Abstract
Multiple myeloma (MM) is a malignancy of plasma cells within the bone marrow characterized by bone loss, renal disease, and immunodeficiency. Recent advances in the understanding of MM pathogenesis have improved established conventional cytotoxic therapy as well as transplantation regimens. Despite these advances, median overall survival is only 3–5 years. Therefore new therapies are urgently needed. Besides thalidomide, whose antimyeloma activity has only recently been defined, a plethora of novel agents, including the thalidomide-derived immunomodulatory drugs and bortezomib, have been identified to directly target the tumor cell or its microenvironment, and thereby inhibit MM cell growth and survival, and to overcome drug resistance. After validation of their preclinical anti-MM activity, several clinical trials are now ongoing to test the efficacy of these novel therapeutics, administered alone or in combination with conventional or other novel therapeutics and bone marrow transplantation. This article reviews the development of MM therapy, from its initial description approximately 150 years ago to the novel therapy regimens of recent years, highlighting that MM may soon become a chronic disease.
Similar content being viewed by others
Notes
The use of trade names is for product identification purposes only and does not imply endorsement.
References
Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004; 351(18): 1860–73
Kyle RA. Five decades of therapy for multiple myeloma: a paradigm for therapeutic models. Leukemia 2005; 19(6): 910–2
Alwall N. Urethane in multiple myeloma: I. Final report of a case treated more than four years with urethane. Acta Med Scand 1952; 144(2): 114–8
Blokhin N, Larionov L, Perevodchikova N, et al. Clinical experiences with sarcolysin in neoplastic diseases. Ann N Y Acad Sci 1958; 68(3): 1128–32
Bergsagel DE, Phase II trials of mitomycin C, AB-100, NSC-1026, L-sarcolysin, and meta-sarcolysin, in the treatment of multiple myeloma. Cancer Chemother Rep 1962; 16: 261–66
Alexanian R, Haut A, Khan AU, et al. Treatment for multiple myeloma: combination chemotherapy with different melphalan dose regimens. JAMA 1969Jun 2; 208(9): 1680–5
Myeloma-Trialists’-Collaborative-Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6633 patients from 27 randomized trials. Myeloma Trialists’ Collaborative Group. J Clin Oncol 1998; 16(12): 3832–42
Bergsagel DE, Bailey AT, Langley GR, et al. The chemotherapy on plasma-cell myeloma and the incidence of acute leukemia. N Engl J Med 1979; 301(14): 743–8
Bergsagel DE. Chemotherapy of myeloma: drug combinations versus single agents, an overview, and comments on acute leukemia in myeloma. Hematol Oncol 1988; 6(2): 159–66
Finnish-Leukaemia-Group. Acute leukaemia and other secondary neoplasms in patients treated with conventional chemotherapy for multiple myeloma: a Finnish Leukaemia Group study. Eur J Haematol 2000; 65(2): 123–7
Cuzick J, Erskine S, Edelman D, et al. A comparison of the incidence of the myelodysplastic syndrome and acute myeloid leukaemia following melphalan and cyclophosphamide treatment for myelomatosis: a report to the Medical Research Council’s working party on leukaemia in adults. Br J Cancer 1987; 55(5): 523–9
Govindarajan R, Jagannath S, Flick JT, et al. Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma. Br j Haematoi 1996; 95(2): 349–53
Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996; 335(2): 91–7
Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 348(19): 1875–83
Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the group myelome-autogreffe. J Clin Oncol 2005; 23(36): 9227–33
Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 2006Feb 20; 24(6): 929–36
Blade J, Rosinol L, Sureda A, et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 2005; 106(12): 3755–9
Morris TC, Velangi M, Jackson G, et al. Less than half of patients aged 65 years or under with myeloma proceed to transplantation: results of a two region population-based survey. Br J Haematoi 2005; 128(4): 510–2
