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Can bisphosphonates improve outcomes in patients with newly diagnosed multiple myeloma?
Critical Reviews in Oncology/Hematology 77 S1 (2011) S24−S30
Can bisphosphonates improve outcomes in patients with newly diagnosed multiple myeloma? Gareth J. Morgan* The Institute of Cancer Research, Royal Marsden NHS Foundation Trust, London, United Kingdom
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Multiple myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Anticancer effects of bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Improving outcomes in multiple myeloma by adding bisphosphonates to antimyeloma therapy . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Early clinical trials of bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. MRC Myeloma IX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Addendum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Keywords: Anticancer Antimyeloma Bisphosphonate Clodronate Myeloma Skeletal-related event Survival Zoledronic acid
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summary Preclinical and clinical evidence suggests that bisphosphonates have anticancer activities both within and outside bone. Early clinical trials of bisphosphonates provided evidence for antimyeloma effects in exploratory analyses in high-risk subsets, and recent trials of zoledronic acid (ZOL) have provided further support of antimyeloma activity. The MRC Myeloma IX trial is an innovative 2×2 factorial trial comparing ZOL and clodronate (CLO) in patients with newly diagnosed multiple myeloma receiving either intensive or nonintensive therapy regimens. Results showed that ZOL significantly reduced skeletal morbidity and significantly improved both progression-free and overall survival versus CLO. Notably, the survival benefit with ZOL remained significant after adjustment for skeletalrelated events, consistent with clinically meaningful antimyeloma activity. Further analyses of these data will provide greater insight into ZOL interactions with primary treatment regimens for multiple myeloma. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction 1.1. Multiple myeloma Multiple myeloma (MM), diagnosed in approximately 102,762 people globally each year [1], is a malignancy * Correspondence: Gareth Morgan, MD. Section of HaematoOncology, The Institute of Cancer Research, Brookes Lawley Building, 15 Cotswold Road, London, Surrey SM2 5NG, United Kingdom. Tel.: +44 (020) 8722 4130; fax: +44 (020) 8722 4432. E-mail address: [email protected] (G.J. Morgan).
characterized by the clonal proliferation of terminally differentiated plasma cells (B cells) in the bone marrow, resulting in excessive production of monoclonal protein (IgG, IgA, or IgH) or immunoglobulin light chain that can lead to renal failure, immunodeficiency, and hyperviscosity of the blood [2,3]. Additionally, 70−95% of MM patients develop osteolytic bone lesions, which are often associated with bone pain and pathologic fractures [4]. The bone marrow microenvironment plays an essential role in the development, maintenance, and progression of myeloma. Interactions between myeloma cells and
1040-8428/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
G.J. Morgan / Critical Reviews in Oncology/Hematology 77 S1 (2011) S24−S30
bone marrow stromal cells may directly increase growth and survival of myeloma cells, as well as contribute to the development of drug resistance [5]. For example, integrin-mediated adhesion of myeloma cells to bone marrow cells increases the expression of promitotic cellcycle proteins (e.g., cyclin D), antiapoptotic proteins (e.g., Bcl-2), and telomerase activity (facilitates immortalization/ loss of senescence) in myeloma cells. Moreover, myeloma– bone interactions stimulate production of interleukin (IL)-6 by bone marrow stromal cells [6,7], promoting myeloma growth and playing a critical role in the progression of myeloma [5,8]. In addition, all patients with abnormal clonal proliferation of plasma cells experience bone loss that may be mediated by osteoclast-activating factors such as IL-6, IL-1b, parathyroid hormone-related protein (PTHrP), hepatocyte growth factor (HGF), and tumor necrosis factor (TNF)-a generated by the interplay between abnormal hematopoietic cells and bone [5,8]. Adhesion of myeloma cells to extracellular matrix proteins in the bone marrow can lead to increased levels of cytokines and growth factors including vascular endothelial growth factor (VEGF), insulin-like growth factors (e.g., IGF1), and members of the TNF superfamily (transforming growth factor b1, C−C chemokine ligand 3, HGF, IL-10). In the bone marrow microenvironment, this dysregulation of growth factors and cytokines stimulates the growth of myeloma cells and increases the proliferation of osteoclasts without concomitant activation of osteoblasts. Thus, the bone marrow microenvironment contributes to the growth and survival of the myeloma clone, and, at the same time, the perturbation of the bone remodeling process creates a vicious cycle that amplifies this growth of myeloma cells and accelerates destruction of the bone. 1.2. Anticancer effects of bisphosphonates Bisphosphonates (BPs) naturally bind to mineralized surfaces such as bone and inhibit osteoclast-mediated bone resorption, as discussed in the article by Terpos et al. [9] in this supplement. The BPs pamidronate (PAM), zoledronic acid (ZOL), and clodronate (CLO; in the European Union but not in the United States) are approved for the treatment of patients with osteolytic lesions from MM for the prevention of skeletal-related events (SREs). In addition to inhibition of malignant osteolysis by their effects on osteoclasts, BPs may affect MM progression by blocking the release of cytokines and growth factors from the bone matrix, thereby breaking the vicious cycle of bone destruction and cancer growth. In addition to slowing unregulated bone resorption, there is strong preclinical evidence from various models of MM suggesting that nitrogen-containing BPs such as ZOL may have anticancer activity including inhibiting angiogenesis, enhancing antitumor immune responses, and directly or indirectly modulating the proliferation and survival of
