Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2013 Jul 2.
Published in final edited form as: Br J Haematol. 2010 Jul 7;151(1):3–15. doi: 10.1111/j.1365-2141.2010.08262.x

Development of target-specific treatments in multiple myeloma

Asher A Chanan-Khan 1, Ivan Borrello 2, Kelvin P Lee 1, Donna E Reece 3
PMCID: PMC3698607  NIHMSID: NIHMS458062  PMID: 20618339

Summary

In the last decade, the novel agents lenalidomide, bortezomib, and thalidomide have dramatically improved outcomes for patients with multiple myeloma (MM). A number of new therapies with precise targets involved in MM cell growth and replication are now in development and have the potential for further improvements. Second-generation proteasome inhibitors and thalidomide derivatives may offer increased efficacy and safety. Investigational therapies with rationally selected targets in MM include inhibitors of histone deacetylase, heat shock protein 90, mammalian target of rapamycin, BCL2, Akt, mitogen-activated protein kinase, and telomerase. In addition, monoclonal antibodies directed against several targets have been developed and many are showing promise in initial clinical trials in MM. Interest in the ancient remedy of arsenic trioxide has been revived because of its proapoptotic effects on mitochondria, despite its established toxicities. In general, combination regimens are proving the most efficacious, which is to be expected given the multiple overlapping pathways responsible for MM growth and progression.

Keywords: multiple myeloma, tanespimycin, lenalidomide, bortezomib, thalidomide

In the last decade, thalidomide, (Glasmacher et al, 2006) bortezomib, (Mikhael et al, 2009) and lenalidomide (Jagannath et al, 2008) have emerged as highly active agents for the treatment of multiple myeloma (MM). Although these agents have dramatically improved outcomes for MM, there is still no cure. MM remains a fatal disease with a median survival of 4 years (Anderson, 2007). More is now known about cellular interactions in the tumour microenvironment and mechanisms that lead to MM and its progression. This has led to new therapies with precise targets involved in MM growth and replication. These new biological therapies may target extra-cellular ligands or other elements of the tumour micro-environment, cell surface or transmembrane receptors, or components of the intracellular signalling cascades (Fig 1) (Anderson, 2007).

Fig 1.

Fig 1

Open in a new tab

Multiple myeloma targets. New biological therapies may target extracellular ligands or other elements of the tumour microenvironment, cell surface or transmembrane receptors, or components of the intracellular signalling cascades. APAF-1, apoptotic protease activating factor 1; ERK, extracellular regulated kinase; FKHR, forkhead in rhabdomyosarcoma; HAT, histone acetyltransferase; HDAC, histone deacetylase; HSP90, heat shock protein 90; IAP, inhibitor of apoptosis protein; IGF-1, insulin-like growth factor-1; IL-6, interleukin-6; IRS-1, Insulin receptor substrate 1; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; TNF, tumour necrosis factor; TNFR1, tumour necrosis factor receptor 1; VEGF, vascular endothelial growth factor; JAK, Janus kinase; PI3K, phosphoinositol-3 kinase; NFKB, nuclear factor kappa B; STAT3, signal transducer and activator of transcription 3; mTOR, mammalian target of rapamycin; PKC, protein kinase C; PKD, protein kinase D.

Combinations of currently available targeted agents

New strategies are evolving that combine novel anti-MM agents and more traditional therapies with the aim of increasing remission rates and extending progression-free survival (PFS) (Reece, 2007). In a small single-arm trial, a response rate of 50% was achieved in patients with relapsed/refractory MM when doxorubicin was added to bortezomib/thalidomide/dexamethasone (Hollmig et al, 2004). Although bortezomib/thalidomide/melphalan/prednisone produced a superior response rate to bortezomib/melphalan/prednisone in newly diagnosed patients with MM [very good partial response (VGPR), 55% vs. 45%; P < 0·001], there were no significant differences in 3-year PFS or overall survival (OS) after 14 months of follow-up (Palumbo et al, 2009).

Current research has shown that lenalidomide may sensitize myeloma cells to bortezomib (Kastritis et al, 2009). In a phase 1 dose-escalation trial of lenalidomide/bortezomib in heavily pretreated patients, 61% of patients achieved a minimal response (MR) or greater, and 8% had a complete response (CR) or near CR. Half of the bortezomib-refractory patients had at least a MR with lenalidomide/bortezomib. Time-to-progression (TTP) was 7·7 months (Richardson et al, 2009a). Peripheral neuropathy occurred in 42% but was grade ≤2 in all cases. Grade ≥3 myelosuppression was common (Richardson et al, 2009a). In a phase 2 study, lenalidomide/bortezomib/dexamethasone produced responses in 84% of relapsed/refractory patients, including CR or near CR in 21% (Anderson et al, 2008).

This combination has also been studied in newly diagnosed MM patients, although the maximum tolerated doses (MTD) of the 3 agents are higher than those utilized in relapsed/refractory disease. The bortezomib/lenalidomide/dexamethasone regimen produced responses in 98–100% of newly diagnosed MM patients (Richardson et al, 2008a) and is currently used as one arm in the several large intergroup phase 3 trials. Very high response rates have also been reported in an interim analysis of a phase 1/2 study of lenalidomide/bortezomib/dexamethasone/pegylated liposomal doxorubicin; 95% of patients with newly diagnosed MM achieved at least a partial response (PR), and 47% had at least a VGPR (Jakubowiak et al, 2009a).

In a phase 3 study comparing thalidomide/dexamethasone incorporated into autologous stem cell transplant (ASCT) to bortezomib/thalidomide/dexamethasone in newly diagnosed MM, 25% of the thalidomide/dexamethasone group attained at least a VGPR compared with 60% of the bortezomib/thalidomide/dexamethasone arm (VGPR; P < 0·001) (Cavo et al, 2007).

Debate continues over the relative efficacy of combining 3 or 4 agents as first-line therapy compared with using combinations of 1 or 2 agents sequentially. Future studies will evaluate which approach is better. Using more 3- or 4-drug combinations may produce higher rates of toxicity and resistance, which may limit use of these agents in subsequent regimens.

Targeted therapies

The median survival for patients with MM has almost doubled since the introduction of bortezomib, lenalidomide, and thalidomide (Kastritis et al, 2008). Unfortunately, most patients still relapse after an initial response to treatment, and multidrug resistance often emerges over time (Kastritis et al, 2009). Researchers have targeted cellular mechanisms with agents that act through the cell-surface receptors by inhibiting signalling pathways, interfering with the cell cycle, inhibiting the unfolded protein response, as well as epigenetic agents, such as hypomethylating compounds and deacetylase inhibitors (Table I) (Ocio et al, 2008; Smith et al, 2010).

Table I.

Targeted cellular mechanisms in multiple myeloma. (Ocio et al, 2008)

Cell surface receptors Signalling pathways Cell cycle UPR Epigenetic
Activators of cell-death receptors NFκB CDK HSP Hypomethylating compounds
TKR Farnesyl-transferase Aurora-kinase Proteasome Deacetylase inhibitors
mAb against plasma cell antigens MAPK
mTOR
Akt		 Aggresome formation
Open in a new tab

CDK, cyclin-dependent kinase; HSP, heat shock protein; mAb, monoclonal antibodies; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NFκB, nuclear factor kappa B inhibitors; TKR, tyrosine-kinase inhibitors; UPR, unfolded protein response inhibitors.

Second-generation proteasome inhibitors

The success of bortezomib has validated proteasome as a target in the treatment of patients with MM. Almost all patients eventually develop resistance to bortezomib but the mechanism of this resistance remains unknown. It is postulated that perhaps an irreversible proteasome inhibitor may induce more complete proteasome inhibition and thus be more efficacious. This has resulted in the development of the second-generation proteasome inhibitors (carfilzomib, salinosporamide) (Mitsiades et al, 2009).

Carfilzomib (PR-171) is an irreversible proteasome inhibitor that binds to the β5 subunit of the 20S proteasome. Its potent and durable activity leads to apoptosis of MM cells through intrinsic and extrinsic caspase pathways (Kuhn et al, 2007). Carfilzomib appears to have activity in bortezomib-resistant cell lines. Carfilzomib may also overcome resistance to dexamethasone and melphalan (Kuhn et al, 2007). Two open-label, phase 2 studies of carfilzomib(Kuhn et al, 2007; Vij et al, 2009) have been conducted in relapsed/refractory MM patients. In the first study in 39 heavily pretreated patients (Jagannath et al, 2009), 26% responded (5 PR; 5 MR). Median TTP was 6·2 months. Adverse events (AEs) included fatigue, anaemia, thrombocytopenia, nausea, upper respiratory infection, creatinine elevations, and diarrhoea. Peripheral neuropathy developed in <10% of patients (Jagannath et al, 2009). In the second study (Vij et al, 2009), patients were less heavily pretreated and the overall response rate (ORR) was 35%. ORR was 57% in bortezomib-naive patients including 1 CR, 2 VGPRs and 5 PRs, and 18% (3 PRs) in bortezomib-exposed patients (Vij et al, 2009).