Saravanamuttu K, Byrne JL, Williams C, et al. Uptake of high-dose therapy and peripheral blood stem cell transplantation in myeloma patients <65 years: the role of the myeloma multi-disciplinary team. Br J Haematoi 2005; 130(2): 318–9
Barlogie B, Jagannath S, Vesole DH, et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood 1997; 89(3): 789–93
Barlogie B, Jagannath S, Desikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 1999; 93(1): 55–65
Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003; 349(26): 2495–502
Cavo M, Zamagni E, Cellini C. Single versus double autologous stem cell transplantation for multiple myeloma: Italian experience [abstract]. Hematol J 2003; 4 Suppl. 1: 560
Sonneveld P, van derHolt B, Segeren CM, Intensive versus double intensive therapy in untreated multiple myeloma: updated analysis of the prospective phase III study Hovon 24-MM. Hematol J 2003; 4 Suppl. 1: 559–60
Fermand JP, Alberti C, Marolleau JP, Single versus double high dose therapy supported with autologous blood stem cell transplantation using unselected or CD34 enriched ABSC: results of a two designed randomized trial in 230 young patients with multiple myeloma. Hematol J 2003; 4 Suppl, 1: S59
Goldschmidt H, Single versus double high dose therapy in multiple myeloma: second analysis of the trial GMMG-HD2. Proceedings Multiple Myeloma 2004 Meeting; 2004 Apr 22–24; Torino, 119
Segeren CM, Sonneveid P, van derHolt B, et al. Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study. Blood 2003; 101(6): 2144–51
Gahrton G, Tura S, Ljungman P, et al. Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 1995; 13(6): 1312–22
Bensinger WI, Buckner CD, Anasetti C, et al, Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood 1996; 88(7): 2787–93
Alyea E, Weiler E, Schlossman R, et al. T-cell: depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect. Blood 2001; 98(4): 934–9
Lokhorst HM, Segeren CM, Verdonck LF, et al. Partially T-cell-depleted allogeneic stem-cell transplantation for first-line treatment of multiple myeloma: a prospective evaluation of patients treated in the phase III study HOVON 24 MM. J Clin Oncol 2003; 21(9): 1728–33
Maloney DG, Sandmaier BM, Mackinnon S, et al. Non-myeloablative transplantation. Hematology (Am Soc Hematol Educ Program) 2002: 392–421
Badros A, Barlogie B, Siegel E, et al. Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 2002; 20(5): 1295–303
Kroger N, Schwerdtfeger R, Kiehl M, et al, Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood 2002; 100(3): 755–60
Maloney DG, Molina AJ, Sahebi F, et al, Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102(9): 3447–54
Bruno B, Rotta M, Patriarca F, et al. Double autologous transplant versus tandem autologus: non myeloablative allogeneic transplant for newly diagnosed multiple myeloma [abstract]. Blood 2005; 106(11): 46
Carella AM, Spriano M, Corsetti MT, et al. Autografting followed closely by nonmyeloablative allografting as consolidation immunotherapy reduces disease progression compared to tandem autografting in multiple myeloma [abstract no. 112]. Blood 2005, 328a
Cavo M, Zamagni E, Tosi P, et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 2005; 106(1): 35–9
Rajkumar SV, Gertz, MA, Kyle A, et al. Current therapy for multiple myeloma. Mayo Clin Proc 2002; 77(8): 813–22
Facon T, Mary JY, Pegourie B, et al, Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood 2006Feb 15; 107(4): 1292–8
Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 1996; 334(8): 488–93
Ludwig FI, Fritz E, Kotzmann H, et al, Erythropoietin treatment of anemia associated with multiple myeloma. N Engl J Med 1990; 322(24): 1693–9
Bociek RG, Armitage JO. Hematopoietic growth factors. CA Cancer J Clin 1996; 46(3): 165–84
Marx RE, Sawatari Y, Fortin M, et al, Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005; 63(11): 1567–75
Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61(9): 1115-7
Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004; 62(5): 527–34
Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer 2002; 2(12): 927–37
Podar K, Hideshima T, Chauhan D, et al. Targeting signalling pathways for the treatment of multiple myeloma. Expert Opin Ther Targets 2005; 9(2): 359–81
Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341(21): 1565–71
Barlogie B, Desikan R, Eddlemon P, et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001; 98(2): 492–4
Rajkumar SV, Fonseca R, Dispenzieri A, et al. Thalidomide in the treatment of relapsed multiple myeloma. Mayo Clin Proc 2000; 75(9): 897–901
Dimopoulos MA, Anagnostopoulos A, Weber D. Treatment of plasma cell dyscrasias with thalidomide and its derivatives. J Clin Oncol 2003; 21(23): 4444–54
D’Amato RJ, Lentzsch S, Anderson KC, et al. Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma. Semin Oncol 2001; 28(6): 597–601
Sampaio EP, Sarno EN, Galilly R, et al. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991; 173(3): 699–703
Hideshima T, Chauhan D, Schlossman R, et al. The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene 2001; 20(33): 4519–27
Mitsiades N, Mitsiades CS, Poulaki V, et al, Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002; 99(12): 4525–30
Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000; 96(9): 2943–50
Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001; 98(1): 210–6
Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 2004; 4(4): 314–22
Weber D, Rankin K, Gavino M, et al, Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003; 21(1): 16–9
Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002; 20(21): 4319–23
Garcia-Sanz R, Gonzalez-Fraile MI, Sierra M, et al. The combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is feasible and can be an option for relapsed/refractory multiple myeloma. Hematol J 2002; 3(1): 43–8
Coleman M, Leonard J, Lyons L, et al. BLT-D (clarithromycin [Biaxin], low-dose thalidomide, and dexamethasone) for the treatment of myeloma and Walden-strom’s macroglobulinemia. Leuk Lymphoma 2002; 43(9): 1777–82
Osman K, Comenzo R, Rajkumar SV. Deep venous thrombosis and thalidomide therapy for multiple myeloma. N Engl J Med 2001; 344(25): 1951–2
Zangari M, Anaissie E, Barlogie B, et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 2001; 98(5): 1614–5
Baz R, Li L, Kottke-Marchant K, et al. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc 2005; 80(12): 1568–74
Yakoub-Agha I, Attal M, Dumontet C, et al. Thalidomide in patients with advanced multiple myeloma: a study of 83 patients: report of the Intergroupe Francophone du Myelome (IFM). Hematol J 2002; 3(4): 185–92
Neben K, Moehler T, Benner A, et al. Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma. Clin Cancer Res 2002; 8(11): 3377–82
Palumbo A, Giaccone L, Bertola A, et al. Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica 2001; 86(4): 399–403
Durie BG. Low-dose thalidomide in myeloma: efficacy and biologic significance. Semin Oncol 2002; 29(6 Suppl. 17): 34–8
Leleu X, Magro L, Fawaz, A, et al. Efficacy of a low dose of thalidomide in advanced multiple myeloma. Blood 2002; 100(4): 1519–20
Johnston RE, Abdalla SH. Thalidomide in low doses is effective for the treatment of resistant or relapsed multiple myeloma and for plasma cell leukaemia. Leuk Lymphoma 2002; 43(2): 351–4
Kees M, Dimou G, Siliaber C, et al. Low dose thalidomide in patients with relapsed or refractory multiple myeloma. Leuk Lymphoma 2003; 44(11): 1943–6
Palumbo A, Bertola A, Falco P, et al. Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma. Hematol J 2004; 5(4): 318–24
Yakoub-Agha I, Hulin C, Doyen C, et al. A multicenter prospective randomized study testing non-inferiority of thalidomide 100mg/day as compared with 400mg/day in patients with refractory/ relapsed multiple myeloma: first results of the final analysis of the IFM 01–02 study [abstract]. Blood 2005; 106(11): 137
Catley L, Tai YT, Chauhan D, et al. Perspectives for combination therapy to overcome drag-resistant multiple myeloma. Drug Resist Updat 2005; 8(4): 205–18
Dimopoulos MA, Repoussis P, Terpos E, et al. Primary treatment with pulsed melphalan, dexamethasone, thalidomide (MDT) for symptomatic patients with multiple myeloma ≥75 years of age [abstract]. Blood 2004; 104: 1482
Palumbo A, Bertola A, Musto P, et al. A prospective randomized trial of oral melphalan, prednisone, thalidomide (MPT) vs oral melphalan, prednisone (MP): an interim analysis [abstract]. Blood 2004; 104: 207