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malignant plasma cells (Table 1) [10−23]. In addition, BPs have demonstrated anticancer synergy with agents that are used in the treatment of myeloma, including dexamethasone, thalidomide, and bortezomib [13,16,20]. Preclinical murine models of MM indicated that nitrogencontaining BPs (e.g., ZOL and PAM) may prolong survival [22,23] via impaired protein prenylation and signaling via pathways such as Ras/Raf/MAPK, consequent to mevalonate pathway inhibition [23]. In addition, accumulation of isopentenyl pyrophosphate (IPP) following nitrogencontaining BP inhibition of the mevalonate pathway activated and induced the replication of an anticancerspecific subset of T cells (Vg9Vd2) in blood samples from MM patients [19]. Therefore, generation of IPP by nitrogencontaining BP-treated cells may play an indirect role in the observed anticancer activities. In contrast to nitrogencontaining BPs such as ZOL, non-nitrogen-containing BPs function as non-hydrolyzable analogues of ATP and do not result in accumulation of specific intermediates such as IPP. These early-generation agents have substantially lower antiresorptive and antimyeloma effects in model systems. Bisphosphonates are an established component of treatment in patients with malignant bone disease and have been used extensively for nearly 2 decades in this setting. In the last few years, clinical evidence of the anticancer benefit of BPs has begun to accumulate. Although much of the early clinical evidence suggesting that BPs may improve cancer-related outcomes derives from retrospective analysis of large controlled studies of patients with advanced cancer, prospective data in other settings are emerging. Gnant et al. reported that the addition of ZOL to standard adjuvant therapy for early breast cancer significantly reduced the risk of disease progression versus no ZOL in premenopausal women ( p = 0.01) [24]. This benefit remained statistically significant ( p = 0.009) even at 62 months, approximately 2 years after ZOL treatment was completed, suggesting lasting effect on disease course [25]. Similarly, results from 2 randomized trials (Medical Research Council [MRC] PR04 and PR05) showed that addition of CLO to standard treatment significantly improved overall survival in patients with bone metastases from prostate cancer (N = 278; hazard ratio [HR] 0.77; p = 0.032), but not in prostate cancer patients without metastases (N = 471; HR 1.12), suggesting that key anticancer effects of BPs may be mediated in bone [26]. Given that the mechanisms of pathogenesis and disease progression in bone in patients with MM are analogous to those observed in patients with bone metastases from solid tumors, it is reasonable that BPs may provide anticancer benefits in patients with MM. Indeed, BPs have demonstrated preclinical anticancer synergy with agents that are used in the treatment of myeloma, including dexamethasone, thalidomide, and bortezomib [13,16,20]. Thus, based on the preclinical evidence of synergy between MM therapies and BPs, and the clinical evidence that
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Table 1 Preclinical evidence of antitumor activity of bisphosphonates in multiple myeloma Study
Agents evaluated
Experimental model
Results/Conclusions
Cell lines Effects on proliferation, apoptosis, and cell adhesion in MM cells Baulch-Brown et al. [10]
ZOL, fluvastatin, and SCH66336
RPMI 8226, U266, OMP2, LP1, and NCI-H929
Caused cell cycle arrest and apoptosis; involves inhibition of geranylgeranylation
Shipman et al. [11]
CLO, PAM, and YM175
U266-B1, JJN-3, and HS-Sultan
Caused cell cycle arrest, DNA fragmentation; altered nuclear morphology
Tassone et al. [12]
ZOL and PAM
XG-1, U266, and IM-9
Inhibited proliferation and induced apoptosis
Ural et al. [13]
ZOL, Thal, and Dex
ARH-77 and RPMI-8226
ZOL inhibited cell growth and induced apoptosis; cytotoxicity was increased by addition of Thal and Dex
Corso et al. [14]
ZOL
Bone-marrow stem cells from myeloma patients
ZOL reduced proliferation, increased apoptosis, and modified the pattern of expression of adhesion molecules involved in plasma-cell binding. ZOL reduced IL-6 production
Zwolak et al. [15]
ZOL
NCI-H929
ZOL released from bone cement reduced number of viable cells
Schmidmaier et al. [16]
ZOL, simvastatin, melphalan, bortezomib
RPMI 8226, U266, OMP2, and NCI-H929
Synergistic induction of apoptosis and reversal of cell-adhesion-mediated drug resistance
Koizumi et al. [17]
ZOL
RPMI 8226 (Dexresistant clone)
ZOL reduced the viability and induced apoptosis of Dex-resistant cells. Small G proteins, Rho and Rap1A, were unprenylated in the ZOL-treated MM cells. Geranylgeraniol rescued ZOL-induced effects
Effects on drug resistance
Immunomodulatory and antiangiogenic effects Uchida et al. [18]
ZOL or mevastatin
RPMI 8226 and U266
Pretreatment of myeloma cells with zoledronic acid or mevastatin increases their sensitivity to lysis by gd T cells
Kunzmann et al. [19]
PAM and IPP
MM patient-derived PBMCs and Daudi, U266, and RPMI 8226
PAM and IPP induced expansion of Vg9Vd2 T cells in PBMC cultures, increased activation and non-MHC-restricted lytic activity of gd T cells. PAM induced (gd T-cell-dependent) depletion of plasma cells in bone marrow mononuclear cell cultures
Moschetta et al. [20]
ZOL and bortezomib
MM patient-derived bone marrow macrophages
Synergistic inhibition of proliferation, adhesion, and migration of macrophages. Reduced transcription of VEGF, PDGF, HGF, and bFGF. Inhibited neovascularization by vasculogenic macrophages on Matrigel, and ERK1/2 and VEGFR2 phosphorylation
Yaccoby et al. [21]
ZOL, PAM, RANKL inhibitor
Human MM xenograft in SCID mice
Inhibited growth and survival of human MM cells derived from intramedullary (within bone) disease
Croucher et al. [22]
ZOL
5T2MM xenograft in C57BL/KaLwRij mice
ZOL reduced formation of osteolytic lesions; reduced paraprotein concentration, bone loss, tumor burden, and angiogenesis. Significantly increased survival
Guenther et al. [23]
ZOL
INA-6 plasmacytoma xenograft in SCID mice
ZOL increased survival. Western blot analysis of tumor homogenates demonstrated the accumulation of unprenylated Rap1A, indicative of the uptake of ZOL by non-skeletal tumors and inhibition of farnesyl pyrophosphate synthase
Animal models
Abbreviations: bFGF, basic fibroblast growth factor; CLO, clodronate; Dex, dexamethasone; HGF, hepatocyte growth factor; IL, interleukin; IPP, isopentenylpyrophosphate; MHC, major histocompatibility complex, MM, multiple myeloma; RANKL, receptor activator of NF-úB ligand; PAM, pamidronate; PBMC, peripheral blood mononuclear cell; PDGF, platelet-derived growth factor; SCID, severe combined immunodeficient; Thal, thalidomide; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2; ZOL, zoledronic acid.
G.J. Morgan / Critical Reviews in Oncology/Hematology 77 S1 (2011) S24−S30
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Table 2 Clinical evidence of antitumor activity of bisphosphonates in multiple myeloma Reference
N
Study arms
Results
Aviles et al. [27]
94
ZOL (4 mg q28d) Placebo
ZOL significantly increased 5-year EFS and OS rates ( p < 0.01 for both)
Berenson et al. [28]
353
ZOL (4 mg q3−4wk) PAM (90 mg q3−4wk)
In patients with high BALP (n = 89), ZOL significantly decreased the risk of death by 55% vs pamidronate ( p = 0.04)
McCloskey et al. [29]
619
CLO (1,600 mg/d) Placebo
Clodronate significantly increased survival in patients (n = 153) with no fractures at baseline vs placebo ( p = 0.006)
Berenson et al. [30]
392
PAM (90 mg IV, monthly) Placebo
Pamidronate significantly increased survival in patients receiving second-line antimyeloma therapy compared with placebo (14 vs 21 months; p = 0.041)
Abbreviations: BALP, bone-specific alkaline phosphatase; CLO, clodronate; EFS, event-free survival; IV, intravenous; OS, overall survival; PAM, pamidronate, ZOL, zoledronic acid.
