Novel therapies for multiple myeloma

Multiple myeloma (MM) is currently an incurable plasma cell malignancy, despite advances in systemic and supportive therapies. High-dose chemotherapy with stem cell support has extended event-free and overall survival, but cures few, if any, patients. New treatments have recently been developed which target the MM cell, the MM cell–host interaction and the bone marrow (BM) microenvironment to overcome drug resistance. Thalidomide and its immunomodulatory derivatives, as well as proteasome inhibitor PS-341, are examples of such agents targeting the tumour cell in its BM milieu, which can achieve responses even in refractory relapsed MM. These novel therapies represent a new treatment paradigm in MM based upon targeting MM–host interactions and offer great promise to improve patient outcome in MM. The BM microenvironment consists of extracellular matrix proteins and BM stromal cells (SCs), osteoblasts and osteoclasts, and plays a crucial role in the pathogenesis of MM cell growth and survival (Hallek et al, 1998; Tricot 2000). Adhesion of MM cells to fibronectin confers protection from apoptosis (Damiano et al, 1999), whereas binding of MM cells to BMSCs induces the transcription and secretion of cytokines, including interleukin 6 (IL-6) (Uchiyama et al, 1993), insulin-like growth factor 1 (IGF-1) (Mitsiades et al, 2002), tumour necrosis factor α (TNF-α) (Hallek et al, 1998; Gupta et al, 2001; Hideshima et al, 2001a), vascular endothelial growth factor (VEGF) (Gupta et al, 2001) and stroma-derived factor 1 (SDF-1) (Hideshima et al, 2002a), which mediate MM cell proliferation, survival, drug resistance and migration. Binding is mediated by adhesion molecules on MM cells, including integrins, immunoglobulin superfamily members, cadherins and selectins. Integrin binding and activation in MM cells occurs through interaction with extracellular matrix (ECM) proteins such as fibronectin, vitronectin, laminin and collagen in the BM microenvironment (Clark & Brugge, 1995). Binding of MM cells to fibronectin through α4β1 or α5β1 integrin inhibits CD95-induced caspase-8 activation and apoptosis by altering the cellular availability of c-Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein-long (c-FLIP), an endogenous inhibitor of CD95-induced apoptosis (Fig 1) (Shain et al, 2002). In addition to inhibiting Fas-mediated apoptosis, MM cell adhesion to fibronectin also confers protection against chemotherapy-induced cell death (Damiano et al, 1999), associated with upregulation of p27kip1 and G1 cell cycle arrest (Hazlehurst et al, 2000). Role of extracellular matrix proteins in MM pathogenesis. Extracellular matrix proteins localize MM cells in BM, and confer resistance to Fas ligand and chemotherapeutics. Adhesion of MM cells to BMSCs is also mediated primarily via integrins and induces increased transcription and secretion of cytokines, including IL-6, VEGF, TNF-α, IGF-1 and SDF-1 (Fig 2). Specifically, binding of MM cells to BMSCs enhances NF-κB-dependent transcription and secretion of IL-6 in BMSCs (Chauhan et al, 1996), which mediates paracrine growth, survival and drug resistance in MM cells (Ogata et al, 1997; Hideshima et al, 2000a). IL-6 triggers proliferation via the Ras/Raf/MEK/MAPK cascade (Ogata et al, 1997; Hallek et al, 1998; Hideshima et al, 2000a), and protection against dexamethasone by PI3K/AKT signalling (Hideshima et al, 2001b) and activation of the SH2 domain, containing protein tyrosine phosphatase (Chauhan et al, 2000). IL-6 also promotes MM cell survival via phosphorylation of STAT3 (signal transducer and activator of transcription 3) and upregulation of antiapoptotic molecules, including Mcl-1 (Puthier et al, 1999a), Bcl-xL (Puthier et al, 1999b) and c-Myc (Kiuchi et al, 1999). IL-6 induces VEGF expression and secretion in patient MM cells (Dankbar et al, 2000) and inhibits the antigen-presenting function of dendritic cells (DC) by blocking the differentiation of monocytes to DC, thereby contributing to the immune compromise that is characteristic of MM (Chomarat et al, 2000; Ratta et al, 2002). Adhesion of MM cells to BMSCs. Signaling cascades in MM cells and BMSCs, as targets of novel therapies. VEGF in the BM milieu triggers growth and migration of both MM and plasma cell leukaemia cells (Podar et al, 2001), augments IL-6 production in BMSCs (Dankbar et al, 2000), and stimulates BM angiogenesis (D'Amato