Abstract
The past decade has witnessed a dramatic increase in the therapeutic options for the treatment of multiple myeloma (MM) with the introduction of novel biologically targeted agents which in turn have resulted in significantly improved outcomes. However, myeloma remains incurable, and ongoing efforts to identify novel therapeutic approaches remain an urgent priority. Newer agents that target tumour and stromal compartments can be categorized as those that target protein dynamics (such as ubiquitin–proteasome system and heat-shock protein 90), drugs modulating anti-MM immune response (IMiDs), antibodies targeting membrane-bound receptors (including CS1, CD38, CD138), epigenetic modulators (DNA methyltransferase and histone deacetylase inhibitors), intracellular-signalling kinase inhibitors (PI3k/Akt/mTOR, MAPK pathways) and compounds disrupting the cell-cycle molecular machinery (such as CDKIs and Aurora kinase inhibitors). This chapter focuses on new therapeutic targets which have shown promising preclinical results and early evidence of anti-MM activity in clinical studies.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Brenner H, Gondos A, Pulte D (2008) Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 111:2521–2526
Kumar SK, Rajkumar SV, Dispenzieri A et al (2008) Improved survival in multiple myeloma and the impact of novel therapies. Blood 111:2516–2520
Kumar SK, Lee JH, Lahuerta JJ et al (2011) Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia 26(1):149–157
Anderson KC (2011) Oncogenomics to target myeloma in the bone marrow microenvironment. Clin Cancer Res 17:1225–1233
Palumbo A, Anderson K (2011) Multiple myeloma. N Engl J Med 364:1046–1060
Richardson PG, Barlogie B, Berenson J et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609–2617
Richardson PG, Sonneveld P, Schuster MW et al (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487–2498
San Miguel JF, Schlag R, Khuageva NK et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906–917
Hideshima T, Chauhan D, Shima Y et al (2000) Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96:2943–2950
Hideshima T, Richardson PG, Anderson KC (2006) Current therapeutic uses of lenalidomide in multiple myeloma. Expert Opin Investig Drugs 15:171–179
Rajkumar SV, Rosinol L, Hussein M et al (2008) 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 26:2171–2177
Dimopoulos M, Spencer A, Attal M et al (2007) Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357:2123–2132
Weber DM, Chen C, Niesvizky R et al (2007) Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357:2133–2142
Orlowski RZ, Nagler A, Sonneveld P et al (2007) Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 25:3892–3901
Rajkumar SV, Jacobus S, Callander N et al (2007) A randomized trial of lenalidomide plus high-dose dexamethasone (RD) versus lenalidomide plus low-dose dexamethasone (Rd) in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. ASH Annual Meeting Abstracts 110:74
Richardson PG, Weller E, Lonial S et al (2010) Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116:679–686
Richardson PG, Weller E, Jagannath S et al (2009) Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol 27:5713–5719
Tai YT, Dillon M, Song W et al (2008) Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood 112:1329–1337
Zonder JA, Mohrbacher AF, Singhal S et al (2011) A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood 120(3):552–559
Richardson PG, Moreau P, Jakubowiak AJ et al (2010) Elotuzumab In combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: interim results of a phase 2 study. ASH Annual Meeting Abstracts 116:986
de Weers M, Tai YT, van der Veer MS et al (2011) Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol 186:1840–1848
Gimsing P, Plesner T, Nahi H et al (2011) A phase I/II, dose-escalation study of daratumumab, A CD38 Mab in patients with multiple myeloma – preliminary safety data. ASH Annual Meeting Abstracts 118:1873
Ikeda H, Hideshima T, Fulciniti M et al (2009) The monoclonal antibody nBT062 conjugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin Cancer Res 15:4028–4037
Kurihara N, Bertolini D, Suda T, Akiyama Y, Roodman GD (1990) IL-6 stimulates osteoclast-like multinucleated cell formation in long term human marrow cultures by inducing IL-1 release. J Immunol 144:4226–4230
Voorhees PM, Chen Q, Kuhn DJ et al (2007) Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clin Cancer Res 13:6469–6478
Neri P, Kumar S, Fulciniti MT et al (2007) Neutralizing B-cell activating factor antibody improves survival and inhibits osteoclastogenesis in a severe combined immunodeficient human multiple myeloma model. Clin Cancer Res 13:5903–5909
Bartlett JB, Dredge K, Dalgleish AG (2004) The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 4:314–322
Lacy MQ, Hayman SR, Gertz MA et al (2009) Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol 27:5008–5014
Lacy MQ, Allred JB, Gertz MA et al (2011) Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood 118:2970–2975
Richardson PG, Siegel DS, Vij R et al (2011) Randomized, open label phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (Pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): phase 2 results. ASH Annual Meeting Abstracts 118:634
Vij R, Wang M, Orlowski R et al (2008) Initial results of PX-171-004, an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients with relapsed myeloma (MM). ASH Annual Meeting Abstracts 112:865
US National Library of Medicine (2011) ClinicalTrials.gov. [online], http://clinicaltrials.gov/ct2/show/NCT01080391
Chauhan D, Tian Z, Zhou B et al (2011) In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res 17:5311–5321