BPs can improve cancer-related outcomes, the potential for added benefit is especially promising in the MM setting. 2. Improving outcomes in multiple myeloma by adding bisphosphonates to antimyeloma therapy 2.1. Early clinical trials of bisphosphonates In early clinical trials of BPs to prevent SREs from MM (Table 2) [27−30], weak signals of antimyeloma benefits were revealed, with effects reaching statistical significance in retrospective analyses of high-risk patient subsets. For example, in the long-term follow-up (8.6 years) of a placebo-controlled trial (N = 619), CLO significantly prolonged overall survival (OS) versus placebo in 153 patients who did not have vertebral fractures at baseline (median OS, 59 months vs 37 months with placebo; p = 0.006) [29]. Similarly, in a long-term trial of intravenous PAM (N = 392) in patients with newly diagnosed or relapsed/refractory MM, PAM significantly increased survival in the subset of patients with MM receiving secondline antimyeloma therapy (14 vs 21 months; p = 0.041) compared with placebo [30]. Small clinical studies have also provided insight into the antimyeloma potential of ZOL. The addition of ZOL to conventional chemotherapy in treatment-naive patients (N = 94) significantly improved 5-year event-free survival (80% vs 52%, respectively) and 5-year overall survival (80% vs 46%, respectively; p < 0.01 for both) compared with conventional therapy alone [27]. 2.2. MRC Myeloma IX Based on the BP anticancer theory and promising early results, a large, more extensive, randomized, controlled trial to evaluate the role of BPs in patients with newly diagnosed MM was designed and conducted by the MRC in the United Kingdom (Table 3) [31,32]. The independent, phase III Myeloma IX trial (N = 1,960) compared the relative efficacy and safety of monthly intravenous ZOL (4 mg) versus daily oral CLO (1,600 mg) when used concurrently with
standard intensive or non-intensive therapy regimens. Therefore, this study compared an early-generation oral bisphosphonate (CLO) with the most recently approved intravenous bisphosphonate in this setting (ZOL), both of which have demonstrated potential survival benefits in early trials. The primary endpoint of this trial was overall survival, and additional endpoints included progression-free survival, response rates, and SREs. Patients were allocated to 2 main pathways, intensive and non-intensive. Younger, fitter patients were allocated to the intensive pathway, which consisted of induction therapy (randomized between standard cytotoxic and thalidomidebased regimens) followed by autologous stem cell transplantation (ASCT). Older patients were allocated to the non-intensive pathway, which consisted of systemic therapy only (randomized between melphalan/prednisone and a thalidomide-based regimen). In each treatment pathway, patients were randomized to oral CLO (1,600 mg/day) or ZOL (4 mg via 15-minute infusion) and treated until disease progression or death. Dosing of ZOL was adjusted in patients with baseline renal impairment and serum creatinine was monitored monthly, per the label [33]. Of 1,960 evaluable patients, 981 received ZOL and 979 received CLO [31]. At the median follow-up of 3.7 years, approximately 60% of patients stayed on treatment until disease progression. Median time on treatment was approximately 1 year across all treatment groups. At the time of the database lock, 11.3% to 13.5% of patients (ZOL and CLO arms, respectively) were still receiving BP treatment. Table 3 Efficacy endpoints reported in the MRC Myeloma IX trial [31] Endpoint
Hazard ratio ZOL vs CLO
p value
Overall survival
0.842
0.0118
Progression-free survival
0.883
0.0179
SREs
0.74
0.0004 [32]
Abbreviations: CLO, clodronate; MRC, Medical Research Council; SRE, skeletal-related event; ZOL, zoledronic acid.
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Zoledronic acid significantly prolonged both progressionfree survival (PFS) and OS ( p = 0.0179 and p = 0.0118, respectively) versus CLO. Zoledronic acid also reduced the proportion of patients with an SRE vs CLO (27.0% vs 35.3%, respectively; p = 0.0004). The improvement in OS was maintained after adjustment for time to first SRE in a Cox model ( p = 0.0178), suggesting that antimyeloma effects likely underlie the OS benefit. Consistent with these benefits, complete or very-good-partial responses were achieved by significantly more patients treated with ZOL in the non-intensive pathway ( p = 0.03). In contrast, ZOL did not significantly improve the response rate in patients allocated to the intensive pathway, perhaps because of the high overall response rate among patients undergoing myeloablative therapy. In addition, ZOL reduced the incidence of SREs regardless of treatment pathway or the presence of bone lesions at baseline [32]. This is the first time that one BP has demonstrated a significant OS advantage over another BP in the overall population of a large randomized study. Both BPs were generally well tolerated, and effects on renal function were similar between treatment groups. The incidence of confirmed osteonecrosis of the jaw (ONJ) was low but significantly higher among ZOL-treated patients (ZOL, 3.6%; CLO, 0.3%), and is consistent with the 2.4% incidence of ONJ reported in a recent retrospective analysis of 548 patients receiving intravenous bisphosphonates for multiple myeloma [34]. Most cases were mild to moderate in severity, and application of preventive dental practices that were established after the initiation of the Myeloma IX trial would likely lower the ONJ risk in this setting. 3. Discussion Bisphosphonates are the standard of care for preventing SREs and treating hypercalcemia of malignancy in patients with MM. Bisphosphonate-mediated anticancer effects demonstrated in preclinical systems are beginning to manifest in the clinical setting in recent trials. The Myeloma IX trial conducted by the MRC is the first independent, large-scale, randomized, prospective trial comparing ZOL with CLO in patients with MM. Importantly, the factorial design of the trial allowed a comparative assessment of the benefit of ZOL and CLO across 4 different primary treatment regimens for patients with newly diagnosed MM. The data from this trial clearly demonstrate that ZOL has a more favorable efficacy profile than CLO across disease recurrence and SRE endpoints when added to standard antimyeloma therapies. Moreover, the survival benefit of ZOL was shown to be independent of SRE benefits. This distinction is important because SREs have been associated with reduced survival in patients with malignant bone disease [35]. Therefore, maintenance of the significant
