In 2004, multiple myeloma was diagnosed in more than 15,000 peoplein the United States and will account for approximately 20% of deathsdue to hematologic malignancies. Although traditional therapies suchas melphalan (Alkeran)/prednisone, combination chemotherapy withVAD (vincristine, doxorubicin [Adriamycin], and dexamethasone), andhigh-dose chemotherapy with stem cell transplantation have shownsome success, median survival remains between 3 to 5 years. Treatmentoptions for patients with multiple myeloma have increased in recentyears, with the promise of improvement in survival. New agents, suchas the proteasome inhibitor bortezomib (Velcade), the antiangiogenicand immunomodulator thalidomide (Thalomid) and its analogs, suchas lenalidomide (Revlimid), together with other small molecules, includingarsenic trioxide (Trisenox), and other targeted therapies, havebeen studied alone and in combination with other antineoplastic therapies,either as induction therapy prior to stem cell transplantation or inpatients with relapsed disease. Bortezomib recently was approved inthe United States for the treatment of multiple myeloma in patientswho have received at least one prior therapy. The use of bortezomibbasedregimens as front-line therapy as well as the use of other agentsin multiple myeloma remain under investigation, and approvals forboth thalidomide and lenalidomide are hoped for soon, with the overallprospect of patient outcome continuing to be increasingly positive.
In 2004, multiple myeloma was diagnosed in more than 15,000 people in the United States and will account for approximately 20% of deaths due to hematologic malignancies. Although traditional therapies such as melphalan (Alkeran)/prednisone, combination chemotherapy with VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone), and high-dose chemotherapy with stem cell transplantation have shown some success, median survival remains between 3 to 5 years. Treatment options for patients with multiple myeloma have increased in recent years, with the promise of improvement in survival. New agents, such as the proteasome inhibitor bortezomib (Velcade), the antiangiogenic and immunomodulator thalidomide (Thalomid) and its analogs, such as lenalidomide (Revlimid), together with other small molecules, including arsenic trioxide (Trisenox), and other targeted therapies, have been studied alone and in combination with other antineoplastic therapies, either as induction therapy prior to stem cell transplantation or in patients with relapsed disease. Bortezomib recently was approved in the United States for the treatment of multiple myeloma in patients who have received at least one prior therapy. The use of bortezomibbased regimens as front-line therapy as well as the use of other agents in multiple myeloma remain under investigation, and approvals for both thalidomide and lenalidomide are hoped for soon, with the overall prospect of patient outcome continuing to be increasingly positive.
In 2004, multiple myeloma was diagnosed in more than 15,000 people and accounted for approximately 11,000 deaths, representing 20% of fatalities due to hematologic malignancies in the United States. Multiple myeloma is a hematologic B-cell malignancy associated with elevated serum and urine immunoglobulins, plasma cell infiltration of the bone marrow, soft-tissue plasmacytomas, and skeletal complications. Traditional therapies for multiple myeloma have included the combination of the alkylating agent melphalan (Alkeran) with the steroid prednisone; combination chemotherapy with VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone); high-dose chemotherapy with autologous stem cell transplantation (SCT); and nonmyeloablative or fully ablative allogeneic transplantation.[2,3] Although many patients respond to treatment, relapse is inevitable and median survival remains between 3 and 5 years[3,4]; hence, the need for new approaches is critical. Multiple new agents for the treatment of multiple myeloma are under clinical examination, including the proteasome inhibitor bortezomib (Velcade), thalidomide (Thalomid) and its analogs such as lenalidomide (Revlimid), and arsenic trioxide (Trisenox), as well as a variety of other therapeutic strategies. This review briefly covers these emerging therapeutics and discusses their potential in myeloma therapy. It is important to note that clinical trials have applied different criteria to measure response to treatment. Commonly used response criteria and modified versions include those of the Southwest Oncology Group (SWOG), the Eastern Cooperative Oncology Group (ECOG), and the European Group for Blood and Marrow Transplantation (EBMT), which all share certain outcome measures (eg, paraprotein reduction). However, the EBMT criteria define response more stringently and are now accepted as the most rigorous standard in drug development. Nevertheless, response rates from various agents should be compared with caution, because the criteria to measure response differ between trials.
