Immunomodulatory drugs in multiple myeloma: from molecular mechanisms of action to clinical practice

References

• Cancer Facts and Figures. American Cancer Society; GA, USA: 2008.
   Google Scholar
• Kyle, R.A., Rajkumar, S.V. Multiple myeloma. N Engl J Med 2004, 351, 1860–1873.
   PubMed Web of Science ®Google Scholar
• Dimopoulos, M.A., Chen, C., Spencer, A., Niesvizky, R., Attal, M., Stadtmauer, E.A., Petrucci, M.T., Yu, Z., Olesnyckyj, M., Zeldis, J.B., Knight, R.D., Weber, D.M. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia 2009, 23, 2147–2152.
   PubMed Web of Science ®Google Scholar
• Hideshima, T., Mitsiades, C., Tonon, G., Richardson, P.G., Anderson, K.C. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 2007, 7, 585–598.
   PubMed Web of Science ®Google Scholar
• Raje, N., Roodman, G.D. Advances in the biology and treatment of bone disease in multiple myeloma. Clin Cancer Res 2011, 17, 1278–1286.
   PubMed Web of Science ®Google Scholar
• Quach, H., Ritchie, D., Stewart, A.K., Neeson, P., Harrison, S., Smyth, M.J., Prince, H.M. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia 2010, 24, 22–32.
   PubMed Web of Science ®Google Scholar
• Lyer, G.. WHO co-ordinated short-term double-blind trial with thalidomide in the treatment of acute lepra reactions with male lepromatous patients. Bull World Health Organization 1971, 45, 719–732.
   Google Scholar
• Kastritis, E., Dimopoulos, M.A. The evolving role of lenalidomide in the treatment of hematologic malignancies. Expert Opin Pharmacother 2007, 8, 497–509.
   PubMed Web of Science ®Google Scholar
• Richardson, P.G., Mitsiades, C., Hideshima, T., Anderson, K.C. Lenalidomide in multiple myeloma. Expert Rev Anticancer Ther 2006, 6, 1165–1173.
   PubMed Web of Science ®Google Scholar
• Brimnes, M.K., Svane, I.M., Johnsen, H.E. Impaired functionality and phenotypic profile of dendritic cells from patients with multiple myeloma. Clin Exp Immunol 2006, 144, 76–84.
   PubMed Web of Science ®Google Scholar
• Brown, R.D., Pope, B., Murray, A., Esdale, W., Sze, D.M., Gibson, J., Ho, P.J., Hart, D., Joshua, D. Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-beta1 and interleukin-10. Blood 2001, 98, 2992–2998.
   PubMed Web of Science ®Google Scholar
• Ratta, M., Fagnoni, F., Curti, A., Vescovini, R., Sansoni, P., Oliviero, B., Fogli, M., Ferri, E., Della Cuna, G.R., Tura, S., Baccarani, M., Lemoli, R.M. Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood 2002, 100, 230–237.
   PubMed Web of Science ®Google Scholar
• Quach, H., Ritchie, D., Stewart, A.K., Neeson, P., Harrison, S., Smyth, M.J., Prince, H.M.. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma Leukemia. 2010, 24, 22–32.
   Google Scholar
• Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T.B., Oukka, M., Weiner, H.L., Kuchroo, V.K. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006, 441, 235–238.
   PubMed Web of Science ®Google Scholar
• LeBlanc, R., Hideshima, T., Catley, L.P., Shringarpure, R., Burger, R., Mitsiades, N., Mitsiades, C., Cheema, P., Chauhan, D., Richardson, P.G., Anderson, K.C., Munshi, N.C. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway. Blood 2004, 103, 1787–1790.
   PubMed Web of Science ®Google Scholar
• Hayashi, T., Hideshima, T., Akiyama, M., Podar, K., Yasui, H., Raje, N., Kumar, S., Chauhan, D., Treon, S.P., Richardson, P., Anderson, K.C. Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol 2005, 128, 192–203.
   PubMed Web of Science ®Google Scholar
• Beyer, M., Kochanek, M., Giese, T., Endl, E., Weihrauch, M.R., Knolle, P.A., Classen, S., Schultze, J.L. In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma. Blood 2006, 107, 3940–3949.
   PubMed Web of Science ®Google Scholar
• Dhodapkar, M.V., Geller, M.D., Chang, D.H., Shimizu, K., Fujii, S., Dhodapkar, K.M., Krasovsky, J. A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma. J Exp Med 2003, 197, 1667–1676.
   PubMed Web of Science ®Google Scholar
• Jarahian, M., Watzl, C., Issa, Y., Altevogt, P., Momburg, F. Blockade of natural killer cell-mediated lysis by NCAM140 expressed on tumor cells. Int J Cancer 2007, 120, 2625–2634.