New thalidomide derivatives (IMiDs)

Pomalidomide is the newest immunomodulating drug (IMiD). It is structurally similar to thalidomide and lenalidomide, with somewhat different activity (Mitsiades et al, 2009). Its mechanism of action includes direct antiproliferative and proapoptotic effects, modulation of adhesion of MM cells to bone marrow stromal cells (BMSC), and suppression of proliferative/antiapoptotic cytokines produced by MM-BMSC interaction (Mitsiades et al, 2009). Pomalidomide also inhibits regulatory T-cell expansion, proliferation, and function (Galustian et al, 2009). In a phase 2 study, 37 patients with relapsed/refractory MM were treated with pomalidomide plus dexamethasone. Patients had previously received 1–3 treatments for MM, and 62% had previous IMiD therapy. ORR was 62% in the overall population, including nine patients with VGPR and 14 with PR. ORR was 29% in patients refractory to lenalidomide. Toxicities were mild, consisting primarily of myelosuppression. Grade 3 neutropenia occurred in 31% of participants, and 16% developed neuropathy (Grade 1–2, 16%; Grade 3, 0%). There were no thromboembolic events (Lacy et al, 2008).

Histone deacetylase inhibitors

These epigenetic agents address the genetic mutations that can lead to cell transformation and support of oncogenic changes (Smith et al, 2010). Overexpression of histone deacetylase (HDAC) by MM cells results in decreased DNA transcription, including transcription of tumour-suppressor genes (Ocio et al, 2008). Inhibition of HDAC reverses these effects, furthering the transcription of tumour-suppressor genes. It also results in accumulation of acetylated histones, which promotes differentiation and/or apoptosis of malignant cells (Mitsiades et al, 2009).

Vorinostat [suberoylanilide hydroxamic acid (SAHA)] is an oral HDAC inhibitor approved for the treatment of cutaneous T-cell lymphoma that is currently being investigated in MM. Vorinostat induces antiproliferative and proapoptotic effects by suppressing transcription of various growth factors and their receptors, caspase inhibitors, oncogenic kinases, DNA synthesis and repair enzymes, and proteasome subunits. It also overcomes the protective influences of IL-6 and BMSCs (Mitsiades et al, 2009).

Given that single-agent vorinostat showed only modest activity in phase 1 studies, (Richardson et al, 2008b) clinical development is now focusing on its use in combination regimens, particularly with bortezomib (Pei et al, 2004). Bortezomib induces a stress response in MM cells, including upregulating transcripts in the ubiquitin-proteasome pathway (Mitsiades et al, 2002). HDAC inhibitors, such as vorinostat, inhibit the aggresomal pathway, which prevents accumulation of misfolded proteins. Combining this activity with a proteasome inhibitor, such as bortezomib, could create synergistic anti-MM activity (Deleu et al, 2009; Mitsiades et al, 2004).

Two small phase 1 studies (Badros et al, 2009a; Weber et al, 2008) that looked at the combination of bortezomib/vorinostat for the treatment of relapsed/refractory MM have been completed with promising results. Both studies were open-label with similar inclusion criteria and both had a dose-escalation design. In the first study,(Weber et al, 2008) patients received escalating doses of vorinostat up to 400 mg daily for 14 d plus bortezomib at doses up to 1·3 mg/m2 on 4 d of each 21-d cycle, but the MTD was not reached. In the second trial (Badros et al, 2009a), an MTD of vorinostat 400 mg + bortezomib 1·3 mg/m2 was established. There were high rates of discontinuations in both trials (72%, 87%). The ORR was similar in the 2 trials (38%, 43%). This was only slightly reduced when the subset of patients with prior bortezomib exposure was analyzed; only PRs were achieved in bortezomib-refractory patients. Disease progression occurred in 10% or less of patients in each trial. AEs were similar in both trials (Weber et al, 2008), (Badros et al, 2009a) and included nausea, vomiting, diarrhoea, thrombocytopenia, and fatigue. In the second trial (Badros et al, 2009a), the most common grade ≥3 toxicities were myelosuppression, fatigue, and diarrhoea.

Panobinostat (LBH589) is a novel hydroxamate analogue HDAC inhibitor (Tan et al, 2010). In a study of patients with a haematological malignancy, 11/15 patients had peripheral blasts; of those, eight patients experienced transient blast cell reductions with a rebound following the 7-d treatment period. Panobinostat was well tolerated with antileukaemic and biological effects. Grade 3 QTcF (QT interval using Fridericia’s correction formula) prolongation was observed in four patients, and was asymptomatic and reversed on study drug discontinuation. Other potentially related toxicities included nausea (40%), diarrhoea (33%), vomiting (33%), hypokalaemia (27%), loss of appetite (13%), and thrombocytopenia (13%) (Giles et al, 2006).

ITF2357 is an oral inhibitor of HDAC. This agent showed limited activity as a single-agent in 19 heavily pretreated patients in relapsed/progressive MM. In an open-label, phase 2 study of ITF2357, no patients had antitumour responses. Six patients, five of whom received dexamethasone, had stable disease (Galli et al, 2010).

Heat shock protein 90 (HSP90) inhibitors

Heat shock proteins (HSPs) are a class of functionally related proteins whose expression increases when cells are exposed to stress, such as elevated temperatures. HSP90 facilitates the folding and stability of numerous signalling molecules that control the growth and survival of cancer cells (Whitesell & Lindquist, 2005). HSP90 is a key molecular chaperone for signal transduction proteins critical to MM cell growth and survival and drug resistance. MM cells produce a large quantity of immunoglobulins that are folded into tertiary structures in the endoplasmic reticulum. HSP90 plays a large role in chaperoning these proteins into formation and disposing of misfolded proteins. HSP90 inhibitors interrupt this chaperoning activity, which leads to accumulation of misfolded proteins, endoplasmic reticulum stress, and ultimately apoptosis (Anderson, 2007; Davenport et al, 2007; Mitsiades et al, 2009; Ocio et al, 2008). Tumour cells also express HSP90 in a uniquely activated state that gives them higher affinity for binding to HSP90 inhibitors (Kamal et al, 2003).

Tanespimycin (KOS-953; 17-AAG) is an HSP90 inhibitor that has demonstrated activity in heavily pretreated patients, both alone and in combination with bortezomib. Most notably, tanespimycin has demonstrated activity in bortezomib- refractory patients. In preclinical investigations, the antitumour synergy observed between tanespimycin and bortezomib suggested that tanespimycin might be protective against bortezomib-induced peripheral neuropathy. To date, tanespimycin treatment of MM has focused on combination with bortezomib. A phase 1/2 study evaluated bortezomib 0·7–1·3 mg/m2 IV bolus followed by tanespimycin 100–340 mg/m2 as an infusion on 4 d of a 21-d cycle as a treatment for relapsed/refractory MM (Richardson et al, 2009b). Of the 72 patients enrolled, 42 received the highest dose of both drugs. Response (>MR) occurred in 48% of bortezomib-naive patients, 23% of bortezomib-pretreated patients, and 13% of bortezomib-refractory patients. Frequent AEs were diarrhoea (60%), nausea (49%), fatigue (49%), thrombocytopenia (40%), and aspartate aminotransferase (AST) elevation (28%), which proved manageable with dose reduction and supportive care. Twenty-one percent of patients had peripheral neuropathy (grade 1–2, 21%; grade 3–4, 0%) (Richardson et al, 2009b).

The TIME-2 study was recently completed (U.S. National Institutes of Health, 2009). This phase 2/3 randomized, open-label trial enrolled 22 patients who received tanespimycin 50, 175, or 340 mg/m2 plus bortezomib (1·3 mg/m2) after failure of ≥3 prior treatment regimens that included bortezomib or lenalidomide (Badros et al, 2009b). The ORR was 14% [1 MR (340 mg/m2), 1 VGPR (175 mg/m2), and 1 PR (175 mg/m2)]. The patient who achieved a PR had received 10 prior treatments, 3 containing bortezomib. Most AEs were Grade 1–2. Common AEs included fatigue (73%), nausea (68%), diarrhoea (64%), constipation (50%), and vomiting (46%). Peripheral neuropathy developed in 25% of patients. Grade 3 peripheral neuropathy occurred in one patient; this patient had discontinued tanespimycin and was receiving bortezomib alone.

Mammalian target of rapamycin inhibitors

Mammalian target of rapamycin (mTOR) is a downstream target of phosphoinositol-3 kinase (PI3K)/Akt. It mediates phosphorylation of proteins involved in regulating protein synthesis and expression and plays a role in cell division and may contribute to pathogenesis in haematological malignancies (http://www.torisel.com/Prescribing-Information.aspx http://www.torisel.com/Prescribing-Information.aspx; Coiffier & Ribrag, 2009; Ocio et al, 2008).

Temsirolimus (CCI-779) is an analogue of the mTOR inhibitor rapamycin. It binds to FKBP-12, an intracellular protein, and the FKBP-12–temsirolimus complex inhibits mTOR activity in the PI3K/Akt pathway (http://www.torisel.com/Prescribing-Information.aspx). Temsirolimus currently is approved in the United States for treatment of advanced renal cell carcinoma (http://www.torisel.com/Prescribing-Information.aspx) and is being investigated for MM and other tumour types (Dancey et al, 2009).

In a phase 2 study, 16 patients with relapsed/refractory MM were treated with temsirolimus 25 mg IV weekly until disease progression. As with many targeted therapies, single-agent activity achieved an ORR of 38% (1 PR, 5 MRs). Median TTP was about 4·6 months. Grade 3/4 toxicities included fatigue, anaemia, neutropenia, thrombocytopenia, interstitial pneumonitis, stomatitis, and diarrhoea (Farag et al, 2009). Phase 1 and 1/2 studies of temsirolimus in 2-drug combinations with bortezomib/lenalidomide/dexamethasone and cixutumumab are underway.

