Skip to main content
NCBI home page
Therapeutic Advances in Hematology logoLink to Therapeutic Advances in Hematology
. 2011 Aug;2(4):213–230. doi: 10.1177/2040620711410097

Experimental Approaches in the Treatment of Multiple Myeloma

Saad A Khan 1, Adam D Cohen 2
PMCID: PMC3573409  PMID: 23556091

Abstract

Myeloma therapy has undergone significant advances in recent years resulting in a marked improvement in survival. Knowledge of the active pathways involved in myeloma pathogenesis has led to the discovery of novel agents and greatly expanded the potential armamentarium available for treatment. This better understanding of the disease and resistance mechanisms has resulted in new agent classes that are being evaluated in preclinical and early clinical studies. In addition, dosing for existing agents is being optimized, and they are being given in new combinations. In this article, we review experimental agents that are showing promise in multiple myeloma treatment. New biological agents in clinical trials hold the promise of efficacy through novel mechanisms of action, with a significant reduction of dose-limiting toxicities compared with classic cytotoxic chemotherapeutics. Second-generation proteasome inhibitors and immunomodulatory agents are furthest along in clinical development, and histone deacetylase inhibitors, heat shock protein 90 inhibitors, Akt inhibitors and monoclonal antibodies are some of the other agents entering later-phase clinical trials. We also review developments in targeting the myeloma stem cell as an exciting new treatment direction.

Keywords: immunomodulatory agent, myeloma, novel therapies, proteasome inhibitor

Introduction

In 2010, more than 20,000 people will have been diagnosed with multiple myeloma in the United States. In the past decade, advances in autologous stem cell transplantation and the introduction of thalidomide, bortezomib, and lenalidomide have significantly improved outcomes for myeloma patients [Kumar et al. 2008]. However, despite these advances and many decades of research into the nature of the disease, over 10,000 patients with myeloma in the USA still die each year [Jemal et al. 2010], and the disease remains incurable. Therefore, it is clear that current therapies are still inadequate, and new strategies need to be found.

Multiple myeloma is due to clonal proliferation of malignant plasma cells which affect multiple organ systems in the body. The malignant phenotype of these cells reflects the dysregulation of multiple cell-intrinsic and cell-extrinsic pathways, which leads to disease pathogenesis and can often vary from patient to patient. This results in a spectrum of disease ranging from asymptomatic to life threatening. With better identification of the processes that lead to disease, targeting the molecular abnormalities that cause cellular dysfunction is becoming the goal of future therapeutics. Thus, novel agents are being developed using the knowledge gained from a better understanding of the pathophysiology of myeloma. In this review, we have focused on presenting preliminary safety and efficacy results from early-stage clinical trials using promising novel agents, all of which have strong preclinical rationale for their exploration in myeloma.

Proteasome inhibition

The ubiquitin-proteasome system plays a critical role in cellular homeostasis through regulation of protein degradation and turnover. Inhibition of the proteasome leads to accumulation of misfolded or obsolete proteins targeted for destruction, and disrupts the normal signaling pathways regulating cell proliferation and survival. This eventually leads to cell cycle arrest and apoptosis through both the intrinsic and extrinsic apoptotic pathways, although the exact mechanisms involved remain incompletely defined [Kuhn et al. 2009; Rajkumar et al. 2005; Adams, 2004]. Proof of the importance of the proteasome for myeloma cell survival was demonstrated by the responses seen in initial clinical studies of the first-in-class proteasome inhibitor bortezomib [Richardson et al. 2005, 2003]. Subsequent studies have demonstrated enhanced efficacy of bortezomib when used in combination with steroids, anthracyclines, alkylating agents, and/or immunomodulatory drugs (IMiDs) in both newly diagnosed and relapsed/refractory myeloma [Richardson et al. 2010c; San-Miguel et al. 2008; Orlowski et al. 2007; Jagannath et al. 2005], and have cemented the place of proteasome inhibition as a current cornerstone of myeloma therapy.

The major toxicity issue with bortezomib is a dose-limiting peripheral neuropathy, which can be severe in 10-15% of patients, leads to dose reductions or discontinuation in up to 40%, and may impact both long-term quality of life and the ability to get subsequent therapies [Bringhen et al. 2010; Harousseau et al. 2010; Mateos et al. 2010b; Richardson et al. 2006]. One recent approach to mitigate this toxicity has been to administer bortezomib on a weekly schedule, rather than the standard day 1, 4, 8, 11 schedule. Several recent studies of bortezomib-based combinations have demonstrated less neurotoxicity and fewer dose reductions and/or discontinuations when given on days 1, 8, 15, and 22 of a 35-day cycle compared with the standard dosing schedule, with response rates, progression-free survival (PFS), and overall survival (OS) that appear comparable to the standard twice-weekly schedule [Bringhen et al. 2010; Mateos et al. 2010b; Reeder et al. 2010].

Another approach has been the development of second-generation proteasome inhibitors with different biochemical characteristics than borte-zomib. Carfilzomib (PR-171) is a synthetic peptide epoxyketone derived from the natural product epoxomicin, and is structurally distinct from bortezomib, lacking the boronic acid moiety [Bennett and Kirk, 2008]. Like bortezomib, it potently inhibits the chymotryptic-like activity of the β5 subunit of the proteasome, but unlike bortezomib it has minimal effect on the caspase-like activity (subunit β1) and no significant off-target activity against nonproteasomal proteases. In addition, carfilzomib binds irreversibly (unlike bortezomib) to the proteasome, with recovery of cellular proteasomal activity dependent on generation of new proteasomes. Initial in vitro studies demonstrated proteasomal inhibition and induction of apoptosis in multiple tumor cell lines and primary myeloma patient samples, with increased potency compared with bortezomib and activity in some bortezomib-resistant lines. Efficacy was increased with more prolonged exposure to carfilzomib in both in vitro and in vivo models [Demo et al. 2007; Kuhn et al. 2007].

Initial phase I studies of carfilzomib explored two schedules: daily × 5 days (repeated every 2 weeks), or daily × 2 days (repeated weekly for 3 out of 4 weeks). Primary toxicities included myelosuppression, fatigue, and transient creatinine increases, with dose-limiting toxicities (DLT's) of thrombocytopenia and febrile neutropenia. Activity was observed on both schedules, including in some patients with bortezomibrefractory myeloma, and grade 3 or 4 neurotoxicity was seen in less than 1% of patients [O'Connor et al. 2009; Stewart et al. 2007]. The daily × 2 days schedule was taken forward into two phase II single-agent trials. In the first study, 266 patients with relapsed and refractory disease (median five prior therapies; prior bortezomib, IMiD, and alkylator required) received carfilzomib at 20 mg/m2 for the first cycle, and at 27 mg m2 for subsequent cycles [Siegel et al. 2010]. A total of 24% of these patients achieved at least a partial response (PR) [0.4% complete response (CR), 4.7% very good partial response (VGPR)] with median duration of response of 7.4 months. An additional 12% achieved minor response (MR) (≥25% reduction of M-protein), and 32% achieved stable disease. A second phase II trial in less heavily treated patients (median two prior therapies) [Vij et al. 2010] showed activity in both bortezomib-treated (ORR 21%, median TTP 8.1 months) and bortezomib-naïve [overall response rate (ORR) 55%, median time to progression (TTP) 11.5 months at the 20-27 mg/m2 dosing schedule] populations. In both of these studies, anemia, thrombocytopenia and neutropenia were the most common grade 3 or higher adverse events, with rare (< 1%) incidence of severe peripheral neuropathy. In addition, carfilzomib has been safely combined with lenalidomide and dexamethasone in phase I/II studies in both relapsed/refractory [Bensinger et al. 2010] and newly diagnosed disease [Jakubowiak et al. 2010b], with promising preliminary efficacy. A phase III trial (ClinicalTrials.gov identifier: NCT01080391) comparing the combination of lenalidomide and dexamethasone with and without carfilzomib is currently recruiting patients with relapsed myeloma. A summary of reported results from clinical trials with carfilzomib is provided in Table 1. In addition, carfilzomib has been safely given in patients with relapsed/refractory myeloma with renal insufficiency, including those with a creatinine clearance of less than 30 ml/min [Badros et al. 2010]. Data on how frequently myeloma-associated renal damage can improve following carfilzomib treatment has not yet been reported.

Table 1.

Myeloma clinical studies with carfilzomib.