Bortezomib The proteasome, a multisubunit protease complex, plays an essential role in protein homeostasis in both normal and neoplastic cells. The proteasome is critical to regulated degradation of proteins involved in essential cellular functions, including protein turnover, cell adhesion, cell-cycle progression, antigen presentation, and inflammation.[8-10] Inhibition of proteasome function offers encouraging possibilities for the treatment of cancer, and various natural and synthetic molecules have been used to study proteasome inhibition in neoplastic cells. However, only bortezomib (formerly known as PS-341), a boronic acid peptide derivative and potent (Ki = 0.6 nM), selective, reversible proteasome inhibitor, has entered trials and been approved for clinical use. Mechanisms of Action
Several mechanisms by which bortezomib elicits antitumor effects in multiple myeloma have been identified. Inhibition of the proteasome with bortezomib has been shown to decrease myeloma cell proliferation through stabilization of the tumor suppressor p53 and the cyclin-dependent kinase inhibitors p21 and p27.[13,14] Bortezomib also promotes apoptosis via stabilization of the proapoptotic Bid and Bax proteins and inhibitor- ÎºBÎ± (IÎºBÎ±), as well as activation of the c-Jun NH2-terminal kinase (JNK), as illustrated in Figure 1.[14-16] Stabilization of IÎºBÎ± has been shown to result in inhibition of nuclear factor ÎºB (NF-ÎºB) activation and to prevent upregulation of the antiapoptotic Bcl-2, Bcl-xL, and XIAP proteins.[17,18] These effects produce an increase in caspase-9-mediated apoptosis. Activated JNK also increases AP-1-mediated upregulation of Fas protein (CD95), which promotes caspase-8-mediated apoptosis.[ 19] Therefore, treatment with bortezomib may ultimately restore an apoptotic phenotype to myeloma cells through increased activation of both the intrinsic and extrinsic pathways. The antitumor activity of bortezomib also occurs in part through indirect effects on the bone marrow microenvironment (Figure 2). Bortezomib has been shown to inhibit the adhesion of myeloma cells with bone marrow stromal cells (BMSCs), thereby preventing the release of cytokines such as interleukin (IL)-6, vascular endothelial growth factor (VEGF), and insulin growth factor-1 (IGF-1). Bortezomib- mediated inhibition of these cytokines, which promote proliferation, survival, and angiogenesis, has resulted in decreased viability of myeloma cells, as well as sensitization to antineoplastic agents. This chemosensitization may also result from inhibition of NF-ÎºB- mediated release of VEGF and IL-6 production by the BMSCs. NF-ÎºB activity also has been associated with chemoresistance, and loss of NF-ÎºB- mediated protection may result in chemosensitization. Importantly, evidence has shown that normal cells are less sensitive to proteasome inhibition than neoplastic cells and that proteasome activity has recovered in normal tissues within 24 hours following treatment.[12,21] Relapsed, Refractory Multiple Myeloma
The results of a number of clinical studies of bortezomib in relapsed and/or refractory multiple myeloma are summarized in Table 1.[22-34] Phase I trials suggested that multiple myeloma is sensitive to proteasome inhibition and that a dosing schedule allowing for a 72-hour interval between individual doses and a drugfree rest period every third week has manageable toxicities.[35,36]
Newly Diagnosed Multiple Myeloma
Bortezomib has also demonstrated activity as monotherapy or in combination regimens in the treatment of patients with newly diagnosed multiple myeloma in a number of preliminary reports (Table 1).[29-34] Although we have shown that single-agent bortezomib on the standard dose and schedule produced an overall response rate of 45% with manageable toxicities in newly diagnosed patients and less peripheral neuropathy compared with other studies, clinical trials of bortezomib- based combinations in this setting appear more promising, with particularly high CR/nCR rates.