Researchers recently evaluated BEZ235, an agent that inhibits PI3K/Akt/mTOR signalling at the levels of PI3K and mTOR. BEZ235 showed the ability to overcome cytokine and stromal protection and Akt overexpression (McMillin et al, 2009). Further studies are needed to elucidate the findings for both of these new agents.

BCL2 inhibitors and other promoters of apoptotic signalling pathways

BCL2 is part of a family of signalling molecules with proapoptotic and antiapoptotic activity (van de Donk et al, 2006). Located in the mitochondrial membrane, BCL2 prevents cell death by inhibiting adapter molecules involved in the activation of caspases in the intrinsic pathway. Overexpression of BCL2 is found in most human tumour types and is associated with prolonged cell survival, aggressive clinical course, drug resistance, and decreased OS (Labi et al, 2008; Moreira et al, 2006).

Oblimersen sodium (G3139) is a BCL2antisense oligonucleotide complementary to the first 6 codons of the BCL2 mRNA open reading frame. It downregulates transcription of BCL2 protein and increases susceptibility of MM cells to cytotoxic therapies (Chanan-Khan et al, 2009; Moreira et al, 2006).

A phase 2 study of oblimersen/thalidomide/dexamethasone was conducted in relapsed/refractory MM (Badros et al, 2005). Nearly 73% of the 33 patients had a response (2 CR, 4 near CR, 12 PR, 6 MR). Pharmacodynamic assessments suggested that response may correlate with BCL2 mRNA levels and polyclonal immunoglobulin M levels. However, a recent phase 3 trial of oblimersen/thalidomide/dexamethasone injection in patients with relapsed/refractory MM failed to demonstrate any advantage of oblimersen in improving TTP (primary end-point) (Chanan-Khan et al, 2009).

Akt inhibitors

Along with PI3K and other upstream and downstream signalling proteins, Akt is part of the cascade that mediates cell proliferation, growth, and antiapoptotic effects (Mitsiades et al, 2009). Studies are currently underway for agents that safely and effectively target the PI3K/Akt pathway in haematological malignancies (Kawauchi et al, 2009).

Perifosine (KRX-0401) is a synthetic novel alkylphospholipid that inhibits both constitutive and cytokine-induced Akt activation, leading to apoptosis of MM cells, including those adhering to BMSCs (Mitsiades et al, 2009). It also activates JNK (Richardson et al, 2008c).

In a phase 1/2 study, perifosine/bortezomib/dexamethasone added at progression produced a ≥MR (2 CR; 7 PR; 14 MR) in 40% of 76 heavily pretreated patients with relapsed/refractory MM (median, 6 prior therapies). Response occurred in 24% with perifosine/bortezomib and another 16% when dexamethasone was added. ORR was 37% among a subgroup of previously bortezomib-refractory patients. Grade 3/4 toxicities included thrombocytopenia, lymphopenia, leucopenia, anaemia, neutropenia, hyponatraemia, proteinuria, and upper respiratory infection. Other AEs included nausea, diarrhoea, fatigue, and myelosuppression. There was no venous thromboembolism and only one patient had worsening of peripheral neuropathy (Richardson et al, 2008c).

In a phase 1 study of perifosine/bortezomib/dexamethasone in 30 less heavily pretreated relapsed/refractory MM patients, the ORR was 50% (2 near-CRs; 3 VGPR; 10 PR). Median TTP for patients achieving a ≥PR was 31 weeks. Grade 3/4 toxicities included neutropenia, hypophosphataemia, thrombocytopenia, anaemia, and fatigue (Jakubowiak et al, 2008).

RPI-1, a novel 2-indolinone Ret tyrosine kinase inhibitor (Cassinelli et al, 2009), microRNAs 15a and 16 (Roccaro et al, 2009), and the SHIP agonist AQX-MN100 (Kennah et al, 2009) have all been investigated in MM cell lines alone or in combination as promising therapies for improved patient outcomes.

MAPK inhibitors

Mitogen-activated protein Kinase (MAPK) is a signalling molecule involved in the regulation of cell proliferation and apoptosis. P38 MAPK inhibitor SCIO-469 inhibits MM cell proliferation and decreases interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion (Ocio et al, 2008). In a preclinical study, p38α-selective inhibitors SCIO-469 and SD-282 reduced human myeloma cell growth in vivo in a dose-dependent manner, and angiogenesis when administered early (Medicherla et al, 2008).

In a phase 2 study of SCIO-469 monotherapy in 62 heavily pretreated relapsed/refractory MM patients, 24% had stable disease (TTP: 50 days) (Siegel et al, 2006). AEs included anaemia, thrombocytopenia, epistaxis, fatigue, and diarrhoea. When bortezomib + SCIO-469 was given to 34 patients at progression or stable disease, 26% had PR, 6% had MR, and 9% had stable disease (TTP: 140 d). AEs with the combination regimen included anaemia, thrombocytopenia, nausea, vomiting, diarrhoea, constipation, abdominal pain, fatigue, pyrexia, anorexia, upper respiratory infection, arthralgia, muscle cramp, dizziness, peripheral neuropathy, and headache.

Anti-IL-6

IL-6 is an extracellular ligand for the JAK/STAT pathway, which promotes plasma cell differentiation, antiapoptosis, and multidrug resistance. IL-6 is the major growth factor for MM cells. In a preclinical study, the fully human anti-IL-6 monoclonal antibody (mAb), 1339, showed antimyeloma activity and inhibition of bone marrow turnover both in vitro and in vivo (Fulciniti et al, 2009).

CNTO328 is a chimeric mAb with high affinity for IL-6. In a phase 2 study in patients with relapsed/refractory MM, no patients treated with CNTO328 monotherapy had a response. In the first 14 patients, dexamethasone was added at progression or if PR was not achieved after 2 cycles. There were 5 PRs when dexamethasone was added to monotherapy. Grade 3/4 AEs included thrombocytopenia, neutropenia, and hyperglycaemia. Other AEs included anaemia, oedema, and upper respiratory tract infection (Voorhees et al, 2008).

Anti-CD56 antibodies

CD56 (neuronal cell adhesion molecule) is a membrane glycoprotein from the immunoglobulin superfamily,(Tassone et al, 2004) expressed on 70–90% of MM cells, (Chanan- Khan et al, 2008a; Damgaard et al, 2009; Martin et al, 2004; Tassone et al, 2004) that plays a role in proliferation and antiapoptosis (Damgaard et al, 2009). huN901-DM1 (IMGN901, BB-10901) is a humanized mAb targeting CD56 that is linked covalently with DM1, a cytotoxic maytanisinoid. After N901 binds to CD56, it is internalized and releases DM1 (Lutz & Whiteman, 2009).

In an ongoing phase 1 study, 18 patients with MM who expressed CD56 and had failed ≥1 prior therapy were treated with huN901-DM1. Three patients each received 40, 60, 75, 90, 112, or 140 mg/m2 once weekly on 2 consecutive weeks of each 3-week cycle. One patient in the 140 mg/m2 group experienced dose-limiting grade 3 fatigue. There were no hypersensitivity reactions, and no patients developed antibodies to huN901 or DM1. Three patients (1 each in the 60, 90, and 112 mg/m2 groups) achieved MR. Eight patients achieved durable stable disease ≥15 weeks, and two patients remained on treatment for ≥42 weeks (Chanan-Khan et al, 2008a).

Anti-CD138 antibodies

CD138 (syndecan-1) is a heparan sulfate proteoglycan that serves as a receptor for epidermal growth factor (EGF) ligands. Binding of EGF ligands stimulates cell growth (Mahtouk et al, 2005). CD138 is overexpressed on plasma cells (Kumar et al, 2004) and almost all MM cells, even after exposure to multiple therapies, making it a useful target at any stage of the disease (Lin et al, 2004; Polson & Sliwkowski, 2009). The extracellular components of CD138 and the heparan sulfate side chains may be shed from the cell surface. Soluble syndecan-1 in serum serves as a prognostic indicator in MM (Kumar et al, 2004; Kyrtsonis et al, 2005; Seidel et al, 2000).

BT062 is a chimeric mAb targeting CD138 that has also been conjugated to DM1. In vitro studies showed that this conjugate was cytotoxic to CD138-expressing MM cells but lacked cytotoxicity against peripheral blood mononuclear cells (Ikeda et al, 2009). It also induced MM cell apoptosis and blocked adhesion of MM cells and BMSCs (Ikeda et al, 2009). In a murine model, it inhibited MM growth, supporting future investigation in clinical trials (Ikeda et al, 2009).

Anti-CS1 antibodies

CS1 is a cell surface glycoprotein that is highly expressed on myeloma cells with minimal expression in normal tissues. A humanized mAb directed against CS1, named elotuzumab (formerly called HuLuc63), has efficacy in preclinical models, (Hsi et al, 2008; Tai et al, 2008; van Rhee et al, 2009) and is now being studied in combination with bortezomib. In a phase 1/2 study of elotuzumab in combination with bortezomib in patients with MM, 44% had ≥PR and 75% had ≥MR (Jakubowiak et al, 2009b). Antibody-mediated cell-mediated cytotoxicity involving natural killer (NK) cells may be an important mechanism of action of elotuzumab. Lenalidomide increases NK cells, thus a combination of elotuzumab/lenalidomide/dexamethasone has considerable appeal. In a phase 1/2 study of elotuzumab in combination with lenalidomide and low-dose dexamethasone, interim results showed saturation of CS1 sites on plasma cells and NK cells in bone marrow and the peripheral compartment; efficacy data showed a manageable AE profile with 92% of patients experiencing ≥PR (Lonial et al, 2009).