Trial Type Population Dosing Toxicities Response
[Stewart et al. 2007] I Myeloma, Hodgkins, non-Hodgkins and Waldenstroms A. 2-week cycle, daily for 5 days A. No DLT 8 myeloma patients; 3 showed PR
A. PX-171–001 B. Daily for 2 days every week for 3 weeks, 4th week off (up to 27 mg/m2). B. 1 grade 4 anemia/thrombocytopenia
B. PX-171–002 [O'Connor et al. 2009] I 29 patients with relapsed/refractory hematological malignancies 1.2–20 mg/m2 daily for 5 days out of 14 day cycles No grade 3/4 neuropathy. 1/3 showed fatigue, nausea. One PR in multiple myeloma MTD of 15 mg/m2 suggested. Antitumor activity noted at >11 mg/m2
Grade 3 febrile neutropenia and grade 4 thrombocytopenia seen at 20 mg/m2
[Siegel et al. 2010] IIb 257 relapsed/refractory myeloma. Prior IMi D, bortezomib, alkylator required Given on days 1, 2, 8, 9, 15, 16 out of a 28-day cycle. Cycle 1: 20 mg/m2, remainder: 27 mg/m2 <1% showed grade 3/4 peripheral neuropathy. Mostly hematologic toxicities 24% PR or better, DOR 7.4 months. 32% with stable disease. 12% with MR
PX-171–003-A1
[Vij et al. 2010] II 34 bortezomib pretreated, 73 bortezomib naïve Given on days 1, 2, 8, 9, 15, 16 out of a 28-day cycle. Bortezomib pretreated: 20 mg/m2; bortezomib naïve: 20 or 20 → 27 mg/m2 Febrile neutropenia and new peripheral neuropathy <1%. 10% grade 3 +anemia, thrombocytopenia or neutropenia ORR: bortezomib pretreated: 18%; bortezomib naïve: 20 mg/m2 46%; 20 → 27 mg/m2 53% DOR > 8 months for bortezomib naïve at 20 mg/m2; 9 months for bortezomib pretreated. 23 patients able to tolerate 12 cycles
[Bensinger et al. 2010] Ib. 67 (29 evaluable) multiple myeloma with 1–3 prior therapies Carfilzomib 10–20 mg/m2 on days 1, 2, 8, 9, 15, 16 out of a 28-day cycle. 1, 2, 15, 16 from cycle 9 onwards. No grade 3 fatigue, neuropathy or thrombosis Thrombocytopenia in 6, anemia in 4, and neutropenia in 6 patients. No DLTs/deaths. ORR 59%, CBR 72%. 21% CR/nCR, 17% Up to 18 cycles given
Lenalidomide 10–25 mg days 1–21. Dexamethasone 40 mg days 1, 8, 15, 22 Grade 3 nonhematoligcal effects seen in 4 patients VGPR, 21% PR
[Jakubowiak et al. 2010a] I/II 24 newly diagnosed patients with multiple myeloma Carfilzomib 20–27 mg/m2 on days 1, 2, 8, 9, 15, 16 out of a 28-day cycle. Dose escalation ongoing at 36 mg/m2. Lenalidomide 25 mg days 1–21. Grade 1 peripheral neuropathy in 2 patients only. Grade 3/4 hematologic toxicities in 8 patients 37% CR/nCR, 63% ≥VGPR, 100% ≥PR 17/19 achieved PR after 1 cycle
Dexamethasone 40/20 weekly (cycle 1–4/5–8
Open in a new tab

CR, complete response; IMiD, immunomodulatory drug; MTD, maximum tolerated dose; nCR, near complete response; ORR, overall response rate; PR, partial response; VGPR, very good partial response; DLT, dose-limiting toxicity; DOR, duration of response; MR, minor response; CBR, clinical benefit rate.

Another second-generation proteasome inhibitor, salinosporamide (NPI-0052), has a more broad mechanism of action; it not only inhibits chymotryptic activity but also the tryptic-like and caspase-like activity of the proteasome. It is an irreversible inhibitor of the proteasome, and has both oral and intravenous formulations. Like carfilzomib, salinosporamide has significant preclinical activity against myeloma cells, including those from patients with bortezomib-refractory disease [Chauhan et al. 2005]. It also demonstrated in vivo synergistic [Chauhan et al. 2010] effects with lenalidomide at low doses in myeloma cells. The combination was associated with decreased multiple myeloma cell migration and angiogenesis. It also showed increased caspase activity, activation of BH-3 protein Bim, and increased Bim translocation to the endoplasmic reticulum with resultant endoplasmic reticulum stress. Bim increases in response to cell stress, and is important in initiating mitochondrial apoptotic signaling utilizing cytochrome-c release and activation of caspase-9 [Chauhan et al. 2010]. Preliminary results were recently reported from a phase I study of NPI-0052 given intravenously every week for 3 out of 4 weeks in 27 patients with relapsed/refractory myeloma [Richardson et al. 2009b]. Dose escalation had reached 0.7 mg/m2 with the maximum tolerated dose (MTD) not yet reached. Toxicities included fatigue, nausea, vomiting, dizziness, diarrhea, headache, and confusion, with no myelosuppression or neuropathy noted. Two minor responses were noted, with eight additional patients achieving stable disease.

Other novel proteasome inhibitors include MLN9708, CEP-18770, and ONX 0912, all of which are orally bioavailable. MLN9708 and CEP-18770 have been shown in preclinical models to be converted into an active agent that reversibly inhibits the chymotrypsin-like proteolytic site of the 20S proteasome [Kupperman et al. 2010; Piva et al. 2008]. ONX 0912 is a tripeptide epoxyketone that is structurally similar to carfilzomib, with equal preclinical potency [Chauhan et al. 2010]. Phase I trials of these oral proteasome inhibitors in patients with myeloma and other relapsed/refractory tumors are ongoing.

Finally, another novel approach is specific targeting of the immunoproteasome, which is highly expressed in hematopoietic cells, and is involved in peptide processing and presentation on major histocompatibility complex I molecules. Selective inhibition of the immunoproteasome may allow for activity in immune cells while sparing other tissues. In vitro studies [Kuhn et al. 2009] of a prototypical agent IPSI-001 showed preferential inhibition of the immunoproteasome. It showed activity against many myeloma cell lines including bortezomib-refractory cells. Synergy with dexamethasone was seen as well. However, clinical studies of this or other immunoproteasome inhibitors are not yet underway.

Immunomodulatory drugs

The microenvironment in which myeloma cells reside not only has stimulatory effects on tumor growth, but also induces an immune suppressor response. Interleukin 6 (IL-6), insulinlike growth factor (IGF), vascular endothelial growth factor, tumor necrosis factor-α (TNF-α) along with other cytokines and chemokines contribute to the immune suppression and myeloma progression [Gorgun et al. 2010]. Thalidomide and lenalidomide directly kill myeloma cells but also affect the microenvironment and immune response. They enhance natural killer cell function, stimulate T-cell proliferation and CD8 + T-cell activation, increase IL-2 and interferon-γ levels while enhancing the immune response to tumor cells [Gorgun et al. 2010].

Pomalidomide (CC-4047) is a second-generation IMiD with more potent immune stimulatory effect and killing of multiple myeloma cells. It suppresses cytokine secretion and has direct antiproliferative and proapoptotic effects on myeloma cells [Hideshima et al. 2000]. In addition, CC-4047 inhibited osteoclastogenesis and bone resorption in vitro, suggesting a potential benefit with respect to myeloma-associated lytic bone disease [Anderson et al. 2006]. Combinations with proteasome inhibitors have shown increased anti-multiple myeloma effect. In the initial phase I study [Schey et al. 2004], pomalidomide was given daily with a MTD of 2 mg/day. This showed mostly hematologic toxicities at higher doses, though even at 2 mg/day grade 4 neutropenia was a DLT in two patients. A total of 13 of 24 patients showed a greater than 50% decrease in paraprotein (see Table 2). A phase II study of 2 mg of continuous daily pomalidomide, in combination with oral dexamethasone 40 mg once weekly in 60 relapsed patients, demonstrated an overall response rate of 63%, including a 40% response rate in the 20 patients with lenalidomiderefractory disease, and 60% in patients with bortezomib-refractory disease. Grade 3/4 toxicities included neutropenia in 32%, anemia in 5% and thrombocytopenia in 3%. Nonhematologic grade 3/4 toxicities included fatigue and pneumonia in 17% and 8%, respectively. Less than 5% of patients experienced grade 3/4 diarrhea, constipation, hyperglycemia and neuropathy. The median OS had not been reached and the PFS was 11.6 months [Lacy et al. 2009].

Table 2.

Myeloma clinical studies with pomalidomide.

Trial Type Population Dosing Toxicities Response
[Schey et al. 2004] I 24 relapsed refractory multiple myeloma (71% IMiD naïve) Daily dosing with escalation levels; 1, 2, 5, 10 mg/day; 3 DVTs, grade 4 neutropenia in 6 (2 at 2 mg/day), 3 had thrombocytopenia grade 3 17% showed CR, 13% VGPR, 25% PR, 17% MR, 25% SD
[Lacy et al. 2009] II 60 relapsed refractory Pomalidomide 2 mg/day for 28-day cycle. Dexamethasone 40 mg on days 1, 8, 15, 22 Grade 3/4 neutropenia in 32%, anemia in 5% and thrombocytopenia in 3%. One grade 3 neuropathy 5% CR, 28% VGPR, 30% PR 74% response with high-risk cytogenetics. 37-60% response in patients refractory to bortezomib/other IMiDs
[Lacy et al. 2010b] II 34 lenalidomide refractory Pomalidomide 2 mg/day for 28-day cycle. Dexamethasone 40 mg on days 1, 8, 15, 22 Grade 3/4 hematologic toxicities (anemia 12%, thrombocytopenia 9%, neutropenia 26%) VGPR in 9%, PR 23%, MR 15%, SD in 35% Active and well tolerated even in lenalidomide refractory patients. DOR 9.1 months, OS 13.9 months
[Richardson et al. 2010b] I/II 38 phase I Pomalidomide 2, 3, 4, 5 mg/day on days 1-21 of 28-day cycle. Dexamethasone 40 mg/week if no response seen Myelosuppression most common grade 3/4 toxicity 1 CR, 6 PR, 5 MR MTD seen as 4 mg/day
[Richardson et al. 2010b] I/II n = 215 randomized phase II (all had prior bortez and lenalidomide)

  1. Pomalidomide 4mg days 1-21 every 28 days (add dexamethasone 40 mg/week if PD)

  2. Pomalidomide 4mg days 1-21 every 28 days plus dexamethasone 40 mg/week

  • Aggregate data presented for both arms: grade 3/4 neutropenia (42%), thrombocytopenia

  • (22%), anemia (20%), neuropathy (5%), infection (31%)

  • Aggregate data:

  • ≥MR = 38% (n = 120 evaluable)
[Lacy et al. 2010b] II 70 lenalidomide and bortezomib refractory patients. Sequential phase II trials: Grade 3/4 neutropenia (A/B): 37%/55%, thrombocytopenia: 11%/13%, anemia: 9%/16% ≥MR: 49% at 2mg, 40% at 4 mg No advantage seen with 4 mg at continuous dosing
A: Pomalidomide 2mg days 1-28
B: Pomalidomide 4mg days 1-28
[Leleu et al. 2010] II 83 lenalidomide and bortezomib refractory Pomalidomide 4 mg, 28-day cycle Myelosuppression similar in both arms A: 30% PR or better DOR 77 days in arm A, 89 days in arm B
B: 47% PR or better
A: daily 1-28
B: days 1-21 only Dexamethasone 40 mg on days 1, 8, 15, 22
Open in a new tab

CR, complete response; DVT, deep vein thrombosis; IMiD, immunomodulatory drug; MTD, maximum tolerated dose; nCR, near complete response; ORR, overall response rate; OS, overall survival; PR, partial response; SD, stable disease; VGPR, very good partial response; DLT, dose-limiting toxicity; DOR, duration of response; MR, minor response; PD, progressive disease.

