Skip to main content

Targeted Therapy of Multiple Myeloma

  • Chapter
  • First Online:
Book cover Impact of Genetic Targets on Cancer Therapy

Part of the book series: Advances in Experimental Medicine and Biology ((volume 779))

Abstract

Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematologic cancer. MM is characterized by the accumulation of malignant plasma cells within the bone marrow, and presents clinically with a broad range of symptoms, including hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. MM is a heterogeneous disease associated with genomic instability, where patients may express multiple genetic abnormalities that affect several oncogenic pathways. Commonly detected genetic aberrations are translocations involving immunoglobulin heavy chain (IgH) switch regions (chromosome 14q32) and oncogenes such as c-maf [t(14:16)], cyclin D1 [t(11:14)], and FGFR3/MMSET [t(4:14)]. Advances in the basic understanding of MM and the development of novel agents, such as the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib, have increased therapeutic response rates and prolonged patient survival. Despite these advances MM remains incurable in the majority of patients, and it is therefore critical to identify additional therapeutic strategies and targets for its treatment. In this chapter, we review the underlying genetic components of MM and discuss the results of recent clinical trials that demonstrate the effectiveness of targeted agents in the management of MM. In addition, we discuss experimental therapies that are currently in clinical development along with their molecular rationale in the treatment of MM.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.

    Article  PubMed  Google Scholar 

  2. Talamo G, Farooq U, Zangari M, et al. Beyond the CRAB symptoms: a study of presenting clinical manifestations of multiple myeloma. Clin Lymphoma Myeloma Leuk. 2010;10:464–8.

    Article  PubMed  Google Scholar 

  3. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516–20.

    Article  PubMed  CAS  Google Scholar 

  4. Stewart AK, Richardson PG, San-Miguel JF. How I treat multiple myeloma in younger patients. Blood. 2009;114(27):5436–43.

    Article  PubMed  CAS  Google Scholar 

  5. Anderson KC, Alsina M, Bensinger W, et al. NCCN clinical practice guidelines in oncology: multiple myeloma. J Natl Compr Canc Netw. 2009;7:908–42.

    PubMed  Google Scholar 

  6. Roodman GD. Pathogenesis of myeloma bone disease. Leukemia. 2009;23:435–41.

    Article  PubMed  CAS  Google Scholar 

  7. Roodman GD, Dougall WC. RANK ligand as a therapeutic target for bone metastases and multiple myeloma. Cancer Treat Rev. 2008;34:92–101.

    Article  PubMed  CAS  Google Scholar 

  8. Berenson JR. Therapeutic options in the management of myeloma bone disease. Semin Oncol. 2010;37 Suppl 1:S20–9.

    Article  PubMed  CAS  Google Scholar 

  9. Zangari M, Zhan F, Tricot G. Bone and paraproteinemias. Curr Opin Support Palliat Care. 2010;4:195–9.

    Article  PubMed  Google Scholar 

  10. Fenton JA, Pratt G, Rawstron AC, et al. Isotype class switching and the pathogenesis of m­ultiple myeloma. Hematol Oncol. 2002;20:75–85.

    Article  PubMed  CAS  Google Scholar 

  11. Gonzalez D, van der Burg M, Garcia-Sanz R, et al. Immunoglobulin gene rearrangements and the pathogenesis of multiple myeloma. Blood. 2007;110:3112–21.

    Article  PubMed  CAS  Google Scholar 

  12. Chesi M, Nardini E, Lim RS, et al. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood. 1998;92:3025–34.

    PubMed  CAS  Google Scholar 

  13. He LZ, Tribioli C, Rivi R, et al. Acute leukemia with promyelocytic features in PML/RARalpha transgenic mice. Proc Natl Acad Sci USA. 1997;94:5302–7.

    Article  PubMed  CAS  Google Scholar 

  14. Wong S, Witte ON. Modeling Philadelphia chromosome positive leukemias. Oncogene. 2001;20:5644–59.

    Article  PubMed  CAS  Google Scholar 

  15. Fiancette R, Amin R, Truffinet V, et al. A myeloma translocation-like model associating CCND1 with the immunoglobulin heavy-chain locus 3′ enhancers does not promote by itself B-cell malignancies. Leuk Res. 2010;34:1043–51.