Chauhan D, Singh AV, Aujay M et al (2010) A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma. Blood 116:4906–4915
Singh AV, Palladino MA, Lloyd GK, Potts BC, Chauhan D, Anderson KC (2010) Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI-0052 (marizomib) in a human plasmacytoma xenograft murine model. Br J Haematol 149:550–559
Chauhan D, Singh AV, Ciccarelli B, Richardson PG, Palladino MA, Anderson KC (2010) Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma. Blood 115:834–845
Richardson PG, Spencer A, Cannell P et al (2011) Phase 1 clinical evaluation of twice-weekly marizomib (NPI-0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple myeloma (MM). ASH Annual Meeting Abstracts 118:302
Chauhan D, Tian Z, Nicholson B et al (2009) Deubiquitylating enzyme USP-7, a novel therapeutic target in multiple myeloma. ASH Annual Meeting Abstracts 114:610
Kuhn DJ, Hunsucker SA, Chen Q, Voorhees PM, Orlowski M, Orlowski RZ (2009) Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors. Blood 113:4667–4676
McMillin DW, Hunter Z, Delmore J et al (2010) MLN4924, a novel investigational NEDD8 activating enzyme inhibitor, exhibits preclinical activity in multiple myeloma and Waldenstrom’s macroglobulinemia through mechanism distinct from existing proteasome inhibitors. ASH Annual Meeting Abstracts 116:2988
Hideshima T, Bradner JE, Wong J et al (2005) Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA 102:8567–8572
Santo L, Hideshima T, Kung AL et al (2010) Selective inhibition of HDAC6 with a new prototype inhibitor (ACY-1215) overcomes bortezomib resistance in multiple myeloma (MM). ASH Annual Meeting Abstracts 116:2997
Mitsiades CS, Mitsiades NS, McMullan CJ et al (2004) Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA 101:540–545
Wolf JL, Siegel D, Matous J et al (2008) A phase II study of oral panobinostat (LBH589) in adult patients with advanced refractory multiple myeloma. ASH Annual Meeting Abstracts 112:2774
Weber DM, Jagannath S, Sobecks R et al (2008) Combination of vorinostat plus bortezomib for the treatment of patients with multiple myeloma who have previously received bortezomib. ASH Annual Meeting Abstracts 112:3711
Richardson P, Weber D, Mitsiades CS et al (2010) A phase I study of vorinostat, lenalidomide, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: excellent tolerability and promising activity in a heavily pretreated population. ASH Annual Meeting Abstracts 116:1951
Siegel DS, Jagannath S, Hajek R et al (2010) Vorinostat combined with bortezomib in patients with relapsed or relapsed and refractory multiple myeloma: update on the Vantage Study Program. ASH Annual Meeting Abstracts 116:1952
Harrison SJ, Quach H, Link E et al (2011) A high rate of durable responses with romidepsin, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma. Blood 118:6274–6283
Deleu S, Lemaire M, Arts J et al (2009) Bortezomib alone or in combination with the histone deacetylase inhibitor JNJ-26481585: effect on myeloma bone disease in the 5T2MM murine model of myeloma. Cancer Res 69:5307–5311
Richardson P, Chanan-Khan AA, Lonial S et al (2006) A multicenter phase 1 clinical trial of tanespimycin (KOS-953) + bortezomib (BZ): encouraging activity and manageable toxicity in heavily pre-treated patients with relapsed refractory multiple myeloma (MM). ASH Annual Meeting Abstracts 108:406
Richardson PG, Chanan-Khan AA, Lonial S et al (2011) Tanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory multiple myeloma: results of a phase 1/2 study. Br J Haematol 153:729–740
Tai YT, Podar K, Catley L et al (2003) Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of beta1-integrin and phosphatidylinositol 3’-kinase/AKT signaling. Cancer Res 63:5850–5858
Hideshima T, Catley L, Raje N et al (2007) Inhibition of Akt induces significant downregulation of survivin and cytotoxicity in human multiple myeloma cells. Br J Haematol 138:783–791
Hideshima T, Catley L, Yasui H et al (2006) Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 107:4053–4062
Gajate C, Mollinedo F (2007) Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood 109:711–719
Richardson PG, Wolf J, Jakubowiak A et al (2011) Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial. J Clin Oncol 29:4243–4249
Hideshima T, Chauhan D, Richardson P, Anderson KC (2005) Identification and validation of novel therapeutic targets for multiple myeloma. J Clin Oncol 23:6345–6350
Shi Y, Hsu JH, Hu L, Gera J, Lichtenstein A (2002) Signal pathways involved in activation of p70S6K and phosphorylation of 4E-BP1 following exposure of multiple myeloma tumor cells to interleukin-6. J Biol Chem 277:15712–15720
Raje N, Kumar S, Hideshima T et al (2004) Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood 104:4188–4193
Frost P, Moatamed F, Hoang B et al (2004) In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. Blood 104:4181–4187
Wan X, Harkavy B, Shen N, Grohar P, Helman LJ (2007) Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26:1932–1940
Sun SY, Rosenberg LM, Wang X et al (2005) Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 65: 7052–7058
Mahindra A, Richardson PG, Hari P et al (2010) Updated results of a phase I study of RAD001 in combination with lenalidomide in patients with relapsed or refractory multiple myeloma with pharmacodynamic and pharmacokinetic analysis. ASH Annual Meeting Abstracts 116:3051
Ghobrial IM, Weller E, Vij R et al (2011) Weekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: a multicentre, phase 1/2, open-label, dose-escalation study. Lancet Oncol 12:263–272
US National Library of Medicine. http://clinicaltrials.gov/ct2/show/NCT01118689 [Dose Escalation Study of INK128 in Relapsed or Refractory Multiple Myeloma or Waldenstrom Macroglobulinemia].