[30-34] Jagannath et al found that bortezomib with dexamethasone (40 mg on the day of and after bortezomib administration) with less than PR after two cycles, or less than CR after four cycles, yielded CR, nCR, or PR in the majority of patients with newly diagnosed multiple myeloma. The combination of bortezomib with dexamethasone also appeared to serve as an appropriate induction therapy prior to stem cell transplantation, because the combination was well tolerated and SCT was feasible. Cavenagh et al conducted a trial of bortezomib, 1.3 mg/m2, on days 1, 4, 8, and 11 for up to four 3-week cycles, with dexamethasone, 40 mg, on days 1 to 4, 8 to 11, and 15 to 18 of cycle 1 and on days 1 to 4 of subsequent cycles and doxorubicin, 0, 4.5, or 9.0 mg/m2, on days 1 to 4 in the front-line setting. In this study, over 20% of patients achieved CR, the vast majority had PR, and stem cell collection was feasible in all but one of 21 patients. The regimen of bortezomib, 1.0 to 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of up to four 6-week cycles or on days 1, 8, 15, and 22 of up to five 5-week cycles, with melphalan, 9.0 mg/m2, and prednisone, 60 mg/m2, on days 1 to 4 also demonstrated impressive activity with manageable toxicity.[ 33] In this phase I/II study, no dose-limiting toxicities were observed with bortezomib treatment for up to 49 weeks. Preliminary data from another study also have demonstrated very encouraging results with the use of bortezomib, thalidomide, and dexamethasone[ 34] in the front-line setting. Thalidomide After its introduction in the 1950s as a sedative, thalidomide was linked to serious birth defects and was consequently removed from the marketplace in the 1960s. It regained its position as a viable therapeutic agent when it was discovered to be efficacious in the treatment of erythema nodosum leprosum and has since been investigated in a variety of conditions.[ 40] Most importantly, although still considered experimental, thalidomide is now commonly used to treat multiple myeloma either as monotherapy or in combination with dexamethasone. Specifically, the efficacy and toxicity of thalidomide have been extensively studied in patients with relapsed, refractory, and newly diagnosed multiple myeloma. Mechanisms of Action
Although the antitumor mechanisms of thalidomide have not been fully defined, evidence suggests that induction of apoptosis, inhibition of cytokine production and angiogenesis, and immune modulation of T cells and natural killer cells are involved.[ 41-43] Thalidomide has been shown to promote apoptosis through the extrinsic pathway via activation of caspase-8 and inhibition of caspase inhibitor of apoptosis protein-2 (cIAP-2) (Figure 1). The antimyeloma activity of thalidomide is also partially attributable to inhibition of the interaction of multiple myeloma cells with BMSCs (Figure 2). The reduced adhesion results in reduced secretion of cytokines, including IL-6, VEGF, and IGF-1, decreased cell viability and angiogenesis, and chemosensitization of multiple myeloma cells. Inhibition of angiogenesis may be important, because microvessel density-a marker for angiogenesis- increases as multiple myeloma progresses, and a high level of angiogenesis is associated with decreased survival. However, because paraprotein responses to thalidomide have not always correlated with differences in microvessel density, other mechanisms such as immunomodulation and effects of adhesion may be key. Importantly, immune modulation by thalidomide appears to involve activation of phosphatidylinositol 3-kinase and increased IL-2 secretion of T lymphocytes as well as natural killer cell-mediated tumor cell lysis. Relapsed, Refractory Multiple Myeloma
The promising preclinical activity of thalidomide prompted a number of clinical trials in patients with multiple myeloma (Table 2).[45,47-55] In a dose-escalation study, 84 patients with relapsed or refractory multiple myeloma following SCT received thalidomide, 200 to 800 mg/d. Major responses (≥ 50% decrease in paraprotein) were observed in 25% of patients. However, the reductions in bone marrow plasma cells appeared to be only partially related to paraprotein reduction. There was no apparent association between paraprotein and bone marrow responses in patients with ≤ 75% paraprotein reduction, and conversely, 15% (4 of 27) of the paraprotein nonresponders who were evaluated exhibited a bone marrow response. Moreover, no change in microvascular density was observed in the patients who responded.