A second phase II study explored this regimen in 34 heavily pretreated patients with lenalidomiderefractory disease [Lacy et al. 2010a]. After a median of five cycles, 11 (34%) of 32 evaluable patients showed at least a partial response, with a duration of response of 9.2 months. Grade 3/4 hematologic toxicities were reported in 53% of patients, and nine patients had grade 1/2 neuropathy. Eight patients with stable disease also had a dose increase to 4 mg/day, and one went on to a PR. Subsequent studies have focused on the bortezomib- and lenalidomide-refractory population, and have found that the pomalidomide dose can be escalated to 4 mg daily, when given on a schedule of 21 out of 28 days, with potentially better tolerability than the continuous schedule [Leleu et al. 2010; Lacy et al. 2010b; Richardson et al. 2010b]. Preliminary results so far have confirmed a PR or better rates between 26% and 42% in this difficult-to-treat population (Table 2), with randomized phase 2 studies comparing the two schedules, and exploring the benefit of dexamethasone, currently ongoing (ClinicalTrials.gov identifiers: NCT01053949 and NCT00833833). The safety and efficacy of pomalidomide in patients with significant renal insufficiency (creatinine > 2.5 mg/dl) has not been explored in clinical trials conducted to date.

Histone deacetylase inhibitors

Histone deacetylase (HDAC) inhibitors regulate gene expression by increasing histone acetylation, but in myeloma they also disrupt cellular function through transcriptional upregulation of death receptors, increased oxidative injury and disruption of chaperone protein function [Mitsiades et al. 2003]. HDAC inhibitors have demonstrated potent preclinical antimyeloma activity, and appear to synergize with other antimyeloma agents, particularly bortezomib [Campbell et al. 2010; Catley et al. 2006; Pei et al. 2004; Mitsiades et al. 2003]. Potential explanations for the synergy include increased apoptosis in cells where bortezomib causes inhibition of nuclear factor-κB, causing disruption of the aggresome and overwhelming the unfolded protein response [Mazumder et al. 2010]. Proteasome inhibition in cells results in accumulation of ubiquitin-conjugated proteins in the perinuclear region as aggresomes, which have a cytoprotective effect. Aggresomes, which require HDAC6 for their formation, are particularly important in proteasome-inhibited malignant cells, and their inhibition enhances bortezomib activity [Nawrocki et al. 2006]. Based on this synergy, as well as the fact that single-agent activity in myeloma has been modest [Niesvizky et al. 2011; Richardson et al. 2008; Wolf et al. 2008], clinical development of the HDAC inhibitors is moving forward in combination with existing agents in myeloma.

The addition of vorinostat (formerly suberoylanilide hydroxamic acid) to bortezomib is associated with antiproliferative and proapoptotic molecular sequelae on myeloma cells, even those resistant to standard or novel therapy [Mitsiades et al. 2003]. The combination suppresses growth factor receptors and transcripts, DNA repair enzymes, caspase inhibitors and proteasome subunits. Two phase I studies in 57 patients showed the combination of bortezomib and vorinostat to be well tolerated and demonstrated responses in roughly 40%, including 33% (five of 15) of patients with bortezomib-refractory disease [Badros et al. 2009; Weber et al. 2008]. Most common grade 1/2 toxicities were fatigue, diarrhea, nausea, and thrombocytopenia, with one grade 4 thrombocytopenia. A phase II trial is underway looking at the combination of vorinostat with bortezomib in refractory myeloma (ClinicalTrials.gov identifier: NCT00773838), and a phase III trial comparing bortezomib plus vorinostat with bortezomib plus placebo (ClinicalTrials.gov identifier: NCT00773747) in patients with relapsed disease is also enrolling. In these studies, the dosing is 400 mg of vorinostat daily on days 1-14 of a 21-day cycle, with standard twice-weekly bortezomib administration. The combination of vorinostat, lenalidomide and dexamethasone was found tolerable in 31 heavily pretreated patients with myeloma in a phase I trial [Richardson et al. 2010b]. A total of 87% showed at least stable disease, with two achieving CR, three VGPR and 11 PR. MTD was not reached, with one DLT consisting of grade 3 diarrhea. Grade 3 neutropenia (26%) was the most common toxicity, followed by thrombocytopenia, anemia, diarrhea and fatigue (10-16%).

Panobinostat (LBH589) is an oral pandeacetylase inhibitor (pan DACi). It also disrupts HSP90 [San-Miguel et al. 2010] and aggresome activity by its HDAC6 inhibition as described above. Like vorinostat, the combination of panobinostat and bortezomib was found to be safe and showed activity in phase I trials, with responses seen in 26 of 38 (68%) patients with relapsed/refractory disease, including 62% of patients with bortezomib-refractory myeloma [San-Miguel et al. 2010]. The combination of panobinostat 20 mg three times weekly with standard dosing of bortezomib and dexamethasone is currently being evaluated in both phase II and phase III studies (ClinicalTrials.gov identifiers: phase II — NCT01083602; phase III — NCT01023308). A phase Ib combination of panobinostat with lenalidomide appeared more toxic [Mateos et al. 2010], with grade 3/4 thrombocytopenia in 44%, neutropenia in 37%, eight DLTs (four hematologic, two cardiac, and one each of fatigue and pneumonia), and two deaths from febrile neutropenia that were likely treatment related.

Phospho-inositol-3 kinase/Akt/mTOR inhibitors

The phospho-inositol-3 kinase (PI3K)/Akt pathway is a cascade that is activated by several cytokines or growth factors and mediates proliferation and antiapoptosis. The mammalian target of rapamycin (mTOR) is a downstream target of PI3K/Akt and phosphatase and tensin homolog (PTEN). This pathway is activated in cells exposed to many antimyeloma agents, including bortezomib [Hideshima et al. 2006], making it a promising target for combination therapies to overcome resistance to conventional agents. Perifosine is a novel, oral alkyl-phospholipid that inhibits constitutive and IL-6/IGF-1-induced Akt activation in multiple myeloma cells [Hideshima et al. 2006]. Akt inhibition leads to cytotoxicity by downregulating survivin, which regulates caspase-3 activity [Hideshima et al. 2007], and also may have caspase-independent effects such as increased autophagy and antiangiogenesis [Schmidt-Hieber et al. 2010].

Perifosine 150 mg daily was studied in a phase II trial [Richardson et al. 2007] in 64 patients with refractory/relapsed multiple myeloma (median four previous therapies, range 1-11). It had modest activity in this single agent setting, which improved with the addition of dexamethasone to a combined PR plus MR of 38%. Nausea, neutropenia and increased creatinine were observed in 30-60% of patients (2-7% grade 3), with grade 3/4 neutropenia seen in 10 patients.

The combination of perifosine and bortezomib was tested in a phase I/II trial [Richardson et al. 2009c]. Standard dose bortezomib and perifosine 50 or 100 mg daily were coadministered to heavily pretreated patients, with dexamethasone added on progression. Grade 3/4 anemia, thrombocytopenia, neutropenia, hyponatremia and diarrhea were seen in over 5%, with one grade 3 neuropathy. A total of 82% of the 73 evaluable patients demonstrated stable disease or better (38% MR or better), with median OS in these patients of 33.4 months. A phase I trial investigated perifosine combined with lenalidomide and dexamethasone [Jakubowiak et al. 2010c]. A total of 30 patients who had received one to four prior treatments were given 50 or 100 mg of perifosine daily with 15 or 25 mg of lenalidomide (days 1-21) and 20 mg of dexamethasone (days 1-4, 9-12 and 17-20 for four cycles, then 20 mg days 1-4) as part of a 28-day cycle. A total of 50% of the patients showed a partial response or better, and the median OS was 30.6 months. Grade 3/4 adverse events included neutropenia (26%), hypophosphatemia (23%), and thrombocytopenia (16%). A phase III trial is currently comparing the addition of 50 mg perifosine or placebo to dexamethasone and standard dose bortezomib in patients with bortezomib-relapsed (but not refractory) disease (ClinicalTrials.gov identifier: NCT01002248).

Another approach to disrupting the PI3K/Akt pathway is to inhibit the downstream effector molecule, mTOR. A phase II study of the intravenous mTOR inhibitor, temsirolimus (CCI-779) in relapsed and/or refractory multiple myeloma showed PRs in one of 16 patients (plus five MRs) and a median TTP of 4.6 months. A phase I/II study of the combination of 25 mg mg of temsirolimus with weekly bortezomib showed an ORR of 47% in 43 patients in the phase II portion, including 21% (MR or better) in bortezomib-refractory disease. The median TTP was 7.3 months, and no grade 3/4 neuropathy was observed, with cytopenias being the most common grade 3/4 toxicities [Ghobrial et al. 2010]. Finally, small molecules that directly inhibit PI3K have been developed and show preclinical activity in myeloma, although clinical data in myeloma are not available to date [McMillin et al. 2009; Harvey and Lonial, 2007].

