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We retrospectively analyzed the clinical features and outcomes in a real-world cohort of adolescents and the young adult (AYA) patients (age between 16 and 39 years) with symptomatic multiple myeloma (MM) registered with the Kansai Myeloma Forum. 26 patients had been diagnosed as symptomatic MM out of 3284 patients. The prevalence of AYA-MM was 0.8% in this cohort. 81% of the patients was received stem cell transplantation, which may improve outcome. Anemia and hypercalcemia might be prognostic factors, however International Staging System failed to predict overall survival. Five patients developed late-onset adverse events which were serious and life-threatening. The 5-year overall survival was 71.0%. We need to develop the new strategy to overcome AYA-MM.

Objectives Although phase 2 studies have confirmed the efficacy of mogamulizumab for adult T-cell leukemia/lymphoma (ATL), real-world data on its benefits are limited. We assessed the benefits of mogamulizumab for relapsed/refractory ATL in clinical practice. Methods We retrospectively analyzed patients with acute- and lymphoma-type ATL. Among 57 patients diagnosed with ATL between January 2008 and August 2018, 42 who received salvage therapy were eligible, including 24 who received mogamulizumab. Results The overall response rate to mogamulizumab was 54.2%. Median survival time (MST) and 1-year overall survival (OS) rate from mogamulizumab initiation were 7.7 months and 42.0%, respectively. Patients with acute-type ATL showed longer MST (15.1 months) and higher 1-year OS (63.6%). MST without skin rash was 5.0 months, and 1-year OS was 34.3%; however, MST with skin rash was not reached and 1-year OS was 66.7%. Among patients who received the salvage therapy, longer MST and higher 1-year OS were observed with mogamulizumab than without mogamulizumab (P = .078; 9.2 vs. 3.9 months; 47.9% vs. 17.6%, respectively). Mogamulizumab administration improved prognosis in patients with acute-type ATL and skin rash. Conclusions In clinical practice, mogamulizumab improved OS in patients with relapsed/refractory ATL, especially those with acute-type ATL and skin rash.

We retrospectively analyzed 51 patients with solitary plasmacytoma diagnosed from October 2002 to September 2018 from a cohort of 3575 patients with plasma cell dyscrasias registered in the Kansai Myeloma Forum. Twenty-seven patients had solitary bone plasmacytoma (SBP) and 24 had extramedullary plasmacytoma (EMP), with prevalence of 0.8% and 0.7%, respectively. The most frequent M protein was IgG (40%) in SBP, whereas non-secretory proteins were most frequent (50%) in EMP. Five-year overall survival was 78.2% in SBP and 80.8% in EMP (P = 0.894). Among patients with SBP, 44% progressed to MM with a median time of 10.5 months (2.4–93.3 months), whereas 8% of EMP patients progressed to MM with a median time of 18.6 months (13.0–24.2 months). The most frequent treatment was radiotherapy (41%) or observation (41%) in SBP, and chemotherapy (54%) in EMP. No statistically significant difference was observed upon univariate analysis of prognostic factors including age, sex, performance status, and IgG M protein. Our results suggest that there are biological differences between SBP and EMP in real-world settings.

Anagrelide is widely used for cytoreductive therapy in patients with essential thrombocythemia who are at high risk for thrombosis. The recommended starting dose in the package insert of anagrelide varies by country. A high starting dose leads to an early onset of action, but causes a higher incidence of adverse events. This relationship indicates that both the onset of action and side effects of anagrelide are dose dependent. We retrospectively compared the efficacy and safety of anagrelide as a first-line drug between patients with essential thrombocythemia who started at 0.5 or 1.0 mg/day. Incidence of total adverse events and anagrelide-related palpitation, discontinuation rates, and the median daily dose of anagrelide were lower in the 0.5 mg/day group than in the 1.0 mg/day group; however, comparable platelet-lowering effects were achieved in both groups. These data suggest that a low starting dose of anagrelide followed by dose escalation may result in fewer adverse events and lower discontinuation rates, while providing desirable platelet-lowering effects. Initiating anagrelide at a lower dose may be a useful approach in actual clinical practice.