   PubMed Web of Science ®Google Scholar
• Fujii, S., Shimizu, K., Steinman, R.M., Dhodapkar, M.V. Detection and activation of human Valpha24+ natural killer T cells using alpha-galactosyl ceramide-pulsed dendritic cells. J Immunol Methods 2003, 272, 147–159.
   PubMedGoogle Scholar
• Wu, L., Adams, M., Carter, T., Chen, R., Muller, G., Stirling, D., Schafer, P., Bartlett, J.B. lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res 2008, 14, 4650–4657.
   PubMed Web of Science ®Google Scholar
• Adams, J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer 2004, 4, 349–360.
   PubMed Web of Science ®Google Scholar
• Chen, D., Frezza, M., Schmitt, S., Kanwar, J., P Dou, Q. Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets 2011, 11, 239–253.
   PubMed Web of Science ®Google Scholar
• Guirgis, A.A., Zahran, M.A., Mohamed, A.S., Talaat, R.M., Abdou, B.Y., Agwa, H.S. Effect of thalidomide dithiocarbamate analogs on the intercellular adhesion molecule-1 expression. Int Immunopharmacol 2010, 10, 806–811.
   Google Scholar
• Wilop, S., van Gemmeren, T.B., Lentjes, M.H., van Engeland, M., Herman, J.G., Brümmendorf, T.H., Jost, E., Galm, O. Methylation-associated dysregulation of the suppressor of cytokine signaling-3 gene in multiple myeloma. Epigenetics 2011, 6, 1047–1052.
   PubMed Web of Science ®Google Scholar
• Dankbar, B., Padró, T., Leo, R., Feldmann, B., Kropff, M., Mesters, R.M., Serve, H., Berdel, W.E., Kienast, J. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood 2000, 95, 2630–2636.
   PubMed Web of Science ®Google Scholar
• Berardi, S., Caivano, A., Ria, R., Nico, B., Savino, R., Terracciano, R., De Tullio, G., Ferrucci, A., De Luisi, A., Moschetta, M., Mangialardi, G., Catacchio, I., Basile, A., Guarini, A., Zito, A., Ditonno, P., Musto, P., Dammacco, F., Ribatti, D., Vacca, A. Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets. Oncogene 2011.
   Google Scholar
• Perez-Andres, M., Almeida, J., Martin-Ayuso, M., De Las Heras, N., Moro, M.J., Martin-Nuñez, G., Galende, J., Cuello, R., Abuín, I., Moreno, I., Domínguez, M., Hernandez, J., Mateo, G., San Miguel, J.F., Orfao, A. Soluble and membrane levels of molecules involved in the interaction between clonal plasma cells and the immunological microenvironment in multiple myeloma and their association with the characteristics of the disease. Int J Cancer 2009, 124, 367–375.
   PubMed Web of Science ®Google Scholar
• Payvandi, F., Wu, L., Haley, M., Schafer, P.H., Zhang, L.H., Chen, R.S., Muller, G.W., Stirling, D.I. Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF-alpha, IL-1beta, and LPS-stimulated human PBMC in a partially IL-10-dependent manner. Cell Immunol 2004, 230, 81–88.
   PubMed Web of Science ®Google Scholar
• Hinson, R.M., Williams, J.A., Shacter, E. Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2. Proc Natl Acad Sci USA 1996, 93, 4885–4890.
   PubMed Web of Science ®Google Scholar
• Breitkreutz, I., Raab, M.S., Vallet, S., Hideshima, T., Raje, N., Mitsiades, C., Chauhan, D., Okawa, Y., Munshi, N.C., Richardson, P.G., Anderson, K.C. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia 2008, 22, 1925–1932.
   PubMed Web of Science ®Google Scholar
• Rieman, D.J., McClung, H.A., Dodds, R.A., Hwang, S.M., Holmes, M.W., James, I.E., Drake, F.H., Gowen, M. Biosynthesis and processing of cathepsin K in cultured human osteoclasts. Bone 2001, 28, 282–289.
   PubMed Web of Science ®Google Scholar
• Hideshima, T., Chauhan, D., Shima, Y., Raje, N., Davies, F.E., Tai, Y.T., Treon, S.P., Lin, B., Schlossman, R.L., Richardson, P., Muller, G., Stirling, D.I., Anderson, K.C. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000, 96, 2943–2950.
   PubMed Web of Science ®Google Scholar
• Dredge, K., Marriott, J.B., Macdonald, C.D., Man, H.W., Chen, R., Muller, G.W., Stirling, D., Dalgleish, A.G. Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer 2002, 87, 1166–1172.