et al, 1994), which is increased in some MM patients (Vacca et al, 1999). High-affinity VEGF receptor fms-like tyrosine kinase (Flt-1), but not fetal liver kinase-1 (Flk-1), is expressed on MM cells, and VEGF activates mitogen-activated protein-kinase (MAPK) signalling and modest MM cell proliferation, as well as protein kinase C-mediated migration of MM cells (Podar et al, 2001). As for IL-6, VEGF inhibits the antigen-presenting function of DC by inhibiting DC maturation, probably contributing to the immune deficits characteristic of MM (Gabrilovich et al, 1996). TNF-α is produced by both MM cells and BMSCs (Garrett et al, 1987; Lichtenstein et al, 1989; Sati et al, 1999), and secretion of TNF-α in BM is significantly higher in those MM patients with bone disease (Davies et al, 2000). TNF-α activates NF-κB and upregulates expression of adhesion molecules [very late antigen 4 (VLA-4) and leucocyte function-associated antigen (LFA-1)] on MM cells and their ligands [vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1)] on BMSCs, and increases MM to BMSC binding (Hideshima et al, 2001a; Li et al, 2000), thereby promoting MM cell survival and protection against apoptotic stimuli (Hideshima et al, 2002b; Mitsiades et al, 2002). This observation highlights the importance of targeting TNF-α and NF-κB to abrogate MM cell–host interactions. In addition to IL-6, VEGF and TNF-α, other cytokines in the BM microenvironment also play a role in MM pathogenesis. IGF-1 secreted by BMSCs enhances growth, survival and drug resistance in MM cells by activating RAS/MAPK and PI3K/AKT pathways, phosphorylation of Bad, and inhibition of apoptosis (Georgii-Hemming et al, 1996; Xu et al, 1997; Tu et al, 2000; Mitsiades et al, 2002). SDF-1 is produced by BMSCs and binds to CXCR4, a seven-transmembrane G protein-coupled chemokine receptor on MM cells (Bleul et al, 1996; Oberlin et al, 1996). SDF-1 promotes proliferation, induces migration and partially protects against dexamethasone-induced apoptosis in MM cells via activation of MAPK and PI3-K/Akt pathways, with downstream activation of Bad and NF-κB (Hideshima et al, 2002a). SDF-1 also increases secretion of IL-6 and VEGF in BMSCs (Hideshima et al, 2002a), and functions as a chemoattractant, which localizes MM cells in the BM milieu (Sanz-Rodriguez et al, 2001). IL-1β is produced mainly by BMSCs and induces IL-6 production in MM cells (Costes et al, 1998), as well as activating osteoclasts (Kawano et al, 1989) and bone resorption. Macrophage inflammatory protein 1α (MIP-1α) secreted by MM cells (Han et al, 2001), as well as the interaction of receptor activator of NF-κB (RANK) on osteoclasts with RANK ligand (RANKL) on osteoblasts and BMSCs, also play important roles in osteolysis. BMSCs produce osteoprotegerin (OPG), which prevents excessive activation of osteoclasts by serving as a decoy receptor and competing with RANK for binding to RANKL. In contrast, ligation of VCAM-1 on BMSCs via α4β1 integrin on MM cells decreases secretion of OPG and increases expression of RANKL, thereby promoting osteolysis (Fig 3) (Michigami et al, 2000; Pearse et al, 2001). Role of MM cell adhesion to BMSCs in activation of osteoclasts. OPG, a decoy receptor for RANKL, prevents the activation of osteoclasts (A). Adhesion of MM cell to BMSCs decreases production of OPG, and increases secretion of IL-6 and MIP-1α which activate osteoclasts (B). The interaction of MM cells with ECM proteins and BMSCs, as well as factors in the BM milieu (cytokines, angiogenesis), therefore, plays a major role in MM pathogenesis. Novel biologically based treatments target not only the MM cell, but also MM cell–host interactions as well as cytokines and their sequelae in the BM milieu. Preclinical and clinical studies already suggest that these therapies can overcome resistance to conventional therapies. The observation that BM angiogenesis is increased and correlates with disease activity in MM (Vacca et al, 1994, 1999), coupled with the antiangiogenic effects of thalidomide (D'Amato et al, 1994), formed the empirical basis for the use of thalidomide in patients with relapsed refractory MM. In a phase II study of thalidomide in patients with MM refractory to conventional or high-dose therapy, > 25% reductions in serum or urine levels of paraprotein were observed in 32% of patients (Singhal et al, 1999). Remarkably, two of 84 patients had complete remission and