OS benefit after adjusting for SREs suggests an underlying anticancer mechanism of action. The data are consistent with those of previous clinical studies in solid-tumor settings in which there is strong involvement with bone, and support a clinically meaningful survival benefit from ZOL in patients with MM. An important aspect of the data derived from the MRC Myeloma IX trial is that ZOL achieved OS and PFS benefits versus CLO in the overall study population, that is, across antimyeloma treatment regimens. The survival benefit parallels the superior response rates observed among ZOL-treated patients. Notably, the differences in OS were apparent within the first few months on study, supporting possible synergy between ZOL and primary antimyeloma therapies, and elevating the importance of initiating ZOL early in the disease course. This is consistent with preclinical data that have shown synergy between ZOL and various antimyeloma agents including thalidomide, melphalan, dexamethasone, and bortezomib [13,16,20]. Notably, the presence of osteolytic lesions is not a prerequisite for BP use in MM patients in the United Kingdom [36]. Consequently, approximately one quarter of the enrolled patients had not yet been diagnosed with myeloma bone disease. Therefore, BP therapy was initiated even earlier than the approved standard in the United States and European Union [37−40]. In addition to insights into BP anticancer activity, the Myeloma IX trial provides an important prospective comparison of the safety profiles of ZOL and CLO. Despite differences in mode of administration (oral for CLO and intravenous for ZOL), renal safety was similar, perhaps because of adherence to renal monitoring protocols. Rates of ONJ were higher for ZOL versus CLO; however, new prevention and management protocols recommended and implemented after this trial completed have been effective in further reducing ONJ risk. The data further reinforce the well-established safety profile of BPs in the MM setting and provide additional clinical evidence to consider ZOL an important and preferred component of antimyeloma therapy in patients with newly diagnosed MM. These data add to the growing body of evidence suggesting that BPs in general, and ZOL in particular, may provide clinically meaningful anticancer benefits in patients with newly diagnosed malignancies [24,25,41]. Further analyses to determine the effects of such early administration of BP therapy are warranted. 4. Addendum Recently, an indirect meta-analysis using data from randomized, controlled, phase III trials of bisphosphonates (i.e., ZOL, CLO, PAM, etidronate, and ibandronate) in patients with MM has provided some insight on their relative efficacy [42]. Using a mixed treatment comparison model to analyze data from 18 trials (total N = 4,970) the
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authors determined that ZOL significantly improved OS compared with CLO (HR 0.83; 95% CI 0.73–0.94), but was not significantly different than PAM (HR 0.84; 95% CI 0.61–1.13) or ibandronate (HR 0.70; 95% CI 0.42–1.11). ZOL also significantly reduced the risk of SREs compared with CLO, PAM, and ibandronate. Overall, the authors concluded that available data show the benefits of ZOL over CLO and PAM, but also highlight the need for a randomized controlled trial comparing ZOL and PAM in MM patients. Conflict of interest statement The author has participated in an advisory board for Novartis. Funding Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. Financial support for the MRC Myeloma IX trial was obtained from the Medical Research Council, with additional funding in the form of unrestricted educational grants from Novartis, Schering Health Care Ltd, Chugai, Pharmion, Celgene, and Ortho Biotech, principally to support trial coordination and the laboratory studies. Acknowledgements Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. I thank Jerome F Sah, PhD, ProEd Communications, Inc.® , for his medical editorial assistance with this manuscript. References [1] World Health Organization: International Agency for Research on Cancer. GLOBOCAN 2008, http://globocan.iarc.fr/ [accessed November 5, 2010]. [2] Kumar SK, Mikhael JR, Buadi FK, Dingli D, Dispenzieri A, Fonseca R, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and RiskAdapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc 2009;84:1095–110. [3] Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009;23:3−9. [4] Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 2001;27: 165−76. [5] Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. Lancet 2009;374:324−39. [6] Chauhan D, Uchiyama H, Akbarali Y, Urashima M, Yamamoto K, Libermann TA, et al. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood 1996;87:1104−12. [7] Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004;104: 607−18. [8] Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2002;2:175−87.
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[9] Terpos E, Dimopoulos MA, Berenson J. Established role of bisphosphonate therapy for prevention of skeletal complications from myeloma bone disease. Crit Rev Oncol Hematol 2011; 77(1):S13−23. [10] Baulch-Brown C, Molloy TJ, Yeh SL, Ma D, Spencer A. Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma. Leuk Res 2007;31:341−52. [11] Shipman CM, Rogers MJ, Apperley JF, Russell RG, Croucher PI. Bisphosphonates induce apoptosis in human myeloma cell lines: a novel anti-tumour activity. Br J Haematol 1997;98:665−72. [12] Tassone P, Forciniti S, Galea E, Morrone G, Turco MC, Martinelli V, et al. Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines. Leukemia 2000;14:841−4. [13] Ural AU, Yilmaz MI, Avcu F, Pekel A, Zerman M, Nevruz O, et al. The bisphosphonate zoledronic acid induces cytotoxicity in human myeloma cell lines with enhancing effects of dexamethasone and thalidomide. Int J Hematol 2003;78:443−9. [14] Corso A, Ferretti E, Lunghi M, Zappasodi P, Mangiacavalli S, De Amici M, et al. Zoledronic acid down-regulates adhesion molecules of bone marrow stromal cells in multiple myeloma: a possible mechanism for its antitumor effect. Cancer 2005;104:118−25. [15] Zwolak P, Manivel JC, Jasinski P, Kirstein MN, Dudek AZ, Fisher J, et al. Cytotoxic effect of zoledronic acid-loaded bone cement on giant cell tumor, multiple myeloma, and renal cell carcinoma cell lines. J Bone Joint Surg Am 2010;92:162−8. [16] Schmidmaier R, Simsek M, Baumann P, Emmerich B, Meinhardt G. Synergistic antimyeloma effects of zoledronate and simvastatin. Anticancer Drugs 2006;17:621−9. [17] Koizumi M, Nakaseko C, Ohwada C, Takeuchi M, Ozawa S, Shimizu N, et al. Zoledronate has an antitumor effect and induces actin rearrangement in dexamethasone-resistant myeloma cells. Eur J Haematol 2007;79:382−91. [18] Uchida R, Ashihara E, Sato K, Kimura S, Kuroda J, Takeuchi M, et al. Gamma delta T cells kill myeloma cells by sensing mevalonate metabolites and ICAM-1 molecules on cell surface. Biochem Biophys Res Commun 2007;354:613−8. [19] Kunzmann V, Bauer E, Feurle J, Weissinger F, Tony HP, Wilhelm M. Stimulation of gammadelta T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. Blood 2000;96:384−92. [20] Moschetta M, Di Pietro G, Ria R, Gnoni A, Mangialardi G, Guarini A, et al. Bortezomib and zoledronic acid on angiogenic and vasculogenic activities of bone marrow macrophages in patients with multiple myeloma. Eur J Cancer 2010;46:420−9. [21] Yaccoby S, Pearse RN, Johnson CL, Barlogie B, Choi Y, Epstein J. Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity. Br J Haematol 2002;116:278−90. [22] Croucher PI, De Hendrik R, Perry MJ, Hijzen A, Shipman CM, Lippitt J, et al. Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res 2003;18:482−92. [23] Guenther A, Gordon S, Tiemann M, Burger R, Bakker F, Green JR, et al. The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation. Int J Cancer 2010;126: 239−46. [24] Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Postlberger S, Menzel C, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009;360:679−91. [25] Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Poestlberger S, Dubsky PC, et al. Mature results from ABCSG-12: adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with endocrine-responsive early breast cancer. J Clin Oncol 2010;28(Suppl):75s [abstract 533].
