bennett, M. K., van Leeuwen, F. W. B., Chanan-Khan, A. A., Orlowski, R. Z.
(2007). Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood
110: 3281-3290
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Garber, A. M., McClellan, M. B.
(2007). Satisfaction Guaranteed -- "Payment by Results" for Biologic Agents. NEJM
357: 1575-1577
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Rajkumar, S. V., Richardson, P. G., Lacy, M. Q., Dispenzieri, A., Greipp, P. R., Witzig, T. E., Schlossman, R., Sidor, C. F., Anderson, K. C., Gertz, M. A.
(2007). Novel Therapy with 2-Methoxyestradiol for the Treatment of Relapsed and Plateau Phase Multiple Myeloma. Clin. Cancer Res.
13: 6162-6167
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Paiva, C. M., Kurtis, B., Mekki, M., Newman, M. A., Singhal, S., Lacouture, M. E.
(2007). Neutrophilic dermatitis associated with bortezomib in a patient with multiple myeloma. Ann Oncol
18: 1744-1745
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Rosinol, L., Oriol, A., Mateos, M. V., Sureda, A., Garcia-Sanchez, P., Gutierrez, N., Alegre, A., Lahuerta, J. J., de la Rubia, J., Herrero, C., Liu, X., Van de Velde, H., San Miguel, J., Blade, J.
(2007). Phase II Pethema Trial of Alternating Bortezomib and Dexamethasone As Induction Regimen Before Autologous Stem-Cell Transplantation in Younger Patients With Multiple Myeloma: Efficacy and Clinical Implications of Tumor Response Kinetics. JCO
25: 4452-4458
[Abstract][Full Text]
Palumbo, A., Falco, P., Corradini, P., Falcone, A., Di Raimondo, F., Giuliani, N., Crippa, C., Ciccone, G., Omede, P., Ambrosini, M. T., Gay, F., Bringhen, S., Musto, P., Foa, R., Knight, R., Zeldis, J. B., Boccadoro, M., Petrucci, M. T.
(2007). Melphalan, Prednisone, and Lenalidomide Treatment for Newly Diagnosed Myeloma: A Report From the GIMEMA Italian Multiple Myeloma Network. JCO
25: 4459-4465
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Kastritis, E., Anagnostopoulos, A., Roussou, M., Toumanidis, S., Pamboukas, C., Migkou, M., Tassidou, A., Xilouri, I., Delibasi, S., Psimenou, E., Mellou, S., Terpos, E., Nanas, J., Dimopoulos, M. A.
(2007). Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone. haematol
92: 1351-1358
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Ludwig, H., Drach, J., Graf, H., Lang, A., Meran, J. G.
(2007). Reversal of acute renal failure by bortezomib-based chemotherapy in patients with multiple myeloma. haematol
92: 1411-1414
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Katzel, J. A., Hari, P., Vesole, D. H.
(2007). Multiple Myeloma: Charging Toward a Bright Future. CA Cancer J Clin
57: 301-318
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Orlowski, R. Z., Nagler, A., Sonneveld, P., Blade, J., Hajek, R., Spencer, A., San Miguel, J., Robak, T., Dmoszynska, A., Horvath, N., Spicka, I., Sutherland, H. J., Suvorov, A. N., Zhuang, S. H., Parekh, T., Xiu, L., Yuan, Z., Rackoff, W., Harousseau, J.-L.
(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. JCO
25: 3892-3901
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Zhang, S., Suvannasankha, A., Crean, C. D., White, V. L., Johnson, A., Chen, C.-S., Farag, S. S.
(2007). OSU-03012, a Novel Celecoxib Derivative, Is Cytotoxic to Myeloma Cells and Acts through Multiple Mechanisms. Clin. Cancer Res.
13: 4750-4758
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Terpos, E., Sezer, O., Croucher, P., Dimopoulos, M.-A.
(2007). Myeloma bone disease and proteasome inhibition therapies. Blood
110: 1098-1104
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Sirohi, B, Powles, R, Lawrence, D, Treleaven, J, Kulkarni, S, Leary, A, Rudin, C, Horton, C, Morgan, G
(2007). An open, randomized, controlled, phase II, single centre, two-period cross-over study to compare the quality of life and toxicity experienced on PEG interferon with interferon-{alpha}2b in patients with multiple myeloma maintained on a steady dose of interferon-{alpha}2b. Ann Oncol
18: 1388-1394
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Davies, F. E., Wu, P., Jenner, M., Srikanth, M., Saso, R., Morgan, G. J.
(2007). The combination of cyclophosphamide, velcade and dexamethasone (CVD) induces high response rates with comparable toxicity to velcade alone (V) and velcade plus dexamethasone (VD). haematol
92: 1149-1150
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Manochakian, R., Miller, K. C., Chanan-Khan, A. A.
(2007). Clinical Impact of Bortezomib in Frontline Regimens for Patients with Multiple Myeloma. The Oncologist
12: 978-990
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Demo, S. D., Kirk, C. J., Aujay, M. A., Buchholz, T. J., Dajee, M., Ho, M. N., Jiang, J., Laidig, G. J., Lewis, E. R., Parlati, F., Shenk, K. D., Smyth, M. S., Sun, C. M., Vallone, M. K., Woo, T. M., Molineaux, C. J., Bennett, M. K.
(2007). Antitumor Activity of PR-171, a Novel Irreversible Inhibitor of the Proteasome. Cancer Res.
67: 6383-6391
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