Heat shock protein-90 inhibitors

Heat shock protein-90 (HSP-90) is a molecular chaperone for proteins that are involved in control of the cell cycle, proliferation and apoptosis. First identified as a class of proteins upregulated in normal cells in response to thermal stress [Ritossa, 1996], HSPs act by preventing protein aggregation and maintaining the conformation, localization and activity of multiple intracellular proteins, including several involved in oncogenesis (reviewed by Isaacs and colleagues [Isaacs et al. 2003]). HSP-90 expression is increased in numerous malignant cell types and enhances their ability to resist apoptosis and maintain viability in the face of stressors such as anoxia or chemotherapy (reviewed by Richardson and colleagues [Richardson et al. 2011]). This makes HSP-90 an attractive target for anticancer therapy

Preclinical studies showed that the HSP-90 inhibitor, tanespimycin (KOS-953, 17-AAG), sensitized multiple myeloma cells to bortezomib and inhibited antiapoptotic/proliferative cascades [Mitsiades et al. 2006]. This synergy was the basis for combination trials using these agents in myeloma. A phase I/II trial of tanespimycin and bortezomib in 72 relapsed/refractory myeloma patients (median of five prior treatments) showed responses in 48% of bortezomib-naïve patients and 13% of bortezomib-refractory patients [Richardson et al. 2009a]. The median duration of response (DOR) was 10.7 months, with three patients in PR through 24 months. Interestingly, there was no grade 3/4 neuropathy seen, consistent with preclinical rodent data suggesting that HSP-90 inhibition may have a neuroprotective effect when combined with bortezomib [Flint et al. 2009]. A phase III trial (ClinicalTrials.gov identifier: NCT00546780) was comparing bortezomib with and without tanespimycin for patients with myeloma in first relapse. However, that study has been halted by the manufacturer with no further details available. Several new HSP-90 inhibitors, including KW-2478 [Nakashima et al. 2010] and NVP-AUY922 [Stuhmer et al. 2008], have confirmed the preclinical efficacy of HSP-90 inhibition in myeloma cells, and are entering clinical testing.

Monoclonal antibodies

Two broad categories of monoclonal antibodies against myeloma exist: those directly targeting the myeloma cell itself, and those targeting growth and/or survival signals provided by the bone marrow microenvironment.

Targeting myeloma cell surface antigens

Targeting B-cell antigens has yielded excellent results in the hematologic malignancies, with anti-CD20 (rituximab and ofatumumab) and anti-CD52 (alemtuzumab) antibodies being well established agents in non-Hodgkin's lymphoma and chronic lymphocytic leukemia. CD40 is a cell-surface antigen expressed on B cells, and mature B-cell malignancies, including myeloma [Horton et al. 2010; Pellat-Deceunynck et al. 1994]. Two humanized anti-CD40 antibodies have been explored clinically in multiple myeloma: dacetuzumab (SGN-40) is an anti-CD40 antibody with mild agonist activity, and HCD122 (Chr 12.12) is a CD40 antagonist. Despite promising preclinical activity [Tai et al. 2005; Hayashi et al. 2003], a phase I trial of SGN-40 in 44 patients with relapsed myeloma showed no objective responses, with stable disease seen in 20% [Hussein et al. 2010]. Common toxicities included grade 1 fatigue (57%), transient elevated transaminases (41%, 9% of which were grade 2/3), ocular inflammation (16%) and a cytokine release syndrome (41% with first dose), which was mitigated with preinfusion steroids. HCD122 similarly showed minimal singleagent activity in myeloma [Bensinger et al. 2006]. Current strategies involving anti-CD40 antibodies include combination approaches with lenalidomide and dexamethasone [Agura et al. 2009], and antibody re-engineering to enhance FcγR binding in order to augment antibody-dependent cellular cytoxicity [Horton et al. 2010], which may improve efficacy of this approach in future clinical studies.

CD56 is expressed on 80% of myeloma cells and is associated with the upregulation of the SOX4 family of transcription factors, which is important in early B-cell and late T-cell development [Iqbal et al. 2010]. Lorvotuzumab mertansine (IMGN901, BB-10901) is an antibody conjugate consisting of DM1 bound to a humanized anti-CD56 antibody. DM1 (mertansine) is a cytotoxic maytansinoid that can be conjugated via disulfide linkages to an antibody against a specific target. Maytansinoids are potent compounds that target microtubules and cause mitotic arrest [Lopus et al. 2010]. The combination binds to CD56 and the antibody-maytansinoid complex is internalized, releasing the active metabolite within the myeloma cell resulting in cell death. The specific targeting avoids the severe side effects that limit the systemic use of DM1 [Erickson et al. 2006; Cassady et al. 2004; Tassone et al. 2004]. As a monotherapy, lorvotuzumab induced responses in five of 28 evaluable patients in a phase I study, with an MTD of 112 mg/m2 per week and four grade 3 toxicities of headache, neuropathy, transaminitis, hyperuricemia, and fatigue seen in three patients [Chanan-Khan et al. 2010]. A phase I combination trial with lenalidomide and dexamethasone is ongoing (ClinicalTrials.gov identifier: NCT00991562).

Elotuzumab is a monoclonal antibody targeting the cell surface glycoprotein CS1. While not expressed in most normal tissue or stem cells, CS1 is found in high levels on myeloma cells regardless of cytogenetic abnormalities [Hsi et al. 2008]. A phase I monotherapy trial showed good tolerability with no MTD reached, but minimal single-agent activity. The primary toxicity was infusion-related reactions [Zonder et al. 2008]. Phase I/II trials showed elotuzumab to be tolerable in combination with full doses of bortezomib or lenalidomide and dexamethasone [Lonial et al. 2010; Jakubowiak et al. 2010a] in patients with previously treated myeloma. In a phase II study, lenalidomide-naïve patients with multiple myeloma who had received one to three prior therapies received 10 or 20 mg/kg of elotuzumab in combination with lenalidomide and dexamethasone [Richardson et al. 2010a]. For the first 28-day cycle, elotuzumab was given weekly, then every 2 weeks for subsequent cycles. Responses were seen in 22/26 (85%) patients (one CR, seven VGPRs and 14 PRs), and serious adverse events were seen in 22%. These included infusion-related reactions (dizziness 15%, nausea 15%, headache 9%) which were ameliorated by augmented premedication with steroids and histamine blockers. Phase III trials comparing lenalidomide and dexamethasone with and without elotuzumab for both relapsed and newly diagnosed myeloma are expected to begin in 2011 (ClinicalTrials.gov identifier: NCT01239797).

Several additional antibodies targeting myeloma surface antigens have entered clinical development, including milatuzumab (anti-CD74) [Kaufman et al. 2009], daratumumab (anti-CD38) [Kong et al. 2010] and BT062 (an anti-CD138-DM4 conjugate) [Jagannath et al. 2010], further expanding the pool of candidate therapeutic antibodies with potential utility in myeloma.

Targeting the myeloma microenvironment

Myeloma has complex and dependent interactions with the microenvironment in which the malignant cells reside. Multiple factors within the bone marrow provide protective signals to myeloma cells, contributing to cell survival and drug resistance. IL-6 is one such factor and normally plays important roles in bone metabolism. In myeloma, it is produced primarily by bone marrow stromal cells and can enhance the growth and survival of myeloma cells. IL-6 receptor binding induces phosphorylation of gp130. This results in activation of three major signaling cascades: Ras/Raf/MEK/ERK, JAK-2/STAT3, and Pi3K/Akt, all of which combine to promote myeloma cell proliferation, survival and drug resistance [Yasui et al. 2006]. A phase I study using a first-generation chimeric anti-IL-6 antibody as a single agent showed limited activity in relapsed/refractory myeloma [van Zaanen et al. 1998].

A newer high-affinity chimeric anti-IL-6 antibody, CNTO 328, was shown to potentiate apoptosis in the presence of dexamethasone by increased caspase activation and DNA fragmentation [Voorhees et al. 2009], and also synergistically increased susceptibility of myeloma cells to bortezomib-induced cell death [Voorhees et al. 2007]. CNTO 328 (siltuximab) did show single-agent clinical activity in a phase I trial in relapsed/refractory lymphoma, myeloma, and Castleman's disease [Kurzrock et al. 2008]. Commonly observed toxicities were generally mild and included upper respiratory or urinary infections, myelosuppression, elevated ALT, hypertriglyceridemia, diarrhea, nausea, fatigue, and headache, with no dose-limiting toxicity identified in 52 patients. Ongoing studies in combination with dexamethasone, melphalan, and/or bortezomib (ClinicalTrials.gov identifiers: NCT00911859 and NCT01266811) should help define the activity of this agent as an adjunct to currently used therapies in myeloma.

B-cell activating factor (BAFF) is a TNF super-family member that can cause activation of nuclear factor κB by classical and alternative pathways, leading to expansion of the B-cell compartment and extended B-cell survival [Baud and Karin, 2009]. BAFF also plays a role in B-cell maturation and immunoglobulin secretion [Zheng et al. 2005], and is overexpressed in the serum and bone marrow environment in myeloma, where it can provide a survival signal to myeloma cells [Tai et al. 2006]. This has made it a rational target in myeloma. A neutralizing anti-BAFF antibody demonstrated significant activity in a myeloma xenograft model [Neri et al. 2007], and LY2127399, a human IgG4 antibody against BAFF, is currently in a phase I trial in combination with bortezomib in relapsed myeloma (ClinicalTrials.gov identifier: NCT00689507).

IGF-1 receptor (IGF-1R) is expressed on myeloma cells, with higher expression in patients with myeloma with one of the translocations associated with poor prognosis, t(4;14) and t(14;16), making it an attractive target for therapy [Bataille et al. 2005]. IGF-1 is produced by myeloma cells as part of an autocrine loop promoting proliferation and survival, as well as by osteoclasts in the bone marrow, and separately confers a poor prognosis in addition to its association with high risk translocations [Sprynski et al. 2009]. Monoclonal antibodies against IGF-1R have had disappointing clinical results as monotherapy in myeloma [Lacy et al. 2007; Moreau et al. 2007]. However, small molecule IGF-1R tyrosine kinase inhibitors (e.g. NVPAEW541, BMS-754807) have shown activity in vitro against myeloma [Carboni et al. 2009; Maiso et al. 2008], and are entering early clinical development.

Other novel agents

Cell cycle and mitotic inhibitors

Cell cycle dysregulation is a common event in malignant plasma cells, with overexpression of cyclin D proteins seen in the majority of myeloma patients [Bergsagel et al. 2005]. Inhibition of cyclin-dependent kinases (CDKs) induces cell-cycle arrest in myeloma cells and sensitizes cells to dexamethasone- or bortezomib-induced apoptosis [Menu et al. 2008; Baughn et al. 2006]. In a phase I trial in combination with bortezomib, the CDK 4/6 inhibitor PD 0332991 was shown to reversibly induce cell cycle arrest in patient myeloma cells, and could feasibly be given with bortezomib, with grade 3 thrombocytopenia and neutropenia as the most common toxicities. A phase II study of this combination is ongoing [Niesvizky et al. 2010].