Telomerase inhibitors

Telomeres are repetitive DNA sequences at the end of chromosomes that protect the chromosomal ends from being recognized as damaged DNA. With each DNA replication, telomeres shorten slightly. After numerous replications, telomeres reach a critically short length that leads to cell cycle arrest and senescence. Continuously dividing cells, such as stem cells, and virtually all cancer cells achieve immortality by upregulating telomerase, an enzyme that restores telomere repeats. Telomerase may help promote neoplasia. Because telomeres in most tumours are short, brief inhibition of telomerase is potentially sufficient to inhibit tumour growth without causing lasting damage to normal cells (Parkinson & Minty, 2007; Phatak & Burger, 2007). Various telomerase inhibitors are in development. GRN163L is an antisense oligonucleotide complementary to the template region of the RNA subunit of telomerase that has recently entered clinical trials. By binding telomerase, GRN163L competitively inhibits its activity,(Parkinson & Minty, 2007) which leads to telomere shortening, cessation of MM cell growth, and promotion of apoptosis in vitro (Shammas et al, 2008).

In an ongoing phase 1 trial, 12 heavily pretreated patients received 3·2, 4·8, or 7·2 mg/kg GRN163L. Treatment-related AEs included thrombocytopenia (6 grade 3, 1 grade 4), neutropenia (6 grade 3/4), anaemia, aPTT prolongation of the activated partial thromboplastin time (2 grade 3), fatigue, nausea, anorexia (1 grade 3), and dizziness. One grade 4 thrombocytopenia at the 7·2 mg/kg was dose limiting (Chanan-Khan et al, 2008b).

Additional agents

Arsenic trioxide

Despite its well-known toxicity, arsenic trioxide (ATO) has been used in traditional Chinese medicine for millennia (Baysan et al, 2007; Ge et al, 2009). Today is it an US Food and Drug Administration-approved treatment for relapsed/refractory acute promyelocytic leukaemia (http://www.trisenox.com/hcp/320-Prescribing-Trisenox.aspx). ATO has activities that might be effective for the treatment of MM. Its most relevant effects involve promotion of apoptosis via the Bcl/caspase signalling pathway, modulation of HSPs and the proteasome/ubiquitin system, and oxidative stress (Baysan et al, 2007; Ge et al, 2009). ATO-induced caspase activation is mediated, in part, by release of mitochondrial intermembrane proteins cytochrome c and apoptosis-inducing factor, along with downregulation of BCL2 (Baysan et al, 2007). Preclinical studies have shown enhancement of ATO-induced toxicity through MEK inhibition in human MM cells lines with the small molecule inhibitors PD184352 or PD325901 (Lunghi et al, 2008).

A recent systematic review found that five of six trials of ATO monotherapy had an ORR of approximately 30% with no CRs (Rollig & Illmer, 2009). One outlying study had a higher response rate (ORR: 73%, CR 33%), but it was a small case series with a high potential for selection bias. The ORRs were highly variable, ranging from 12% to 100%, when ATO was combined with various chemotherapy agents in 10 studies, with little indication of how much the ATO contributed to this effect. However, bonafide myeloma cell resistance (either primary or acquired) to ATO in vitro or in vivo (in patients) has been difficult to demonstrate (Bahlis et al, 2002), suggesting that multiple/simultaneous mechanisms of action are involved that prevent the development of drug resistance. Side effects include sensory neuropathy and corrected QT prolongation (Rollig & Illmer, 2009).

A randomized phase 2 trial evaluated the addition of ATO with ascorbic acid to high-dose melphalan in patients with MM undergoing ASCT. The combination was generally well tolerated and there was no adverse effect of ATO plus ascorbic acid on melphalan pharmacokinetics (Qazilbash et al, 2008).

Plitidepsin

Plitidepsin, a cyclodepsipeptide, induced MM cell death in vitro through activation of p38 and c-jun NH2-terminal kinase signalling, as well as caspase activation and Fas/CD95 translocation to lipid rafts (Mitsiades et al, 2008). In addition, plitidepsin interferes with MM cell proliferation and cell cycle progression (Caers et al, 2008). A phase 2 study was conducted in 51 relapsed/refractory MM patients who had received a median of 4 prior therapies. Among 47 patients who received plitidepsin monotherapy, the ORR was 15% (2 PR, 5 MR), TTP was 3 months, and median OS was 17 months. The 18 patients who also received plitidepsin/dexamethasone achieved an ORR of 22% (2 PR, 2 MR), which increased the ORR in the entire study to 19% (4 PR, 5 MR) and the TTP to 4·7 months. Another 28 patients had stable disease. Grade 3/4 AEs included fatigue, muscle weakness, myalgias, myopathy, serum creatine phosphokinase elevations, and liver enzyme abnormalities. There were no significant haematological effects or neuropathies (Mateos et al, 2008).

Targeted therapies: where we stand

In less than 10 years, thalidomide, bortezomib, and lenalidomide have dramatically changed myeloma therapeutics and increased OS and PFS. These agents have now been incorporated into conventional cytotoxic and transplantation regimens and are also used as a treatment for newly diagnosed MM. Continued efforts in further development of these compounds in patients with myeloma have clearly improved PFS and OS.

Today, many more novel agents targeting numerous critical pathways are in clinical trials and in preclinical development (Fig 1, Table II) (Anderson, 2007; Burton et al, 2004; Chen-Kiang et al, 2008; Cohen et al, 2009; Erlichman, 2009; Ocio et al, 2008; Pennati et al, 2008; Rosenblatt & Avigan, 2008; Santo et al, 2008; Shammas et al, 2008). Numerous other agents that target different pathways within plasma cells and BMSCs are in the pipeline, and in the next few years we will probably have more agents on which to build new treatment regimens. These new targeted therapies hold great promise for the treatment of MM, and combinations of new agents will probably become the backbone of the antimyeloma regimens of the future.

Table II.

Additional targeted therapies in early development for multiple myeloma.

Target Agents in development Stage of development for multiple myeloma
Proteasome Salinosporamide (NPI-0052) Phase 1
ONX 0912 (formerly PR-047) Preclinical (phase 1 to begin in 2010)
S-2209 Preclinical
HSP90 Retaspimycin (IPI-504) Phase 1
Alvespimycin (KOS-1022, 17-DMAG) Phase 1
VER-52296/NVP-AUY922 Phase 1
SNX-5422 Phase 1
STA-9090 Phase 1/2 in haematological malignancies
AT13387 Phase 1
VEGF VEGF receptor inhibitor: bevacizumab Phase 2
VEGF receptor inhibitor: pazopanib Phase 2
TNF-related apoptosis-inducing ligand (TRAIL) and FAS (CD95) Antibodies (eg, mapatumumab) and other agents (eg, Mega-FAS) that activate these receptors Phase 2
IL-6 and TNF Atiprimod Phase 1
c-KIT/PDGFR Dasatinib Phase 2
FGF-3 receptor [in patients carrying the t(4;14) translocation] Dovitinib Phase 1
Masitinib (AB1010) Phase 2
IGF-1 Antibody that blocks IGF-1 ligand-receptor binding: Phase 1
AVE-1642
HDAC Panobinostat (LBH589) Phase 2
Depsipeptide Phase 1/2
ITF2357 Phase 2
CS1 Elotuzumab (HuLuc63) Phase 1/2
CD40 SGN-40 Phase 1
HCD122 (formerly CHIR-12·12) Phase 1
CD74 Milatuzumab (humanized anti-CD74 monoclonal antibody) Phase 1/2
Farnesyl transferase Tipifarnib Phase 2
Heparanase SST0001 Preclinical
MAPK AZD6244 Phase 2
CDKs PD 0332991 – inhibits CDK4/6 Phase 1/2
AT7519 – multi-CDK inhibitor Phase 1 (phase 2 to begin in 2010)
Bcl-2 AT-101 Phase 1/2
ABT-263 Phase 1
GX15-070 Phase 1/2
Survivin Antisense oligonucleotide LY2181308; ribozymes targeting BIRC5 mRNA; small interfering RNAs that suppress survivin; small molecule antagonists that inhibit survivin phosphorylation, expression, or binding to HSP90 Phase 1
Aurora A kinase ENMD-981693 Preclinical
MLN8237 Phase 1/2
Various myeloma-specific tumour antigens Vaccines that stimulate T-cell response to these antigens: WTI peptide, idiotype, survivin; dendritic cells loaded with whole myeloma cells; dendritic cells loaded with idiotype, survivin, or other tumour antigens; intratumoural injections of naive dendritic cells Phase 2
Multiple targets Arsenic trioxide Phase 2/3
Open in a new tab

CDKs, cyclin-dependent kinases; HSP90, heat shock protein 90; IGF-1, insulin-like growth factor-1; IL-6, interleukin-6; MAPK, mitogen-activated protein kinase; PDGFR, platelet-derived growth factor receptor; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor.