   PubMed Web of Science ®Google Scholar
• Dredge, K., Horsfall, R., Robinson, S.P., Zhang, L.H., Lu, L., Tang, Y., Shirley, M.A., Muller, G., Schafer, P., Stirling, D., Dalgleish, A.G., Bartlett, J.B. Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. Microvasc Res 2005, 69, 56–63.
   PubMed Web of Science ®Google Scholar
• Mileshkin, L., Honemann, D., Gambell, P., Trivett, M., Hayakawa, Y., Smyth, M., Beshay, V., Ritchie, D., Simmons, P., Milner, A.D., Zeldis, J.B., Prince, H.M. Patients with multiple myeloma treated with thalidomide: evaluation of clinical parameters, cytokines,angiogenic markers, mast cells and marrow CD57+ cytotoxic T cells as predictors of outcome. Haematologica 2007, 92, 1075–1082.
   PubMed Web of Science ®Google Scholar
• Chu, Z.L., McKinsey, T.A., Liu, L., Gentry, J.J., Malim, M.H., Ballard, D.W. Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control. Proc Natl Acad Sci USA 1997, 94, 10057–10062.
   PubMed Web of Science ®Google Scholar
• Kreuz, S., Siegmund, D., Scheurich, P., Wajant, H. NF-kappaB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling. Mol Cell Biol 2001, 21, 3964–3973.
   PubMed Web of Science ®Google Scholar
• Rajkumar, S.V., Hayman, S., Gertz, M.A., Dispenzieri, A., Lacy, M.Q., Greipp, P.R., Geyer, S., Iturria, N., Fonseca, R., Lust, J.A., Kyle, R.A., Witzig, T.E. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002, 20, 4319–4323.
   PubMed Web of Science ®Google Scholar
• Cavo, M., Zamagni, E., Tosi, P., Cellini, C., Cangini, D., Tacchetti, P., Testoni, N., Tonelli, M., de Vivo, A., Palareti, G., Tura, S., Baccarani, M. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica 2004, 89, 826–831.
   PubMed Web of Science ®Google Scholar
• Rajkumar, S.V., Rosiñol, L., Hussein, M., Catalano, J., Jedrzejczak, W., Lucy, L., Olesnyckyj, M., Yu, Z., Knight, R., Zeldis, J.B., Bladé, J. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol 2008, 26, 2171–2177.
   PubMed Web of Science ®Google Scholar
• Cavo, M., Zamagni, E., Tosi, P., Tacchetti, P., Cellini, C., Cangini, D., de Vivo, A., Testoni, N., Nicci, C., Terragna, C., Grafone, T., Perrone, G., Ceccolini, M., Tura, S., Baccarani, M.; Bologna 2002 study. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 2005, 106, 35–39.
   PubMed Web of Science ®Google Scholar
• Macro, M., Divine, M., Uzunhan, Y., et al. Dexamethasone + thalidomide compared to VAD as a pre-trasplant treatment in newly diagnosed multiple myeloma: a randomized trial. Blood 2006, 108.
   Google Scholar
• Cavo, M., Zamanni, E., Tosi, P., Tacchetti, P., Cellini, C., Cangini, D. et al. Superiority of Thalidomide and dezametazone over Vincristine-doxorubicin-Dexametazon (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 2005, 106, 35–39.
   PubMed Web of Science ®Google Scholar
• Cavo, M., Tacchetti, P., Patriarca, F., Petrucci, M.T., Pantani, L., Galli, M., Di Raimondo, F., Crippa, C., Zamagni, E., Palumbo, A., Offidani, M., Corradini, P., Narni, F., Spadano, A., Pescosta, N., Deliliers, G.L., Ledda, A., Cellini, C., Caravita, T., Tosi, P., Baccarani, M.; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 2010, 376, 2075–2085.
   PubMed Web of Science ®Google Scholar
• Zervas, K., Mihou, D., Katodritou, E., Pouli, A., Mitsouli, C.H., Anagnostopoulos, A., Delibasi, S., Kyrtsonis, M.C., Anagnostopoulos, N., Terpos, E., Zikos, P., Maniatis, A., Dimopoulos, M.A.; Greek Myeloma Study Group. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group. Ann Oncol 2007, 18, 1369–1375.
   PubMed Web of Science ®Google Scholar
• Stewart, A.K., Chen, C.I., Howson-Jan, K., White, D., Roy, J., Kovacs, M.J., Shustik, C., Sadura, A., Shepherd, L., Ding, K., Meyer, R.M., Belch, A.R. Results of a multicenter randomized phase II trial of thalidomide and prednisone maintenance therapy for multiple myeloma after autologous stem cell transplant. Clin Cancer Res 2004, 10, 8170–8176.