eight patients had > 90% reduction in paraprotein. Of note, microvessel density (MVD) in patient BM was unchanged, even in patients who responded to thalidomide, suggesting that thalidomide may have mechanisms of anti-MM activity other than antiangiogenesis. Adverse events were generally mild to moderate and included constipation, neuropathy, weakness and somnolence; these events increased in incidence with higher doses. Severe adverse events were rare and significant myelosuppression was observed in fewer than 5% of patients. After 12 months of follow-up, event-free and overall survival for all patients were estimated at 22% and 58% respectively (Singhal et al, 1999). Update of this experience in 169 patients confirmed ≥ 50% reduction in 30% of patients, near complete remission in 14%, with 2-year event-free and overall survival rates of 20% and 48% respectively (Barlogie et al, 2001). Patients with a normal karyotype, low (< 0·5%) plasma-cell labelling index and β2-microglobulin ≤3 mg/l had an improved outcome. Other groups have reported similar results using thalidomide to treat patients with relapsed and/or refractory MM (Rajkumar et al, 2000; Hus et al, 2001; Tosi et al, 2001). Based upon these promising results, more recent studies have explored the combination of thalidomide with chemotherapeutic agents and/or dexamethasone. Fifty per cent of patients with advanced disease, refractory to either thalidomide or dexamethasone alone, responded to dexamethasone/thalidomide combination treatment (Weber et al, 1999). Moreover, the use of thalidomide/dexamethasone as initial therapy for MM achieved a 64% response rate, without precluding subsequent collection of PBSCs for transplantation (Rajkumar et al, 2001). Close monitoring is recommended when using combined therapy, as deep venous thrombosis and toxic epidermal necrolysis have been reported in patients treated with thalidomide in combination with high-dose dexamethasone or anthracyclines (Tseng et al, 1996; Osman et al, 2001). Thalidomide appears to have multiple mechanisms of anti-MM activity (Raje & Anderson, 1999), including: directly inducing G1 growth arrest or apoptosis in MM cells (Hideshima et al, 2000b); acting in the BM microenvironment by decreasing MM cell adhesion and related drug resistance (Damiano et al, 1999), and by inducing cytokine (IL-6, VEGF and TNF-α) transcription and secretion (Uchiyama et al, 1993; Chauhan et al, 1996; Gupta et al, 2001); inhibiting BM angiogenesis (D'Amato et al, 1994), which is increased in MM patients (Vacca et al, 1999); augmenting anti-MM immunity (Haslett et al, 1998), with stimulation of natural killer cell responses (Davies et al, 2001). We have recently studied the mechanism of anti-MM activity of thalidomide derivatives known as immunomodulatory drugs (IMiDs), which have significantly higher potency at inducing apoptosis or growth arrest in MM cells resistant to melphalan, doxorubicin and dexamethasone (Hideshima et al, 2000b). The IMiDs reduce the secretion of IL-6 and VEGF triggered by the binding of MM cells to BMSCs, and inhibit angiogenesis (Gupta et al, 2001). Previous studies showed that the IMiDs stimulated T-cell proliferation as well as IL-2 and IFN-γ production (Corral et al, 1999), and our recent study showed that NK-cell immunity was induced both in the BM microenvironment in vitro and in patients treated with thalidomide or IMiDs (Davies et al, 2001). We have recently developed a severe combined immunodeficient (SCID) mouse model in which human MM cells were injected subcutaneously along with Matrigel. In this model, tumour growth and associated angiogenesis was inhibited and host survival was prolonged, to a greater extent with IMiDs than with thalidomide treatment (Lentzsch et al, 2002). Gene microarray profiling and proteomic analysis of human MM samples before and after treatment in this model will identify in vivo targets of IMiDs, as well as mechanisms of resistance. Based on these promising preclinical studies, we performed a phase I study of IMiD CC-5013 (Richardson et al, 2002). Twenty-five patients with MM refractory to and/or relapsed after high-dose therapies and transplant or treatment with thalidomide received increasing doses from 5 to 50 mg/d of oral CC-5013. Side-effects were few, even at the highest dose, in the first month; one of 13 patients who received 50 mg/d experienced grade 4 leucocytopenia. Most importantly, no