Facon T, Mary JY, Hulin C, et al. Randomized clinical trial comparing melphalan-prednisone (MP), MP-thalidomide (MP-THAL) and high-dose therapy using melphalan 100 mg/mL (MEL 100) for newly diagnosed myeloma patients aged 65–75 years: interim analysis of the IFM 99-06 Trial on 350 Patients [abstract]. Blood 2004; 104: 206
Palumbo A, Bringhen S, Musto P, et al. Oral melphalan, prednisone and thalidomide for multiple myeloma [abstract no. 779]. Blood 2005, 230a
Palumbo A, Ambrosini MT, Pregno P, et al. Velcade™ plus melphalan, prednisone, and thalidomide (V-MPT) for advanced multiple myeloma [abstract no. 2553]. Blood 2005; 106(11): 717a
Richardson PG, Schlossman RL, Weiler E, et al. Immunomodulatory drug CC-5013 overcomes drag resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002; 100(9): 3063–7
Schey SA, Fields P, Bartiett JB, et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol 2004; 22(16): 3269–76
Richardson P, Jagannath S, Schlossman R, et al. A multi-center, randomized, phase II study to evaluate the efficacy and safety of two CDC-5013 dose regimens when used alone or in combination with dexamethasone (Dex) for the treatment of relapsed or refractory multiple myeloma (MM). Blood 2002; 100(11): 105a
Richardson PG, Jagannath S, Hussein MA, et al. A multicenter, single-arm, open-label study to evaluate the safety and efficacy of single-agent lenalidomide in subjects with relapsed and refractory multiple myeloma [abstract no. PO.737]. Hematol J 2005; 90 Suppl. 1: 154
Weber DM, Chen C, Niesvizky R, et al. A multicenter, randomized, parallel-group, double-blind, placebo-controlled study of lenalidomide plus dexamethasone versus dexamethasone alone in previously treated subjects with multiple myeloma [abstract]. Hematol J 2005; 90 Suppl. 1: 155
Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with CC-5013 (lenalidomide; Revlimid™) plus dexamethasone (Rev/Dex) for newly diagnosed myeloma (MM) [abstract]. Blood 2004; 104: 331
Palumbo A, Falco P, Musto P, et al. Oral Revlimid plus melphalan and prednisone (R-MP) for newly diagnosed multiple myeloma [abstract no. 785]. Blood 2005; 11: 173
Richardson PG, Schlossman R, Munshi N, et al. A phase 1 trial of lenalidomide (REVLIMID®) with bortezomib (VELCADE®) in relapsed and refractory multiple myeloma [abstract no. 365]. Blood 2005; 106(11): 137
Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer 2004; 4(5): 349–60
Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001; 61(7): 3071–6
Lee AH, Iwakoshi NN, Anderson KC, et al. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci U S A 2003; 100(17): 9946–51
Hideshima T, Mitsiades C, Akiyama M, et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 2003; 101(4): 1530–4
Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 2002; 20(22): 4420–7
Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348(26): 2609–17
Richardson P, Sonneveld P, Schuster M, et al. Bortezomib demonstrates superior efficacy to high-dose dexamethasone in relapsed multiple myeloma: final report of the APEX Study [abstract]. Blood 2004; 104(11): 336
Richardson P, Sonneveld P, Schuster M, et al. Bortezomib continues to demonstrate superior efficacy compared with high-dose dexamethasone in relapsed multiple myeloma: updated results of the APEX trail [abstract no. 2547]. Blood 2005; 106(11): 715a
Anderson KC. Bortezomib therapy for myeloma. Curr Hematol Rep 2004; 3(1): 65
Chauhan D, Hideshima T, Mitsiades C, et al. Proteasome inhibitor therapy in multiple myeloma. Mol Cancer Ther 2005; 4(4): 686–92
Paterson JL, Li Z, Wen XY, et al. Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma. Br J Haematol 2004; 124(5): 595–603
Grand EK, Chase AJ, Heath C, et al. Targeting FGFR3 in multiple myeloma: inhibition of t (4;14)-positive cells by SU5402 and PD173074. Leukemia 2004; 18(5): 962–6
Trudel S, Ely S, Farooqi Y, et al. Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t (4; 14) myeloma. Blood 2004; 103(9): 3521–8
Trudel S, Li ZH, Wei E, et al. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t (4; 14) multiple myeloma. Blood 2005; 105(7): 2941–8