In contrast to traditional chemotherapeutics, these new compounds target not only the myeloma cell but also the microenvironment that allows the myeloma cell to survive and proliferate. It is also hoped that the new targeted therapies will have fewer toxicities, because they have less effect on normal cells. Like most cancers, MM is not the result of a single protein abnormality; rather it results from multiple pathways with feedback loops and redundancies. Therefore, inhibition of a single target is rarely enough to prevent activation of downstream transducers (Erlichman, 2009). Consequently, targeted therapies are often more efficacious in combination regimens than as monotherapy. Rational choices must be made in determining which agents to combine, based on mechanisms that are likely to provide synergistic efficacy without synergistic toxicity (Anderson, 2007; Mitsiades et al, 2009). Risk stratification, concurrent medical problems, and patterns of disease growth or relapse will be used to direct selection of therapeutic agents and combination regimens. For example, patients with high-risk cytogenetics may benefit more from a bortezomib-based combination regimen; while those with renal impairment will need to avoid lenalidomide, but benefit from proteasome inhibitors (bortezomib and carfilzomib).

The role of dexamethasone in the overall treatment strategy is also being questioned. Immunomodulating agents, such as lenalidomide, are often used in combination with dexamethasone and improved biological understanding of the effect of lenalidomide on immune effector cells may suggest that lenalidomide alone or in combination with non-immunosuppressive agents may be a reasonable initial approach. Furthermore, patient profiles based on concurrent medical conditions, such as hypertension, diabetes mellitus and depression, may direct the selection of antimyeloma therapeutic agents. Thus, the transition of multiple myeloma to a chronic treatable condition is a prospect on the horizon as new agents with lesser toxicities are demonstrating impressive efficacy.

Future studies will focus on combinations that not only exhibit synergistic effects in preclinical studies but also improved toxicity. Furthermore, the design should allow for evaluation of each agent’s contribution to the overall treatment effect.

Acknowledgments

We would like to thank Lauren Cerruto and AOI Communications, L.P., for medical, editorial, and graphics assistance in the preparation of this manuscript. This study was sponsored by Bristol-Myers Squibb (and previously Kosan Biosciences).

Footnotes

Disclosures

Dr Chanan-Khan is on a speakers bureau and receives honoraria from Celgene Corporation, ImmunoGen, Inc., and Millennium Pharmaceuticals. Drs Borrello and Lee have no conflicts of interest with regard to the publication of this manuscript. Dr Reece receives research funds and honoraria from Ortho Biotech and Celgene Corporation. She also receives research funds from Merck & Co., Inc.