   PubMed Web of Science ®Google Scholar
• Attal, M., Harousseau, J.L., Leyvraz, S., Doyen, C., Hulin, C., Benboubker, L., Yakoub Agha, I., Bourhis, J.H., Garderet, L., Pegourie, B., Dumontet, C., Renaud, M., Voillat, L., Berthou, C., Marit, G., Monconduit, M., Caillot, D., Grobois, B., Avet-Loiseau, H., Moreau, P., Facon, T.; Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 2006, 108, 3289–3294.
   PubMed Web of Science ®Google Scholar
• Facon, T., Mary, J., Harousseau, J., Huguet, F., Berthou, C., Grosbois, et al. Superiority of melphalan-prednisone (MP) + thalidomide (THAL) over MP and autologous stem cell transplantation in the treatment of newly diagnosed elderly patients with multiple myeloma. J Clin Oncol 2006, 24,(S18).
   Google Scholar
• Palumbo, A., Bringhen, S., Liberati, A.M., Caravita, T., Falcone, A., Callea, V., Montanaro, M., Ria, R., Capaldi, A., Zambello, R., Benevolo, G., Derudas, D., Dore, F., Cavallo, F., Gay, F., Falco, P., Ciccone, G., Musto, P., Cavo, M., Boccadoro, M. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood 2008, 112, 3107–3114.
   PubMed Web of Science ®Google Scholar
• 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., Azaïs, I., Decaux, O., Garderet, L., Mathiot, C., Fontan, J., Lafon, I., Virion, J.M., Moreau, P. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009, 27, 3664–3670.
   PubMed Web of Science ®Google Scholar
• Waage, A., Gimsing, P., Fayers, P., Abildgaard, N., Ahlberg, L., Björkstrand, B., Carlson, K., Dahl, I.M., Forsberg, K., Gulbrandsen, N., Haukås, E., Hjertner, O., Hjorth, M., Karlsson, T., Knudsen, L.M., Nielsen, J.L., Linder, O., Mellqvist, U.H., Nesthus, I., Rolke, J., Strandberg, M., Sørbø, J.H., Wisløff, F., Juliusson, G., Turesson, I.; Nordic Myeloma Study Group. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood 2010, 116, 1405–1412.
   PubMed Web of Science ®Google Scholar
• Palumbo, A., Bringhen, S., Rossi, D., Cavalli, M., Larocca, A., Ria, R., Offidani, M., Patriarca, F., Nozzoli, C., Guglielmelli, T., Benevolo, G., Callea, V., Baldini, L., Morabito, F., Grasso, M., Leonardi, G., Rizzo, M., Falcone, A.P., Gottardi, D., Montefusco, V., Musto, P., Petrucci, M.T., Ciccone, G., Boccadoro, M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol 2010, 28, 5101–5109.
   PubMed Web of Science ®Google Scholar
• Kneller, A., Raanani, P., Hardan, I., Avigdor, A., Levi, I., Berkowicz, M., Ben-Bassat, I. Therapy with thalidomide in refractory multiple myeloma patients - the revival of an old drug. Br J Haematol 2000, 108, 391–393.
   PubMed Web of Science ®Google Scholar
• Singhal, S., Mehta, J., Desikan, R., Ayers, D., Roberson, P., Eddlemon, P., Munshi, N., Anaissie, E., Wilson, C., Dhodapkar, M., Zeddis, J., Barlogie, B. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999, 341, 1565–1571.
   PubMed Web of Science ®Google Scholar
• Mohty, M., Attal, M., Marit, G., Bulabois, C.E., Garban, F., Gratecos, N., Rio, B., Vernant, J.P., Sotto, J.J., Cahn, J.Y., Blaise, D., Jouet, J.P., Facon, T., Yakoub-Agha, I. Thalidomide salvage therapy following allogeneic stem cell transplantation for multiple myeloma: a retrospective study from the Intergroupe Francophone du Myélome (IFM) and the Société Française de Greffe de Moelle et Thérapie Cellulaire (SFGM-TC). Bone Marrow Transplant 2005, 35, 165–169.
   PubMed Web of Science ®Google Scholar
• Lacy, M.Q., Gertz, M.A., Dispenzieri, A., Hayman, S.R., Geyer, S., Kabat, B., Zeldenrust, S.R., Kumar, S., Greipp, P.R., Fonseca, R., Lust, J.A., Russell, S.J., Kyle, R.A., Witzig, T.E., Bergsagel, P.L., Stewart, A.K., Rajkumar, S.V. 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.