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[26] Dearnaley DP, Mason MD, Parmar MK, Sanders K, Sydes MR. Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol 2009;10:872−6. [27] Aviles A, Nambo MJ, Neri N, Castaneda C, Cleto S, HuertaGuzman J. Antitumor effect of zoledronic acid in previously untreated patients with multiple myeloma. Med Oncol 2007;24:227−30. [28] Berenson J, Dimopoulos M, Chen Y-M. Improved survival in patients with multiple myeloma and high BALP levels treated with zoledronic acid compared with pamidronate: univariate and multivariate models of hazard ratios. Presented at 48th ASH Annual Meeting and Exposition, 2006 [abstract 3589]. [29] McCloskey EV, Dunn JA, Kanis JA, MacLennan IC, Drayson MT. Long-term follow-up of a prospective, double-blind, placebocontrolled randomized trial of clodronate in multiple myeloma. Br J Haematol 2001;113:1035−43. [30] Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol 1998;16:593–602. [31] Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 2010;376:1989−99. [32] Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Drayson MT, et al. Optimising bone disease in myeloma; zoledronic acid plus thalidomide combinations improve survival and bone endpoints: results of the Myeloma IX trial. Presented at 52nd ASH Annual Meeting and Exposition, 2010 [abstract 311]. [33] Zometa (zoledronic acid) injection [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2008. [34] Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 2008;23:826−36. [35] Saad F, Lipton A, Cook R, Chen YM, Smith M, Coleman R. Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer 2007;110:1860−7. [36] UK–Nordic Guidelines Working Group. UK Myeloma Forum and the Nordic Myeloma Study Group: Guidelines on the Diagnosis and Management of Multiple Myeloma 2005, http://www.bcshguidelines.com/ documents/multiplemyeloma_feb_2006.pdf [accessed November 5, 2010]. [37] Anderson KC, Alsina M, Bensinger W, Biermann JS, ChananKhan A, Comenzo RL, et al. Multiple myeloma. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2007;5:118−47. [38] Harrouseau JL, Greil R, Kloke O. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of multiple myeloma. Ann Oncol 2005;16(Suppl 1):i45−7. [39] Kyle RA, Yee GC, Somerfield MR, Flynn PJ, Halabi S, Jagannath S, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 2007;25:2464−72. [40] Lacy MQ, Dispenzieri A, Gertz MA, Greipp PR, Gollbach KL, Hayman SR, et al. Mayo Clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc 2006;81:1047−53.
[41] Brufsky AM, Bosserman LD, Caradonna RR, Haley BB, Jones CM, Moore HC, et al. Zoledronic acid effectively prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST study 36-month follow-up results. Clin Breast Cancer 2009;9:77−85. [42] Mhaskar R, Redzepovic J, Wheatley K, Clark O, Glasmacher A, Miladinovic B, et al. Comparative effectiveness of bisphosphonates in multiple myeloma. Presented at 52nd ASH Annual Meeting and Exposition, 2010 [abstract 3028].
Biography Gareth Morgan, PhD, FRCP, FRCPath, is Professor of Haematology at The Institute of Cancer Research (ICR) and Head of the Haemato-Oncology Clinical Unit at The Royal Marsden NHS Foundation Trust. After attending medical school at the University Hospital of Wales, Professor Morgan completed a PhD and trained in the molecular genetics and management of blood cell cancers at the ICR. He left the ICR to join the University of Leeds, where he set up his own research group studying the molecular genetics of non-Hodgkin’s lymphoma and myeloma. Professor Morgan’s research interests include the treatment and management of leukaemias, lymphomas, and myelomas. He is actively involved in research into the genetic basis of myeloma and how this can be used in the clinical environment. His work has focussed on the translation of information derived from the molecular analysis of the pathogenesis of malignant cells into the clinic using novel targeted treatment strategies. Professor Morgan is currently Principal Investigator of a number of Phase I, II, and III studies as well as serving on independent data monitoring committees. He is a Principal Investigator on the MRC Myeloma X trial as well as on a number of innovative phase I studies in both AML and myeloma. He has served as Scientific Secretary of the British Society of Haematology and on the UK Myeloma forum. He has been instrumental in the establishment of the European Myeloma Network. He is a Director for Myeloma UK, a national charity, and is a Scientific Advisor to the International Myeloma Foundation and is on the Board of the UK Stem Cell Bank. Professor Morgan is widely published, with over 200 high impact factor peer-reviewed articles. He reviews for a number of journals and sits on a number of grant-governing bodies both in the UK and internationally.
Can bisphosphonates improve outcomes in patients with newly diagnosed multiple myeloma? Gareth J. Morgan* The Institute of Cancer Research, Royal Marsden NHS Foundation Trust, London, United Kingdom
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Multiple myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Anticancer effects of bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Improving outcomes in multiple myeloma by adding bisphosphonates to antimyeloma therapy . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Early clinical trials of bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. MRC Myeloma IX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Addendum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
article
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Keywords: Anticancer Antimyeloma Bisphosphonate Clodronate Myeloma Skeletal-related event Survival Zoledronic acid
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summary Preclinical and clinical evidence suggests that bisphosphonates have anticancer activities both within and outside bone. Early clinical trials of bisphosphonates provided evidence for antimyeloma effects in exploratory analyses in high-risk subsets, and recent trials of zoledronic acid (ZOL) have provided further support of antimyeloma activity. The MRC Myeloma IX trial is an innovative 2×2 factorial trial comparing ZOL and clodronate (CLO) in patients with newly diagnosed multiple myeloma receiving either intensive or nonintensive therapy regimens. Results showed that ZOL significantly reduced skeletal morbidity and significantly improved both progression-free and overall survival versus CLO. Notably, the survival benefit with ZOL remained significant after adjustment for skeletalrelated events, consistent with clinically meaningful antimyeloma activity. Further analyses of these data will provide greater insight into ZOL interactions with primary treatment regimens for multiple myeloma. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction 1.1. Multiple myeloma Multiple myeloma (MM), diagnosed in approximately 102,762 people globally each year [1], is a malignancy * Correspondence: Gareth Morgan, MD. Section of HaematoOncology, The Institute of Cancer Research, Brookes Lawley Building, 15 Cotswold Road, London, Surrey SM2 5NG, United Kingdom. Tel.: +44 (020) 8722 4130; fax: +44 (020) 8722 4432. E-mail address: [email protected] (G.J. Morgan).