Inhibitors of aurora kinases and kinesin spindle proteins, two classes of proteins involved in regulating mitotic progression, have shown promising preclinical activity against myeloma cell lines and primary myeloma patient samples, with induction of mitotic arrest and blockade of cellular proliferation [Tunquist et al. 2010; Hose et al. 2009; Shi et al. 2007]. A phase I study of MLN8237, an oral aurora-A kinase inhibitor, in relapsed/refractory hematologic malignancies found the MTD to be 45 mg daily for 14 out of 28 days, with thrombocytopenia (36%), neutropenia (46%), and asthenia (32%) as the most common toxicities of all grades, with myelosuppression as the DLT [Padmanabhan et al. 2010]. Expansion of the MTD in this study, as well as a separate phase I trial evaluating the combination of MLN 8237 and bortezomib in patients with myeloma, are ongoing. A phase I trial of ARRY-520, an intravenous kinesin spindle protein inhibitor, in relapsed/refractory myeloma (median five prior therapies) found the MTD to be 1.5 mg/m2 on days 1, 2 every 14 days. Dose-limiting toxicity was febrile neutropenia, which was ameliorated by adding filgrastim with each cycle, and mucositis. Ten of 23 evaluable patients (43%) achieved stable disease or better, and phase II dose expansion is ongoing [Shah et al. 2010].

Plitidepsin

Plitidepsin is an antitumor agent derived from the marine tunicate Aplidium albicans that activates p38 pathways and Jun N-terminal kinase signaling [Mitsiades et al. 2008]. It is also involved in caspase activation and Fas/CD95 translocation to lipid rafts, and can induce myeloma cell apoptosis in vitro even in the presence of protective bone marrow stromal cells. In a phase II study plitidepsin was administered to 51 heavily pretreated patients with myeloma [Mateos et al. 2010b]. The most common grade 3/4 toxicities were anemia (29%), thrombocytopenia (18%), creatine phosphokinase (CPK) elevation (14%), ALT elevation (28%), and fatigue (16%). Singleagent activity was observed, with an ORR (MR or better) of 13%, which improved to 22% with the addition of dexamethasone. A phase III study of plitidepsin plus dexamethasone versus dexamethasone alone in patients whose disease relapsed after three to six prior therapies (including bortezomib and an IMiD) is currently recruiting (ClinicalTrials.gov identifier: NCT01102426).

Targeting the myeloma stem cell

Much attention in anticancer therapy has recently been focused on stem cells as perhaps the ‘holy grail’ of eradicating disease. This is of particular interest in myeloma as immunoglobulin gene rearrangement and idiotype provide a method for assessing clonal relationships [Ghosh and Matsui, 2009]. Myeloma plasma cells that express CD138 have been shown to have limited clonogenic potential, whereas CD138− cells are much fewer in number and do have clonogenic potential, suggesting stem cell-like properties [Brennan and Matsui, 2009]. These cells with clonogenic potential also express CD45, CD19, CD20, and CD22. Although their numbers are small, these phenotypic B cells with clonogenic potential do demonstrate relative resistance to many antimyeloma therapies. CD138− cells demonstrated less responsiveness to glucocorticoids, lenalidomide, bortezomib, and alkylating agents than CD138 + cells [Matsui et al. 2008].

In addition, targeting CD138− cells presents other challenges. They have complex interactions with their microenvironment, including growth regulation via the Hedgehog pathway [Peacock et al. 2007]. This pathway can be activated by Hedgehog ligands that are secreted in both a paracrine and autocrine manner. These bind to the transmembrane receptor called Patched (Ptch1), which leads to loss of repression of Smoothened (Smo). This results in modulation of the transcription factor Gli, which in turn leads to transcription of target genes [Matsui et al. 2008]. Activation of the Hedgehog pathway resulted in cancer stem cell self-renewal and expansion, while inhibition induced terminal differentiation and loss of clonogenic growth potential [Matsui et al. 2008]. In mouse models, Hedgehog inhibition by cyclopamine combined with inhibition of the Wnt signaling pathway resulted in significantly reduced tumor burden and prolonged survival [Tricot et al. 2010].

The Hedgehog pathway inhibitor BMS-833923 is currently undergoing phase I trials in patients with myeloma with bortezomib, lenalidomide/dexamethasone and as a single agent.

The ability of stem cells to remain quiescent and the drug transporters they possess make them particularly difficult targets. In addition, there remains controversy over the exact nature and phenotype (and some would argue, existence) of the myeloma stem cell, and the discovery that some CD34 + CD138 + myeloma cells also have the ability to grow independently [Kuranda et al. 2010] indicates that our understanding of stem cells in myeloma needs to expand. However, as new pathways are identified, agents directed against clonogenic myeloma cells may eventually play as important a role as treatment against differentiated plasma cells.

Rituximab

Because clonogenic precursors in myeloma have been reported to express B-cell antigens, such as CD20, and because 10 −15% of patients with myeloma will have some level of CD20 expression on their CD138 + mature plasma cells [Robillard et al. 2003], rituximab has been explored as an antimyeloma therapy. It has shown in vitro ability to cause antibody-dependent cellular lysis and limit tumor growth [Matsui et al. 2008]. The literature on rituximab use in patients with myeloma consists largely of case series and small trials, with relatively disappointing results [Kapoor et al. 2008]. In the largest prospective study reported [Treon et al. 2002], five out of 19 previously treated patients showed stable disease, with one showing PR to rituximab. Only patients with CD20 + plasma cells showed any clinical benefit, a pattern seen in most of the other reported studies as well [Kapoor et al. 2008]. Thus, so far, the notion that clonogenic myeloma precursors can be eliminated through targeting CD20 + cells has yet to be borne out clinically.

Summary/future directions

Antimyeloma therapy represents an exciting field in hematology. When thalidomide was noted to have single-agent activity against myeloma in 1999, it was the first new agent to do so in more than 30 years [Singhal et al. 1999]. Since then, great strides have been made in slowing down disease mortality, but clearly more is needed. We know much more about myeloma, and further breakthroughs are more likely to come from rational targeting of the disease than the fortuitous rediscovery of older drugs. Targeting the differentiated disease-causing cells in myeloma has yielded significant results and will remain the main focus of experimental therapy, though attempts to identify and target the myeloma stem cell continue, with the goal of inducing durable and perhaps even permanent responses. Identifying resistance mechanisms and better administration methods have allowed us to use existing agents for longer and in more powerful combinations. The isolation of accessory pathways that gain prominence in myeloma cells exposed to existing drugs have led to novel agent combinations that disrupt these pathways and overcome resistance. Finally, even as new versions of existing agents with less toxicity are identified and replace the old standards, entirely new classes are demonstrating activity in early-stage clinical trials. These developments give hope that the newer myeloma treatments will be even more efficacious and better tolerated than the breakthrough agents of the last decade.

Acknowledgements

The authors wish to thank Russell Schilder, MD for critical review of the manuscript.

Footnotes

This research received no specific grant from any funding agency in the public, commercial, or not for-profit sectors.

SAK has no conflicts of interest to declare. ADC has received honoraria from Millenium, Celgene, and Onyx.

