A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma
Paul G. Richardson, M.D., Bart Barlogie, M.D., Ph.D., James Berenson, M.D., Seema Singhal, M.D., Sundar Jagannath, M.D., David Irwin, M.D., S. Vincent Rajkumar, M.D., Gordan Srkalovic, M.D., Melissa Alsina, M.D., Raymond Alexanian, M.D., David Siegel, M.D., Robert Z. Orlowski, M.D., David Kuter, M.D., Ph.D., Steven A. Limentani, M.D., Stephanie Lee, M.D., Teru Hideshima, M.D., Ph.D., Dixie-Lee Esseltine, M.D., Michael Kauffman, M.D., Ph.D., Julian Adams, Ph.D., David P. Schenkein, M.D., and Kenneth C. Anderson, M.D.
Background Bortezomib, a boronic acid dipeptide, is a novelproteasome inhibitor that has been shown in preclinical andphase 1 studies to have antimyeloma activity.
Methods In this multicenter, open-label, nonrandomized, phase2 trial, we enrolled 202 patients with relapsed myeloma thatwas refractory to the therapy they had received most recently.Patients received 1.3 mg of bortezomib per square meter of body-surfacearea twice weekly for 2 weeks, followed by 1 week without treatment,for up to eight cycles (24 weeks). In patients with a suboptimalresponse, oral dexamethasone (20 mg daily, on the day of andthe day after bortezomib administration) was added to the regimen.The response was evaluated according to the criteria of theEuropean Group for Blood and Marrow Transplantation and confirmedby an independent review committee.
Results Of 193 patients who could be evaluated, 92 percent hadbeen treated with three or more of the major classes of agentsfor myeloma, and in 91 percent, the myeloma was refractory tothe therapy received most recently. The rate of response tobortezomib was 35 percent, and those with a response included7 patients in whom myeloma protein became undetectable and 12in whom myeloma protein was detectable only by immunofixation.The median overall survival was 16 months, with a median durationof response of 12 months. Grade 3 adverse events included thrombocytopenia(in 28 percent of patients), fatigue (in 12 percent), peripheralneuropathy (in 12 percent), and neutropenia (in 11 percent).Grade 4 events occurred in 14 percent of patients.
Conclusions Bortezomib, a member of a new class of anticancerdrugs, is active in patients with relapsed multiple myelomathat is refractory to conventional chemotherapy.
Source Information
From the Dana–Farber Cancer Institute, Boston (P.G.R., S.L., T.H., K.C.A.); University of Arkansas, Little Rock (B.B.); Cedars–Sinai Medical Center, Los Angeles (J.B.); Northwestern University Medical Center, Chicago (S.S.); St. Vincent's Catholic Medical Center, New York (S.J.); Alta Bates Cancer Center, Berkeley, Calif. (D.I.); Mayo Clinic, Rochester, Minn. (S.V.R.); Cleveland Clinic Foundation, Cleveland (G.S.); H. Lee Moffitt Cancer Center, Tampa, Fla. (M.A.); M.D. Anderson Cancer Center, Houston (R.A.); Carol G. Simon Cancer Center, Morristown, N.J. (D.S.); University of North Carolina, Chapel Hill (R.Z.O.); Massachusetts General Hospital, Boston (D.K.); Charlotte Medical Clinic, Charlotte, N.C. (S.A.L.); and Millennium Pharmaceuticals, Cambridge, Mass. (D.-L.E., M.K., J.A., D.P.S.).
Address reprint requests to Dr. Richardson at the Department of Adult Oncology, Dana–Farber Cancer Institute, 44 Binney St., Dana 1B12, Boston, MA 02115, or at paul_richardson{at}dfci.harvard.edu.
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(2007). Relationship Between Depth of Response and Outcome in Multiple Myeloma. JCO
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Dimopoulos, M. A., Souliotis, V. L., Anagnostopoulos, A., Bamia, C., Pouli, A., Baltadakis, I., Terpos, E., Kyrtopoulos, S. A., Sfikakis, P. P.
(2007). Melphalan-induced DNA damage in vitro as a predictor for clinical outcome in multiple myeloma. haematol
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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.
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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
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Garber, A. M., McClellan, M. B.
(2007). Satisfaction Guaranteed -- "Payment by Results" for Biologic Agents. NEJM
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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.
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Poulaki, V., Mitsiades, C. S., Kotoula, V., Negri, J., McMillin, D., Miller, J. W., Mitsiades, N.
(2007). The Proteasome Inhibitor Bortezomib Induces Apoptosis in Human Retinoblastoma Cell Lines In Vitro. IOVS
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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
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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
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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
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Cavaletti, G., Nobile-Orazio, E.
(2007). Bortezomib-induced peripheral neurotoxicity: still far from a painless gain. haematol
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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
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Li, B., Jia, N., Waning, D. L., Yang, F.-C., Haneline, L. S., Chun, K. T.
(2007). Cul4A is required for hematopoietic stem-cell engraftment and self-renewal. Blood
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Murakawa, Y., Sonoda, E., Barber, L. J., Zeng, W., Yokomori, K., Kimura, H., Niimi, A., Lehmann, A., Zhao, G. Y., Hochegger, H., Boulton, S. J., Takeda, S.