We report six cases of autoimmune acquired coagulation factor VIII deficiency, which is a rare bleeding disorder. It is an autoimmune disease, however, there are various causes. We experienced cases with malignancy, co-exist with another autoimmune disease, pregnancy, and unknown epidemiology with repeated bleeding episode. All patients were controlled the acute bleeding phase and they have been under treatment with immunosuppression.

Objectives This study aimed to investigate real-world data of ixazomib plus lenalidomide and dexamethasone (IRd) therapy for patients with relapsed and refractory multiple myeloma (RRMM). Methods We retrospectively analyzed 122 patients treated with IRd at 16 centers from May 2017 to January 2019 by using the Kansai Myeloma Forum database. Result At the start of IRd, the median age was 72 years, 66.7% of patients had IgG type, and the median number of prior therapies was 4, comprising bortezomib (85.4%) and lenalidomide (89.3%)-based regimens. Disease progression and adverse events accounted for treatment discontinuation in 46 and 32 patients, respectively. The median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 11.9 months. Sensitivity to bortezomib did not affect the PFS, whereas lenalidomide-refractory patients had significantly lower PFS than lenalidomide-sensitive patients, who were comparable to TOURMALINE-MM1 study. The patients with IgG type had significantly better PFS and OS than those with non-IgG type. Conclusion This study presents the largest real-world data of patients treated with IRd in Asia. However, in real clinical practice, the patient background is different from the TOURMALINE-MM1 study, and IRd showed poor efficacy, especially in the non-IgG type and lenalidomide-refractory patients with RRMM.

Shosaku Nomura,Tomoki Ito,Hideaki Yoshimura,Masaaki Hotta,Takahisa Nakanishi,Shinya Fujita,Aya Nakaya,Atsushi Satake,Kazuyoshi Ishii First Department of Internal Medicine, Kansai Medical University,Osaka, Japan Background: Thrombosis is one of the complications in the clinical course of multiple myeloma (MM). Vascular endothelial cells and/or the hemostatic-coagulatory system are thought to play an important role in thrombosis of MM. In addition to melphalan-prednisone (Mel-P) therapy, several new therapeutic drugs such as lenalidomide or bortezomib have been developed and show effectiveness against MM. However, these new drugs also have risk of therapy-related thrombosis.Methods: We assessed 103 MM patients and 30 healthy controls, using enzyme-linked immunosorbent assays to evaluate five biomarkers: platelet-derived microparticles (PDMP), plasminogen activator inhibitor-1 (PAI-1), high mobility group box protein-1 (HMGB1), endothelial protein C receptor (EPCR), and soluble vascular cell adhesion molecule-1 (sVCAM-1). The effects of Mel-P, bortezomib, and lenalidomide on the plasma concentrations of these biomarkers were investigated.Results: The plasma concentrations of PDMP, PAI-1, HMGB1, EPCR, and sVCAM-1 were higher in MM patients than in healthy controls. Mel-P, bortezomib, and lenalidomide therapies all reduced biomarker levels after treatment. However, when only patients with higher levels of EPCR were compared, differences were seen between the three therapies in the elevation of PDMP, HMGB1, and PAI-1.Conclusion: These results suggest that both MM and therapies for MM can induce a hypercoagulable state. The elevated risk of thrombosis conferred by hypercoagulability increases patient morbidity and mortality. Attention should be paid to therapy-related thrombosis when new therapeutic regimens are selected for MM patients.Keywords: multiple myeloma, bortezomib, lenaridomide, thrombosis, biomarker

Highlights • The prevalence of pPCL was 1.2%. • Treatment with novel agents and transplantation may yield a better prognosis. • Hypercalcemia at diagnosis was suggested to predict worse outcomes., We retrospectively analyzed twenty-six patients with primary plasma cell leukemia (pPCL) registered from May 2005 until April 2015 by the Kansai Myeloma Forum. Twenty patients received novel agents (bortezomib or lenalidomide), and their median survival of was 34 months. The median survival of patients who underwent autologous stem cell transplantation (SCT) was 40 months, those undergoing allogeneic SCT 55 months, and those undergoing both types of SCT (auto–allo) 61 months; whereas for those who did not undergo SCT it was 28 months (p = 0.845). The only statistically significant risk factor identified by multivariate analysis was hypercalcemia.