Chen j, Lee BH, Williams IR, et al. FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies. Oncogene 2005; 24(56): 8259–67
Negri J, Mitsiades N, Deng Q, et al. PKC412 Is a Multi-targeting kinase inhibitor with activity against multiple myeloma in vitro and in vivo [abstract no. 247]. Blood 2005; 106(11): 128
Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006; 6(1): 38–51
Mitsiades N, Mitsiades CS, Richardson PG, et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 2003; 101(10): 4055–62
Catley L, Weisberg E, Tai YT, et al. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood 2003; 102(7): 2615–22
Catley L, Tai YT, Hideshima T, et al. Novel hydroxamic acid-derived HDAC inhibitor LBH589 potently activates intrinsic and extrinsic apoptotic pathways, and induces tubulin hyperacetylation in multiple myeloma [abstract]. Blood 2005; 106: 1578
Podar K, Anderson KC. The pathophysiological role of VEGF in hematological malignancies: therapeutic implications. Blood 2005; 105(4): 1383–95
Bisping G, Leo R, Wenning D, et al. Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma. Blood 2003; 101(7): 2775–83
Casanovas O, Hicklin DJ, Bergers G, et al. Drug resistance by evasion of antiangi-ogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005; 8(4): 299–309
Thomas AL, Morgan B, Drevs J, et al. Vascular endothelial growth factor receptor tyrosine kinase inhibitors. PTK787/ZK 222584. Semin Oncol 2003; 30(3 Suppl. 6): 32–8
Lin B, Podar K, Gupta D, et al. The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment. Cancer Res 2002; 62(17): 5019–26
Kumar R, Hopper TM, Miller CG, et al. Discovery and biological evaluation of GW654652: a pan inhibitor of VEGF receptors [abstract]. Proc Am Assoc Cancer Res 2003; 44(9): 9
Ferrara N, Hillan KJ, Gerber HP, et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004; 3(5): 391–400
Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349(5): 427–34
Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003; 21(16): 3127–32
Bisping G, Kropff M, Wenning D, et al. Targeting receptor kinases by a novel indolinone derivative in multiple myeloma, abrogation of stroma-derived interleukin-6 secretion and induction of apoptosis in cytogenetically defined subgroups. Blood 2006; 105(5): 2079–89
Tai YT, Catley LP, Mitsiades CS, et al. Mechanisms by which SGN-40, a humanized anti-CD40 antibody, induces cytotoxicity in human multiple myeloma cells: clinical implications. Cancer Res 2004; 64(8): 2846–52
Tai YT, Catley L, Li XF, et al. Immunomodulatory drug Lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications [abstract]. Blood 2005; 106: 150
Bezieau S, Avet-Loiseau H, Moisan JP, et al. Activating Ras mutations in patients with plasma-cell disorders. a reappraisal. Blood 2002; 100(3): 1101–2; 1103
Bezieau S, Devilder MC, Avet-Loiseau H, et al. High incidence of N and K-Ras activating mutations in multiple myeloma and primary plasma cell leukemia at diagnosis. Hum Mutat 2001; 18(3): 212–24
Rowley M, Liu P, VanNess B. Heterogeneity in therapeutic response of genetically altered myeloma cell lines to interleukin 6, dexamethasone, doxorubicin, and melphalan. Blood 2000; 96(9): 3175–80
Ochiai N, Uchida R, Fuchida S, et al. Effect of farnesyl transferase inhibitor R115777 on the growth of fresh and cloned myeloma cells in vitro. Blood 2003; 102(9): 3349–53
Adjei AA, Davis JN, Bruzek LM, et al. Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines. Clin Cancer Res 2001; 7(5): 1438–45
Cortes J, Albitar M, Thomas D, et al. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood 2003; 101(5): 1692–7
Beaupre DM, Cepero E, Obeng EA, et al. R115777 induces Ras-independent apoptosis of myeloma cells via multiple intrinsic pathways. Mol Cancer Ther 2004; 3(2): 179–86
Alsina M, Fonseca R, Wilson EF, et al. Faniesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma. Blood 2004; 103(9): 3271–7
Chauhan D, Li G, Shringarpure R, et al. Blockade of Hsp27 overcomes bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res 2003; 63(19): 6174–7
Chauhan D, Li G, Hideshima T, et al. Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance. Blood 2003; 102(9): 3379–86