    Article  PubMed  CAS  Google Scholar 

  16. Rasmussen T, Theilgaard-Monch K, Hudlebusch HR, et al. Occurrence of dysregulated oncogenes in primary plasma cells representing consecutive stages of myeloma pathogenesis: indications for different disease entities. Br J Haematol. 2003;123:253–62.

    Article  PubMed  CAS  Google Scholar 

  17. Nahi H, Sutlu T, Jansson M, et al. Clinical impact of chromosomal aberrations in multiple myeloma. J Intern Med. 2011;269:137–47.

    Article  PubMed  CAS  Google Scholar 

  18. Chang H, Qi C, Yi QL, et al. p53 Gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation. Blood. 2005;105:358–60.

    Article  PubMed  CAS  Google Scholar 

  19. Knight R. IMiDs: a novel class of immunomodulators. Semin Oncol. 2005;32:S24–30.

    Article  PubMed  CAS  Google Scholar 

  20. Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood. 2008;111:3968–77.

    Article  PubMed  CAS  Google Scholar 

  21. Paravar T, Lee DJ. Thalidomide: mechanisms of action. Int Rev Immunol. 2008;27:111–35.

    Article  PubMed  CAS  Google Scholar 

  22. Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327:1345–50.

    Article  PubMed  CAS  Google Scholar 

  23. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133–42.

    Article  PubMed  CAS  Google Scholar 

  24. Gay F, Hayman SR, Lacy MQ, et al. Lenalidomide plus dexamethasone versus thalidomide plus dexamethasone in newly diagnosed multiple myeloma: a comparative analysis of 411 patients. Blood. 2010;115:1343–50.

    Article  PubMed  CAS  Google Scholar 

  25. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24:1934–9.

    Article  PubMed  CAS  Google Scholar 

  26. Obeng EA, Carlson LM, Gutman DM, et al. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107:4907–16.

    Article  PubMed  CAS  Google Scholar 

  27. Cenci S, Mezghrani A, Cascio P, et al. Progresively impaired proteasomal capacity during terminal plasma cell differentiation. EMBO J. 2006;25:1104–13.

    Article  PubMed  CAS  Google Scholar 

  28. Chauhan D, Hideshima T, Anderson KC. Targeting proteasomes as therapy in multiple myeloma. Adv Exp Med Biol. 2008;615:251–60.

    Article  PubMed  CAS  Google Scholar 

  29. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609–17.

    Article  PubMed  CAS  Google Scholar 

  30. Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007;110:3281–90.

    Article  PubMed  CAS  Google Scholar 

  31. O’Connor OA, Stewart AK, Vallone M, et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res. 2009;15:7085–91.

    Article  PubMed  CAS  Google Scholar 

  32. Singh AV, Palladino MA, Lloyd GK, et al. Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI-0052 (marizomib) in a human plasmacytoma xenograft murine model. Br J Haematol. 2010;149:550–9.

    Article  PubMed  CAS  Google Scholar 

  33. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone co­mbination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679–86.

    Article  PubMed  CAS  Google Scholar 

  34. Kim TY, Bang YJ, Robertson KD. Histone deacetylase inhibitors for cancer therapy. Epigenetics. 2006;1:14–23.

    Article  PubMed  Google Scholar 

  35. Kikuchi J, Wada T, Shimizu R, et al. Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma. Blood. 2010;116:406–17.

    Article  PubMed  CAS  Google Scholar 

  36. Richardson P, Mitsiades C, Colson K, et al. Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma. Leuk Lymphoma. 2008;49:502–7.

    Article  PubMed  CAS  Google Scholar 

  37. Badros A, Burger AM, Philip S, et al. Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res. 2009;15:5250–7.

    Article  PubMed  CAS  Google Scholar 

  38. Mazumder A, Vesole DH, Jagannath S. Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: a case series illustrating utility in clinical practice. Clin Lymphoma Myeloma Leuk. 2010;10:149–51.

    Article  PubMed  CAS  Google Scholar 

  39. Niesvizky R, Ely S, Mark T, et al. Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma. Cancer. 2011;117:336–42.

    Article  PubMed  CAS  Google Scholar 

  40. Santo L, Hideshima T, Kung AL, Tseng JC, Tang D, Yang M, et al. Preclinical activity, pharmacodynamic and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood. 2012;19:2579–89. Epub ahead of print.