References

  1. Adams J. (2004) The proteasome: A suitable antineoplastic target. Nat Rev Cancer 4: 349–360 [DOI] [PubMed] [Google Scholar]
  2. Agura E., Niesvizky R., Matous J., Munshi N., Hussein M., Parameswaran R., et al. (2009) Dacetuzumab (SGN-40), lenalidomide, and weekly dexamethasone in relapsed or refractory multiple myeloma: Multiple responses observed in a phase Ib study. Blood (ASH Annual Meeting Abstracts) 114: 2870 [Google Scholar]
  3. Anderson G., Gries M., Kurihara N., Honjo T., Anderson J., Donnenberg V., et al. (2006) Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1. Blood 107: 3098–3105 [DOI] [PubMed] [Google Scholar]
  4. Badros A., Burger A.M., Philip S., Niesvizky R., Kolla S.S., Goloubeva O., et al. (2009) Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 15: 5250–5257 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Badros A. Z., Vij R., Martin T., Zonder J. A., Wong A. F., Woo T., et al. (2010) Phase II study of carfilzomib in patients with relapsed/refractory multiple myeloma and renal insufficiency. J Clin Oncol (ASCO Annual Meeting Abstracts) 28: 8128 [Google Scholar]
  6. Bataille R., Robillard N., Avet-Loiseau H., Harousseau J.L., Moreau P. (2005) CD221 (IGF-1R) is aberrantly expressed in multiple myeloma, in relation to disease severity. Haematologica 90: 706–707 [PubMed] [Google Scholar]
  7. Baud V., Karin M. (2009) Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov 8: 33–40 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Baughn L.B., Di Liberto M., Wu K., Toogood P.L., Louie T., Gottschalk R., 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 [DOI] [PubMed] [Google Scholar]
  9. Bennett M.K., Kirk C.J. (2008) Development of proteasome inhibitors in oncology and autoimmune diseases. Curr Opin Drug Discov Devel 11: 616–625 [PubMed] [Google Scholar]
  10. Bensinger W., Jagannath S., Becker P.S., Anderson K.C., Stadtmauer E.A., Aukerman L., et al. (2006) A phase 1 dose escalation study of a fully human, antagonist anti-CD40 antibody, HCD 122 (formerly CHIR-12.12), in patients with relapsed and refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts) 108: 3575 [Google Scholar]
  11. Bensinger W., Wang M., Orlowski R., Alsina M., Martin T., Singhal S., et al. (2010) Dose-escalation study of carfilzomib (CFZ) plus lenalidomide (LEN) plus low-dose dexamethasone (Dex)(CRd) in relapsed/refractory multiple myeloma (R/R MM). J Clin Oncol (ASCO Annual Meeting Abstracts) 28(15 Suppl): 8029 [Google Scholar]
  12. Bergsagel P.L., Kuehl W.M., Zhan F., Sawyer J., Barlogie B., Shaughnessy J., Jr (2005) Cyclin D dysregulation: An early and unifying pathogenic event in multiple myeloma. Blood 106: 296–303 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Brennan S.K., Matsui W. (2009) Cancer stem cells: Controversies in multiple myeloma. J Mol Med 87: 1079–1085 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Bringhen S., Larocca A., Rossi D., Cavalli M., Genuardi M., Ria R., et al. (2010) Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 116: 4745–4753 [DOI] [PubMed] [Google Scholar]
  15. Campbell R.A., Sanchez E., Steinberg J., Shalitin D., Li Z.W., Chen H., et al. (2010) Vorinostat enhances the antimyeloma effects of melphalan and bortezomib. Eur J Haematol 84: 201–211 [DOI] [PubMed] [Google Scholar]
  16. Carboni J.M., Wittman M., Yang Z., Lee F., Greer A., Hurlburt W., et al. (2009) BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR. Mol Cancer Ther 8: 3341–3349 [DOI] [PubMed] [Google Scholar]
  17. Cassady J.M., Chan K.K., Floss H.G., Leistner E. (2004) Recent developments in the may-tansinoid antitumor agents. Chem Pharm Bull (Tokyo) 52: 1–26 [DOI] [PubMed] [Google Scholar]
  18. Catley L., Weisberg E., Kiziltepe T., Tai Y.T., Hideshima T., Neri P., et al. (2006) Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 108: 3441–3449 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Chanan-Khan A., Wolf J.L., Garcia J., Gharibo M., Jagannath S., Manfredi D., et al. (2010) Efficacy analysis from phase I study of lorvotuzumab mertansine (IMGN901), used as monotherapy, in patients with heavily pretreated CD56-positive multiple myeloma — a preliminary efficacy analysis. Blood (ASH Annual Meeting Abstracts) 116: 1962 [Google Scholar]
  20. Chauhan D., Catley L., Li G., Podar K., Hideshima T., Velankar M., et al. (2005) A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from bortezomib. Cancer Cell 8: 407–419 [DOI] [PubMed] [Google Scholar]
  21. Chauhan D., Singh A.V., Aujay M., Kirk C.J., Bandi M., Ciccarelli B., 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 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Demo S.D., Kirk C.J., Aujay M.A., Buchholz T.J., Dajee M., Ho M.N., et al. (2007) Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 67: 6383–6391 [DOI] [PubMed] [Google Scholar]
  23. Erickson H.K., Park P.U., Widdison W.C., Kovtun Y.V., Garrett L.M., Hoffman K., et al. (2006) Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res 66: 4426–4433 [DOI] [PubMed] [Google Scholar]
  24. Flint O.P., Kwagh J., Wang F., Moulin F., Oberdoerster J., Berman D., et al. (2009) Tanespimycin prevents bortezomib toxicity and preserves neuronal morphology in primary rat dorsal root ganglion cultures. Blood (ASH Annual Meeting Abstracts) 114: 2847 [Google Scholar]
  25. Ghobrial I.M., Weller E., Vij R., Munshi N.C., Banwait R., Rourke M., et al. (2010) Final results of the phase I/II trial of weekly bortezomib in combination with temsirolimus (CCI-779) in relapsed or relapsed/refractory multiple myeloma specifically in patients refractory to bortezomib. Blood (ASH Annual Meeting Abstracts) 116: 990 [Google Scholar]
  26. Ghosh N., Matsui W. (2009) Cancer stem cells in multiple myeloma. Cancer Lett 277: 1–7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Gorgun G., Calabrese E., Soydan E., Hideshima T., Perrone G., Bandi M., et al. (2010) Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood 116: 3227–3237 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Harousseau J.L., Palumbo A., Richardson P.G., Schlag R., Dimopoulos M.A., Shpilberg O., et al. (2010) Superior outcomes associated with complete response in newly diagnosed multiple myeloma patients treated with nonintensive therapy: Analysis of the phase 3 vista study of bortezomib plus melphalanprednisone versus melphalan-prednisone. Blood 116: 3743–3750 [DOI] [PubMed] [Google Scholar]
  29. Harvey R.D., Lonial S. (2007) PI3 kinase/AKT pathway as a therapeutic target in multiple myeloma. Future Oncol 3: 639–647 [DOI] [PubMed] [Google Scholar]
  30. Hayashi T., Treon S.P., Hideshima T., Tai Y.T., Akiyama M., Richardson P., et al. (2003) Recombinant humanized anti-CD40 monoclonal antibody triggers autologous antibody-dependent cell-mediated cytotoxicity against multiple myeloma cells. Br J Haematol 121: 592–596 [DOI] [PubMed] [Google Scholar]
  31. Hideshima T., Chauhan D., Shima Y., Raje N., Davies F.E., Tai Y.T., et al. (2000) Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96: 2943–2950 [PubMed] [Google Scholar]
  32. Hideshima T., Catley L., Yasui H., Ishitsuka K., Raje N., Mitsiades C., 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 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Hideshima T., Catley L., Raje N., Chauhan D., Podar K., Mitsiades C., et al. (2007) Inhibition of AKT induces significant downregulation of survivin and cytotoxicity in human multiple myeloma cells. Br J Haematol 138: 783–791 [DOI] [PubMed] [Google Scholar]
  34. Horton H.M., Bernett M.J., Peipp M., Pong E., Karki S., Chu S.Y., et al. (2010) Fc-engineered anti-CD40 antibody enhances multiple effector functions and exhibits potent in vitro and in vivo antitumor activity against hematologic malignancies. Blood 116: 3004–3012 [DOI] [PubMed] [Google Scholar]
  35. Hose D., Reme T., Meissner T., Moreaux J., Seckinger A., Lewis J., et al. (2009) Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma. Blood 113: 4331–4340 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Hussein M., Berenson J.R., Niesvizky R., Munshi N., Matous J., Sobecks R., et al. (2010) A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma. Haematologica 95: 845–848 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Hsi E.D., Steinle R., Balasa B., Szmania S., Draksharapu A., Shum B.P., et al. (2008) CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res 14: 2775–2784 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Iqbal M.S., Otsuyama K., Shamsasenjan K., Asaoku H., Kawano M.M. (2010) CD56 expression in human myeloma cells derived from the neurogenic gene expression: Possible role of the SRY-HMG box gene, SOX4. Int J Hematol 91: 267–275 [DOI] [PubMed] [Google Scholar]
  39. Isaacs J.S., Xu W., Neckers L. (2003) Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell. 2003 Mar; 3(3): 213–217 [DOI] [PubMed] [Google Scholar]
  40. Jagannath S., Chanan-Khan A.A., Heffner L.T., Avigan D., Lutz R.J., Uherek C., et al. (2010) BT062, an antibody-drug conjugate directed against CD138, shows clinical activity in a phase I study in patients with relapsed or relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts) 116: 3060 [Google Scholar]
  41. Jagannath S., Durie B.G., Wolf J., Camacho E., Irwin D., Lutzky J., et al. (2005) Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 129:776–783 [DOI] [PubMed] [Google Scholar]
  42. Jakubowiak A.J., Benson D.M., Bensinger W., Siegel D.S., Zimmerman T.M., Mohrbacher A., et al. (2010a) Elotuzumab in combination with bortezomib in patients with relapsed/refractory multiple myeloma: Updated results of a phase 1 study. Blood (ASH Annual Meeting Abstracts) 116: 3023 [Google Scholar]
  43. Jakubowiak A.J., Dytfeld D., Jagannath S., Vesole D.H., Anderson T.B., Nordgren B.K., et al. (2010b) Carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma: Initial results of phase I/II MMRC trial. Blood (ASH Annual Meeting Abstracts) 116: 862 [Google Scholar]
  44. Jakubowiak A.J., Richardson P.G., Zimmerman T.M., Alsina M., Kaufman J.L., Kandarpa M., et al. (2010c) Final phase I results of perifosine in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts) 116: 3064 [Google Scholar]