Chauhan D, Auclair D, Robinson EK, et al. Identification of genes regulated by dexamethasone in multiple myeloma ceils using oligonucieotide arrays. Oncogene 2002; 21(9): 1346–58
Hideshima T, Podar K, Chauhan D, et al. p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. Oncogene 2004Nov 18; 23(54): 8766–76
Mitsiades N, Mitsiades CS, Poulaki V, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 2002; 99(22): 14374–9
Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Anti-myeloma activity of heat shock protein-90 inhibition. Blood 2006Feb 1; 107(3): 1092–100
Abraham RT. Identification of TOR signaling complexes: more TORC for the cell growth engine. Cell 2002; 111(1): 9–12
Hosoi H, Dilling MB, Liu LN, et al. Studies on the mechanism of resistance to rapamycin in human cancer cells. Mol Pharmacol 1998; 54(5): 815–24
Nelsen CJ, Rickheim DG, Tucker MM, et al. Evidence that cyclin D1 mediates both growth and proliferation downstream of TOR in hepatocytes. J Biol Chem 2003; 278(6): 3656–63
Hu L, Shi Y, Hsu JH, et al. Downstream effectors of oncogenic ras in multiple myeloma cells. Blood 2003; 101(8): 3126–35
Gera JF, Mellinghoff IK, Shi Y, et al. AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem 2004; 279(4): 2737–46
Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 2000; 19(56): 6680–6
Frost P, Moatomed F, Hoang B, et al. In vivo anti-tumor effects of the mTOR inhibitor, CCI-779, against human multiple myeloma cells in a xenograft model. Blood 2004Dec 15; 104(13): 4181–7
Raje N, Kumar S, Hideshima T, et al. Combination of the mTOR inhibitor rapamycin and Revlimid™ (CC-5013) has synergistic activity in multiple myeloma. Blood 2004Dec 15; 104(13): 4188–93
Hideshima T, Catley L, Yasui H, et al. Perifosine, an oral bioactive novel alkyl-phospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma (MM) cells [abstract no. 250]. Blood 2005; 106(11): 128
Huston A, Singha U, Alsayed Y, et al. The role of the AKT inhibitor perifosine in migration and adhesion in multiple myeloma (MM) [abstract no. 2509]. Blood 2005; 106(11): 267
Huston A, Francis L, Alsayed Y, et al. Combination of the AKT inhibitor perifosine with the HSP90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) has synergistic activity in multiple myeloma (MM) [abstract no. 1592]. Blood 2005; 106(11): 219
Sinha R, David E, Zeilter E, et al. Combination of Akt/PKB inhibition (perifosine) and farnesyl transferase inhibition (tipifarnib) results in increased cell death in myeloma cell lines [abstract no. 1568]. Blood 2005; 106(11): 218
Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA 2005; 102(24): 8567–72
Macherla VR, Mitchell SS, Manam RR, et al. Structure-activity relationship studies of salinosporamide A (NPI-0052), a novel marine derived proteasome inhibitor. J Med Chem 2005; 48(11): 3684–7
Chauhan D, Catley L, Li G, et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from bortezomib. Cancer Cell 2005; 8(5): 407–19
Ishitsuka K, Hideshima T, Hamasaki M, et al. Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multiple myeloma cells primarily via caspase-independent AIF/Endo G pathway. Oncogene 2005; 24(38): 5888–96
Raje N, Kumar S, Hideshima T, et al. Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood 2005; 106(3): 1042–7
Boissy P, Andersen TL, Abdallah BM, et al. Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation. Cancer Res 2005; 65(21): 9943–52
Yasui H, Hideshima T, Hamasaki M, et al. SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma. Blood 2005; 106(2): 706–12
Hamasaki M, Hideshima T, Tassone P, et al. Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo. Blood 2005; 105(11): 4470–6
Yasui H, Hideshima T, Raje N, et al. FTY720 induces apoptosis in multiple myeloma cells and overcomes drug resistance. Cancer Res 2005; 65(16): 7478–84
Akiyama M, Hideshima T, Hayashi T, et al. Cytokiues modulate telomerase activity in a human multiple myeloma cell line. Cancer Res 2002; 62(13): 3876–82
Akiyama M, Hideshima T, Shammas MA, et al. Effects of oligonucleotide N3′->P5′ thio-phosphoramidate (GRN163) targeting telomerase RNA in human multiple myeloma cells. Cancer Res 2003; 63(19): 6187–94
