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Introduction: Deferasirox is an oral iron chelator, approved worldwide for the treatment of chronic iron overload due to transfusion. Deferasirox was permitted two years ago in Japan, but there is little known regarding its efficacy and tolerability in clinical practice. Methods: We conducted a retrospective study of 18 patients with transfusion-dependent anemias treated by deferasirox at our institution. The starting dose was individualized and ranged from 6.4 to 26.3 mg/kg/day. Routine clinical laboratory data were followed, and serum ferritin was assessed every 4 weeks. Results: The mean serum ferritin level of 18 patients at the time of deferasirox induction was 3162 ng/ml. Ten of 18 patients could sustain deferasirox treatment for at least 6 months, at an average maintenance dose of 10.8 mg/kg/day. Serum ferritin reduction was observed in 4 patients, at doses less than 20 mg/kg/day. Eighty-nine percent of the patients had adverse events, and 13 of them in all ultimately discontinued. Myelodysplastic syndrome (MDS) patients showed poor tolerability. Severe infections of grade 3 or more were documented in 6 patients, and 2 of them were fatal. Conclusions: The potential for beneficial iron chelation of deferasirox at less than the recommended 20 mg/kg dose was demonstrated. On the contrary, poor tolerability was documented, with adverse events such as severe infections, especially in MDS patients. Although it was not clearly demonstrated that deferasirox was responsible for impaired immunity, careful watching is required to administrate deferasirox.

We here report the case of a young Japanese woman diagnosed with chronic active Epstein-Barr virus (EBV) infection. Intensive therapy with the CHOP regimen was partially able to control virus expansion, but various central nervous system symptoms appeared and gradually progressed. EBV-encoded RNA, detected using in situ hybridization, disclosed the presence of EBV in liver and bone marrow tissue, and real-time PCR revealed the presence of EBV in the cerebrospinal fluid (CSF) and serum. CD3+CD4+CD8-CD56- T-cell expansion in the peripheral blood (PB) and CSF was also observed. Atrophic brain changes were progressive, and the patient died of central nervous system disturbance and pulmonary hemorrhage a year after diagnosis. Autopsy revealed that EBV-infected T lymphocytes with a phenotype similar to those seen in PB and CSF had infiltrated multiple organs: the lymph nodes, bone marrow, endocardium, pericardium, myocardium, spleen, liver, and spinal cord. There have been few previous reports of severe degenerative changes in the myocardium, liver, and spinal cord in patients with EBV infection. Although EBV occasionally infiltrates the central nervous system and brain, atrophic changes mediated by EBV are rare. The autopsy results of this case suggest the possibility of EBV-mediated, severe degenerative changes in multiple organs.

Basophils play an important role in allergic inflammation and are pathologically related to hematological disturbances, such as iron deficiency anemia and myeloproliferative disorders; however, they are only rarely encountered in lymphoid malignancies. Here, we report the case of a 33-year-old man with a bulky mass of the small intestine, multiple paraaortic lymphoadenopathy, pleural effusion, and ascites, who was diagnosed as a case of de novo CD5+ diffuse large B cell lymphoma (DLBCL). This patient showed a marked elevation of the basophil count in the peripheral blood, which appeared to run in parallel with the tumor burden. High dose chemotherapy followed by autologous peripheral blood cell transplantation yielded complete remission, and the patient has remained disease free for 5 years. To the best of our knowledge, this is the first report of a case of de novo CD5+ DLBCL showing marked elevation of the PB basophil count.

Primary cardiac lymphoma is extremely rare and is associated with a poor prognosis. In most cases, cardiac involvement occurs as a late symptom and the diagnosis is thus delayed. We herein report a 35-year-old woman with cardiac diffuse large B-cell lymphoma (DLBCL) with breast infiltration. The patient was admitted to our hospital based on an initial presentation with dyspnea on exertion, chest pain, and a hard mass of the left breast. Echocardiography revealed a mass in the right atrium wall and interatrial septum, and massive pericardial effusion. ECG showed atrioventoricular block. We promptly performed a needle biopsy of the breast mass, which showed CD5-positive DLBCL, non-GCB type. The serum HIV reaction was negative. We thus diagnosed this patient as having cardiac and breast CD5-positive DLBCL, stage IVA, based on the massive pericardial effusion. The patient's prognosis was apparently poor. Therefore, she received 3 cycles of R-CHOP chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT), resulting in a complete response. In general, cardiac lymphoma is associated with high mortality and has a poor prognosis. This case demonstrates that rapid and appropriate diagnosis, and immediate intensive chemotherapy followed by PBSCT might be necessary for the treatment of extranodal lymphoma indicative of a poor prognosis.