Cirstea D, Hideshima T, Santo L et al (2010) Disruption of DEPTOR/mTORC1/mTORC2 signaling cascade using a novel selective mtor kinase inhibitor azd8055 results in growth arrest and apoptosis in multiple myeloma cells. ASH Annual Meeting Abstracts 116:791
McMillin DW, Ooi M, Delmore J et al (2009) Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res 69:5835–5842
Bergsagel PL, Kuehl WM (2005) Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 23:6333–6338
Baughn LB, Di Liberto M, Wu K et al (2006) A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res 66:7661–7667
Santo L, Vallet S, Hideshima T et al (2010) AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3beta Âactivation and RNA polymerase II inhibition. Oncogene 29:2325–2336
Santo L, Vallet S, Hideshima T et al (2008) AT7519, a novel small molecule multi-cyclin dependent kinase inhibitor, induces apoptosis in multiple myeloma VIA GSK3{beta}. ASH Annual Meeting Abstracts 112:251
Dutta-Simmons J, Zhang Y, Gorgun G et al (2009) Aurora kinase A is a target of Wnt/beta-catenin involved in multiple myeloma disease progression. Blood 114:2699–2708
Evans RP, Naber C, Steffler T et al (2008) The selective Aurora B kinase inhibitor AZD1152 is a potential new treatment for multiple myeloma. Br J Haematol 140:295–302
Hose D, Reme T, Meissner T et al (2009) Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma. Blood 113:4331–4340
Negri JM, McMillin DW, Delmore J et al (2009) In vitro anti-myeloma activity of the Aurora kinase inhibitor VE-465. Br J Haematol 147(5):672–676
Shammas MA, Koley H, Bertheau RC et al (2008) Telomerase inhibitor GRN163L inhibits myeloma cell growth in vitro and in vivo. Leukemia 22:1410–1418
Bezieau S, Devilder MC, Avet-Loiseau H et al (2001) High incidence of N and K-Ras activating mutations in multiple myeloma and primary plasma cell leukemia at diagnosis. Hum Mutat 18:212–224
Alsina M, Fonseca R, Wilson EF et al (2004) 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 103:3271–3277
Yanamandra N, Colaco NM, Parquet NA et al (2006) Tipifarnib and bortezomib are synergistic and overcome cell adhesion-mediated drug resistance in multiple myeloma and acute myeloid leukemia. Clin Cancer Res 12:591–599
Lonial S, Francis D, Karanes C et al (2008) A phase I MMRC clinical trial testing the combination of bortezomib and tipifarnib in relapsed/refractory multiple myeloma. ASH Annual Meeting Abstracts 112:3706
Richardson PG, Mitsiades C, Schlossman R, Munshi N, Anderson K (2007) New drugs for myeloma. Oncologist 12:664–689
Mahindra A, Laubach J, Raje N, Munshi N, Richardson PG, Anderson K (2012) Latest advances and current challenges in the treatment of multiple myeloma. Nat Rev Clin Oncol 9:135–143
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Mahindra, A., Laubach, J., Mitsiades, C., Richardson, P. (2013). Novel Agents in Multiple Myeloma. In: Munshi, N., Anderson, K. (eds) Advances in Biology and Therapy of Multiple Myeloma. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5260-7_9
Download citation
DOI: https://doi.org/10.1007/978-1-4614-5260-7_9
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-5259-1
Online ISBN: 978-1-4614-5260-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)