Shammas MA, Shmookler Reis RJ, Akiyama M, et al. Telomerase inhibition and cell growth arrest by G-quadruplex interactive agent in multiple myeloma. Mol Cancer Ther 2003; 2(9): 825–33
Hideshima T, Chauhan D, Richardson P, et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 2002; 277(19): 16639–47
Hideshima T, Chauhan D, Hayashi T, et al. Antitumor activity of lysophosphatidic acid acyltransferase-beta inhibitors, a novel class of agents, in multiple myeloma. Cancer Res 2003; 63(23): 8428–36
Chauhan D, Li G, Podar K, et al. The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance. Blood 2004; 103(8): 3158–66
van deDonk NW, Kamphuis MM, Lokhorst HM, et al. The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells. Leukemia 2002; 16(7): 1362–71
van deDonk NW, Kamphuis MM, vanKessel B, et al. inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels. Blood 2003; 102(9): 3354–62
Hideshima T, Akiyama M, Hayashi T, et al. Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu. Blood 2003; 101(2): 703–5
Chauhan D, Catley L, Hideshima T, et al. 2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells. Blood 2002; 100(6): 2187–94
Chauhan D, Li G, Auclair D, et al. identification of genes regulated by 2-methoxyestradiol (2ME2) in multiple myeloma cells using oligonucleotide arrays. Blood 2003; 101(9): 3606–14
Pelliniemi TT, Irjala K, Mattila K, et al. Immunoreactive interleukin-6 and acute phase proteins as prognostic factors in multiple myeloma. Finnish Leukemia Group. Blood 1995; 85(3): 765–71
Bataille R, Klein B. The bone-resorbing activity of interleukin-6. J Bone Miner Res 1991; 6(10): 1143–6
Klein B, Wijdenes J, Zhang XG, et al. Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia. Blood 1991; 78(5): 1198–204
Brochier J, Legouffe E, Liautard J, et al. Immunomodulating IL-6 activity by murine monoclonal antibodies. Int J Immunopharmacol 1995; 17(1): 41–8
Kyrstsonis MC, Dedoussis G, Baxevanis C, et al. Serum interleukin-6 (IL-6) and interleukin-4 (IL-4) in patients with multiple myeloma (MM). Br J Haematol 1996; 92(2): 420–2
Levy Y, Tsapis A, Brouet JC. interleukin-6 antisense oligonucleotides inhibit the growth of human myeloma cell lines. J Clin Invest 1991; 88(2): 696–9
Sporeno E, Savino R, Ciapponi L, et al. Human interleukin-6 receptor super-antagonists with high potency and wide spectrum on multiple myeloma cells. Blood 1996; 87(11): 4510–9
Villunger A, Egle A, Kos M, et al. Constituents of autocrine IL-6 loops in myeloma cell lines and their targeting for suppression of neoplastic growth by antibody strategies. Int J Cancer 1996; 65(4): 498–505
Tassone P, Forciniti S, Galea E, et al. Synergistic induction of growth arrest and apoptosis of human myeloma cells by the IL-6 super-antagonist Sant7 and dexamethasone. Cell Death Differ 2000; 7(3): 327–8
Tassone P, Galea E, Forciniti S, et al. The IL-6 receptor super-antagonist Sant7 enhances antiproliferative and apoptotic effects induced by dexamethasone and zoledronic acid on multiple myeloma ceils. Int J Oncol 2002; 21(4): 867–73
Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell 2004; 5(3): 221–30
Gerth K, Bedorf N, Hofle G, et al. Epothilons A and B. antifungal and cytotoxic compounds from sorangium cellulosum (myxobacteria): production, physico-chemical and biological properties. J Antibiot (Tokyo) 1996; 49(6): 560–3
Lin B, Catley L, LeBIanc R, et al. Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo. Blood 2005Jan 1; 105(1): 350–7
Acknowledgments
This work was supported by grants from the National Institutes of Health (RO 50947, PO-1 78378, SPORE P50 CA10070) and the Doris Duke Distinguished Clinical Research Scientist Award (to K.C. Anderson). P.G. Richardson has received honoraria from Celgene and Millenium. The authors have no potential conflicts of interest directly relevant to the contents of this article.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Podar, K., Hideshima, T., Tai, YT. et al. Emerging Therapies for Multiple Myeloma. Am J Cancer 5, 141–153 (2006). https://doi.org/10.2165/00024669-200605030-00001
Published:
Issue Date:
DOI: https://doi.org/10.2165/00024669-200605030-00001