Despite numerous attempts to uncover the mechanism of other iatrogenic immunodeficiency-associated lymphoproliferative diseases (OIIA-LPDs), this mechanism remains poorly understood, especially in rheumatoid arthritis (RA) patients. We analyzed the data on 23 patients with LPDs and RA. Patients were categorized into three groups according to whether they had methotrexate (MTX); MTX-regressive LPDs, MTX-persistent LPDs or other drugs-mediated LPDs. The LPDs seen in OIIA-LPDs-RA might have a unique behavior to think about several rare phenotypes. The overall survival of all patients was 74% at 5 years, and those of the three groups were 100%, 64% and 60%, respectively. Among the 6 patients who died, 4 had LPDs that were detected late, and thus adequate treatment was not given. In addition, several patients with diffuse large B cell lymphoma with a complex karyotype achieved complete remission (CR). Only one among the 17 patients who achieved CR relapsed. OIIA-LPDs-RA appeared to have a better prognosis than other more common types of lymphomas. Regarding RA treatment, various anti-RA drugs were given to the patients after developing LPDs, including MTX, but no recurrent patients were documented.

Bortezomib is a potent agent for multiple myeloma (MM); however, severe treatment-related toxicities such as peripheral neuropathy have been observed in conjunction with its use. In this study, we present the cases of 9 patients with refractory MM whose administration schedule was modified from twice weekly to an interval of once weekly or longer mainly due to adverse events. The average duration from diagnosis to the time of bortezomib induction was 56 months. The schedule was changed to the modified administration according to the physician's discretion. The average duration of modified treatment was 16 months. Six patients with IgG or IgA subtype showed more than a minor response. One patient with BJP had stable disease for 3 years, and the other BJP-type patient with extramedullary plasmacytomas showed remarkable tumor regression. The treatment-related toxicities of this strategy were mild and tolerable. To our knowledge, this is the first report of the administration of bortezomib at intervals longer than once weekly.

An 83-year-old woman had been suffering from palpitations and fatigue for a month. An annual screening test revealed an increased WBC count so she was referred to our hospital. CBC showed extremely elevated WBC count (186,300/microl), in which the population of blastic eosinophils was over 90%. The eosinophils expressed CD7/13/33/34/DR, and the karyotype demonstrated 47,XX,+8. The fusion gene of FIP1-LP/PDGFRalpha in peripheral blood was negative. As plural effusion due to the underlying disease progressively worsened, she was given prednisolone and hydroxyurea, but the effect was limited. Steroid pulse therapy and imatinib (100 mg/day) were administrated. As a result, a prompt response was observed. The WBC count rapidly decreased, but tumor lysis syndrome led to acute renal failure and disseminated intravasucular coagulation appeared. Supportive therapies such as artificial dialysis and transfusions were conducted, but unfortunately she died because of alveolar hemorrhage.

Rheumatoid arthritis (RA) is an autoimmune disease mediated by inflammatory processes mainly at the joints. Recently, awareness of Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disorder (T-LPD) has been heightened for its association with methotraxate usage in RA patients. In the contrary, acute myeloid leukemia with multilineage dysplasia (AML-MLD) has never been documented to be present concomitantly with the above two conditions. In this report we present a case of an autopsy-proven co-existence of AML-MLD and EBV-associated T-LPD in a patient with RA.