References

  1. Anderson KC. Targeted therapy of multiple myeloma based upon tumor-microenvironmental interactions. Experimental Hematology. 2007;35:155–162. doi: 10.1016/j.exphem.2007.01.024. [DOI] [PubMed] [Google Scholar]
  2. Anderson KC, Jagannath S, Jakubowiak A, Lonial S, Raje N, Schlossman R, Munshi N, Knight R, Esseltine D, Richardson PG. Phase II study of lenalidomide (Len), bortezomib (Bz), and dexamethasone (Dex) in patients (pts) with relapsed or relapsed and refractory multiple myeloma (MM) Journal of Clinical Oncology (ASCO Meeting Abstracts) 2008;26:465s, Abstract 8545. [Google Scholar]
  3. Badros AZ, Goloubeva O, Rapoport AP, Ratterree B, Gahres N, Meisenberg B, Takebe N, Heyman M, Zwiebel J, Streicher H, Gocke CD, Tomic D, Flaws JA, Zhang B, Fenton RG. Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients. Journal of Clinical Oncology. 2005;23:4089– 4099. doi: 10.1200/JCO.2005.14.381. [DOI] [PubMed] [Google Scholar]
  4. Badros A, Burger AM, Philip S, Niesvizky R, Kolla SS, Goloubeva O, Harris C, Zwiebel J, Wright JJ, Espinoza-Delgado I, Baer MR, Holleran JL, Egorin MJ, Grant S. Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clinical Cancer Research. 2009a;15:5250–5257. doi: 10.1158/1078-0432.CCR-08-2850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Badros AZ, Richardson PG, Albitar M, Jagannath S, Tarantolo S, Wolf JL, Messina M, Berman D, Anderson KC. Tanespimycin + bortezomib in relapsed/refractory myeloma patients: results from the TIME-2 study. Blood (ASH Annual Meeting Abstracts) 2009b;114:742, Abstract 1871. [Google Scholar]
  6. Bahlis NJ, McCafferty-Grad J, Jordan-McMurry I, Neil J, Reis I, Kharfan-Dabaja M, Eckman J, Goodman M, Fernandez HF, Boise LH, Lee KP. Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clinical Cancer Research. 2002;8:3658–3668. [PubMed] [Google Scholar]
  7. Baysan A, Yel L, Gollapudi S, Su H, Gupta S. Arsenic trioxide induces apoptosis via the mitochondrial pathway by upregulating the expression of Bax and Bim in human B cells. International Journal of Oncology. 2007;30:313–318. [PubMed] [Google Scholar]
  8. Burton JD, Ely S, Reddy PK, Stein R, Gold DV, Cardillo TM, Goldenberg DM. CD74 is expressed by multiple myeloma and is a promising target for therapy. Clinical Cancer Research. 2004;10:6606–6611. doi: 10.1158/1078-0432.CCR-04-0182. [DOI] [PubMed] [Google Scholar]
  9. Caers J, Menu E, De Raeve H, Lepage D, Van Valckenborgh E, Van Camp B, Alvarez E, Vanderkerken K. Antitumour and antiangiogenic effects of Aplidin in the 5TMM syngeneic models of multiple myeloma. British Journal of Cancer. 2008;98:1966–1974. doi: 10.1038/sj.bjc.6604388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cassinelli G, Ronchetti D, Laccabue D, Mattioli M, Cuccuru G, Favini E, Nicolini V, Greco A, Neri A, Zunino F, Lanzi C. Concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, JAK2 and BCMA in human multiple myeloma cells by multi-kinase targeting. Biochemical Pharmacology. 2009;78:1139–1147. doi: 10.1016/j.bcp.2009.06.023. [DOI] [PubMed] [Google Scholar]
  11. Cavo M, Patriarca F, Tacchetti P, Galli M, Perrone G, Petrucci MT, Brioli A, Bringhen S, Pantani L, Tosi P, Crippa C, Zamagni E, Di Raimondo F, Narni F, Cellini C, Ceccolini M, Pescosta N, Goldaniga MC, Montefusco V, Callea V, De Stefano V, Caravita T, Boccadoro M, Baccarani M. Bortezomib (Velcade®)-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD) in preparation for autologous stem-cell (SC) transplantation (ASCT) in newly diagnosed multiple myeloma (MM) Blood (ASH Annual Meeting Abstracts) 2007;110:121, Abstract 73. [Google Scholar]
  12. Chanan-Khan AA, Gharibo M, Jagannath S, Munshi NC, Anderson KC, DePaolo D, Lee KP, Miller K, Guild R, Zildjian S, Qin A. Phase I Study of IMGN901 in Patients with Relapsed and Relapsed/Refractory CD56-Positive Multiple Myeloma. Blood (ASH Annual Meeting Abstracts) 2008a;112:1263, Abstract 3689. [Google Scholar]
  13. Chanan-Khan AA, Munshi NC, Hussein MA, Elias L, Benedetti F, Smith J, Khor S-P, Huff CA. Results of a Phase I Study of GRN163L, a Direct Inhibitor of Telomerase, in Patients with Relapsed and Refractory Multiple Myeloma (MM) Blood (ASH Annual Meeting Abstracts) 2008b;112:1263, Abstract 3688. [Google Scholar]
  14. Chanan-Khan AA, Niesvizky R, Hohl RJ, Zimmerman TM, Christiansen NP, Schiller GJ, Callander N, Lister J, Oken M, Jagannath S. Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma. Leukaemia & Lymphoma. 2009;50:559–565. doi: 10.1080/10428190902748971. [DOI] [PubMed] [Google Scholar]
  15. Chen-Kiang S, Di Liberto M, Louie T, Liang J, Jayabalan DS, Ely S, Moore MA, Niesvizky R, Huang X. Targeting Cdk4/6 in combination therapy of chemoresistant multiple myeloma. Journal of Clinical Oncology (ASCO Meeting Abstracts) 2008;26:454s, Abstract 8503. [Google Scholar]
  16. Cohen S, Haimovich J, Hollander N. Dendritic cell-based therapeutic vaccination against myeloma: vaccine formulation determines efficacy against light chain myeloma. Journal of Immunology. 2009;182:1667–1673. doi: 10.4049/jimmunol.182.3.1667. [DOI] [PubMed] [Google Scholar]
  17. Coiffier B, Ribrag V. Exploring mammalian target of rapamycin (mTOR) inhibition for treatment of mantle cell lymphoma and other hematologic malignancies. Leukaemia & Lymphoma. 2009;50:1916–1930. doi: 10.3109/10428190903207548. [DOI] [PubMed] [Google Scholar]
  18. Damgaard T, Knudsen LM, Dahl IM, Gimsing P, Lodahl M, Rasmussen T. Regulation of the CD56 promoter and its association with proliferation, anti-apoptosis and clinical factors in multiple myeloma. Leukaemia & Lymphoma. 2009;50:236–246. doi: 10.1080/10428190802699332. [DOI] [PubMed] [Google Scholar]
  19. Dancey JE, Curiel R, Purvis J. Evaluating temsirolimus activity in multiple tumors: a review of clinical trials. Seminars in Oncology. 2009;36(Suppl 3):S46–S58. doi: 10.1053/j.seminoncol.2009.10.010. [DOI] [PubMed] [Google Scholar]
  20. Davenport EL, Moore HE, Dunlop AS, Sharp SY, Workman P, Morgan GJ, Davies FE. Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells. Blood. 2007;110:2641–2649. doi: 10.1182/blood-2006-11-053728. [DOI] [PubMed] [Google Scholar]
  21. Deleu S, Menu E, Van Valckenborgh E, Van Camp B, Fraczek J, Vande Broek I, Rogiers V, Vanderkerken K. Histone deacetylase inhibitors in multiple myeloma. Hematology Reviews. 2009;1:1, e9. doi: 10.1038/leu.2009.121. [DOI] [PubMed] [Google Scholar]
  22. van de Donk NW, Bloem AC, van der Spek E, Lokhorst HM. New treatment strategies for multiple myeloma by targeting BCL-2 and the mevalonate pathway. Current Pharmaceutical Design. 2006;12:327–340. doi: 10.2174/138161206775201974. [DOI] [PubMed] [Google Scholar]
  23. Erlichman C. Tanespimycin: the opportunities and challenges of targeting heat shock protein 90. Expert Opinion on Investigational Drugs. 2009;18:861–868. doi: 10.1517/13543780902953699. [DOI] [PubMed] [Google Scholar]
  24. Farag SS, Zhang S, Jansak BS, Wang X, Kraut E, Chan K, Dancey JE, Grever MR. Phase II trial of temsirolimus in patients with relapsed or refractory multiple myeloma. Leukemia Research. 2009;33:1475–1480. doi: 10.1016/j.leukres.2009.01.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Fulciniti M, Hideshima T, Vermot-Desroches C, Pozzi S, Nanjappa P, Shen Z, Patel N, Smith ES, Wang W, Prabhala R, Tai YT, Tassone P, Anderson KC, Munshi NC. A high-affinity fully human anti-IL-6 mAb, 1339, for the treatment of multiple myeloma. Clinical Cancer Research. 2009;15:7144–7152. doi: 10.1158/1078-0432.CCR-09-1483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Galli M, Salmoiraghi S, Golay J, Gozzini A, Crippa C, Pescosta N, Rambaldi A. A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma. Annals of Hematology. 2010;89:185–190. doi: 10.1007/s00277-009-0793-8. [DOI] [PubMed] [Google Scholar]
  27. Galustian C, Meyer B, Labarthe MC, Dredge K, Klaschka D, Henry J, Todryk S, Chen R, Muller G, Stirling D, Schafer P, Bartlett JB, Dalgleish AG. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunology, Immunotherapy. 2009;58:1033– 1045. doi: 10.1007/s00262-008-0620-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ge F, Lu XP, Zeng HL, He QY, Xiong S, Jin L. Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009;8:3006–3019. doi: 10.1021/pr9001004. [DOI] [PubMed] [Google Scholar]
  29. Giles F, Fischer T, Cortes J, Garcia-Manero G, Beck J, Ravandi F, Masson E, Rae P, Laird G, Sharma S, Kantarjian H, Dugan M, Albitar M, Bhalla K. A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clinical Cancer Research. 2006;12:4628–4635. doi: 10.1158/1078-0432.CCR-06-0511. [DOI] [PubMed] [Google Scholar]
  30. Glasmacher A, Hahn C, Hoffmann F, Naumann R, Goldschmidt H, von Lilienfeld-Toal M, Orlopp K, Schmidt-Wolf I, Gorschluter M. A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma. British Journal Haematology. 2006;132:584–593. doi: 10.1111/j.1365-2141.2005.05914.x. [DOI] [PubMed] [Google Scholar]
  31. Hollmig K, Stover J, Talamo G, Fassas A, Lee C-K, Anaissie E, Tricot G, Barlogie B. Bortezomib (Velcade™) + adriamycin™ + thalidomide + dexamethasone (VATD) as an effective regimen in patients with refractory or relapsed multiple myeloma (MM) Blood (ASH Annual Meeting Abstracts) 2004;104:659a, Abstract 2399. [Google Scholar]
  32. Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum BP, Huseni M, Powers D, Nanisetti A, Zhang Y, Rice AG, van Abbema A, Wong M, Liu G, Zhan F, Dillon M, Chen S, Rhodes S, Fuh F, Tsurushita N, Kumar S, Vexler V, Shaughnessy JD, Jr, Barlogie B, van Rhee F, Hussein M, Afar DE, Williams MB. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clinical Cancer Research. 2008;14:2775–2784. doi: 10.1158/1078-0432.CCR-07-4246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ikeda H, Hideshima T, Fulciniti M, Lutz RJ, Yasui H, Okawa Y, Kiziltepe T, Vallet S, Pozzi S, Santo L, Perrone G, Tai YT, Cirstea D, Raje NS, Uherek C, Dalken B, Aigner S, Osterroth F, Munshi N, Richardson P, Anderson KC. The monoclonal antibody nBT062 conjugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clinical Cancer Research. 2009;15:4028–4037. doi: 10.1158/1078-0432.CCR-08-2867. [DOI] [PubMed] [Google Scholar]