Highlights • Patient with chronic myeloid leukemia in the chronic phase developed myodesopsia. • Patient was in molecular response in bone marrow. • It was an isolated central nervous system blast crisis., A 49-year-old woman diagnosed with chronic myeloid leukemia in the chronic phase was started on dasatinib treatment, after which she complained of myodesopsia. Nineteen months after diagnosis, the patient again complained of myodesopsia and developed bilateral optic neuritis. Cerebrospinal fluid analysis revealed an increase in blasts, although peripheral blood and bone marrow examination confirmed that the patient remained in a molecular response to tyrosine kinase inhibitor (TKI) therapy. The patient was diagnosed with an isolated central nervous system blast crisis, a rare occurrence with second-generation TKI therapy, and the initial presentation of myodesopsia represented a symptom of this condition.

Highlights • The use of eltrombopag was expanded to cover AA in Japan in August 2017. • The overall response rate was 55% (6/11). • Four patients had recovery of all three cell lineages, and two patients had only neutrophil recovery. • Stage at the initial assessment, the neutrophil-to-lymphocyte ratio and platelet counts were significantly different between the responders and non-responders., Background Although eltrombopag has recently been approved for treating AA, the effects of its clinical use remain unknown. Methods We retrospectively analyzed 11 patients with AA, who had been treated with eltrombopag from August 2017 to May 2018. Results Overall response rate was 55%. There was tri-lineage recovery in four patients and platelet recovery in two. The reactive time was within 8 weeks after treatment initiation. Stage at the initial assessment, the neutrophil-to-lymphocyte ratio and platelet counts were significantly different between the responders and non-responders. Conclusion Eltrombopag is a promising agent for treating patients with any degree of AA.

Lenalidomide is an immunomodulatory drug administered orally in the treatment of multiple myeloma. Some elderly patients require a reduced lenalidomide dose because of comorbidities and/or adverse events. This study investigated the actual dose of lenalidomide in elderly patients, finding that most received reduced (5-10 mg) doses. The most common reasons for dose reduction were renal dysfunction (54% of patients), fatigue (grade ≥3; 20%), hematologic disorder (grade ≥3; 14%), and rash (grade ≥3; 9%). Their median time to progression was 11.8 months and their median overall survival was 39.2 months. The overall response rate was 73%, including 17% with a complete response, 19% with a very good partial response, and 37% with a partial response. These results showed that, contrary to western countries, most patients were treated with a reduced dose of lenalidomide in Japan. However, it is suggested that continued treatment with a tolerable dose may yield favorable outcomes.

Hideaki Yoshimura, Masaaki Hotta,Takahisa Nakanishi, Shinya Fujita,Aya Nakaya,Atsushi Satake,Tomoki Ito,Kazuyoshi Ishii,Shosaku Nomura First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan Background: Biosimilar granulocyte colony-stimulating factor (G-CSF) has recently been introduced into clinical practice. G-CSFs are used to mobilize CD34+ cells and accelerate engraftment after transplantation. However, in Asia, particularly in Japan, data for peripheral blood stem cell (PBSC) mobilization by this biosimilar G-CSF are currently lacking. Therefore, the clinical efficacy and safety of biosimilar G-CSF for hematopoietic stem cell transplantation needs to be evaluated in a Japanese context.Materials and methods: The subjects included two groups of patients with malignant lymphoma and multiple myeloma. All patients received chemotherapy priming for the mobilization of PBSCs. All patients were treated with chemotherapy followed by the administration of either the biosimilar G-CSF, filgrastim XM02 (FBNK), or the originators, filgrastim, or lenograstim.Results: There were no significant differences among FBNK, filgrastim, and lenograstim treatments in the numbers of CD34+ cells in harvested PBSCs, the scores for granulocyte/macrophage colony forming units, or for malignant lymphoma and multiple myeloma patients evaluated as separate or combined cohorts. In addition, there were no significant differences in safety, side effects, complications, or the time to engraftment after autologous hematopoietic stem cell transplantation.Conclusion: Biosimilar FBNK shows the same efficacy and safety as originator G-CSFs for facilitating bone marrow recovery in Japanese malignant lymphoma and multiple myeloma patients undergoing stem cell transplantation. In addition, it is less expensive than the originators, reducing hospitalization costs. Keywords: G-CSF, biosimilar, peripheral blood stem cell, hematological malignancy, autologous hematopoietic stem cell transplantation