   PubMed Web of Science ®Google Scholar
• Rajkumar, S.V., Jacobus, S., Callander, N. et al. A randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E403): a trial coordinated by the Eastern Cooperative Oncology Group. Blood 2007;110.
   Google Scholar
• Kumar, S., Dispenzieri, A., Lacy, M.Q. et al. Impact of lenalidomide on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma. Leukemia 2007, 21, 2035–2042.
   PubMed Web of Science ®Google Scholar
• Mazumder, A., Kaufman, J., Niesvizky, R., Lonial, S., Vesole, D., Jagannath, S. Effect of lenalidomide therapy on mobilization of peripheral blood stem cells in previously untreated multiple myeloma patients. Leukemia 2008, 22, 1280–1; author reply 1281.
   PubMed Web of Science ®Google Scholar
• Paripati, H., Stewart, A.K., Cabou, S., Dueck, A., Zepeda, V.J., Pirooz, N., Ehlenbeck, C., Reeder, C., Slack, J., Leis, J.F., Boesiger, J., Torloni, A.S., Fonseca, R., Bergsagel, P.L. Compromised stem cell mobilization following induction therapy with lenalidomide in myeloma. Leukemia 2008, 22, 1282–1284.
   PubMed Web of Science ®Google Scholar
• Mark, T., Stern, J., Furst, J.R., Jayabalan, D., Zafar, F., LaRow, A., Pearse, R.N., Harpel, J., Shore, T., Schuster, M.W., Leonard, J.P., Christos, P.J., Coleman, M., Niesvizky, R. Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma. Biol Blood Marrow Transplant 2008, 14, 795–798.
   PubMed Web of Science ®Google Scholar
• Richardson, P.G., Jagannath, S., Raje, N., et al. Safety and efficacy of lenalidomide, bortezomib and dexamethasone in patients with newly diagnosed multiple myeloma: a phase I/II study [abstract]. J Clin Oncol 2008, 26, 459s.
   Google Scholar
• Dimopoulos, M.A., Chen, C., Spencer, A., Niesvizky, R., Attal, M., Stadtmauer, E.A., Petrucci, M.T., Yu, Z., Olesnyckyj, M., Zeldis, J.B., Knight, R.D., Weber, D.M.. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia 2009, 23, 2147–2520.
   PubMed Web of Science ®Google Scholar
• Jerome Lipper Multiple Myeloma Center. Dana-Farber Cancer Institute and Massachusetts General Hospital. Harvard Medical School, Boston, Massachusetts. The Treatment of Multiple Myeloma Patients Not Eligible. Mediterranean journal of Hematology and infectious disease. Vol 2 n. 2 2010.
   Google Scholar
• Baz, R., Walker, E., Karam, M.A., Choueiri, T.K., Jawde, R.A., Bruening, K., Reed, J., Faiman, B., Ellis, Y., Brand, C., Srkalovic, G., Andresen, S., Knight, R., Zeldis, J., Hussein, M.A. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann Oncol 2006, 17, 1766–1771.
   PubMed Web of Science ®Google Scholar
• Kumar, S.K., Lacy, M.Q., Hayman, S.R., Stewart, K., Buadi, F.K., Allred, J., Laumann, K., Greipp, P.R., Lust, J.A., Gertz, M.A., Zeldenrust, S.R., Bergsagel, P.L., Reeder, C.B., Witzig, T.E., Fonseca, R., Russell, S.J., Mikhael, J.R., Dingli, D., Rajkumar, S.V., Dispenzieri, A.. Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial. Am J Hematol 2011, 86, 640–645.
   PubMed Web of Science ®Google Scholar
• Gandhi, A.K., Kang, J., Capone, L., Parton, A., Wu, L., Zhang, L.H., Mendy, D., Lopez-Girona, A., Tran, T., Sapinoso, L., Fang, W., Xu, S., Hampton, G., Bartlett, J.B., Schafer, P. Dexamethasone synergizes with lenalidomide to inhibit multiple myeloma tumor growth, but reduces lenalidomide-induced immunomodulation of T and NK cell function. Curr Cancer Drug Targets 2010, 10, 155–167.
   PubMed Web of Science ®Google Scholar
• Rajkumar, S.V., Jacobus, S., Callander, N.S., Fonseca, R., Vesole, D.H., Williams, M.E., Abonour, R., Siegel, D.S., Katz, M., Greipp, P.R.; Eastern Cooperative Oncology Group. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010, 11, 29–37.
   PubMed Web of Science ®Google Scholar
• Morita, C.T., Jin, C., Sarikonda, G., Wang, H. Nonpeptide antigens, presentation mechanisms, and immunological memory of human Vgamma2Vdelta2 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens. Immunol Rev 2007, 215, 59–76.