The initial results of this study were confirmed by Barlogie and colleagues[ 47] and Rajkumar and colleagues.[ 48] Using a similar dosing schedule and response criteria, these studies demonstrated major response rates of 30% and 25% in 169 and 16 heavily pretreated patients, respectively. Response to thalidomide resulted in improvements in hematologic parameters.[ 45,48] A small percentage of patients with nonresponsive disease by paraprotein in the initial trial by Singhal and colleagues exhibited improvements in hematologic indicators. The most common toxicities reported in these trials included confusion, constipation, depression, dizziness, edema, incoordination, mood changes/depression, nausea, rash, sensory neuropathy, sedation and somnolence, tremor, and weakness or fatigue.[45,47,48] Newly Diagnosed Symptomatic Multiple Myeloma
Evidence suggests that thalidomide in combination with dexamethasone is effective as a front-line therapy. In a phase II trial in 50 patients, 64% of patients with high-risk disease who received thalidomide, 200 mg/d, with high-dose dexamethasone achieved a major response (as determined by standard ECOG criteria [≥ 50% decrease in serum and urine paraprotein and ≥ 50% decrease of soft-tissue plasmacytomas or, if assessed by urine paraprotein alone, ≥ 90% decrease]). The efficacy of the thalidomide/dexamethasone combination is further supported by the results of a dose-escalation study of thalidomide, 100 to 400 mg/d, and dexamethasone, 20 mg/m2, in which responses (≥ 75% reduction in paraprotein) were noted in 72% of patients.[ 50]. In an ECOG-coordinated phase III study (E1A00), patients with newly diagnosed disease were treated with either high-dose dexamethasone at 40 mg/d according to the Mayo regimen or dexamethasone at 40 mg/d similarly administered, along with thalidomide at 200 mg/d. The combination regimen resulted in a 63% response rate with 4% CR compared with 41% response rate for the dexamethasonealone arm (P < .05). Thalidomide-based therapy also has shown encouraging results as an induction therapy before SCT, with the thalidomide/dexamethasone combination apparently having no negative impact on stem cell collection,[49,51,56] and early data suggest that there is no impact on lymphocyte reconstitution.[ 56] Preliminary evidence suggests that thalidomide can work with standard induction regimens to overcome resistance. Combinations of thalidomide (50-400 mg/d) with VAD allowed sufficient tumor reduction (all four patients achieved PR or better) in patients with disease resistant to VAD induction therapy, and peripheral blood SCT proceeded with engraftment within approximately 2 weeks. In patients with newly diagnosed symptomatic multiple myeloma not receiving SCT, a regimen of thalidomide (100 mg/d) with standard melphalan and prednisone resulted in promising activity in a preliminary report. The most common toxicities (≥ 20%) reported in these trials included constipation, edema, neuropathy, fatigue, sedation, rash/dry skin, tremor, and elevated alkaline phosphatase.[ 49,50] Major adverse events associated with thalidomide regimens that required discontinuation of the drug included thromboembolic events and infection, suggesting a requirement for prophylactic anticoagulation and antibiotics. Furthermore, thalidomide combined with VAD resulted in reported toxicities of cardiac toxicity, constipation, fatigue, and peripheral neuropathy. Potential drug-drug interactions limited thalidomide dose escalation due to severe skin toxicity early in one trial, resulting in a final recommended dose of 200 mg/d. Other studies in which thalidomide was used as monotherapy have demonstrated that doses of up to 800 mg/d could be administered to patients with relapsed, refractory disease,[45,47,48] leading the authors to suggest that the combination with dexamethasone may have contributed to this dose-limiting toxicity and that the thalidomide dose should be kept low when used in this combination.[ 49] Although the combination appears efficacious in this treatmentnaive patient population, reduced doses of thalidomide may result in decreased responses in more difficultto- treat patients, as well as the development of drug resistance due to the potential for insufficient dose intensity. That said, a dose effect for thalidomide remains an area of debate, and lower doses (eg, 100 mg/d) are widely used. A recent multicenter study in patients relapsing after SCT suggested that doses can be individualized to tolerance and response but that side effects were both dose- and duration-dependent, further emphasizing the challenge posed by thalidomide-related side effects. The use of thalidomide as maintenance therapy following SCT is also being studied.[59,60] A preliminary analysis of a large trial conducted by the Intergroupe Francophone du Myelome has shown that thalidomide as maintenance therapy at 100 mg/d improved both progression-free and eventfree survival. The final results of this study are eagerly anticipated. Therapeutic Analogs
In an effort to reduce thalidomideassociated toxicity, analogs such as lenalidomide and CC-4047 (Actimid), both referred to as immunomodulatory derivatives (IMiDs), have entered clinical trials. Although the exact mechanisms by which thalidomide or its analogs exert their anticancer effect remain to be fully defined, these agents appear to have potent antiangiogenic, directly apoptotic, antiadhesive, growth factor-inhibitory,[62-64] and immunomodulatory[ 42,65] effects. The range of activity exhibited by thalidomide and the IMiDs is illustrated by their differential effects on the degree of T-cell proliferation and cytokine production.[ 65] Although most of the available information on the efficacy and toxicity of these analogs is preliminary, the data appear very encouraging for the treatment of patients with relapsed and/or refractory multiple myeloma.