  34. Jagannath S, Richardson PG, Zeldenrust S, Alsina M, Wride K, Zeldis JB, Knight R, Olesnyckyj M, Anderson KC. Long-term responses observed with lenalidomide therapy for patients with relapsed or refractory multiple myeloma. Journal of Clinical Oncology (ASCO Meeting Abstracts) 2008;26:460s, Abstract 8525. [Google Scholar]
  35. Jagannath S, Vij R, Stewart K, Somlo G, Jakubowiak A, Trudel S, Schwartz R, Siegel D, Kunkel L The Multiple Myeloma Research C. Final results of PX-171-003-A0, part 1 of an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM) Journal of Clinical Oncology (ASCO Meeting Abstracts) 2009;27:435s, Abstract 8504. [Google Scholar]
  36. Jakubowiak A, Richardson P, Zimmerman TM, Alsina M, Kaufman JL, Harvey C, Brozo C, Kendall T, McAllister A, Hideshima T, Sportelli P, Gardner L, Anderson KC, Giusti K. Phase I results of perifosine (KRX-0401) in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (MM) Blood (ASH Annual Meeting Abstracts) 2008;112:1264, Abstract 3691. [Google Scholar]
  37. Jakubowiak AJ, Hofmeister CC, Campagnaro EL, Zimmerman TM, Schlossman RL, Lonial S, Reece DE, Kaminski MS, Anderson KC, Richardson PG. Lenalidomide, bortezomib, pegylated liposomal doxorubicin hydrochloride, and dexamethasone in newly diagnosed multiple myeloma: initial results of phase I/II MMRC trial. Journal of Clinical Oncology (ASCO Meeting Abstracts) 2009a;27:438s, Abstract 8517. [Google Scholar]
  38. Jakubowiak AJ, Bensinger W, Siegel D, Zimmerman TM, Van Tornout JM, Zhao C, Singhal A, Anderson K. Phase 1/2 study of elotuzumab in combination with bortezomib in patients with multiple myeloma with one to three prior therapies: interim results. Blood (ASH Annual Meeting Abstracts) 2009b;114:1491, Abstract 3876. [Google Scholar]
  39. Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC, Burrows FJ. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature. 2003;425:407–410. doi: 10.1038/nature01913. [DOI] [PubMed] [Google Scholar]
  40. Kastritis E, Zervas K, Symeonidis A, Terpos E, Delimpassi S, Anagnostopoulos N, Michali E, Zomas A, Katodritou I, Gika D, Pouli A, Christoulas D, Roussou M, Economopoulos T, Dimopoulos MA. Improved survival of patients with multiple myeloma after the introduction of novel agents and the applicability of the International Staging System (ISS) an analysis of the Greek Myeloma Study Group (GMSG) Blood (ASH Annual Meeting Abstracts) 2008;112:244, Abstract 655. doi: 10.1038/leu.2008.402. [DOI] [PubMed] [Google Scholar]
  41. Kastritis E, Palumbo A, Dimopoulos MA. Treatment of relapsed/refractory multiple myeloma. Seminars in Hematology. 2009;46:143–157. doi: 10.1053/j.seminhematol.2009.01.004. [DOI] [PubMed] [Google Scholar]
  42. Kawauchi K, Ogasawara T, Yasuyama M, Otsuka K, Yamada O. The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anti-Cancer Agents in Medicinal Chemistry. 2009;9:550–559. doi: 10.2174/187152009788451851. [DOI] [PubMed] [Google Scholar]
  43. Kennah M, Yau TY, Nodwell M, Krystal G, Andersen RJ, Ong CJ, Mui AL. Activation of SHIP via a small molecule agonist kills multiple myeloma cells. Experimental Hematology. 2009;37:1274–1283. doi: 10.1016/j.exphem.2009.08.001. [DOI] [PubMed] [Google Scholar]
  44. Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk KD, Sun CM, Demo SD, Bennett MK, van Leeuwen FW, Chanan- Khan AA, Orlowski RZ. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007;110:3281–3290. doi: 10.1182/blood-2007-01-065888. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Kumar S, Blood E, Oken MM, Greipp PR. Prognostic Value of Syndecan-1 in Multiple Myeloma and its Relationship with Other Prognostic Factors. Blood (ASH Annual Meeting Abstracts) 2004;104:660a, Abstract 2402. [Google Scholar]
  46. Kyrtsonis M-C, Vassilakopoulos TP, Papadogiannis A, Tzenou T, Kalpadakis C, Antoniadis A, Dimopoulou MN, Siakantaris MP, Kokoris SI, Dimitriadou EM, Angelopoulou MK, Plata E, Tsaftaridis P, Pangalis GA. Serum Soluble Syndecan-1 Levels at Diagnosis Constitute an Independent Prognostic Factor of Survival in Myeloma That May Further Differentiate Patients within the ISS Stages. Blood (ASH Annual Meeting Abstracts) 2005;106:951a, Abstract 3404. [Google Scholar]
  47. Labi V, Grespi F, Baumgartner F, Villunger A. Targeting the Bcl-2-regulated apoptosis pathway by BH3 mimetics: a breakthrough in anticancer therapy? Cell Death and Differentiation. 2008;15:977–987. doi: 10.1038/cdd.2008.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Lacy MQ, Hayman SR, Gertz MA, Allred JB, Mandrekar SJ, Dispenzieri A, Zeldenrust SR, Kumar S, Greipp PR, Lust JA, Russell SJ, Buadi F, Kyle RA, Bergsagel PL, Fonseca R, Roy V, Mikhael J, Stewart AK, Rajkumar SV. Pomalidomide (CC4047) plus low-dose dexamethasone (pom/dex) is highly effective therapy in relapsed multiple myeloma. Blood (ASH Annual Meeting Abstracts) 2008;112:320, Abstract 866. [Google Scholar]
  49. Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. American Journal of Clinical Pathology. 2004;121:482–488. doi: 10.1309/74R4-TB90-BUWH-27JX. [DOI] [PubMed] [Google Scholar]
  50. Lonial S, Vij R, Harousseau J, Facon T, Kaufman J, Mazumder A, Moreau P, Leleu X, Fry J, Singhal A, Jagannath S. Phase 1/2 study of elotuzumab in combination with lenalidomide and low dose dexamethasone in relapsed or refractory multiple myeloma: interim results. Blood (ASH Annual Meeting Abstracts) 2009;114:179, Abstract 432. doi: 10.1200/JCO.2011.37.2649. [DOI] [PubMed] [Google Scholar]
  51. Lunghi P, Giuliani N, Mazzera L, Lombardi G, Ricca M, Corradi A, Cantoni AM, Salvatore L, Riccioni R, Costanzo A, Testa U, Levrero M, Rizzoli V, Bonati A. Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways. Blood. 2008;112:2450–2462. doi: 10.1182/blood-2007-10-114348. [DOI] [PubMed] [Google Scholar]
  52. Lutz RJ, Whiteman KR. Antibody-maytansinoid conjugates for the treatment of myeloma. mAbs. 2009;1:548–551. doi: 10.4161/mabs.1.6.10029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Mahtouk K, Cremer FW, Reme T, Jourdan M, Baudard M, Moreaux J, Requirand G, Fiol G, De Vos J, Moos M, Quittet P, Goldschmidt H, Rossi J-F, Hose D, Klein B. Syndecan-1 Is Essential for the Myeloma Cell Growth Factor Activity of EGF-Family Ligands in Multiple Myeloma. Blood (ASH Annual Meeting Abstracts) 2005;106:186a, Abstract 626. doi: 10.1038/sj.onc.1209699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Martin P, Santon A, Bellas C. Neural cell adhesion molecule expression in plasma cells in bone marrow biopsies and aspirates allows discrimination between multiple myeloma, monoclonal gammopathy of uncertain significance and polyclonal plasmacytosis. Histopathology. 2004;44:375–380. doi: 10.1111/j.1365-2559.2004.01834.x. [DOI] [PubMed] [Google Scholar]
  55. Mateos M-V, Cibeira MT, Richardson P, Blade J, Prosper F, Oriol A, de la Rubia J, Alegre A, Lahuerta JJ, Garcia-Sanz R, Mitsiades CS, Espinoza J, Anderson KC, Miguel JFS. Final results of a phase II trial with plitidepsin (Aplidin®) alone and in combination with dexamethasone in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts) 2008;112:1268, Abstract 3700. [Google Scholar]
  56. McMillin DW, Ooi M, Delmore J, Negri J, Hayden P, Mitsiades N, Jakubikova J, Maira SM, Garcia-Echeverria C, Schlossman R, Munshi NC, Richardson PG, Anderson KC, Mitsiades CS. Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Research. 2009;69:5835–5842. doi: 10.1158/0008-5472.CAN-08-4285. [DOI] [PubMed] [Google Scholar]
  57. Medicherla S, Reddy M, Ying J, Navas TA, Li L, Nguyen AN, Kerr I, Hanjarappa N, Protter AA, Higgins LS. p38alpha-selective MAP kinase inhibitor reduces tumor growth in mouse xenograft models of multiple myeloma. Anticancer Research. 2008;28:3827–3833. [PubMed] [Google Scholar]
  58. Mikhael JR, Belch AR, Prince HM, Lucio MN, Maiolino A, Corso A, Petrucci MT, Musto P, Komarnicki M, Stewart AK. 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. British Journal Haematology. 2009;144:169–175. doi: 10.1111/j.1365-2141.2008.07409.x. [DOI] [PubMed] [Google Scholar]
  59. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Treon SP, Munshi NC, Richardson PG, Hideshima T, Anderson KC. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proceedings of the National Academy of Sciences of the United States of America. 2002;99:14374–14379. doi: 10.1073/pnas.202445099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Hideshima T, Akiyama M, Chauhan D, Munshi N, Gu X, Bailey C, Joseph M, Libermann TA, Richon VM, Marks PA, Anderson KC. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proceedings of the National Academy of Sciences of the United States of America. 2004;101:540–545. doi: 10.1073/pnas.2536759100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Mitsiades CS, Ocio EM, Pandiella A, Maiso P, Gajate C, Garayoa M, Vilanova D, Montero JC, Mitsiades N, McMullan CJ, Munshi NC, Hideshima T, Chauhan D, Aviles P, Otero G, Faircloth G, Mateos MV, Richardson PG, Mollinedo F, San-Miguel JF, Anderson KC. Aplidin, a marine organism-derived compound with potent antimyeloma activity in vitro and in vivo. Cancer Research. 2008;68:5216–5225. doi: 10.1158/0008-5472.CAN-07-5725. [DOI] [PubMed] [Google Scholar]