characterized by the clonal proliferation of terminally differentiated plasma cells (B cells) in the bone marrow, resulting in excessive production of monoclonal protein (IgG, IgA, or IgH) or immunoglobulin light chain that can lead to renal failure, immunodeficiency, and hyperviscosity of the blood [2,3]. Additionally, 70−95% of MM patients develop osteolytic bone lesions, which are often associated with bone pain and pathologic fractures [4]. The bone marrow microenvironment plays an essential role in the development, maintenance, and progression of myeloma. Interactions between myeloma cells and
1040-8428/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
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bone marrow stromal cells may directly increase growth and survival of myeloma cells, as well as contribute to the development of drug resistance [5]. For example, integrin-mediated adhesion of myeloma cells to bone marrow cells increases the expression of promitotic cellcycle proteins (e.g., cyclin D), antiapoptotic proteins (e.g., Bcl-2), and telomerase activity (facilitates immortalization/ loss of senescence) in myeloma cells. Moreover, myeloma– bone interactions stimulate production of interleukin (IL)-6 by bone marrow stromal cells [6,7], promoting myeloma growth and playing a critical role in the progression of myeloma [5,8]. In addition, all patients with abnormal clonal proliferation of plasma cells experience bone loss that may be mediated by osteoclast-activating factors such as IL-6, IL-1b, parathyroid hormone-related protein (PTHrP), hepatocyte growth factor (HGF), and tumor necrosis factor (TNF)-a generated by the interplay between abnormal hematopoietic cells and bone [5,8]. Adhesion of myeloma cells to extracellular matrix proteins in the bone marrow can lead to increased levels of cytokines and growth factors including vascular endothelial growth factor (VEGF), insulin-like growth factors (e.g., IGF1), and members of the TNF superfamily (transforming growth factor b1, C−C chemokine ligand 3, HGF, IL-10). In the bone marrow microenvironment, this dysregulation of growth factors and cytokines stimulates the growth of myeloma cells and increases the proliferation of osteoclasts without concomitant activation of osteoblasts. Thus, the bone marrow microenvironment contributes to the growth and survival of the myeloma clone, and, at the same time, the perturbation of the bone remodeling process creates a vicious cycle that amplifies this growth of myeloma cells and accelerates destruction of the bone. 1.2. Anticancer effects of bisphosphonates Bisphosphonates (BPs) naturally bind to mineralized surfaces such as bone and inhibit osteoclast-mediated bone resorption, as discussed in the article by Terpos et al. [9] in this supplement. The BPs pamidronate (PAM), zoledronic acid (ZOL), and clodronate (CLO; in the European Union but not in the United States) are approved for the treatment of patients with osteolytic lesions from MM for the prevention of skeletal-related events (SREs). In addition to inhibition of malignant osteolysis by their effects on osteoclasts, BPs may affect MM progression by blocking the release of cytokines and growth factors from the bone matrix, thereby breaking the vicious cycle of bone destruction and cancer growth. In addition to slowing unregulated bone resorption, there is strong preclinical evidence from various models of MM suggesting that nitrogen-containing BPs such as ZOL may have anticancer activity including inhibiting angiogenesis, enhancing antitumor immune responses, and directly or indirectly modulating the proliferation and survival of
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malignant plasma cells (Table 1) [10−23]. In addition, BPs have demonstrated anticancer synergy with agents that are used in the treatment of myeloma, including dexamethasone, thalidomide, and bortezomib [13,16,20]. Preclinical murine models of MM indicated that nitrogencontaining BPs (e.g., ZOL and PAM) may prolong survival [22,23] via impaired protein prenylation and signaling via pathways such as Ras/Raf/MAPK, consequent to mevalonate pathway inhibition [23]. In addition, accumulation of isopentenyl pyrophosphate (IPP) following nitrogencontaining BP inhibition of the mevalonate pathway activated and induced the replication of an anticancerspecific subset of T cells (Vg9Vd2) in blood samples from MM patients [19]. Therefore, generation of IPP by nitrogencontaining BP-treated cells may play an indirect role in the observed anticancer activities. In contrast to nitrogencontaining BPs such as ZOL, non-nitrogen-containing BPs function as non-hydrolyzable analogues of ATP and do not result in accumulation of specific intermediates such as IPP. These early-generation agents have substantially lower antiresorptive and antimyeloma effects in model systems. Bisphosphonates are an established component of treatment in patients with malignant bone disease and have been used extensively for nearly 2 decades in this setting. In the last few years, clinical evidence of the anticancer benefit of BPs has begun to accumulate. Although much of the early clinical evidence suggesting that BPs may improve cancer-related outcomes derives from retrospective analysis of large controlled studies of patients with advanced cancer, prospective data in other settings are emerging. Gnant et al. reported that the addition of ZOL to standard adjuvant therapy for early breast cancer significantly reduced the risk of disease progression versus no ZOL in premenopausal women ( p = 0.01) [24]. This benefit remained statistically significant ( p = 0.009) even at 62 months, approximately 2 years after ZOL treatment was completed, suggesting lasting effect on disease course [25]. Similarly, results from 2 randomized trials (Medical Research Council [MRC] PR04 and PR05) showed that addition of CLO to standard treatment significantly improved overall survival in patients with bone metastases from prostate cancer (N = 278; hazard ratio [HR] 0.77; p = 0.032), but not in prostate cancer patients without metastases (N = 471; HR 1.12), suggesting that key anticancer effects of BPs may be mediated in bone [26]. Given that the mechanisms of pathogenesis and disease progression in bone in patients with MM are analogous to those observed in patients with bone metastases from solid tumors, it is reasonable that BPs may provide anticancer benefits in patients with MM. Indeed, BPs have demonstrated preclinical anticancer synergy with agents that are used in the treatment of myeloma, including dexamethasone, thalidomide, and bortezomib [13,16,20]. Thus, based on the preclinical evidence of synergy between MM therapies and BPs, and the clinical evidence that
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Table 1 Preclinical evidence of antitumor activity of bisphosphonates in multiple myeloma Study
Agents evaluated
Experimental model
Results/Conclusions
Cell lines Effects on proliferation, apoptosis, and cell adhesion in MM cells Baulch-Brown et al. [10]
ZOL, fluvastatin, and SCH66336
RPMI 8226, U266, OMP2, LP1, and NCI-H929
Caused cell cycle arrest and apoptosis; involves inhibition of geranylgeranylation
Shipman et al. [11]
CLO, PAM, and YM175
U266-B1, JJN-3, and HS-Sultan
Caused cell cycle arrest, DNA fragmentation; altered nuclear morphology
Tassone et al. [12]
ZOL and PAM
XG-1, U266, and IM-9
Inhibited proliferation and induced apoptosis
Ural et al. [13]
ZOL, Thal, and Dex
ARH-77 and RPMI-8226
ZOL inhibited cell growth and induced apoptosis; cytotoxicity was increased by addition of Thal and Dex
Corso et al. [14]
ZOL
Bone-marrow stem cells from myeloma patients
ZOL reduced proliferation, increased apoptosis, and modified the pattern of expression of adhesion molecules involved in plasma-cell binding. ZOL reduced IL-6 production
Zwolak et al. [15]
ZOL
NCI-H929
ZOL released from bone cement reduced number of viable cells
Schmidmaier et al. [16]
ZOL, simvastatin, melphalan, bortezomib
RPMI 8226, U266, OMP2, and NCI-H929
Synergistic induction of apoptosis and reversal of cell-adhesion-mediated drug resistance
Koizumi et al. [17]
ZOL
RPMI 8226 (Dexresistant clone)
ZOL reduced the viability and induced apoptosis of Dex-resistant cells. Small G proteins, Rho and Rap1A, were unprenylated in the ZOL-treated MM cells. Geranylgeraniol rescued ZOL-induced effects
Effects on drug resistance
Immunomodulatory and antiangiogenic effects Uchida et al. [18]
ZOL or mevastatin
RPMI 8226 and U266
Pretreatment of myeloma cells with zoledronic acid or mevastatin increases their sensitivity to lysis by gd T cells
Kunzmann et al. [19]
PAM and IPP
MM patient-derived PBMCs and Daudi, U266, and RPMI 8226
PAM and IPP induced expansion of Vg9Vd2 T cells in PBMC cultures, increased activation and non-MHC-restricted lytic activity of gd T cells. PAM induced (gd T-cell-dependent) depletion of plasma cells in bone marrow mononuclear cell cultures
Moschetta et al. [20]
ZOL and bortezomib
MM patient-derived bone marrow macrophages
Synergistic inhibition of proliferation, adhesion, and migration of macrophages. Reduced transcription of VEGF, PDGF, HGF, and bFGF. Inhibited neovascularization by vasculogenic macrophages on Matrigel, and ERK1/2 and VEGFR2 phosphorylation
Yaccoby et al. [21]
ZOL, PAM, RANKL inhibitor
Human MM xenograft in SCID mice
Inhibited growth and survival of human MM cells derived from intramedullary (within bone) disease
Croucher et al. [22]
ZOL
5T2MM xenograft in C57BL/KaLwRij mice
ZOL reduced formation of osteolytic lesions; reduced paraprotein concentration, bone loss, tumor burden, and angiogenesis. Significantly increased survival
Guenther et al. [23]
ZOL
INA-6 plasmacytoma xenograft in SCID mice
ZOL increased survival. Western blot analysis of tumor homogenates demonstrated the accumulation of unprenylated Rap1A, indicative of the uptake of ZOL by non-skeletal tumors and inhibition of farnesyl pyrophosphate synthase
Animal models
Abbreviations: bFGF, basic fibroblast growth factor; CLO, clodronate; Dex, dexamethasone; HGF, hepatocyte growth factor; IL, interleukin; IPP, isopentenylpyrophosphate; MHC, major histocompatibility complex, MM, multiple myeloma; RANKL, receptor activator of NF-úB ligand; PAM, pamidronate; PBMC, peripheral blood mononuclear cell; PDGF, platelet-derived growth factor; SCID, severe combined immunodeficient; Thal, thalidomide; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2; ZOL, zoledronic acid.
