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.
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Jakob, C., Egerer, K., Liebisch, P., Turkmen, S., Zavrski, I., Kuckelkorn, U., Heider, U., Kaiser, M., Fleissner, C., Sterz, J., Kleeberg, L., Feist, E., Burmester, G.-R., Kloetzel, P.-M., Sezer, O.
(2007). Circulating proteasome levels are an independent prognostic factor for survival in multiple myeloma. Blood
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Dreicer, R., Petrylak, D., Agus, D., Webb, I., Roth, B.
(2007). Phase I/II Study of Bortezomib Plus Docetaxel in Patients with Advanced Androgen-Independent Prostate Cancer. Clin. Cancer Res.
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Sekimoto, E., Ozaki, S., Ohshima, T., Shibata, H., Hashimoto, T., Abe, M., Kimura, N., Hattori, K., Kawai, S., Kinoshita, Y., Yamada-Okabe, H., Tsuchiya, M., Matsumoto, T.
(2007). A Single-Chain Fv Diabody against Human Leukocyte Antigen-A Molecules Specifically Induces Myeloma Cell Death in the Bone Marrow Environment. Cancer Res.
67: 1184-1192
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Lorch, J. H., Thomas, T. O., Schmoll, H.-J.
(2007). Bortezomib Inhibits Cell-Cell Adhesion and Cell Migration and Enhances Epidermal Growth Factor Receptor Inhibitor-Induced Cell Death in Squamous Cell Cancer. Cancer Res.
67: 727-734
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Chatterjee, M., Jain, S., Stuhmer, T., Andrulis, M., Ungethum, U., Kuban, R.-J., Lorentz, H., Bommert, K., Topp, M., Kramer, D., Muller-Hermelink, H. K., Einsele, H., Greiner, A., Bargou, R. C.
(2007). STAT3 and MAPK signaling maintain overexpression of heat shock proteins 90{alpha} and {beta} in multiple myeloma cells, which critically contribute to tumor-cell survival. Blood
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Duan, J., Friedman, J., Nottingham, L., Chen, Z., Ara, G., Van Waes, C.
(2007). Nuclear factor-{kappa}B p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101. Molecular Cancer Therapeutics
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Belch, A, Kouroukis, C., Crump, M, Sehn, L, Gascoyne, R., Klasa, R, Powers, J, Wright, J, Eisenhauer, E.
(2007). A phase II study of bortezomib in mantle cell lymphoma: the National Cancer Institute of Canada Clinical Trials Group trial IND.150. Ann Oncol
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Fonseca, R.
(2007). Strategies for Risk-Adapted Therapy in Myeloma. ASH Education Book
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Richardson, P., Mitsiades, C., Schlossman, R., Ghobrial, I., Hideshima, T., Chauhan, D., Munshi, N., Anderson, K.
(2007). The Treatment of Relapsed and Refractory Multiple Myeloma. ASH Education Book
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Baz, R, Walker, E, Karam, M., Choueiri, T., Jawde, R., Bruening, K, Reed, J, Faiman, B, Ellis, Y, Brand, C, Srkalovic, G, Andresen, S, Knight, R, Zeldis, J, Hussein, M.
(2006). Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann Oncol
17: 1766-1771
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Chanan-Khan, A. A., Sonneveld, P., Schuster, M. W., Irwin, D., Stadtmauer, E. A., Facon, T., Harousseau, J.-L., Ben-Yehuda, D., Lonial, S., Goldschmidt, H., Reece, D. E., Neuwirth, R. B., Anderson, K. C., Richardson, P. G.
(2006). Analysis of Varicella Zoster Virus Reactivation among Bortezomib-Treated Patients in the APEX Study.. ASH ANNUAL MEETING ABSTRACTS
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Lonial, S.