Multiple myeloma (MM) is a neoplasm of plasma cells that often remains fatal despite the use of high-dose chemotherapy with hematopoietic stem cell transplantation. In the clinical setting, the introduction of novel agents, such as proteasome inhibitors and immunomodulatory drugs, has improved the clinical outcomes of both patients with newly diagnosed MM and patients with advanced MM. However, most patients eventually relapse and develop drug resistance. T-LAK cell-originated protein kinase (TOPK), also known as PDZ-binding kinase (PBK), is a mitogen-activated protein kinase kinase (MAPKK)-like serine/threonine kinase that plays a critical role in many cellular functions, such as cell proliferation, apoptotic cell death, and inflammation, in normal tissues. Because the expression of TOPK is up-regulated during mitosis and is activated by the Cdk1/cyclin B1 complex, TOPK is thought to have a role in cytokinesis. While the expression of TOPK is very low in most normal human tissues except for testis and placenta, it is overexpressed in various malignant neoplasms, indicating its crucial role in tumorigenesis. Phosphorylation of TOPK leads to the activation of the MAPK signaling pathway including p38 and Ras extracellular signal-regulated kinase (ERK). Moreover, TOPK interacts with p53 tumor suppressor protein and inhibits its function. Ribosomal protein S6 kinase (RSK2) is a downstream target of the ERK/MAPK signaling cascade and it has a pivotal role in cell survival and proliferation. Recent studies suggest that RSK2 inhibition induces apoptotic cell death and sensitizes MM cells to lenalidomide. Suppression of p53 function is also involved in MM progression. Taken together, these data suggest that TOPK might be an attractive target for new therapeutic agents against this incurable hematological malignancy. HI-TOPK-032, which is a potent and specific inhibitor of TOPK, occupies the ATP-binding site of TOPK and thereby suppresses TOPK kinase activity. In the present study, we investigated the role of TOPK/PBK in MM as a potential therapeutic target by using HI-TOPK-032. MTSand trypan blue dye exclusion assays showed that HI-TOPK-032 inhibited the proliferation of various MM cell lines, including U266, RPMI8226, MM1.S, OPM-2, and KMS-11, in a dose- (0 to 10 mM) and time- (0 to 72 h) dependent manner. To examine the mechanisms behind the growth inhibition effect induced by HI-TOPK-032, assays for apoptotic cell death were performed; these assays demonstrated that HI-TOPK-032 induced both early and late apoptosis in MM cells. To investigate the molecular mechanisms of HI-TOPK-032-induced cell death in MM cells, the expression of various cell death-associated proteins and down-stream molecules of TOPK was examined. Western blotting analysis showed that HI-TOPK-032 arrested cell growth and induced apoptotic cell death in MM cells in a dose-dependent manner by reducing t he phosphorylation of ERK and RSK2, thereby reducing the expression of the target molecules of RSK2, i.e., MCL1 and c-Myc. Moreover, HI-TOPK-032 induced p53 expression in a dose-dependent manner. We next examined the effects of HI-TOPK-032 on bortezomib (BTZ)-resistant MM cells, which represent an urgent issue in clinics and for which a therapeutic solution is important. Interestingly, HI-TOPK-032 inhibited the proliferation of both BTZ-sensitive wild-type KMS cells and BTZ-resistant KMS cells, suggesting that BTZ resistance can be overcome by targeting TOPK. Because our results showed that HI-TOPK-032 reduced the phosphorylation of RSK2, and previous studies have suggested that RSK2 inhibition sensitized MM cells to lenalidomide, we next studied the effects of HI-TOPK-032 in combination with lenalidomide on MM cell growth. HI-TOPK-032 and lenalidomide synergisticallyinduced growth arrest in not only lenalidomide-sensitive MM cells, but also in lenalidomide-resistant cells. To determine whether HI-TOPK-032 can re-sensitize BTZ-resistant cells to the anti-MM activity of BTZ, the effects of the combination of HI-TOPK-032 and BTZ were tested using an MTS assay. Interestingly, HI-TOPK-032 was able to re-sensitize BTZ-resistant MM cells to BTZ. These results indicate that the inhibition of TOPK may serve as an attractive therapeutic option for both patients with BTZ- or lenalidomide-resistant MM. In conclusion, these data suggest that TOPK/PBK can be a promising molecular target for the treatment of MM. Disclosures Kizaki: Nippon Shinyaku Co., Ltd.: Research Funding; Ono Phranacutical Co., Ltd.: Consultancy; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Chugai Phrarmaceutical Co., Ltd.: Research Funding.