    Article  CAS  Google Scholar 

  41. Davenport EL, Moore HE, Dunlop AS, et al. Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells. Blood. 2007;110:2641–9.

    Article  PubMed  CAS  Google Scholar 

  42. Mitsiades CS, Mitsiades NS, McMullan DJ, et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood. 2006;107:1092–100.

    Article  PubMed  CAS  Google Scholar 

  43. Okawa Y, Hideshima T, Steed P, et al. SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK. Blood. 2009;113:846–55.

    Article  PubMed  CAS  Google Scholar 

  44. Richardson PG, Chanan-Khan AA, Alsina M, et al. Tanespimycin monotherapy in relapsed multiple myeloma: results of a phase 1 dose-escalation study. Br J Haematol. 2010;150:438–45.

    PubMed  CAS  Google Scholar 

  45. Richardson PG, Badros AZ, Jagannath S, et al. Tanespimycin with bortezomib: activity in relapsed/refractory patients with multiple myeloma. Br J Haematol. 2010;150:428–37.

    PubMed  CAS  Google Scholar 

  46. Kumar S, Lacy MQ, Dispenzieri A, et al. Single agent dexamethasone for pre-stem cell transplant induction therapy for multiple myeloma. Bone Marrow Transplant. 2004;34:485–90.

    Article  PubMed  CAS  Google Scholar 

  47. Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: the second decade. Cell. 1995;83:835–9.

    Article  PubMed  CAS  Google Scholar 

  48. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8:627–44.

    Article  PubMed  CAS  Google Scholar 

  49. Pene F, Claessens YE, Muller O, et al. Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene. 2002;21:6587–97.

    Article  PubMed  CAS  Google Scholar 

  50. Stromberg T, Dimberg A, Hammarberg A, et al. Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. Blood. 2004;103:3138–47.

    Article  PubMed  CAS  Google Scholar 

  51. Frost P, Moatamed F, Hoang B, et al. In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. Blood. 2004;104:4181–7.

    Article  PubMed  CAS  Google Scholar 

  52. Yan H, Frost P, Shi Y, et al. Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Cancer Res. 2006;66:2305–13.

    Article  PubMed  CAS  Google Scholar 

  53. Francis LK, Alsayed Y, Leleu X, et al. Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma. Clin Cancer Res. 2006;12:6826–35.

    Article  PubMed  CAS  Google Scholar 

  54. Raje N, Kumar S, Hideshima T, et al. Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood. 2004;104:4188–93.

    Article  PubMed  CAS  Google Scholar 

  55. Harvey RD, Lonial S. PI3 kinase/AKT pathway as a therapeutic target in multiple myeloma. Future Oncol. 2007;3:639–47.

    Article  PubMed  CAS  Google Scholar 

  56. Farag SS, Zhang S, Jansak BS, et al. Phase II trial of temsirolimus in patients with relapsed or refractory multiple myeloma. Leuk Res. 2009;33:1475–80.

    Article  PubMed  CAS  Google Scholar 

  57. Georgii-Hemming P, Wiklund HJ, Ljunggren O, et al. Insulin-like growth factor I is a growth and survival factor in human multiple myeloma cell lines. Blood. 1996;88:2250–8.

    PubMed  CAS  Google Scholar 

  58. Ge NL, Rudikoff S. Insulin-like growth factor I is a dual effector of multiple myeloma cell growth. Blood. 2000;96:2856–61.

    PubMed  CAS  Google Scholar 

  59. Lacy MQ, Alsina M, Fonseca R, et al. Phase I, pharmacokinetic and pharmacodynamic study of the anti-insulinlike growth factor type 1 receptor monoclonal antibody CP-751,871 in patients with multiple myeloma. J Clin Oncol. 2008;26:3196–203.

    Article  PubMed  CAS  Google Scholar 

  60. Moreau P, Cavallo F, Leleu X, Hulin C, Amiot M, Descamps G, Facon T, Boccadoro M, Mignard D, Harousseau JL. Phase I study of the anti insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody, AVE1642, as single agent and in combination with bortezomib in patients with relapsed multiple myeloma. Leukemia. 2011;25(5):872–4.

    Article  PubMed  CAS  Google Scholar 

  61. Borset M, Hjorth-Hansen H, Seidel C, et al. Hepatocyte growth factor and its receptor c-met in multiple myeloma. Blood. 1996;88:3998–4004.