Arsenic Trioxide Arsenic, a naturally occurring element, has been put to diverse uses, including the preservation of wood and as a pesticide, and the trioxide form of arsenic (Trisenox) is approved for the treatment of acute promyelocytic leukemia. Currently, arsenic trioxide is under study for the treatment of other cancers, including multiple myeloma. Mechanisms of Action
Preclinical evidence suggests that arsenic trioxide exerts its anticancer effects through a variety of mechanisms, including a decrease in cell proliferation via cell-cycle arrest; the induction of apoptosis associated with mitochondrial transmembrane potential breakdown, cytochrome c release, and caspase activation; antiangiogenesis; interaction with immune effector cells; and the induction of a pro-oxidant state. A study with arsenic trioxide using patient myeloma cells in SCID mice demonstrated activity in vivo, supporting the antimyeloma activity observed in in vitro models. Clinical Trials
In a phase I study conducted by Rousselot and colleagues, arsenic trioxide administration did not result in CR or PR in any of 10 patients with relapsed or refractory disease. In a phase II clinical trial, Munshi and coworkers reported short-lasting responses in 3 of 14 patients receiving the drug. In these early-phase studies using a relatively low daily dose of arsenic trioxide (0.15 mg/kg) in patients with relapsed or refractory disease, clinically significant toxicities (deep vein thrombosis, encephalitis, fatigue, hepatic toxicity, infections, leukoneutropenia, and neuropathy) were reported,[77,78] suggesting the need for the development of more optimized dosing. Several researchers studied the effects of a larger dose (0.25 mg/kg) administered on a less intensive schedule in patients with relapsed or refractory multiple myeloma. These modifications resulted in 33% of patients having a greater than 25% decrease in paraprotein levels. Arsenic trioxide has been studied as part of combination regimens with ascorbic acid. Preclinical evidence suggests that ascorbic acid depletes intracellular levels of the antioxidant glutathione through the conversion of dehydroascorbic acid to ascorbate, which may, in turn, increase the response of cells to the pro-oxidant effect of arsenic trioxide. In a small phase I study, two of six patients with relapsed or refractory multiple myeloma who received arsenic trioxide, 0.15 or 0.25 mg/kg/d, with ascorbic acid, 1,000 mg/d, for 5 days per week for 5 weeks followed by 2 weeks of rest, demonstrated a 48% to 58% decrease in paraprotein. In this study, normal bone marrow cells were less sensitive to treatment than myeloma cells, suggesting that the use of arsenic trioxide can have a notable impact on disease while minimizing the effects on normal bone marrow. In preliminary studies, arsenic trioxide was combined with dexamethasone and ascorbic acid and with melphalan and ascorbic acid.[83,84] The preliminary findings of these trials suggest that in combination with dexamethasone or melphalan and ascorbic acid, arsenic trioxide can induce clinically significant responses with manageable toxicity.