Background: Substantial efficacy has been demonstrated with bortezomib (Bor)-containing regimens for the treatment of refractory/relapsed (RR) patients with transplant-ineligible (TI) multiple myeloma (MM). However, the dosing schedules for induction therapy and the significance of maintenance therapy using Bor in clinical settings have yet to be standardized. Discontinuations and dose reduction of Bor owing to severe adverse events (AEs) such as peripheral neuropathy (PN) and infection are frequent causes of adjustments to the standard 9 cycles of Bor/dexamethasone (BD) therapy used for induction in clinical practice. We have previously demonstrated that a change in Bor administration to a schedule of weekly or longer intervals had similar or greater efficacy for patients with RR-MM including transplant-eligible (Tokuhira M, et al. Leuk Res. 35:591-7, 2011). To investigate the efficacy of this modified Bor dosing schedule in the treatment focusing of TI-RR-MM, we retrospectively analyzed 22 patients receiving weekly-BD induction followed by a modified schedule of biweekly or longer intervals using Bor as maintenance therapy in a single institution. Methods: Data on the 22 TI-RR-MM patients treated with BD therapy in our institution were retrospectively analyzed. The induction therapy consisted of intravenous injections of Bor (1.3 mg/m2) on days 1, 8, 15, and 22 in combination with dexamethasone (10–20 mg) on days 1 and 2 after Bor infusion, every 5 weeks. After BD induction, Bor maintenance was initiated with a schedule of biweekly or longer intervals. The dose of BD could be reduced based on AEs or other social aspects at the discretion of the treating physician. Overall survival (OS) was defined as the period between BD initiation of treatment to the last follow-up. Results: The median age of patients at the time of BD induction was 72.6 years (range, 49–84 years), and the subtypes of MM were the IgG type in 14 patients, IgA type in 6 patients, and BJP in 2 patients. Twelve patients were men and 10 were women. On the basis of the International Staging System classification, the clinical stage was I in 3 patients, II in 16 patients, and III in 3 patients. The median number of prior treatment regimens was 2.0 (range, 1–6). The median follow-up duration was 4.3 years (inter-quartile range, 3.0–7.8 years). Ten patients were alive, and 12 patients had died at the time of reporting. The median duration from the start of the first line treatment to BD initiation was 1.8 years (range, 0.1–14.8 years). The median number of BD induction cycles was 2.0 (range, 1–6), and 8 patients (36%) achieved a partial response (PR), although the other 14 patients (64%) showed stable disease or only a minimal response. Although AEs such as PN and gastrointestinal tract symptoms developed in 10 of 22 patients during BD induction, all 22 patients could move on to the maintenance phase. The median duration of Bor maintenance was 14.5 months (range, 1.8–76.5 months). Three patients were still receiving maintenance therapy at the time of reporting. Six patients (27.2%) received maintenance therapy for over 2 years, and 3 (13.6%) received it for over 4 years. The median OS was 3.6 years (range, 0.4–6.5 years), and the duration of Bor therapy from induction to the last administration was 2.5 years. The median progression free survival was 1.6 years (range, 0.3–6.5 years). During maintenance therapy, 5 patients achieved a PR. The reasons for cessation of Bor maintenance therapy were AEs in 8 patients and progressive disease in 11 patients. No patient died during Bor administration in this study. Discussion: We retrospectively analyzed 22 TI-RR-MM patients receiving modified BD therapy. Pantani L et al. reported the results of using BD therapy for 85 RR-MM patients, and demonstrated that twice-weekly Bor administration resulted in a clinical response rate of 19% and a median OS of 22 months (Ann Hematol, 2014). Although the clinical response rate in our study was inferior to that of Pantani L et al., the median OS in our study was superior (3.6 years) than those of previous reports. Because the majority of patients in this study were frail or elderly, the early decision to change to maintenance therapy before they developed severe AEs resulted in a good clinical outcome and a longer OS. Continuing BD therapy without a satisfactory molecular response might be an attractive therapeutic approach for TI-RR-MM patients. Disclosures No relevant conflicts of interest to declare.