(2006). When "the same" is really "different". Blood
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Richardson, P. G., Blood, E., Mitsiades, C. S., Jagannath, S., Zeldenrust, S. R., Alsina, M., Schlossman, R. L., Rajkumar, S. V., Desikan, K. R., Hideshima, T., Munshi, N. C., Kelly-Colson, K., Doss, D., McKenney, M. L., Gorelik, S., Warren, D., Freeman, A., Rich, R., Wu, A., Olesnyckyj, M., Wride, K., Dalton, W. S., Zeldis, J., Knight, R., Weller, E., Anderson, K. C.
(2006). A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood
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Reinstein, E., Ciechanover, A.
(2006). Narrative review: protein degradation and human diseases: the ubiquitin connection.. ANN INTERN MED
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Fanucchi, M. P., Fossella, F. V., Belt, R., Natale, R., Fidias, P., Carbone, D. P., Govindan, R., Raez, L. E., Robert, F., Ribeiro, M., Akerley, W., Kelly, K., Limentani, S. A., Crawford, J., Reimers, H.-J., Axelrod, R., Kashala, O., Sheng, S., Schiller, J. H.
(2006). Randomized Phase II Study of Bortezomib Alone and Bortezomib in Combination With Docetaxel in Previously Treated Advanced Non-Small-Cell Lung Cancer. JCO
24: 5025-5033
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Ottenheijm, C. A. C., Heunks, L. M. A., Li, Y.-P., Jin, B., Minnaard, R., van Hees, H. W. H., Dekhuijzen, P. N. R.
(2006). Activation of the Ubiquitin-Proteasome Pathway in the Diaphragm in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med.
174: 997-1002
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Sanchorawala, V.
(2006). Light-Chain (AL) Amyloidosis: Diagnosis and Treatment. CJASN
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Fisher, R. I., Bernstein, S. H., Kahl, B. S., Djulbegovic, B., Robertson, M. J., de Vos, S., Epner, E., Krishnan, A., Leonard, J. P., Lonial, S., Stadtmauer, E. A., O'Connor, O. A., Shi, H., Boral, A. L., Goy, A.
(2006). Multicenter Phase II Study of Bortezomib in Patients With Relapsed or Refractory Mantle Cell Lymphoma. JCO
24: 4867-4874
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Mateos, M.-V., Hernandez, J.-M., Hernandez, M.-T., Gutierrez, N.-C., Palomera, L., Fuertes, M., Diaz-Mediavilla, J., Lahuerta, J.-J., de la Rubia, J., Terol, M.-J., Sureda, A., Bargay, J., Ribas, P., de Arriba, F., Alegre, A., Oriol, A., Carrera, D., Garcia-Larana, J., Garcia-Sanz, R., Blade, J., Prosper, F., Mateo, G., Esseltine, D.-L., van de Velde, H., Miguel, J.-F. S.
(2006). Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood
108: 2165-2172
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Mileshkin, L., Stark, R., Day, B., Seymour, J. F., Zeldis, J. B., Prince, H. M.
(2006). Development of Neuropathy in Patients With Myeloma Treated With Thalidomide: Patterns of Occurrence and the Role of Electrophysiologic Monitoring. JCO
24: 4507-4514
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Li, M., Cortez, S., Nakamachi, T., Batuman, V., Arimura, A.
(2006). Pituitary Adenylate Cyclase-Activating Polypeptide Is a Potent Inhibitor of the Growth of Light Chain-Secreting Human Multiple Myeloma Cells.. Cancer Res.
66: 8796-8803
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Versari, D., Herrmann, J., Gossl, M., Mannheim, D., Sattler, K., Meyer, F. B., Lerman, L. O., Lerman, A.
(2006). Dysregulation of the Ubiquitin-Proteasome System in Human Carotid Atherosclerosis. Arterioscler. Thromb. Vasc. Bio.