  45. Jemal A., Siegel R., Xu J., Ward E. (2010) Cancer statistics, 2010. CA Cancer J Clin 60: 277–300 [DOI] [PubMed] [Google Scholar]
  46. Kapoor P., Greipp P.T., Morice W.G., Rajkumar S.V., Witzig T.E., Greipp P.R. (2008) Anti-CD20 monoclonal antibody therapy in multiple myeloma. Br J Haematol 141: 135–148 [DOI] [PubMed] [Google Scholar]
  47. Kaufman J.L., Niesvizky R., Stadtmauer E.A., Chanan-Khan A., Siegel D.S., Horne H., et al. (2009) Dose-escalation trial of milatuzumab (humanized anti-CD74 monoclonal antibody) in multiple myeloma. J Clin Oncol (ASCO Annual Meeting Abstracts) 27: 8593. [DOI] [PubMed] [Google Scholar]
  48. Kong S.-Y., Li X.-F., Nahar S., Song W., de Weers M., Parren P.W.H.I., et al. (2010) Daratumumab directly induces human multiple myeloma cell death and acts synergistically with conventional and novel anti-myeloma drugs. Blood (ASH Annual Meeting Abstracts) 116: 3013 [Google Scholar]
  49. Kuhn D.J., Chen Q., Voorhees P.M., Strader J.S., Shenk K.D., Sun C.M., et al. (2007) Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 110: 3281–3290 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Kuhn D.J., Hunsucker S.A., Chen Q., Voorhees P.M., Orlowski M., Orlowski R.Z. (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 [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Kumar S.K., Rajkumar S.V., Dispenzieri A., Lacy M.Q., Hayman S.R., Buadi F.K., et al. (2008) Improved survival in multiple myeloma and the impact of novel therapies. Blood 111: 2516–2520 [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Kupperman E., Lee E.C., Cao Y., Bannerman B., Fitzgerald M., Berger A., et al. (2010) Evaluation of the proteasome inhibitor Mln9708 in preclinical models of human cancer. Cancer Res 70: 1970–1980 [DOI] [PubMed] [Google Scholar]
  53. Kuranda K., Berthon C., Dupont C., Wolowiec D., Leleu X., Polakowska R., et al. (2010) A subpopulation of malignant CC34+CC138+B7-H1+plasma cells is present in multiple myeloma patients. Exp Hematol 38: 124–131 [DOI] [PubMed] [Google Scholar]
  54. Kurzrock R., Fayad L., Voorhees P., Furman R.R., Lonial S., Borghaei H., et al. (2008) A phase I study of CNTO 328, an anti-interleukin-6 monoclonal antibody in patients with B-cell nonhodgkin's lymphoma, multiple myeloma, or Castleman's disease. Blood (ASH Annual Meeting Abstracts) 112: 1009 [Google Scholar]
  55. Lacy M.Q., Alsina M., Roberts L., Fonseca R., Melvin C., Yin D., et al. (2007) Phase 1 dose escalation study of the monoclonal antibody against the insulin like growth factor I receptor CP-751,871 in patients with multiple myeloma. Blood (ASH Annual Meeting Abstracts) 110: 1171 [Google Scholar]
  56. Lacy M.Q., Hayman S.R., Gertz M.A., Dispenzieri A., Buadi F., Kumar S., et al. (2009) Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol 27: 5008–5014 [DOI] [PubMed] [Google Scholar]
  57. Lacy M.Q., Hayman S.R., Gertz M.A., Short K.D., Dispenzieri A., Kumar S., et al. (2010a) Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia 24: 1934–1939 [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Lacy M.Q., Mandrekar S., Gertz M.A., Hayman S.R., Short K.D., Buadi F., et al. (2010b) Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: Comparison of two dosing strategies in dual-refractory disease. Blood (ASH Annual Meeting Abstracts) 116: 863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Leleu X., Attal M., Moreau P., Duhamel A., Fermand J.P., Michalet M., et al. (2010) Phase 2 study of 2 modalities of pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. IFM 2009-02. Blood (ASH Annual Meeting Abstracts) 116: 859
  60. Lonial S., Vij R., Harousseau J., Facon T., Moreau P., Leleu X., et al. (2010) Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma: A phase I/II study. J Clin Oncol (ASCO Annual Meeting Abstracts) 28(15 Suppl): 8020. [DOI] [PubMed] [Google Scholar]
  61. Lopus M., Oroudjev E., Wilson L., Wilhelm S., Widdison W., Chari R., et al. (2010) Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol Cancer Ther 9: 2689–2699 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Maiso P., Ocio E.M., Garayoa M., Montero J.C., Hofmann F., Garcia-Echeverria C., et al. (2008) The insulin-like growth factor-I receptor inhibitor NVP-AEW541 provokes cell cycle arrest and apoptosis in multiple myeloma cells. Br J Haematol 141: 470–482 [DOI] [PubMed] [Google Scholar]
  63. Mateos M.V., Cibeira M.T., Richardson P.G., Prosper F., Oriol A., de la Rubia J., et al. (2010a) Phase II clinical and pharmacokinetic study of plitidepsin 3-hour infusion every two weeks alone or with dexamethasone in relapsed and refractory multiple myeloma. Clin Cancer Res 16: 3260–3269 [DOI] [PubMed] [Google Scholar]
  64. Mateos M., Spencer A., Taylor K., Lonial S., De La Rubia J., Facon T., et al. (2010b) Phase Ib study of oral panobinostat (LBH589) plus lenalidomide (LEN) plus dexamethasone (DEX) in patients (Pts) with relapsed (Rel) or Rel and refractory (Ref) multiple myeloma (MM). J Clin Oncol (ASCO Annual Meeting Abstracts) 28(15 Suppl): 8030 [Google Scholar]
  65. Matsui W., Wang Q., Barber J.P., Brennan S., Smith B.D., Borrello I., et al. (2008) Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 68: 190–197 [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Mazumder A., Vesole D.H., Jagannath S. (2010) Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: A case series illustrating utility in clinical practice. Clin Lymphoma Myeloma Leuk 10: 149–151 [DOI] [PubMed] [Google Scholar]
  67. McMillin D.W., Ooi M., Delmore J., Negri J., Hayden P., Mitsiades N., 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 [DOI] [PubMed] [Google Scholar]
  68. Menu E., Garcia J., Huang X., Di Liberto M., Toogood P.L., Chen I., et al. (2008) A novel therapeutic combination using PD 0332991 and bortezomib: Study in the 5T33MM myeloma model. Cancer Res 68: 5519–5523 [DOI] [PubMed] [Google Scholar]
  69. Mitsiades N., Mitsiades C.S., Richardson P.G., McMullan C., Poulaki V., Fanourakis G., et al. (2003) Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 101: 4055–4062 [DOI] [PubMed] [Google Scholar]
  70. Mitsiades C.S., Mitsiades N.S., Mcmullan C.J., Poulaki V., Kung A.L., Davies F.E., et al. (2006) Antimyeloma activity of heat shock protein-90 inhibition. Blood 107: 1092–1100 [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Mitsiades C.S., Ocio E.M., Pandiella A., Maiso P., Gajate C., Garayoa M., et al. (2008) Aplidin, a marine organism-derived compound with potent antimyeloma activity in vitro and in vivo. Cancer Res 68: 5216–5225 [DOI] [PubMed] [Google Scholar]
  72. Moreau P., Hulin C., Facon T., Boccadoro M., Mery-Mignard D., Deslandes A., et al. (2007) Phase I study of AVE1642 anti IGF-1R monoclonal antibody in patients with advanced multiple myeloma. Blood (ASH Annual Meeting Abstracts) 110: 1166 [Google Scholar]
  73. Nakashima T., Ishii T., Tagaya H., Seike T., Nakagawa H., Kanda Y., et al. (2010) New molecular and biological mechanism of antitumor activities of KW-2478, a novel nonansamycin heat shock protein 90 inhibitor, in multiple myeloma cells. Clin Cancer Res 16: 2792–2802 [DOI] [PubMed] [Google Scholar]
  74. Nawrocki S.T., Carew J.S., Pino M.S., Highshaw R. A., Andtbacka R. H., Dunner K., Jr, et al. (2006) Aggresome disruption: A novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res 66: 3773–3781 [DOI] [PubMed] [Google Scholar]
  75. Neri P., Kumar S., Fulciniti M.T., Vallet S., Chhetri S., Mukherjee S., 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 [DOI] [PubMed] [Google Scholar]
  76. Niesvizky R., Ely S., Mark T., Aggarwal S., Gabrilove J.L., Wright J.J., et al. (2011) Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma. Cancer 117: 336–342 [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Niesvizky R., Lentzsch S., Badros A.Z., Chanan-Khan A.A., Singhal S.B., Zonder J.A., et al. (2010) A phase I study of PD 0332991: Complete CDK4/6 inhibition and tumor response in sequential combination with bortezomib and dexamethasone for relapsed and refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts) 116: 860 [Google Scholar]
  78. O'Connor O.A., Stewart A.K., Vallone M., Molineaux C.J., Kunkel L.A., Gerecitano J.F., et al. (2009) 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 15: 7085–7091 [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Padmanabhan S., Shea T.C., Vose J.M., Reeder C.B., Berdeja J.G., McDonagh K.T., et al. (2010) Phase I study of an investigational aurora A kinase inhibitor MLN8237 in patients with advanced hematologic malignancies. Blood (ASH Annual Meeting Abstracts) 116: 2799 [Google Scholar]
  80. Peacock C.D., Wang Q., Gesell G.S., Corcoran-Schwartz I.M., Jones E., Kim J., et al. (2007) Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci USA 104: 4048–4053 [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Pei X.Y., Dai Y., Grant S. (2004) Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res 10: 3839–3852 [DOI] [PubMed] [Google Scholar]
  82. Pellat-Deceunynck C., Bataille R., Robillard N., Harousseau J.L., Rapp M.J., Juge-Morineau N., et al. (1994) Expression of CD28 and CD40 in human myeloma cells: A comparative study with normal plasma cells. Blood 84: 2597–2603 [PubMed] [Google Scholar]
  83. Piva R., Ruggeri B., Williams M., Costa G., Tamagno I., Ferrero D., et al. (2008) Cep-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood 111: 2765–2775 [DOI] [PubMed] [Google Scholar]
  84. Rajkumar S.V., Richardson P.G., Hideshima T., Anderson K.C. (2005) Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 23: 630–639 [DOI] [PubMed] [Google Scholar]
  85. Reeder C.B., Reece D.E., Kukreti V., Chen C., Trudel S., Laumann K., et al. (2010) Once-versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood 115: 3416–3417 [DOI] [PubMed] [Google Scholar]
  86. Richardson P.G., Barlogie B., Berenson J., Singhal S., Jagannath S., Irwin D., et al. (2003) A Phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348: 2609–2617 [DOI] [PubMed] [Google Scholar]