Multiple myeloma (MM) is a neoplasm of plasma cells that is often fatal, despite the use of high dose chemotherapy and hematopoietic stem cell transplantation. Although new therapeutic approaches, including novel agents such as thalidomide, lenalidomide, and bortezomib (a proteasome inhibitor), are now used clinically and have improved the outcome of patients with MM, most patients eventually relapse, and it remains an incurable disease. Wnt/β-catenin signaling plays a critical role in both cell proliferation and differentiation in normal tissue. β-catenin, a key player and downstream effector in canonical Wnt signaling, is involved in the regulation of cell fate, proliferation, and self renewal of stem cells. The activation of Wnt signaling is aberrantduring the pathogenesis of various malignant neoplasms, and it has been suggested that Wnt/β-catenin signaling is involved in the regulation of cancer stem cells. When the Wnt signaling pathway is activated, stabilized β-catenin translocates to the nucleus, where it interacts with T-cell factor, followed by transcription of target genes such as c-myc, cyclin D1 and survivin. Nuclear β-catenin also recruits the co-activator, cyclic AMP response element-binding protein (CBP), which is essential for hematopoietic cell proliferation and hematopoietic stem cell self renewal, or its related homolog p300, which is involved in hematopoietic cell differentiation. Recent studies have shown that CBP and p300 have distinct functions in the regulation of β-catenin expression: CBP promotes β-catenin expression, whereas p300 inhibits β-catenin expression. In the context of hematological malignancies, β-catenin is overexpressed in myeloma-derived cell lines and primary myeloma cells, whereas expression is very low in normal plasma cells. Myeloma cells are maintained by several growth factors and cytokines, including Wnt ligands secreted by stromal cells in the bone marrow. These data suggest that Wnt/β-catenin signaling contributes to the pathogenesis of MM and thus might be a promising target for the treatment of this incurable hematological malignancy. Moreover, it has been reported that CBP, rather than p300, plays an important role in the expression of apurinic endonuclease/redox factor-1, an important regulator of multidrug resistance, in retinoic acid-induced chemo-resistant myeloma cells, suggesting that CBP is involved in the acquisition of drug resistance. Taken together with the previous data, Wnt/β-catenin signaling, especially CBP, might be an attractive target for new therapeutic agents against MM. ICG-001, small-molecule inhibitor of the canonical Wnt signaling pathway, specifically binds to CBP, thereby disrupting CBP/β-catenin interaction. In the present study, we investigated the role of Wnt/β-catenin signaling in myeloma cells using ICG-001. MTS and trypan blue dye exclusion assays showed that ICG-001 inhibits the proliferation of U266, RPMI8226, and KMS myeloma cell lines in a dose- (0-15 μM) and time- (0-72 h) dependent manner. Assays for apoptotic cell death were performed to determine the cause of growth inhibition by ICG-001 and demonstrated that ICG-001 induced both early and late apoptosis in myeloma cells. To investigate the molecular mechanisms of ICG-001-induced cell death in myeloma cells, the expression of various cell-death associated proteins and down-stream molecules of Wnt/β-catenin signaling was examined. Western blotting analysis showed that ICG-001 arrested cell growth and induced apoptotic cell death in myeloma cells by reducing the expression of three β-catenin target molecules: survivin, cyclin D1, and c-Myc. We next examined the effects of ICG-001 on bortezomib (BTZ)-resistant MM cells. BTZ resistance is an urgent issue in clinics, and therapeutic approaches for overcoming BTZ resistance are important. Interestingly, ICG-001 inhibited the proliferation of both BTZ-sensitive wild-type KMS and BTZ-resistant KMS cells, suggesting that targeting CBP may overcome BTZ-resistance. Furthermore, when combined with cyclosporine, which inhibits non-canonical Wnt/β-catenin signaling, ICG-001 synergistically induced the growth arrest of myeloma cells by inducing apoptotic cell death. These results indicate that inhibition of Wnt/β-catenin signaling may be an attractive therapeutic option both for patients with newly diagnosed MM and for those in a refractory or relapsed state. Disclosures No relevant conflicts of interest to declare.