26: 2132-2139
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Richardson, P. G., Briemberg, H., Jagannath, S., Wen, P. Y., Barlogie, B., Berenson, J., Singhal, S., Siegel, D. S., Irwin, D., Schuster, M., Srkalovic, G., Alexanian, R., Rajkumar, S. V., Limentani, S., Alsina, M., Orlowski, R. Z., Najarian, K., Esseltine, D., Anderson, K. C., Amato, A. A.
(2006). Frequency, Characteristics, and Reversibility of Peripheral Neuropathy During Treatment of Advanced Multiple Myeloma With Bortezomib. JCO
24: 3113-3120
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Huck, B., Egger, M., Bertz, H., Peyerl-Hoffman, G., Kern, W. V., Neumann-Haefelin, D., Falcone, V.
(2006). Human metapneumovirus infection in a hematopoietic stem cell transplant recipient with relapsed multiple myeloma and rapidly progressing lung cancer.. J. Clin. Microbiol.
44: 2300-2303
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Hideshima, T., Catley, L., Yasui, H., Ishitsuka, K., Raje, N., Mitsiades, C., Podar, K., Munshi, N. C., Chauhan, D., Richardson, P. G., Anderson, K. C.
(2006). Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood
107: 4053-4062
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Yang, C. H., Gonzalez-Angulo, A. M., Reuben, J. M., Booser, D. J., Pusztai, L., Krishnamurthy, S., Esseltine, D., Stec, J., Broglio, K. R., Islam, R., Hortobagyi, G. N., Cristofanilli, M.
(2006). Bortezomib (VELCADE(R)) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits. Ann Oncol
17: 813-817
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Olivier, S., Close, P., Castermans, E., de Leval, L., Tabruyn, S., Chariot, A., Malaise, M., Merville, M.-P., Bours, V., Franchimont, N.
(2006). Raloxifene-Induced Myeloma Cell Apoptosis: A Study of Nuclear Factor-{kappa}B Inhibition and Gene Expression Signature. Mol. Pharmacol.
69: 1615-1623
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Miyakoshi, S., Kami, M., Yuji, K., Matsumura, T., Takatoku, M., Sasaki, M., Narimatsu, H., Fujii, T., Kawabata, M., Taniguchi, S., Ozawa, K., Oshimi, K.
(2006). Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myeloma. Blood
107: 3492-3494
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Kober, T., Hulsewede, H., Bohlius, J., Engert, A.
(2006). Fourth biannual report of the Cochrane Haematological Malignancies Group.. JNCI J Natl Cancer Inst
98: E1-E1
[Full Text]
van de Donk, N. W. C. J., Kroger, N., Hegenbart, U., Corradini, P., Miguel, J. F. S., Goldschmidt, H., Perez-Simon, J. A., Zijlmans, M., Raymakers, R. A., Montefusco, V., Ayuk, F. A., van Oers, M. H. J., Nagler, A., Verdonck, L. F., Lokhorst, H. M.
(2006). Remarkable activity of novel agents bortezomib and thalidomide in patients not responding to donor lymphocyte infusions following nonmyeloablative allogeneic stem cell transplantation in multiple myeloma. Blood
107: 3415-3416
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Kisselev, A. F., Callard, A., Goldberg, A. L.
(2006). Importance of the Different Proteolytic Sites of the Proteasome and the Efficacy of Inhibitors Varies with the Protein Substrate. J. Biol. Chem.
281: 8582-8590
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Cavo, M., Baccarani, M.
(2006). The Changing Landscape of Myeloma Therapy. NEJM
354: 1076-1078
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Berenson, J. R., Yang, H. H., Sadler, K., Jarutirasarn, S. G., Vescio, R. A., Mapes, R., Purner, M., Lee, S.-p., 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. JCO
24: 937-944
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Dubois, D., Dhawan, R., van de Velde, H., Esseltine, D., Gupta, S., Viala, M., de la Loge, C.
(2006). Descriptive and Prognostic Value of Patient-Reported Outcomes: The Bortezomib Experience in Relapsed and Refractory Multiple Myeloma. JCO
24: 976-982
[Abstract][Full Text]
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