   PubMed Web of Science ®Google Scholar
• 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.; Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007, 357, 2133–2142.
   PubMed Web of Science ®Google Scholar
• Dimopoulos, M., Spencer, A., Attal, M., Prince, H.M., Harousseau, J.L., Dmoszynska, A., San Miguel, J., Hellmann, A., Facon, T., Foà, R., Corso, A., Masliak, Z., Olesnyckyj, M., Yu, Z., Patin, J., Zeldis, J.B., Knight, R.D.; Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007, 357, 2123–2132.
   PubMed Web of Science ®Google Scholar
• Stadtmauer, E., Weber, D., Dimopoulos, M. et al. Klenalidomide in combination with dexamethasone is more effective than dexamethasone at first relapse in relapsed multiple myeloma. Blood (aSH Annual Meeting Abstrtact) 2006, 108.
   Google Scholar
• Wang, M., Knight, R., Dimiopolus, M. et al. Effect of Len/Dex in MM despite TAL resistance. Hematologica 2007, 92.
   Google Scholar
• Avet-Loiseau, H., Attal, M., Moreau, P., Charbonnel, C., Garban, F., Hulin, C., Leyvraz, S., Michallet, M., Yakoub-Agha, I., Garderet, L., Marit, G., Michaux, L., Voillat, L., Renaud, M., Grosbois, B., Guillerm, G., Benboubker, L., Monconduit, M., Thieblemont, C., Casassus, P., Caillot, D., Stoppa, A.M., Sotto, J.J., Wetterwald, M., Dumontet, C., Fuzibet, J.G., Azais, I., Dorvaux, V., Zandecki, M., Bataille, R., Minvielle, S., Harousseau, J.L., Facon, T., Mathiot, C. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood 2007, 109, 3489–3495.
   PubMed Web of Science ®Google Scholar
• Palumbo, A., Falco, P., Corradini, P., Falcone, A., Di Raimondo, F., Giuliani, N., Crippa, C., Ciccone, G., Omedè, P., Ambrosini, M.T., Gay, F., Bringhen, S., Musto, P., Foà, R., Knight, R., Zeldis, J.B., Boccadoro, M., Petrucci, M.T.; GIMEMA–Italian Multiple Myeloma Network. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA–Italian Multiple Myeloma Network. J Clin Oncol 2007, 25, 4459–4465.
   PubMed Web of Science ®Google Scholar
• Bahlis, N.J., Mansoor, A., Lategan, J.C. et al. Lenalidomide overcomes poor prognosis conferred by deletion of chromosome 13 and t(13;14) in muliple myeloma: MM016 trail. Blood (ASH annual meeting abstracts) 2006, 108.
   Google Scholar
• Khan, M.L., Reeder, C.B., Kumar, S.K., Lacy, M.Q., Reece, D.E., Dispenzieri, A., Gertz, M.A., Greipp, P., Hayman, S., Zeldenhurst, S., Dingli, D., Lust, J., Russell, S., Laumann, K.M., Mikhael, J.R., Leif Bergsagel, P., Fonseca, R., Vincent Rajkumar, S., Keith Stewart, A. A comparison of lenalidomide/dexamethasone versus cyclophosphamide/lenalidomide/dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly diagnosed multiple myeloma. Br J Haematol 2012, 156, 326–333.
   PubMed Web of Science ®Google Scholar
• McCarthy, P.L., Owzar, K., Anderson, K.C., et al. Phase III inter group study of lenalidomide versus placebo maintenance therapy following single autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma: CALGB 100104 [abstract]. ASH Annu Meet Abstr 2010, 116, 37.
   Google Scholar
• Attal, M., Lauwers, V.C., Marit, G., et al. Maintenance treatment with lenalidomide after transplantation for myeloma: final analysis of the IFM 2005-02 [abstract]. ASH Annu Meet Abstr 2010, 116, 310.
   Google Scholar
• Lioznov, M., El-Cheikh, J. Jr, Hoffmann, F., Hildebrandt, Y., Ayuk, F., Wolschke, C., Atanackovic, D., Schilling, G., Badbaran, A., Bacher, U., Fehse, B., Zander, A.R., Blaise, D., Mohty, M., Kröger, N. Lenalidomide as salvage therapy after allo-SCT for multiple myeloma is effective and leads to an increase of activated NK (NKp44(+)) and T (HLA-DR(+)) cells. Bone Marrow Transplant 2010, 45, 349–353.