  87. Richardson P, Sonneveld P., Schuster M.W., Irwin D., Stadtmauer E.A., Facon T., et al. (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352: 2487–2498 [DOI] [PubMed] [Google Scholar]
  88. Richardson P., Briemberg H., Jagannath S., Wen P.Y., Barlogie B., Berenson J., et al. (2006) Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24: 3113–3120 [DOI] [PubMed] [Google Scholar]
  89. Richardson P., Lonial S., Jakubowiak A., Krishnan A., Wolf J., Densmore J., et al. (2007) Multi-center phase II study of perifosine (KRX-0401) alone and in combination with dexamethasone (dex) for patients with relapsed or relapsed/refractory multiple myeloma (MM): Promising activity as combination therapy with manageable toxicity. Blood (ASH Annual Meeting Abstracts) 110: 1164 [Google Scholar]
  90. Richardson P., Mitsiades C., Colson K., Reilly E., Mcbride L., Chiao J., et al. (2008) Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma. Leuk Lymphoma 49: 502–507 [DOI] [PubMed] [Google Scholar]
  91. Richardson P., Chanan-Khan A., Lonial S., Krishnan A., Carroll M., Alsina M., et al. (2009a) Tanespimycin plus bortezomib in patients with relapsed and refractory multiple myeloma: Final results of a phase I/II study. J Clin Oncol (ASCO Annual Meeting Abstracts) 27: 8503 [Google Scholar]
  92. Richardson P., Hofmeister C., Jakubowiak A., Zimmerman T.M., Spear M.A., Palladino M.A., et al. (2009b) Phase 1 clinical trial of the novel structure proteasome inhibitor NPI-0052 in patients with relapsed and relapsed/refractory multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts) 114: 431 [Google Scholar]
  93. Richardson P., Wolf J.L., Jakubowiak A.J., Zonder J.A., Lonial S., Irwin D.H., et al. (2009c) Perifosine in combination with bortezomib and dexamethasone extends progression-free survival and overall survival in relapsed/refractory multiple myeloma patients previously treated with bortezombib: Updated phase I/II trial results. Blood (ASH Annual Meeting Abstracts) 114: 1869 [Google Scholar]
  94. Richardson P.G., Moreau P., Jakubowiak A.J., Facon T., Jagannath S., Vij R., et al. (2010a) Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: Interim results of a phase 2 study. Blood (ASH Annual Meeting Abstracts) 116: 986 [Google Scholar]
  95. Richardson P.G., Siegel D., Baz R., Kelley S.L., Munshi N.C., Sullivan D., et al. (2010b) A phase 1/2 multi-center, randomized, open label dose escalation study to determine the maximum tolerated dose, safety, and efficacy of pomalidomide alone or in combination with low-dose dexamethasone in patients with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide and bortezomib. Blood (ASH Annual Meeting Abstracts) 116: 864 [Google Scholar]
  96. Richardson P.G., Weller E., Lonial S., Jakubowiak A.J., Jagannath S., Raje N.S., et al. (2010c) Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116: 679–686 [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Richardson P., Mitsiades C.S., Laubach J.P., Lonial S., Chanan-Khan A.A., Anderson K.C. (2011) Inhibition of heat shock protein 90 (HSP90) as a therapeutic strategy for the treatment of myeloma and other cancers. Br J Haematol 152(4): 367–79 [DOI] [PubMed] [Google Scholar]
  98. Ritossa F. (1996) Discovery of the heat shock response. Cell Stress Chaperones 1: 97–98 [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Robillard N., Avet-Loiseau H., Garand R., Moreau P., Pineau D., Rapp M.J., et al. (2003) CD20 is associated with a small mature plasma cell morphology and t(11;14) in multiple myeloma. Blood 102: 1070–1071 [DOI] [PubMed] [Google Scholar]
  100. San Miguel J., Schlag R., Khuageva N.K., Dimopoulos M.A., Shpilberg O., Kropff M., et al. (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359: 906–917 [DOI] [PubMed] [Google Scholar]
  101. San-Miguel J.F., Sezer O., Siegel D.S., Guenther A., Blade J., Prosser I.W., et al. (2010) Phase Ib study of oral panobinostat (LBH589) plus intravenous bortezomib in patients (Pts) with relapsed (Rel) or Rel and refractory (Ref) multiple myeloma (MM). J Clin Oncol (ASCO Annual Meeting Abstracts) 28(15 Suppl): 8001 [Google Scholar]
  102. Schey S.A., Fields P., Bartlett J.B., Clarke I.A., Ashan G., Knight R.D., et al. (2004) Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol 22: 3269–3276 [DOI] [PubMed] [Google Scholar]
  103. Schmidt-Hieber M., Dabrowski R., Weimann A., Aicher B., Lohneis P., Busse A., et al. (2010) In vitro cytotoxicity of the novel antimyeloma agents perifosine, bortezomib and lenalidomide against different cell lines. Invest New Drugs 16, November [Epub ahead of print]. [DOI] [PubMed] [Google Scholar]
  104. Shah J.J., Zonder J.A., Cohen A., Webert D., Thomas S., Wang M., et al. (2010) A phase I/II trial of the KSP inhibitor ARRY-520 in relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts) 116: 1959 [Google Scholar]
  105. Shi Y., Reiman T., Li W., Maxwell C.A., Sen S., Pilarski L., et al. (2007) Targeting aurora kinases as therapy in multiple myeloma. Blood 109: 3915–3921 [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Siegel D.S., Martin T., Wang M., Vij R., Jakubowiak A.J., Jagannath S., et al. (2010) Results of PX-171-003-A1, an open-label, single-arm, phase 2 (Ph 2) study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts) 116: 985 [Google Scholar]
  107. Singhal S., Mehta J., Desikan R., Ayers D., Roberson P., Eddlemon P., et al. (1999) Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565–1571 [DOI] [PubMed] [Google Scholar]
  108. Sprynski A.C., Hose D., Caillot L., Reme T., Shaughnessy J.D., Jr, Barlogie B., et al. (2009) The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor. Blood 113: 4614–4626 [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Stewart A.K., O'Connor O.A., Alsina M., Trudel S., Urquilla P.R., Vallone M.K., et al. (2007) Phase I evaluation of carfilzomib (PR-171) in hematological malignancies: Responses in multiple myeloma and Waldenstrom's macroglobulinemia at welltolerated doses. J Clin Oncol (ASCO Annual Meeting Abstracts) 25(18 Suppl): 8003 [Google Scholar]
  110. Stuhmer T., Zollinger A., Siegmund D., Chatterjee M., Grella E., Knop S., et al. (2008) Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma. Leukemia 22: 1604–1612 [DOI] [PubMed] [Google Scholar]
  111. Tai Y.T., Li X.F., Breitkreutz I., Song W., Neri P., Catley L., et al. (2006) Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment. Cancer Res 66: 6675–6682 [DOI] [PubMed] [Google Scholar]
  112. Tai Y.T., Li X.F., Catley L., Coffey R., Breitkreutz I., Bae J., et al. (2005) Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: Clinical implications. Cancer Res 65: 11712–11720 [DOI] [PubMed] [Google Scholar]
  113. Tassone P., Gozzini A., Goldmacher V., Shammas M.A., Whiteman K.R., Carrasco D.R., et al. (2004) In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2′-deacSetyl-N2′-(3-mercapto-1-oxopropyl)-maytansine against CD56+multiple myeloma cells. Cancer Res 64: 4629–4636 [DOI] [PubMed] [Google Scholar]
  114. Treon S.P., Pilarski L.M., Belch A.R., Kelliher A., Preffer F.I., Shima Y., et al. (2002) CD20-directed serotherapy in patients with multiple myeloma: Biologic considerations and therapeutic applications. J Immunother 25: 72–81 [DOI] [PubMed] [Google Scholar]
  115. Tricot G.J., Yang Y., Xu C., Xu H., Zeng M., Zangari M., et al. (2010) Targeting myeloma stem cells through simultaneous inhibition of Wnt and Hedgehog (Hh) signaling pathways. Blood (ASH Annual Meeting Abstracts) 116: 615 [Google Scholar]
  116. Tunquist B.J., Woessner R.D., Walker D.H. (2010) Mcl-1 stability determines mitotic cell fate of human multiple myeloma tumor cells treated with the kinesin spindle protein inhibitor ARRY-520. Mol Cancer Ther 9: 2046–2056 [DOI] [PubMed] [Google Scholar]
  117. van Zaanen H.C., Lokhorst H.M., Aarden L.A., Rensink H.J., Warnaar S.O., van der Lelie J., et al. (1998) Chimaeric anti-interleukin 6 monoclonal antibodies in the treatment of advanced multiple myeloma: A phase I dose-escalating study. Br J Haematol 102: 783–790 [DOI] [PubMed] [Google Scholar]
  118. Vij R., Siegel D., Kaufman J., Jakubowiak A., Stewart A., Jagannath S., et al. (2010) Results of an ongoing open-label, phase II study of carfilzomib in patients with relapsed and/or refractory multiple myeloma (R/R MM). J Clin Oncol (ASCO Annual Meeting Abstracts) 28(15 Suppl): 8000 [Google Scholar]
  119. Voorhees P.M., Chen Q., Kuhn D.J., Small G.W., Hunsucker S.A., Strader J.S., et al. (2007) Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in pre-clinical models of multiple myeloma. Clin Cancer Res 13: 6469–6478 [DOI] [PubMed] [Google Scholar]
  120. Voorhees P.M., Chen Q., Small G.W., Kuhn D.J., Hunsucker S.A., Nemeth J.A., et al. (2009) Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death. Br J Haematol 145: 481–490 [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Weber D., Badros A.Z., Jagannath S., Siegel D., Richon V., Rizvi S., et al. (2008) Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: Early clinical experience. Blood (ASH Annual Meeting Abstracts) 112: 871 [Google Scholar]
  122. Wolf J.L., Siegel D., Matous J., Lonial S., Goldschmidt H., Schmitt S., et al. (2008) A phase II study of oral panobinostat (LBH589) in adult patients with advanced refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts) 112: 2774 [Google Scholar]
  123. Yasui H., Hideshima T., Richardson P.G., Anderson K.C. (2006) Novel therapeutic strategies targeting growth factor signalling cascades in multiple myeloma. Br J Haematol 132: 385–397 [DOI] [PubMed] [Google Scholar]
  124. Zheng Y., Gallucci S., Gaughan J.P., Gross J.A., Monestier M. (2005) A role for B cell-activating factor of the TNF family in chemically induced autoimmunity. J Immunol 2005 Nov 1; 175(9): 6163–6168 [DOI] [PubMed] [Google Scholar]
  125. Zonder J.A., Singhal S., Bensinger W., Mohrbacher A., Hussein M.A., Munshi N.C., et al. (2008) Phase I study of elotuzumab (HuLuc63) in relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts) 112: 2273 [Google Scholar]

Articles from Therapeutic Advances in Hematology are provided here courtesy of SAGE Publications

RESOURCES