    PubMed  CAS  Google Scholar 

  62. Derksen PW, de Gorter DJ, Meijer HP, et al. The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma. Leukemia. 2003;17:764–74.

    Article  PubMed  CAS  Google Scholar 

  63. Hov H, Holt RU, Rø TB, Fagerli UM, Hjorth-Hansen H, Baykov V, Christensen JG, Waage A, Sundan A, Børset M. A selective c-met inhibitor blocks an autocrine hepatocyte growth factor growth loop in ANBL-6 cells and prevents migration and adhesion of myeloma cells. Clin Cancer Res. 2004;10(19):6686–94.

    Article  PubMed  CAS  Google Scholar 

  64. Maloney DG, Donovan K, Hamblin TJ. Antibody therapy for treatment of multiple myeloma. Semin Hematol. 1999;36:30–3.

    PubMed  CAS  Google Scholar 

  65. Kapoor P, Greipp PT, Morice WG, et al. Anti-CD20 monoclonal antibody therapy in multiple myeloma. Br J Haematol. 2008;141:135–48.

    Article  PubMed  CAS  Google Scholar 

  66. Zojer N, Kirchbacher K, Vesely M, et al. Rituximab treatment provides no clinical benefit in patients with pretreated advanced multiple myeloma. Leuk Lymphoma. 2006;47:1103–9.

    Article  PubMed  CAS  Google Scholar 

  67. Moreau P, Voillat L, Benboukher L, et al. Rituximab in CD20 positive multiple myeloma. Leukemia. 2007;21:835–6.

    Article  PubMed  CAS  Google Scholar 

  68. Kovalchuk AL, Kim JS, Park SS, et al. IL-6 transgenic mouse model for extraosseous plasmacytoma. Proc Natl Acad Sci U S A. 2002;99:1509–14.

    Article  PubMed  CAS  Google Scholar 

  69. van Rhee F, Fayad L, Voorhees P, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol. 2010;28:3701–8.

    Article  PubMed  CAS  Google Scholar 

  70. Hunsucker SA, Magarotto V, Kuhn DJ, et al. Blockade of interleukin-6 signaling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma. Br J Haematol. 2011;152:579–92.

    Article  PubMed  CAS  Google Scholar 

  71. Voorhees PM, Chen Q, Small GW, et al. Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death. Br J Haematol. 2009;145:481–90.

    Article  PubMed  CAS  Google Scholar 

  72. Fulciniti M, Hideshima T, Vermot-Desroches C, et al. A high-affinity fully human anti-IL-6 mAb, 1339, for the treatment of multiple myeloma. Clin Cancer Res. 2009;15:7144–52.

    Article  PubMed  CAS  Google Scholar 

  73. van Rhee F, Szmania SM, Dillon M, et al. Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma. Mol Cancer Ther. 2009;8:2616–24.

    Article  PubMed  CAS  Google Scholar 

  74. Lesage D, Troussard X, Sola B. The enigmatic role of cyclin D1 in multiple myeloma. Int J Cancer. 2005;115:171–6.

    Article  PubMed  CAS  Google Scholar 

  75. Marsaud V, Tchakarska G, Andrieux G, et al. Cyclin K and cyclin D1b are oncogenic in myeloma cells. Mol Cancer. 2010;9:103.

    Article  PubMed  CAS  Google Scholar 

  76. Tchakarska G, Le Lan-Leguen A, Roth L, et al. The targeting of the sole cyclin D1 is not adequate for mantle cell lymphoma and myeloma therapies. Haematologica. 2009;94:1781–2.

    Article  PubMed  CAS  Google Scholar 

  77. Raje N, Hideshima T, Mukherjee S, et al. Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma. Leukemia. 2009;23:961–70.

    Article  PubMed  CAS  Google Scholar 

  78. Dispenzieri A, Gertz MA, Lacy MQ, et al. Flavopiridol in patients with relapsed or refractory multiple myeloma: a phase 2 trial with clinical and pharmacodynamic end-points. Haematologica. 2006;91:390–3.