   PubMed Web of Science ®Google Scholar
• Mitsiades, N., Mitsiades, C.S., Richardson, P.G., Poulaki, V., Tai, Y.T., Chauhan, D., Fanourakis, G., Gu, X., Bailey, C., Joseph, M., Libermann, T.A., Schlossman, R., Munshi, N.C., Hideshima, T., Anderson, K.C. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 2003, 101, 2377–2380.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Cavo, M., Tacchetti, P., Patriarca, F., Petrucci, M.T., Pantani, L., Galli, M., Di Raimondo, F., Crippa, C., Zamagni, E., Palumbo, A., Offidani, M., Corradini, P., Narni, F., Spadano, A., Pescosta, N., Deliliers, G.L., Ledda, A., Cellini, C., Caravita, T., Tosi, P., Baccarani, M.; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 2010 18, 2075–2085.
   Google Scholar
• Palumbo, A., Bringhen, S., Rossi, D. et al. A prospective randomized phase III study of bortezomib, melphalan, prednisone and thalidomide (VMPT) versus bortezomib, melphalan and prednisone (VMP) in elderly newly diagnosed myeloma. patients. Blood 2008, 112.
   Google Scholar
• Schey, S.A., Fields, P., Bartlett, J.B., Clarke, I.A., Ashan, G., Knight, R.D., Streetly, M., Dalgleish, A.G. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol 2004, 22, 3269–3276.
   PubMed Web of Science ®Google Scholar
• Streetly, M.J., Gyertson, K., Daniel, Y., Zeldis, J.B., Kazmi, M., Schey, S.A. Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation. Br J Haematol 2008, 141, 41–51.
   PubMed Web of Science ®Google Scholar
• Schey, S., Ramasamy, K. Pomalidomide therapy for myeloma. Expert Opin Investig Drugs 2011, 20, 691–700.
   PubMed Web of Science ®Google Scholar
• Lacy, M.Q., Hayman, S.R., Gertz, M.A., Dispenzieri, A., Buadi, F., Kumar, S., Greipp, P.R., Lust, J.A., Russell, S.J., Dingli, D., Kyle, R.A., Fonseca, R., Bergsagel, P.L., Roy, V., Mikhael, J.R., Stewart, A.K., Laumann, K., Allred, J.B., Mandrekar, S.J., Rajkumar, S.V. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol 2009, 27, 5008–5014.
   PubMed Web of Science ®Google Scholar
• Lacy, M.Q., Hayman, S.R., Gertz, M.A., Short, K.D., Dispenzieri, A., Kumar, S., Greipp, P.R., Lust, J.A., Russell, S.J., Dingli, D., Zeldenrust, S., Fonseca, R., Bergsagel, P.L., Roy, V., Mikhael, J.R., Stewart, A.K., Laumann, K., Allred, J.B., Mandrekar, S.J., Rajkumar, S.V., Buadi, F. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia 2010, 24, 1934–1939.
   PubMed Web of Science ®Google Scholar
• Leleu, X., Attal, M., Moreau, P. et al. Phase 2 study of 2 modalitiesof pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. IFM 2009-02 [abstract]. ASH Annu Meet Abstr 2010, 116, 859.
   Google Scholar
• Lacy, M., Mandrekar, S., Gertz, M.A.A. et al. Pomalidomide plus lowdose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of two dosing strategies in dual-refractorydisease [abstract]. ASH Annu Meet Abstr 2010, 116, 863.
   Google Scholar
• Antonio, Palumbo, Francesca, Gay, Patrizia, Falco, Claudia, Crippa, Vittorio, Montefusco, Francesca, Patriarca, Fausto, Rossini, Simona, Caltagirone, Giulia, Benevolo, Norbert, Pescosta, Tommasina, Guglielmelli, Sara, Bringhen, Massimo, Offidani, Nicola, Giuliani, Maria Teresa, Petrucci, Pellegrino, Musto, Anna Marina, Liberati, Giuseppe, Rossi, Paolo, Corradini, Mario Boccadoro, Bortezomib. As Induction Before Autologous Transplantation, Followed by Lenalidomide As Consolidation-Maintenance in Untreated Multiple Myeloma Patients Journal of Clinical Oncology 5 _ February 10 2010.
   Google Scholar
• Sinha, S., Lacy, M., Mikhael, J., Hayman, S., Buadi, F., Detweiler-Short, K., Dispenzieri, A., Gertz, M., Dingli, D., Rajkumar, S.V., Kumar, S.K. Response to salvage therapies and outcome in patients with multiple myeloma relapsing after pomalidomide therapy. Leukemia 2011.