constipation, somnolence or neuropathy was observed. Two-thirds of patients had decreases in paraprotein > 25%, and 80% patients experienced at least stabilization of paraprotein. Based on this most promising anti-MM activity and very favourable side-effect profile, phase II trials will examine its efficacy in patients with newly diagnosed MM, at time of first relapse, and as maintenance therapy. Proteasome inhibitors inhibit the degradation of ubiquinated proteins, including cell cycle regulatory proteins, such as cyclins and cyclin-dependent kinase inhibitors, which regulate cell cycle progression (King et al, 1996). Moreover, these agents induce apoptosis of tumour cells, in spite of the accumulation of p21 and p27, irrespective of their p53 wild-type or mutant status (Lopes et al, 1997; Herrmann et al, 1998). Accumulation of Bax induced by proteasome inhibitors can overcome the survival effect of Bcl-2 and increase cytochrome c-dependent apoptosis (Li & Dou, 2000). Proteasome inhibitors can also overcome drug resistance induced by NF-κB activation, by inhibiting degradation of IκB and p105 precursors of the p50 subunit of NF-κB (Palombella et al, 1994). Specifically, the proteasome inhibitor PS-341 directly inhibits proliferation and induces apoptosis in both human MM cell lines and freshly isolated patients' MM cells which are resistant to melphalan, doxorubicin and dexamethasone (Hideshima et al, 2001c). PS-341 inhibits p42/44 MAPK growth signalling triggered by IL-6 and induces apoptosis, despite the induction of p21 and p27, in p53 wild-type and p53 mutant MM cells. It enhances the anti-MM activity of dexamethasone and overcomes IL-6-mediated protection against dexamethasone-induced apoptosis. Importantly, PS-341 inhibits the paracrine growth of human MM cells in the BM milieu by decreasing their adherence to BMSCs and related NF-κB-dependent induction of IL-6 secretion in BMSCs. Moreover, proliferation and MAPK growth signalling of those residual adherent MM cells is also inhibited. Gene microarry profiling reveals that PS-341 triggers transcriptional changes, including increased apoptotic signalling, decreased growth and survival signalling, transient upregulation of ubiquitin/proteasome cascades, and induction of stress responses (Mitsiades et al, 2002). Most recent studies show that PS-341 also inhibits DNA repair (unpublished observation) and that PS-341 may restore the sensitivity of MM cells to conventional DNA-damaging therapeutic agents, including doxorubicin and melphalan (unpublished observation), suggesting the efficacy of combination therapies to overcome drug resistance. We have shown that PS-341 decreases in vivo growth of human MM cells and associated angiogenesis, as well as prolongs host survival, in a SCID mouse model (LeBlanc et al, 2002). After phase I trials established the maximally tolerated dose of PS-341, a phase II multicentre trial of PS-341 was performed in 202 patients with refractory relapsed MM (unpublished observation). In the first cohort of 78 patients, remarkable anti-MM activity was observed in this heavily pretreated population. Specifically, 54 of 70 (77%) evaluable patients had either stabilization or decrease in their MM paraprotein, including > 25% reduction in 47% of patients and > 90% decreases in 20% of patients. Complete remissions, evidenced by absence of paraprotein on immunofixation and clearing of BM plasma cells, were documented. Toxicities including fatigue, diarrhoea, thrombocytopenia and peripheral neuropathy were in most cases manageable; importantly, thrombocytopenia and neuropathy were observed primarily in patients in whom these were present prior to PS-341 treatment. As predicted by our in vitro studies (Hideshima et al, 2001c), the addition of dexamethasone to PS-341 benefited 24 of 25 patients who had only stable disease or progressed on single-agent PS-341 (unpublished observations). Given these very promising preclinical phase I and phase II clinical trials, a phase III trial, comparing PS-341 with dexamethasone for treatment of relapsed MM, is now ongoing in the United States, Canada and Europe. NF-κB is an attractive target in the BM milieu as it regulates expression of adhesion molecules on MM cells and BMSCs, as well as related binding and related tumour cell resistance, and regulates cytokine production in the BM milieu (Chauhan et al, 1996; Hideshima et al, 2002b; Mitsiades et