G.J. Morgan / Critical Reviews in Oncology/Hematology 77 S1 (2011) S24−S30
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Table 2 Clinical evidence of antitumor activity of bisphosphonates in multiple myeloma Reference
N
Study arms
Results
Aviles et al. [27]
94
ZOL (4 mg q28d) Placebo
ZOL significantly increased 5-year EFS and OS rates ( p < 0.01 for both)
Berenson et al. [28]
353
ZOL (4 mg q3−4wk) PAM (90 mg q3−4wk)
In patients with high BALP (n = 89), ZOL significantly decreased the risk of death by 55% vs pamidronate ( p = 0.04)
McCloskey et al. [29]
619
CLO (1,600 mg/d) Placebo
Clodronate significantly increased survival in patients (n = 153) with no fractures at baseline vs placebo ( p = 0.006)
Berenson et al. [30]
392
PAM (90 mg IV, monthly) Placebo
Pamidronate significantly increased survival in patients receiving second-line antimyeloma therapy compared with placebo (14 vs 21 months; p = 0.041)
Abbreviations: BALP, bone-specific alkaline phosphatase; CLO, clodronate; EFS, event-free survival; IV, intravenous; OS, overall survival; PAM, pamidronate, ZOL, zoledronic acid.
BPs can improve cancer-related outcomes, the potential for added benefit is especially promising in the MM setting. 2. Improving outcomes in multiple myeloma by adding bisphosphonates to antimyeloma therapy 2.1. Early clinical trials of bisphosphonates In early clinical trials of BPs to prevent SREs from MM (Table 2) [27−30], weak signals of antimyeloma benefits were revealed, with effects reaching statistical significance in retrospective analyses of high-risk patient subsets. For example, in the long-term follow-up (8.6 years) of a placebo-controlled trial (N = 619), CLO significantly prolonged overall survival (OS) versus placebo in 153 patients who did not have vertebral fractures at baseline (median OS, 59 months vs 37 months with placebo; p = 0.006) [29]. Similarly, in a long-term trial of intravenous PAM (N = 392) in patients with newly diagnosed or relapsed/refractory MM, PAM significantly increased survival in the subset of patients with MM receiving secondline antimyeloma therapy (14 vs 21 months; p = 0.041) compared with placebo [30]. Small clinical studies have also provided insight into the antimyeloma potential of ZOL. The addition of ZOL to conventional chemotherapy in treatment-naive patients (N = 94) significantly improved 5-year event-free survival (80% vs 52%, respectively) and 5-year overall survival (80% vs 46%, respectively; p < 0.01 for both) compared with conventional therapy alone [27]. 2.2. MRC Myeloma IX Based on the BP anticancer theory and promising early results, a large, more extensive, randomized, controlled trial to evaluate the role of BPs in patients with newly diagnosed MM was designed and conducted by the MRC in the United Kingdom (Table 3) [31,32]. The independent, phase III Myeloma IX trial (N = 1,960) compared the relative efficacy and safety of monthly intravenous ZOL (4 mg) versus daily oral CLO (1,600 mg) when used concurrently with
standard intensive or non-intensive therapy regimens. Therefore, this study compared an early-generation oral bisphosphonate (CLO) with the most recently approved intravenous bisphosphonate in this setting (ZOL), both of which have demonstrated potential survival benefits in early trials. The primary endpoint of this trial was overall survival, and additional endpoints included progression-free survival, response rates, and SREs. Patients were allocated to 2 main pathways, intensive and non-intensive. Younger, fitter patients were allocated to the intensive pathway, which consisted of induction therapy (randomized between standard cytotoxic and thalidomidebased regimens) followed by autologous stem cell transplantation (ASCT). Older patients were allocated to the non-intensive pathway, which consisted of systemic therapy only (randomized between melphalan/prednisone and a thalidomide-based regimen). In each treatment pathway, patients were randomized to oral CLO (1,600 mg/day) or ZOL (4 mg via 15-minute infusion) and treated until disease progression or death. Dosing of ZOL was adjusted in patients with baseline renal impairment and serum creatinine was monitored monthly, per the label [33]. Of 1,960 evaluable patients, 981 received ZOL and 979 received CLO [31]. At the median follow-up of 3.7 years, approximately 60% of patients stayed on treatment until disease progression. Median time on treatment was approximately 1 year across all treatment groups. At the time of the database lock, 11.3% to 13.5% of patients (ZOL and CLO arms, respectively) were still receiving BP treatment. Table 3 Efficacy endpoints reported in the MRC Myeloma IX trial [31] Endpoint
Hazard ratio ZOL vs CLO
p value
Overall survival
0.842
0.0118
Progression-free survival
0.883
0.0179
SREs
0.74
0.0004 [32]
Abbreviations: CLO, clodronate; MRC, Medical Research Council; SRE, skeletal-related event; ZOL, zoledronic acid.