    PubMed  CAS  Google Scholar 

  79. Holkova B, Perkins EB, Ramakrishnan V, Tombes MB, Shrader E, Talreja N, Wellons MD, Hogan KT, Roodman GD, Coppola D, Kang L, Dawson J, Stuart RK, Peer C, Figg Sr WD, Kolla S, Doyle A, Wright J, Sullivan DM, Roberts JD, Grant S. Phase I trial of bortezomib (PS-341; NSC 681239) and alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory B-cell neoplasms. Clin Cancer Res. 2011;17(10):3388–97.

    Article  PubMed  CAS  Google Scholar 

  80. Saunders A, Core LJ, Lis JT. Breaking barriers to transcription elongation. Nat Rev Mol Cell Biol. 2006;7:557–67.

    Article  PubMed  CAS  Google Scholar 

  81. Tong WG, Chen R, Plunkett W, Siegel D, Sinha R, Harvey RD, Badros AZ, Popplewell L, Coutre S, Fox JA, Mahadocon K, Chen T, Kegley P, Hoch U, Wierda WG. Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma. J Clin Oncol. 2010;28(18):3015–22.

    Article  PubMed  CAS  Google Scholar 

  82. Santo L, Vallet S, Hideshima T, Cirstea D, Ikeda H, Pozzi S, Patel K, Okawa Y, Gorgun G, Perrone G, Calabrese E, Yule M, Squires M, Ladetto M, Boccadoro M, Richardson PG, Munshi NC, Anderson KC, Raje N. AT7519, a novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma. Oncogene. 2010;29(16):2325–36.

    Article  PubMed  CAS  Google Scholar 

  83. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, Mitsiades CS. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904–17.

    Article  PubMed  CAS  Google Scholar 

  84. Santra M, Zhan F, Tian E, et al. A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood. 2003;101:2374–6.

    Article  PubMed  CAS  Google Scholar 

  85. Quintero-Rivera F, El-Sabbagh Badr R, Rao PN. FGFR3 amplification in the absence of IGH-FGFR3 fusion t(4;14) in myeloma. Cancer Genet Cytogenet. 2009;195:92–3.

    Article  PubMed  CAS  Google Scholar 

  86. Krejci P, Murakami S, Prochazkova J, et al. NF449 is a novel inhibitor of fibroblast growth factor receptor 3 (FGFR3) signaling active in chondrocytes and multiple myeloma cells. J Biol Chem. 2010;285:20644–53.

    Article  PubMed  CAS  Google Scholar 

  87. Xin X, Abrams TJ, Hollenbach PW, et al. CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice. Clin Cancer Res. 2006;12:4908–15.

    Article  PubMed  CAS  Google Scholar 

  88. Trudel S, Stewart AK, Rom E, et al. The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. Blood. 2006;107:4039–46.

    Article  PubMed  CAS  Google Scholar 

  89. Matsui W, Wang Q, Barber JP, et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res. 2008;68:190–7.

    Article  PubMed  CAS  Google Scholar 

  90. Huff CA, Matsui W. Multiple myeloma cancer stem cells. J Clin Oncol. 2008;26:2895–900.

    Article  PubMed  Google Scholar 

  91. Mueller MM, Fusenig NE. Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004;4:839–49.

    Article  PubMed  CAS  Google Scholar 

  92. McMillin DW, Delmore J, Weisberg E, Negri JM, Geer DC, Klippel S, Mitsiades N, Schlossman RL, Munshi NC, Kung AL, Griffin JD, Richardson PG, Anderson KC, Mitsiades CS. Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nat Med. 2010;16(4):483–9.

    Article  PubMed  CAS  Google Scholar 

  93. Rajkumar SV, Mesa RA, Fonseca R, et al. Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis. Clin Cancer Res. 2002;8:2210–6.

    PubMed  Google Scholar 

  94. Ria R, Roccaro AM, Merchionne F, et al. Vascular endothelial growth factor and its receptors in multiple myeloma. Leukemia. 2003;17:1961–6.

    Article  PubMed  CAS  Google Scholar 

  95. Kumar S, Witzig TE, Timm M, et al. Expression of VEGF and its receptors by myeloma cells. Leukemia. 2003;17:2025–31.

    Article  PubMed  CAS  Google Scholar 

  96. Van Meter ME, Kim ES. Bevacizumab: current updates in treatment. Curr Opin Oncol. 2010;22:586–91.

    Article  PubMed  CAS  Google Scholar 

  97. Zangari M, Anaissie E, Stopeck A, et al. Phase II study of SU5416, a small molecule vascular endothelial growth factor tyrosine kinase receptor inhibitor, in patients with refractory multiple myeloma. Clin Cancer Res. 2004;10:88–95.