  62. Mitsiades CS, Hideshima T, Chauhan D, McMillin DW, Klippel S, Laubach JP, Munshi NC, Anderson KC, Richardson PG. Emerging treatments for multiple myeloma: beyond immunomodulatory drugs and bortezomib. Seminars in Hematology. 2009;46:166–175. doi: 10.1053/j.seminhematol.2009.02.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Moreira JN, Santos A, Simoes S. Bcl-2-targeted antisense therapy (Oblimersen sodium): towards clinical reality. Reviews on Recent Clinical Trials. 2006;1:217–235. doi: 10.2174/157488706778250050. [DOI] [PubMed] [Google Scholar]
  64. Ocio EM, Mateos MV, Maiso P, Pandiella A, San-Miguel JF. New drugs in multiple myeloma: mechanisms of action and phase I/II clinical findings. The Lancet Oncology. 2008;9:1157– 1165. doi: 10.1016/S1470-2045(08)70304-8. [DOI] [PubMed] [Google Scholar]
  65. Palumbo AP, Bringhen S, Rossi D, Berretta S, Montefusco V, Peccatori J, Galli M, Carella A, Omede P, Boccadoro M Italian Multiple Myeloma N. A phase III study of VMPT versus VMP in newly diagnosed elderly myeloma patients. Journal of Clinical Oncology (ASCO Meeting Abstracts) 2009;27:437s, Abstract 8515. [Google Scholar]
  66. Parkinson EK, Minty F. Anticancer therapy targeting telomeres and telomerase: current status. BioDrugs. 2007;21:375–385. doi: 10.2165/00063030-200721060-00005. [DOI] [PubMed] [Google Scholar]
  67. Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clinical Cancer Research. 2004;10:3839–3852. doi: 10.1158/1078-0432.CCR-03-0561. [DOI] [PubMed] [Google Scholar]
  68. Pennati M, Folini M, Zaffaroni N. Targeting survivin in cancer therapy. Expert Opinion on Therapeutic Targets. 2008;12:463–476. doi: 10.1517/14728222.12.4.463. [DOI] [PubMed] [Google Scholar]
  69. Phatak P, Burger AM. Telomerase and its potential for therapeutic intervention. British Journal of Pharmacology. 2007;152:1003–1011. doi: 10.1038/sj.bjp.0707374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Polson AG, Sliwkowski MX. Toward an effective targeted chemotherapy for multiple myeloma. Clinical Cancer Research. 2009;15:3906–3907. doi: 10.1158/1078-0432.CCR-09-0572. [DOI] [PubMed] [Google Scholar]
  71. Qazilbash MH, Saliba RM, Nieto Y, Parikh G, Pelosini M, Khan FB, Jones RB, Hosing C, Mendoza F, Weber DM, Wang M, Popat U, Alousi A, Anderlini P, Champlin RE, Giralt S. Arsenic trioxide with ascorbic acid and high-dose melphalan: results of a phase II randomized trial. Biology of Blood and Marrow Transplantation. 2008;14:1401–1407. doi: 10.1016/j.bbmt.2008.09.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Reece DE. Management of multiple myeloma: the changing landscape. Blood Reviews. 2007;21:301–314. doi: 10.1016/j.blre.2007.07.001. [DOI] [PubMed] [Google Scholar]
  73. van Rhee F, Szmania SM, Dillon M, van Abbema AM, Li X, Stone MK, Garg TK, Shi J, Moreno-Bost AM, Yun R, Balasa B, Ganguly B, Chao D, Rice AG, Zhan F, Shaughnessy JD, Jr, Barlogie B, Yaccoby S, Afar DE. Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma. Molecular Cancer Therapeutics. 2009;8:2616–2624. doi: 10.1158/1535-7163.MCT-09-0483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Richardson P, Lonial S, Jakubowiak A, Jagannath S, Raje NS, Avigan D, Ghobrial IM, Schlossman RL, Mazumder A, Munshi NC, Vesole DH, Joyce R, Doss D, Warren DL, Hayes SW, Kaster S, Delaney C, Lauria M, Mitsiades C, Hideshima T, Knight RD, Esseltine D-L, Anderson KC. Lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed multiple myeloma: encouraging efficacy in high risk groups with updated results of a Phase I/II study. Blood (ASH Annual Meeting Abstracts) 2008a;112:41, Abstract 92. [Google Scholar]
  75. Richardson P, Mitsiades C, Colson K, Reilly E, McBride L, Chiao J, Sun L, Ricker J, Rizvi S, Oerth C, Atkins B, Fearen I, Anderson K, Siegel D. Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma. Leukaemia & Lymphoma. 2008b;49:502–507. doi: 10.1080/10428190701817258. [DOI] [PubMed] [Google Scholar]
  76. Richardson P, Wolf J, Jakubowiak A, Zonder J, Lonial S, Irwin DH, Densmore J, Krishnan A, Raje N, Bar MH, Allerton JP, Schlossman R, Ghobrial IM, Munshi NC, Martin T, Laubach J, Colson K, Dean S, Tocco D, Steinfield E, Kendall T, O’Riley K, Hideshima T, Sportelli P, Gardner L, Anderson KC. Phase I/II results of a multicenter trial of perifosine (KRX- 0401) + bortezomib in patients with relapsed or relapsed/refractory multiple myeloma who were previously relapsed from or refractory to bortezomib. Blood (ASH Annual Meeting Abstracts) 2008c;112:321, Abstract 870. [Google Scholar]
  77. Richardson PG, Weller E, Jagannath S, Avigan DE, Alsina M, Schlossman RL, Mazumder A, Munshi NC, Ghobrial IM, Doss D, Warren DL, Lunde LE, McKenney M, Delaney C, Mitsiades CS, Hideshima T, Dalton W, Knight R, Esseltine DL, Anderson KC. Multicenter, Phase I, Dose-Escalation Trial of Lenalidomide Plus Bortezomib for Relapsed and Relapsed/Refractory Multiple Myeloma. Journal of Clinical Oncology. 2009a;27:5713–5719. doi: 10.1200/JCO.2009.22.2679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Richardson PG, Chanan-Khan A, Lonial S, Krishnan A, Carroll M, Alsina M, Albitar M, Berman D, Kaplita S, Anderson K. Tanespimycin plus bortezomib in patients with relapsed and refractory multiple myeloma: final results of a phase I/II study. American Society of Clinical Oncology (ASCO) 2009b;27:8503. [Google Scholar]
  79. Roccaro AM, Sacco A, Thompson B, Leleu X, Azab AK, Azab F, Runnels J, Jia X, Ngo HT, Melhem MR, Lin CP, Ribatti D, Rollins BJ, Witzig TE, Anderson KC, Ghobrial IM. MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma. Blood. 2009;113:6669–6680. doi: 10.1182/blood-2009-01-198408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Rollig C, Illmer T. The efficacy of arsenic trioxide for the treatment of relapsed and refractory multiple myeloma: a systematic review. Cancer Treatment Reviews. 2009;35:425–430. doi: 10.1016/j.ctrv.2009.04.007. [DOI] [PubMed] [Google Scholar]
  81. Rosenblatt J, Avigan D. Cellular immunotherapy for multiple myeloma. Best Practice & Research Clinical Haematology. 2008;21:559–577. doi: 10.1016/j.beha.2008.07.007. [DOI] [PubMed] [Google Scholar]
  82. Santo L, Vallet S, Hideshima T, Cirstea D, Pozzi S, Vaghela N, Ikeda H, Okawa Y, Gorgun G, Perrone G, Calabrese E, Squires MS, Ladetto M, Munshi NC, Boccadoro M, Anderson KC, Raje N. AT7519, a novel small molecule multi-cyclin dependent kinase inhibitor, induces apoptosis in multiple myeloma VIA GSK3{beta} Blood (ASH Annual Meeting Abstracts) 2008;112:99, Abstract 251. [Google Scholar]
  83. Seidel C, Sundan A, Hjorth M, Turesson I, Dahl IM, Abildgaard N, Waage A, Borset M. Serum syndecan-1: a new independent prognostic marker in multiple myeloma. Blood. 2000;95:388–392. [PubMed] [Google Scholar]
  84. Shammas MA, Koley H, Bertheau RC, Neri P, Fulciniti M, Tassone P, Blotta S, Protopopov A, Mitsiades C, Batchu RB, Anderson KC, Chin A, Gryaznov S, Munshi NC. Telomerase inhibitor GRN163L inhibits myeloma cell growth in vitro and in vivo. Leukemia. 2008;22:1410–1418. doi: 10.1038/leu.2008.81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Siegel DS, Krishnan A, Lonial S, Chatta G, Alsina M, Jagannath S, Richardson P, Hohl RJ, Lust JA, Bensinger W, Carrum G, Moreb J, Simic A, Barlogie B, Maziarz RT, Anderson KC, Lin J, Lowe A, Vetticaden S, Zhu J. Phase II trial of SCIO- 469 as monotherapy (M) or in combination with bortezomib (MB) in relapsed refractory multiple myeloma (MM) Blood (ASH Annual Meeting Abstracts) 2006;108:1022a, Abstract 3580. [Google Scholar]
  86. Smith EM, Boyd K, Davies FE. The potential role of epigenetic therapy in multiple myeloma. British Journal of Haematology. 2010;148:702–713. doi: 10.1111/j.1365-2141.2009.07976.x. [DOI] [PubMed] [Google Scholar]
  87. Tai YT, Dillon M, Song W, Leiba M, Li XF, Burger P, Lee AI, Podar K, Hideshima T, Rice AG, van Abbema A, Jesaitis L, Caras I, Law D, Weller E, Xie W, Richardson P, Munshi NC, Mathiot C, Avet-Loiseau H, Afar DE, Anderson KC. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood. 2008;112:1329–1337. doi: 10.1182/blood-2007-08-107292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Tan J, Cang S, Ma Y, Petrillo RL, Liu D. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. Journal of Hematology & Oncology. 2010;3:5. doi: 10.1186/1756-8722-3-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Tassone P, Gozzini A, Goldmacher V, Shammas MA, Whiteman KR, Carrasco DR, Li C, Allam CK, Venuta S, Anderson KC, Munshi NC. In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2′-deacetyl-N2′-(3-mercapto- 1-oxopropyl)-maytansine against CD56+ multiple myeloma cells. Cancer Research. 2004;64:4629–4636. doi: 10.1158/0008-5472.CAN-04-0142. [DOI] [PubMed] [Google Scholar]
  90. U.S. National Institutes of Health. [Accessed 25 August 2009.];A study of tanespimycin (KOS- 953) in patients with relapsed-refractory multiple myeloma (TIME-2) 2009 http://clinicaltrials.gov/ct2/show/NCT00514371.
  91. Vij R, Wang M, Orlowski R, Stewart AK, Jagannath S, Kukreti V, Le MH, Kunkel L, Siegel D Multiple Myeloma Research Consortium. PX-171-004, a multicenter phase II study of carfilzomib (CFZ) in patients with relapsed myeloma: an efficacy update. Journal of Clinical Oncology (ASCO Meeting Abstracts) 2009;27:443s, Abstract 8537. [Google Scholar]
  92. Voorhees PM, Manges RF, Sonneveld P, Somlo G, Jagannath S, Zweegman S, Munteanu M, Vermeulen JT, Xie H, Orlowski RZ. Phase II study evaluating the efficacy and safety of CNTO328 in combination with dexamethasone for patients with relapsed/refractory multiple myeloma (MM) Journal of Clinical Oncology. 2008;26:8593. [Google Scholar]
  93. Weber D, Badros AZ, Jagannath S, Siegel D, Richon V, Rizvi S, Garcia-Vargas J, Reiser D, Anderson KC. Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: early clinical experience. Blood (ASH Annual Meeting Abstracts) 2008;112:322, Abstract 871. [Google Scholar]
  94. Whitesell L, Lindquist SL. HSP90 and the chaperoning of cancer. Nature Reviews Cancer. 2005;5:761–772. doi: 10.1038/nrc1716. [DOI] [PubMed] [Google Scholar]

RESOURCES