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Zoledronic acid significantly prolonged both progressionfree survival (PFS) and OS ( p = 0.0179 and p = 0.0118, respectively) versus CLO. Zoledronic acid also reduced the proportion of patients with an SRE vs CLO (27.0% vs 35.3%, respectively; p = 0.0004). The improvement in OS was maintained after adjustment for time to first SRE in a Cox model ( p = 0.0178), suggesting that antimyeloma effects likely underlie the OS benefit. Consistent with these benefits, complete or very-good-partial responses were achieved by significantly more patients treated with ZOL in the non-intensive pathway ( p = 0.03). In contrast, ZOL did not significantly improve the response rate in patients allocated to the intensive pathway, perhaps because of the high overall response rate among patients undergoing myeloablative therapy. In addition, ZOL reduced the incidence of SREs regardless of treatment pathway or the presence of bone lesions at baseline [32]. This is the first time that one BP has demonstrated a significant OS advantage over another BP in the overall population of a large randomized study. Both BPs were generally well tolerated, and effects on renal function were similar between treatment groups. The incidence of confirmed osteonecrosis of the jaw (ONJ) was low but significantly higher among ZOL-treated patients (ZOL, 3.6%; CLO, 0.3%), and is consistent with the 2.4% incidence of ONJ reported in a recent retrospective analysis of 548 patients receiving intravenous bisphosphonates for multiple myeloma [34]. Most cases were mild to moderate in severity, and application of preventive dental practices that were established after the initiation of the Myeloma IX trial would likely lower the ONJ risk in this setting. 3. Discussion Bisphosphonates are the standard of care for preventing SREs and treating hypercalcemia of malignancy in patients with MM. Bisphosphonate-mediated anticancer effects demonstrated in preclinical systems are beginning to manifest in the clinical setting in recent trials. The Myeloma IX trial conducted by the MRC is the first independent, large-scale, randomized, prospective trial comparing ZOL with CLO in patients with MM. Importantly, the factorial design of the trial allowed a comparative assessment of the benefit of ZOL and CLO across 4 different primary treatment regimens for patients with newly diagnosed MM. The data from this trial clearly demonstrate that ZOL has a more favorable efficacy profile than CLO across disease recurrence and SRE endpoints when added to standard antimyeloma therapies. Moreover, the survival benefit of ZOL was shown to be independent of SRE benefits. This distinction is important because SREs have been associated with reduced survival in patients with malignant bone disease [35]. Therefore, maintenance of the significant
OS benefit after adjusting for SREs suggests an underlying anticancer mechanism of action. The data are consistent with those of previous clinical studies in solid-tumor settings in which there is strong involvement with bone, and support a clinically meaningful survival benefit from ZOL in patients with MM. An important aspect of the data derived from the MRC Myeloma IX trial is that ZOL achieved OS and PFS benefits versus CLO in the overall study population, that is, across antimyeloma treatment regimens. The survival benefit parallels the superior response rates observed among ZOL-treated patients. Notably, the differences in OS were apparent within the first few months on study, supporting possible synergy between ZOL and primary antimyeloma therapies, and elevating the importance of initiating ZOL early in the disease course. This is consistent with preclinical data that have shown synergy between ZOL and various antimyeloma agents including thalidomide, melphalan, dexamethasone, and bortezomib [13,16,20]. Notably, the presence of osteolytic lesions is not a prerequisite for BP use in MM patients in the United Kingdom [36]. Consequently, approximately one quarter of the enrolled patients had not yet been diagnosed with myeloma bone disease. Therefore, BP therapy was initiated even earlier than the approved standard in the United States and European Union [37−40]. In addition to insights into BP anticancer activity, the Myeloma IX trial provides an important prospective comparison of the safety profiles of ZOL and CLO. Despite differences in mode of administration (oral for CLO and intravenous for ZOL), renal safety was similar, perhaps because of adherence to renal monitoring protocols. Rates of ONJ were higher for ZOL versus CLO; however, new prevention and management protocols recommended and implemented after this trial completed have been effective in further reducing ONJ risk. The data further reinforce the well-established safety profile of BPs in the MM setting and provide additional clinical evidence to consider ZOL an important and preferred component of antimyeloma therapy in patients with newly diagnosed MM. These data add to the growing body of evidence suggesting that BPs in general, and ZOL in particular, may provide clinically meaningful anticancer benefits in patients with newly diagnosed malignancies [24,25,41]. Further analyses to determine the effects of such early administration of BP therapy are warranted. 4. Addendum Recently, an indirect meta-analysis using data from randomized, controlled, phase III trials of bisphosphonates (i.e., ZOL, CLO, PAM, etidronate, and ibandronate) in patients with MM has provided some insight on their relative efficacy [42]. Using a mixed treatment comparison model to analyze data from 18 trials (total N = 4,970) the
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authors determined that ZOL significantly improved OS compared with CLO (HR 0.83; 95% CI 0.73–0.94), but was not significantly different than PAM (HR 0.84; 95% CI 0.61–1.13) or ibandronate (HR 0.70; 95% CI 0.42–1.11). ZOL also significantly reduced the risk of SREs compared with CLO, PAM, and ibandronate. Overall, the authors concluded that available data show the benefits of ZOL over CLO and PAM, but also highlight the need for a randomized controlled trial comparing ZOL and PAM in MM patients. Conflict of interest statement The author has participated in an advisory board for Novartis. Funding Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. Financial support for the MRC Myeloma IX trial was obtained from the Medical Research Council, with additional funding in the form of unrestricted educational grants from Novartis, Schering Health Care Ltd, Chugai, Pharmion, Celgene, and Ortho Biotech, principally to support trial coordination and the laboratory studies. Acknowledgements Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. I thank Jerome F Sah, PhD, ProEd Communications, Inc.® , for his medical editorial assistance with this manuscript. References [1] World Health Organization: International Agency for Research on Cancer. GLOBOCAN 2008, http://globocan.iarc.fr/ [accessed November 5, 2010]. [2] Kumar SK, Mikhael JR, Buadi FK, Dingli D, Dispenzieri A, Fonseca R, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and RiskAdapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc 2009;84:1095–110. [3] Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009;23:3−9. [4] Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 2001;27: 165−76. [5] Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. Lancet 2009;374:324−39. [6] Chauhan D, Uchiyama H, Akbarali Y, Urashima M, Yamamoto K, Libermann TA, et al. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood 1996;87:1104−12. [7] Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004;104: 607−18. [8] Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2002;2:175−87.
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Biography Gareth Morgan, PhD, FRCP, FRCPath, is Professor of Haematology at The Institute of Cancer Research (ICR) and Head of the Haemato-Oncology Clinical Unit at The Royal Marsden NHS Foundation Trust. After attending medical school at the University Hospital of Wales, Professor Morgan completed a PhD and trained in the molecular genetics and management of blood cell cancers at the ICR. He left the ICR to join the University of Leeds, where he set up his own research group studying the molecular genetics of non-Hodgkin’s lymphoma and myeloma. Professor Morgan’s research interests include the treatment and management of leukaemias, lymphomas, and myelomas. He is actively involved in research into the genetic basis of myeloma and how this can be used in the clinical environment. His work has focussed on the translation of information derived from the molecular analysis of the pathogenesis of malignant cells into the clinic using novel targeted treatment strategies. Professor Morgan is currently Principal Investigator of a number of Phase I, II, and III studies as well as serving on independent data monitoring committees. He is a Principal Investigator on the MRC Myeloma X trial as well as on a number of innovative phase I studies in both AML and myeloma. He has served as Scientific Secretary of the British Society of Haematology and on the UK Myeloma forum. He has been instrumental in the establishment of the European Myeloma Network. He is a Director for Myeloma UK, a national charity, and is a Scientific Advisor to the International Myeloma Foundation and is on the Board of the UK Stem Cell Bank. Professor Morgan is widely published, with over 200 high impact factor peer-reviewed articles. He reviews for a number of journals and sits on a number of grant-governing bodies both in the UK and internationally.