(2007). Inhibitors of the Proteasome Suppress Homologous DNA Recombination in Mammalian Cells. Cancer Res.
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Katzel, J. A., Hari, P., Vesole, D. H.
(2007). Multiple Myeloma: Charging Toward a Bright Future. CA Cancer J Clin
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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
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Cilloni, D., Martinelli, G., Messa, F., Baccarani, M., Saglio, G.
(2007). Nuclear factor {kappa}B as a target for new drug development in myeloid malignancies. haematol
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Zappasodi, P., Dore, R., Castagnola, C., Astori, C., Varettoni, M., Mangiacavalli, S., Lazzarino, M., Corso, A.
(2007). Rapid Response to High-Dose Steroids of Severe Bortezomib-Related Pulmonary Complication in Multiple Myeloma. JCO
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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
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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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Kiziltepe, T., Hideshima, T., Ishitsuka, K., Ocio, E. M., Raje, N., Catley, L., Li, C.-Q., Trudel, L. J., Yasui, H., Vallet, S., Kutok, J. L., Chauhan, D., Mitsiades, C. S., Saavedra, J. E., Wogan, G. N., Keefer, L. K., Shami, P. J., Anderson, K. C.
(2007). JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells. Blood
110: 709-718
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Wang, H.-Q., Du, Z.-X., Zhang, H.-Y., Gao, D.-X.
(2007). Different Induction of GRP78 and CHOP as a Predictor of Sensitivity to Proteasome Inhibitors in Thyroid Cancer Cells. Endocrinology
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Cairo, M. S.
(2007). Myelofibrosis with myeloid metaplasia: targeted therapy. Blood
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Giuliani, N., Morandi, F., Tagliaferri, S., Lazzaretti, M., Bonomini, S., Crugnola, M., Mancini, C., Martella, E., Ferrari, L., Tabilio, A., Rizzoli, V.
(2007). The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients. Blood
110: 334-338
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Wagner-Ballon, O., Pisani, D. F., Gastinne, T., Tulliez, M., Chaligne, R., Lacout, C., Aurade, F., Villeval, J.-L., Gonin, P., Vainchenker, W., Giraudier, S.
(2007). Proteasome inhibitor bortezomib impairs both myelofibrosis and osteosclerosis induced by high thrombopoietin levels in mice. Blood
110: 345-353
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Kiziltepe, T., Hideshima, T., Catley, L., Raje, N., Yasui, H., Shiraishi, N., Okawa, Y., Ikeda, H., Vallet, S., Pozzi, S., Ishitsuka, K., Ocio, E. M., Chauhan, D., Anderson, K. C.
(2007). 5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells. Molecular Cancer Therapeutics
6: 1718-1727
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Kobune, M., Chiba, H., Kato, J., Kato, K., Nakamura, K., Kawano, Y., Takada, K., Takimoto, R., Takayama, T., Hamada, H., Niitsu, Y.
(2007). Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism. Molecular Cancer Therapeutics
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Treon, S. P., Hunter, Z. R., Matous, J., Joyce, R. M., Mannion, B., Advani, R., Cook, D., Songer, J., Hill, J., Kaden, B. R., Sharon, D., Steiss, R., Leleu, X., Branagan, A. R., Badros, A.
(2007). Multicenter Clinical Trial of Bortezomib in Relapsed/Refractory Waldenstrom's Macroglobulinemia: Results of WMCTG Trial 03-248. Clin. Cancer Res.
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Richardson, P. G., Mitsiades, C., Schlossman, R., Munshi, N., Anderson, K.
(2007). New Drugs for Myeloma. The Oncologist
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Kim, S. J., Kim, J., Cho, Y., Seo, B. K., Kim, B. S.
(2007). Combination Chemotherapy with Bortezomib, Cyclophosphamide and Dexamethasone may be Effective for Plasma Cell Leukemia. Jpn J Clin Oncol
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Kristinsson, S. Y., Landgren, O., Dickman, P. W., Derolf, A. R., Bjorkholm, M.
(2007). Patterns of Survival in Multiple Myeloma: A Population-Based Study of Patients Diagnosed in Sweden From 1973 to 2003. JCO
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Chen, C. I., Kouroukis, C. T., White, D., Voralia, M., Stadtmauer, E., Stewart, A. K., Wright, J. J., Powers, J., Walsh, W., Eisenhauer, E.
(2007). Bortezomib Is Active in Patients With Untreated or Relapsed Waldenstrom's Macroglobulinemia: A Phase II Study of the National Cancer Institute of Canada Clinical Trials Group. JCO
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Mulligan, G., Mitsiades, C., Bryant, B., Zhan, F., Chng, W. J., Roels, S., Koenig, E., Fergus, A., Huang, Y., Richardson, P., Trepicchio, W. L., Broyl, A., Sonneveld, P., Shaughnessy, J. D. Jr, Leif Bergsagel, P., Schenkein, D., Esseltine, D.-L., Boral, A., Anderson, K. C.
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