Other Therapies In addition to the therapeutic agents already discussed, a variety of other agents are under investigation for the treatment of multiple myeloma. These agents are being explored as monotherapy and in combinations as part of chemotherapeutic regimens in early and advanced disease. Preliminary evidence supports the use of a diverse spectrum of agents. The evidence for some novel agents, such as the retinoid 13-cis-retinoic acid (isotretinoin), the estradiol metabolism product 2ME2, erythropoietic agents, the bcl-2 antisense G3139, O6-alkylguanine DNA alkyltransferase inhibitor O6-benzylguanine,[ 91] and the active metabolite of irinotecan (SN38), is far from conclusive, and other strategies may offer more encouraging prospects. Preliminary reports have suggested that modulation of the immune system (eg, via vaccines consisting of tumor-primed dendritic cells or killed tumor cells with granulocyte macrophage colonystimulating factor-secreting cells) could be useful following autologous transplantation. Further reports have suggested that manipulation of the immune system through the modulation of IL activity, such as inhibition of the IL-1Î± receptor or increasing the level of IL-12, would have antimyeloma effects. In addition to immune modulation, the use of targeted radiotherapy for the treatment of multiple myeloma is supported by preliminary evidence. Studies have examined the use of a radiolabeled B-lymphocyte stimulator protein to target immunoglobulinproducing cells, as well as the use of radioactive bone-targeting agents such as SM-153-EDTMP and Ho- 166-DOTMP.[98-100] The evidence for the use of anti- CD20 antibodies paints a more complicated picture. Several preliminary reports offer differing conclusions. One report suggested that rituximab (Rituxan) may have antitumor effects when administered after autologous SCT. However, in relation to historical controls, another report suggested that such treatment could result in a notable shortening of the time to relapse following SCT. Preclinical work with combinations of novel agents offers new areas to explore. For example, IMiDs have been shown to potentiate bortezomib activity in inducing apoptosis in a multiple myeloma cell line (MM.1S) and in patient cells. The use of novel agents such as IMiDs, arsenic trioxide, and bortezomib[ 105] in combination with tumor necrosis factor-related apoptosisinducing ligand (TRAIL), a novel therapeutic agent, has been reported preclinically, providing the basis for clinical studies that are now ongoing. Finally, the farnesyltransferase inhibitor (FTI) tipifarnib (Zarnestra) may be another novel approach to the treatment of multiple myeloma. FTIs have been shown to inhibit growth and induce apoptosis in drug-resistant myeloma cells. Furthermore, a recent phase II study of 43 patients with relapsed multiple myeloma found that tipifarnib given at 300 mg twice daily resulted in disease stabilization but no responses. The most common grade 3/4 toxicities included fatigue, nausea, diarrhea, anemia, thrombocytopenia, and neuropathy. Further clinical investigation of this novel agent in the treatment of multiple myeloma is warranted. Conclusions The number of new agents and combinations under investigation for the treatment of multiple myeloma and the elucidation of their mechanisms of action offer hope to patients with multiple myeloma, especially those with relapsed, refractory disease. Newer and more effective therapeutic strategies directly target the myeloma cell and also alter the bone marrow microenvironment. These effects result in decreased viability of myeloma cells as well as chemosensitization of myeloma cells to other antineoplastic agents. Bortezomib, a first-in-class proteasome inhibitor, is the first agent in more than a decade to be approved in the United States and the European Union for the treatment of relapsed and refractory multiple myeloma in patients who have received at least two prior therapies and show disease progression. More recently, this drug received full approval in the United States for the treatment of multiple myeloma patients who have received at least one prior therapy. Preliminary results of clinical trials with bortezomib as monotherapy or in combination regimens with dexamethasone, melphalan, prednisone, doxorubicin, and/or thalidomide in the front-line treatment of multiple myeloma have shown activity and manageable toxicity. The high rates of CR and nCR in these bortezomib-based regimens suggest new possibilities for combinations of novel agents as an alternative to autologous transplantation, and further investigation is warranted. The use of bortezomib as induction therapy prior to SCT is also under clinical investigation. Thalidomide as monotherapy or in combination regimens has shown activity in relapsed and/or refractory as well as newly diagnosed multiple myeloma in clinical trials. The thalidomide analogs lenalidomide and CC-4047 have not been associated with the same toxicities as thalidomide in phase I and phase II studies. Lenalidomide has also demonstrated impressive clinical activity in phase II studies and has been shown to be strikingly effective in combination with high-dose dexamethasone at interim analysis in two large phase III trials. Arsenic trioxide has been tolerable but has produced limited activity in relapsed and/or refractory disease. Numerous other novel agents, alone or in combination regimens both with standard and other new drugs, have demonstrated activity and are under clinical investigation in the treatment of multiple myeloma. As an example, in an ongoing phase I trial, a combination of lenalidomide and bortezomib has been well tolerated and has shown remarkable activity in advanced myeloma, even in patients who had received either agent alone. This approach reflects a new treatment paradign in the management of this disease and together with molecular advances in genomics, proteomics, and the accelerated approach to translational drug development now evident in myeloma, offers real hope for significant improvements in patient outcome.
Dr. Richardson is a member of the advisory boards and speakers bureaus for Celgene and Millennium. Dr. Anderson receives grant support from Novartis, Millennium, and Celgene.
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