Abstract 2939 Multiple myeloma (MM) remains incurable despite the use of conventional and high-dose chemotherapy with stem cell transplantation. However, novel agents such as thalidomide, lenalidomide, and bortezomib have already achieved promising clinical results. In particular, bortezomib, a proteasome inhibitor, is widely used in the treatment of MM and has remarkable clinical effects in both refractory/relapsed and newly diagnosed patients. However, acquired drug resistance and serious toxicities such as peripheral neuropathy are often triggered by bortezomib in the clinical settings. Therefore, novel targeted agents with less toxicity are necessary to overcome bortezomib-resistance and improve clinical outcomes in MM. We have previously reported that 1'-acetoxychavicol acetate (ACA), a component of a traditional Asian condiment obtained from the rhizomes of the commonly used ethno-medicinal plant Languas galanga, has an inhibitory effect on NF-κB, and induces cell death in MM cells both in vitro and in vivo (Cancer Res, 2005; 65: 4417). With the aim of discovering more potent NF-κB inhibitors, we subsequently developed several ACA analogs based on quantitative structure-activity relationship (QSAR) analysis. This showed that a novel benzhydrol-type analog of ACA (TM-233) exhibited greater inhibition of NF-κB activity in MM cells when compared with ACA. In the present study, we examined the effects of TM-233 on various MM cells, including those resistant to bortezomib and we investigated the molecular mechanism of TM-233-induced cell death in these cells. TM-233 inhibited cell proliferation and induced cell death in various MM cell lines (U266, RPMI8226, and MM-1S cells) in a time (0–48 hours)- and dose (0–5 μM)- dependent manner. Similarly potent activity was observed against primary MM cells. Exposure of bone marrow mononuclear cells from 3 patients with MM to TM-233 revealed selective activity under the same conditions as for cell lines. Moreover, TM-233 did not inhibit colony formation in CD34-positive cells from human umbilical cord blood; therefore, TM-233 did not influence the normal blood cells. We next investigated the effects of TM-233 on the various signaling pathways including JAK/STAT and NF-κB in MM cells. TM-233 activated apoptosis-related caspase-3, -8, -9, and PARP, suggesting that cell death related to TM-233 is mediated by both mitochondrial- and Fas-dependent pathways. Furthermore, treatment with TM-233 inhibited constitutive activation of JAK2 and STAT3, and then downregulated the expression of anti-apoptotic Mcl-1 protein, but not that of Bcl-2 and Bcl-xL proteins. TM-233 directly bound and activated the transcription of the Mcl-1 gene promoter, suggesting that TM-233-induced cell death in MM cells down-regulated Mcl-1 via modulation of the JAK/STAT pathway. In addition, the DNA-binding activity of NF-κB in MM cells was inhibited by the treatment of TM-233. Further, TM-233 rapidly decreased the nuclear expression of NF-κB, but increased the accumulation of cytosol NF-κB, suggesting that TM-233 inhibits the translocation of NF-κB from the cytosol to the nucleus. These results indicate that TM-233 induced cell death in MM cells occurs via both JAK/STAT and NF-κB pathways. We finally examined the effects of TM-233 on bortezomib-resistant MM cells. We have recently established the bortezomib-resistant MM cell lines, KMS-11/BTZ and OPM-2/BTZ (Leukemia 2010; 24: 1506). We found that these cells have a unique point mutation, G322A, in the gene encoding the proteasome b5 subunit, resulting in bortezomib-resistance mediated through prevention of the accumulation of unfolded proteins and fatal ER stress. TM-233, but not bortezomib, inhibited cellular proliferation and induced cell death in KMS-11/BTZ and OPM-2/BTZ cells in a time- and dose-dependent manner. Interestingly, the combination of TM-233 and bortezomib significantly induced cell death in these bortezomib-resistant MM cells via inhibition of NF-κB activity. These results indicate that TM-233 could overcome bortezomib resistance in MM cells by acting according to a different mechanism from that of bortezomib, possibly inhibition of the JAK/STAT pathway. In conclusion, TM-233, a novel analog of ACA, might be a more potent NF-κB inhibitor than ACA and could overcome bortezomib-resistance in MM cells. Further studies investigating clinical applications are necessary and may yield interesting results. Disclosures: Iida: Janssen Pharmaceutical K.K.: Honoraria. Kizaki:Janssen Pharmaceutical K.K.: Honoraria.