al, 2002). Moreover, IMiDs, PS-341 and arsenic trioxide all inhibit NF-κB activation in addition to their other bioactivities (Hideshima et al, 2001a,c; Hayashi et al, 2002). To define the selective effect of blocking NF-κB activation in the MM BM microenvironment, we recently used PS-1145, a specific IκB kinase inhibitor to block phosphorylation of IκBα and the resulting nuclear translocation of NF-κB (Hideshima et al, 2002b). PS-1145 only partially inhibited the proliferation of isolated MM cells; however, it markedly inhibited proliferation of MM cells adherent to BMSCs, as well as NF-κB-dependent constitutive and MM adhesion-induced IL-6 secretion. These studies demonstrated that inhibition of NF-κB by PS-1145 can overcome the growth and survival advantage conferred both by tumour cell binding to BMSCs and cytokine secretion in the BM milieu, and highlight the importance of studying the effect of novel agents not only on isolated tumour cells, but also on MM cells in their BM microenvironment. Arsenic trioxide is an old drug which achieved remarkable clinical responses in patients with APL (Shen et al, 1997). We have recently shown that ATO induces apoptosis even of drug-resistant MM cell lines and patient cells via caspase-9 activation, enhances MM cell apoptosis induced by dexamethasone, and can overcome the antiapoptotic effects of IL-6 by blocking both activation of STAT3 and upregulation of Mcl-1 (Hayashi et al, 2002). Our study further demonstrated that ATO also acts in the BM microenvironment to inhibit TNF-α-induced MM cell binding to BMSCs by blocking NF-κB activation and resultant ICAM-1 expression, inhibits IL-6 and VEGF secretion induced by MM cell adhesion, and blocks proliferation of MM cells adherent to BMSCs. It has been reported that ATO induces depolarization of mitochondrial transmembrane thereby increasing levels of by cytochrome and activation of et al, 1999), and that ATO cell cycle arrest by upregulation of p21 protein and subsequent apoptosis et al, 2000). ATO augments et al, 2001), suggesting that it may against MM cells. In results of phase clinical trials of ATO in patients with refractory or MM, of evaluable patients had decreases in or stable disease after ATO grade and diarrhoea, and were observed et al, 2001). which an inhibitor of ATO et al, 2001), has been combined with of patients achieved responses or stabilization of disease, with similar et al, 2001). Our studies show that dexamethasone enhances the effects of ATO in vitro (Hayashi et al, 2002), the basis for an ongoing clinical trial of this combination therapy. is a natural of with low binding to and with and antiangiogenic effects et al, 1994). We have recently demonstrated that inhibits growth and induced apoptosis in MM cells, including drug-resistant cell lines and MM patients' cells, dexamethasone-induced apoptosis and the effects of IL-6 (Chauhan et al, 2002). Moreover, decreased survival of BMSCs, as well as secretion of VEGF and IL-6 triggered by adhesion of MM cells to BMSCs. Our studies further of mitochondrial cytochrome and by activation of and apoptosis in was also in vivo in a model, evidenced by inhibition of MM cell growth and associated angiogenesis, as well as of host phase II trials in MM are currently is a tyrosine kinase inhibitor which inhibits VEGF by binding directly to the binding of VEGF et al, 2000). It is most specific for kinase receptor but can also inhibit and other III tyrosine kinase with We have recently shown that directly inhibits proliferation of MM cells lines and patient MM cells which as well as inhibiting MM cell migration et al, 2002). This enhances anti-MM activity of dexamethasone and overcomes the effect of Importantly, can inhibit the secretion of IL-6 induced by the binding of MM cells to BMSCs, as well as the resultant proliferation of adherent MM cells. I clinical trials are and phase II trials will in MM. of the role of the BM microenvironment both for disease pathogenesis and as a target for novel has promising Specifically, now preclinical and clinical promise of new biologically based treatments upon targeting both MM cells and the BM microenvironment. New therapeutic such as those in this used or with conventional or novel offer great promise to overcome drug resistance and improve patient outcome in MM. This study was in by Multiple to and of The and the to

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