    Article  PubMed  CAS  Google Scholar 

  98. Kovacs MJ, Reece DE, Marcellus D, et al. A phase II study of ZD6474 (zactima, a selective inhibitor of VEGFR and EGFR tyrosine kinase in patients with relapsed multiple myeloma–NCIC CTG IND.145. Invest New Drugs. 2006;24:529–35.

    PubMed  CAS  Google Scholar 

  99. Prince HM, Honemann D, Spencer A, et al. Vascular endothelial growth factor inhibition is not an effective therapeutic strategy for relapsed or refractory multiple myeloma: a phase 2 study of pazopanib (GW786034). Blood. 2009;113:4819–20.

    Article  PubMed  CAS  Google Scholar 

  100. Alsina M, Fonseca R, Wilson EF, et al. Farnesyltransferase 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;103:3271–7.

    Article  PubMed  CAS  Google Scholar 

  101. Chanan-Khan AA, Niesvizky R, Hohl RJ, et al. Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma. Leuk Lymphoma. 2009;50:559–65.

    Article  PubMed  CAS  Google Scholar 

  102. Tsimberidou AM, Waddelow T, Kantarjian HM, et al. Pilot study of recombinant human soluble tumor necrosis factor (TNF) receptor (p75) fusion protein (TNFR:Fc; Enbrel) in patients with refractory multiple myeloma: increase in plasma TNF alpha levels during treatment. Leuk Res. 2003;27:375–80.

    Article  PubMed  CAS  Google Scholar 

  103. Dispenzieri A, Gertz MA, Lacy MQ, Geyer SM, Greipp PR, Rajkumar SV, Kimlinger T, Lust JA, Fonseca R, Allred J, Witzig TE. A phase II trial of imatinib in patients with refractory/relapsed myeloma. Leuk Lymphoma. 2006;47(1):39–42.

    Article  PubMed  CAS  Google Scholar 

  104. Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471(7339):467–72.

    Article  PubMed  CAS  Google Scholar 

  105. 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;98:492–4.

    Article  PubMed  CAS  Google Scholar 

  106. Mileshkin L, Biagi JJ, Mitchell P, et al. Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age. Blood. 2003;102:69–77.

    Article  PubMed  CAS  Google Scholar 

  107. Tosi P, Zamagni E, Cellini C, et al. Salvage therapy with thalidomide in patients with advanced relapsed/refractory multiple myeloma. Haematologica. 2002;87:408–14.

    PubMed  CAS  Google Scholar 

  108. Rajkumar SV, Gertz MA, Lacy MQ, et al. Thalidomide as initial therapy for early-stage myeloma. Leukemia. 2003;17:775–9.

    Article  PubMed  CAS  Google Scholar 

  109. Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006;24:431–6.

    Article  PubMed  CAS  Google Scholar 

  110. Richardson P, Jagannath S, Hussein M, et al. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 2009;114:772–8.

    Article  PubMed  CAS  Google Scholar 

  111. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123–32.

    Article  PubMed  CAS  Google Scholar 

  112. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomized controlled trial. Lancet Oncol. 2010;11:29–37.

    Article  PubMed  CAS  Google Scholar 

  113. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487–98.

    Article  PubMed  CAS  Google Scholar 

  114. Jagannath S, Durie BG, Wolf J, et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol. 2005;129:776–83.

    Article  PubMed  CAS  Google Scholar 

  115. Orlowski RZ, Nagler A, Sonneveld P, et al. 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. J Clin Oncol. 2007;25:3892–901.

    Article  PubMed  CAS  Google Scholar 

  116. Mikhael JR, Belch AR, Prince HM, et al. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program. Br J Haematol. 2009;144:169–75.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nathan G. Dolloff .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Dolloff, N.G., Talamo, G. (2013). Targeted Therapy of Multiple Myeloma. In: El-Deiry, W. (eds) Impact of Genetic Targets on Cancer Therapy. Advances in Experimental Medicine and Biology, vol 779. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6176-0_9

Download citation

Publish with us

Policies and ethics