Abstract 3837 Poster Board III-773 Multiple myeloma (MM) is a plasma cell malignancy that remains incurable despite the use of conventional chemotherapy. Recent advances in the field of cell biology could lead to new therapeutic agents based upon molecular targeting, such as thalidomide and proteasome inhibitor bortezomib. These agents have remarkable activity against both newly diagnosed and refractory patients with MM, but prolonged exposure to them may result in the development of de novo drug resistance. Thus, it is necessary to identify and validate novel agents with less toxicity to overcome drug resistance and to improve the clinical outcome of MM. Progression and chemoresistance are thought to involve IL-6, whose expression is induced by NF-κB, through its regulation of the growth and survival of MM cells. IL-6 leads to constitutive activation of STAT3, which in turn results in the expression of high levels of Mcl-1. Thus, the constitutive activation of both NF-κB and STAT3 plays an important role in MM cell proliferation, and both molecules are important targets for the treatment of MM. Auranofin (AF: RIDAURA®; GSK) is a coordinated gold compound that has been widely used for the treatment of rheumatoid arthritis based on its anti-inflammatory properties through the inhibition of NF-κB activation. Therefore, assuming that AF has the potency to induce apoptosis in MM cells by interfering with NF-κB and STAT pathways, it may become a candidate for a novel therapeutic agent. To address our hypothesis, the effects of AF on inducing apoptosis of various MM cells were examined. Further, the molecular mechanism of AF-induced apoptosis in MM cells was investigated. AF inhibited the growth of U266 cells in a time- and dose-dependent manner with IC50 of 50 nM at 24 h. AF significantly induced cell cycle arrest at the G1 phase and subsequent apoptosis of U266 cells. AF-induced apoptosis in various human MM cell lines and CD138-positive plasma cells from patients with MM involved the activation of caspases-3, -8, and -9. Treatment with AF inhibited the constitutive and IL-6-induced activation of STAT3, and then downregulated the expression of Mcl-1 but not that of Bcl-2 or Bcl-xL proteins. To clarify the biological significance of Mcl-1 in AF-induced apoptosis of MM cells, Mcl-1 expression vector (pEGFP-hmcl-1) and control vector were introduced into U266 cells (designated as U266/mcl and U266/neo cells). Induction of apoptosis by AF was abrogated in U266/mcl, but not in U266/neo cells. We next examined the effect of AF on the DNA binding activity of STAT3. Electrophoretic mobility gel shift assay (EMSA) using U266 nuclear extracts demonstrated that IL-6-induced STAT3 binding activity was inhibited by the presence of AF. These results suggest that AF inhibits the IL-6-induced JAK/STAT pathway selectively and induces apoptosis in MM cells via the downregulation of Mcl-1. In addition, AF downregulated the activation of NF-κB in an IκB-independent manner, and also inhibited DNA binding activity in U266 cells. Although NF-κB inhibitory peptide (SN-50) did not directly induce the expression of Mcl-1, the combination of SN-50 with AF reduced the levels of Mcl-1, suggesting that inhibition of NF-κB potentiates the apoptotic effect of AF. Finally, our in vitro data prompted us to examine whether or not the effects of AF are equally valid in a clinical settings. The protocol for assessing the clinical benefit of oral administration of AF (RIDAURA®) in patients with relapsed or refractory MM was approved by the Ethics Committee of Saitama Medical University. Since 2008, 7 patients with refractory MM were treated with oral RIDAURA® 6 mg daily. The median follow-up for patients was 7.5 months. All 7 patients responded to AF, including one PR (partial response) and 6 SD (stable disease) with no progression. No adverse events have been observed to date. Details of the clinical outcome will be presented. In conclusion, gold compound AF inhibited constitutive activation of both STAT3 and NF-κB, resulting in the downregulation of anti-apoptotic Mcl-1 protein in MM cells with clinical relevance. A low pharmacological concentration (50 nM) of AF is widely employed for the treatment of rheumatoid arthritis without any side effects; therefore, it may be used to treat MM without the risk of severe toxicity. We propose that AF (RIDAURA®) may have potential use as a new molecular-targeted agent for the treatment of MM. Disclosures: Off Label Use: Auranofin in the treatment of multiple myeloma.