   Google Scholar
• Cavo, M., Zamagni, E., Cellini, C., Tosi, P., Cangini, D., Cini, M., Valdrè, L., Palareti, G., Masini, L., Tura, S., Baccarani, M. Deep-vein thrombosis in patients with multiple myeloma receiving first-line thalidomide-dexamethasone therapy. Blood 2002, 100, 2272–2273.
   PubMed Web of Science ®Google Scholar
• Barbui, T., Falanga, A. Thalidomide and thrombosis in multiple myeloma. J Thromb Haemost 2003, 1, 421–422.
   PubMed Web of Science ®Google Scholar
• Dicato, M. Venous thromboembolic events and erythropoiesis-stimulating agents: an update. Oncologist 2008, 13 Suppl 3, 11–15.
   Google Scholar
• Zakarija, A., Kwaan, H.C.. Adverse effects of drugs on hemostatic function. Seminars in thrombosis and hemostasis 2007, 33, 355–364.
   PubMed Web of Science ®Google Scholar
• Castelli, R., Ferrari, B., Cortelezzi, A., Guariglia, A. Thromboembolic complications in malignant haematological disorders. Curr Vasc Pharmacol 2010, 8, 482–494.
   PubMedGoogle Scholar
• Barbui, T., Finazzi, G., Grassi, A., Marchioli, R. Thrombosis in cancer patients treated with hematopoietic growth factors–a meta-analysis. On behalf of the Subcommittee on Haemostasis and Malignancy of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1996, 75, 368–371.
   PubMed Web of Science ®Google Scholar
• Furlan, M., Robles, R., Lämmle, B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood 1996, 87, 4223–4234.
   PubMed Web of Science ®Google Scholar
• Tsai, H.M. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 1996, 87, 4235–4244.
   PubMed Web of Science ®Google Scholar
• Howard, R.A., Dores, G.M., Curtis, R.E., Anderson, W.F., Travis, L.B. Merkel cell carcinoma and multiple primary cancers. Cancer Epidemiol Biomarkers Prev 2006, 15, 1545–1549.
   PubMed Web of Science ®Google Scholar
• Dong, C., Hemminki, K. Second primary neoplasms among 53 159 haematolymphoproliferative malignancy patients in Sweden, 1958-1996: a search for common mechanisms. Br J Cancer 2001, 85, 997–1005.
   PubMed Web of Science ®Google Scholar
• Palumbo, S., Bringhen, S., Zweegmann, G., Luparelli, T., Caravita, P., Musto, R., Hajek, A., Spencer, M., Dimopulos, P., Sonnevel. Secondary malignancies in elderly Myeloma patients Abstract 13 th International Myeloma Workshop Paris France May 3-6, 2011.
   Google Scholar
• A.P. Palumbo, M. Delforge, J., catalno, R., Haiek, M., Krpff, M.T., Petrucci, Z., Yu, M., Mei, A., Dimopulos et al. Incidence of second primary malignancy (SPM) in melphal prednisone-lenalidomide combination followed by lenalidomide maintenance (MP-R) in newly diagnosed multiple myeloma patients age 65 or older. J Clin Oncol 29, 2011.
   Google Scholar
• Voisin, S., Hamidou, M., Lefrançois, A., Sigaud, M., Mahé, B., Trossaërt, M. Acquired von Willebrand syndrome associated with monoclonal gammopathy: a single-center study of 36 patients. Medicine (Baltimore) 2011, 90, 404–411.
   PubMed Web of Science ®Google Scholar
• Cugno, M., Castelli, R., Cicardi, M. Angioedema due to acquired C1-inhibitor deficiency: a bridging condition between autoimmunity and lymphoproliferation. Autoimmun Rev 2008, 8, 156–159.
   PubMed Web of Science ®Google Scholar
• Yi, Q. Immunotherapy in multiple myeloma: current strategies and future prospects. Expert Rev Vaccines 2003, 2, 391–398.
   PubMedGoogle Scholar
• Schafer, P., Gandhi, A.K., Zhang, L., Kang, J., Capone, L., Bartlett, J.B.. Opposing Effects of Dexamethasone on Lenalidomide Activity in Multiple Myeloma: Additive/Synergistic Effects on Anti-Proliferative Activity on Myeloma Cells and Antagonistic Effects on Immune Function [abstract]. Blood 2008, 112, 2761a.
   Google Scholar
• Pellagatti, A., Jädersten, M., Forsblom, A.M., Cattan, H., Christensson, B., Emanuelsson, E.K., Merup, M., Nilsson, L., Samuelsson, J., Sander, B., Wainscoat, J.S., Boultwood, J., Hellström-Lindberg, E. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. Proc Natl Acad Sci USA 2007, 104, 11406–11411.
   PubMed Web of Science ®Google Scholar