Pure red cell aplasia (PRCA) is a rare disorder characterized by marked erythroid hypoplasia with maturation arrest in the bone marrow. Secondary acquired PRCA may be associated with hematologic disorders. A few case reports have described PRCA associated with multiple myeloma (MM). However, the clinical course and mechanism of PRCA associated with MM remain unknown. We herein report two cases of PRCA associated with MM in patients undergoing treatment with lenalidomide. Keywords: Pure red cell aplasia, Multiple myeloma, Lenalidomide

We report the case of a man who developed myelodysplastic syndrome (MDS) and refractory cytopenia of unilineage dysplasia, 5 months after aortic valve replacement surgery. He also developed fever of unknown origin. After bone marrow- and other laboratory examinations, he was diagnosed with tuberculosis.

A 63-year-old man was diagnosed with a rare variant of acute promyelocytic leukemia (APL) with t(4;17)(q12; q21) that showed atypical morphological features and two different clinical symptoms. He was started on standard induction chemotherapy for acute myeloid leukemia, which decreased myeloblast numbers; however, APL-like blasts remained. He then received a salvage therapy that added all-trans retinoic acid (ATRA). After ATRA commenced, APL-like blasts disappeared and cytogenetic analysis became normal. However, myeloblasts subsequently increased, and he became resistant. In summary, this patient exhibited two different clinical courses of acute myeloid leukemia and APL.

Background: Neutrophil-to-lymphocyte ratio (NLR) has been recognized as a poor prognostic indicator in various solid tumors. Methods: We retrospectively analyzed 530 patients with de novo DLBCL who were diagnosed from April 2002 to November 2017. Results: The median age of patients was 69 (range, 20–95) years, and 59% were male. The optimal cutoff for NLR was 5.2. NLR (5.2) was not associated with overall and progression free survival. Conclusion: Our study failed to reveal the predictive value of NLR and demonstrated that the NCCN-IPI might be the most powerful predictor in DLBCL. Keywords: Neutrophil-to-lymphocyte ratio, Diffuse large B cell lymphoma, NCCN-IPI

In a canine model of pre-sensitization using donor blood transfusions, 100% of historical control dogs receiving 9.2 Gy total body irradiation (TBI) conditioning before dog leukocyte antigen (DLA)-identical marrow grafts had graft rejection. In this pre-sensitization model, we investigated whether the addition of monoclonal antibody (mAb)- based targeted radioimmunotherapy (RIT) with astatine-211 ((211)At) to TBI could overcome graft rejection. (211)At is an alpha-particle-emitting isotope, which has a short path length, very high energy, and a short t 1/2 of 7.2 hours, which allowed targeting radiation to the T cells responsible for graft rejection. Normal canine recipients were given three preceding transfusions of unirradiated whole blood on days -24, -17, -10 before transplant from their DLA-identical marrow donors. (211)At-anti-CD45 mAb was administered on day -3, and TBI followed by marrow grafts on day 0. Six of the seven dogs (86%) achieved sustained engraftment as assessed by 100% donor chimerism in mononuclear cells, granulocytes, and CD3(+) T cells. One dog receiving the lowest CD34(+) cell content (0.35 × 10(6) cells/kg) rejected the graft. There were no late rejections in dogs followed up to one year. Graft-versus-host disease (GVHD) was seen in one dog. (211)At-anti-CD45 mAb in combination with TBI as conditioning was successful in abrogating graft rejection in 86% of dogs in this pre-sensitization model. (211)At-anti-CD45 mAb conditioning with TBI may serve as a novel promising strategy to overcome graft rejection in heavily transfused patients with red cell disorders.

Reactivation of hepatitis B virus (HBV) infection is a well-recognized and potentially fatal complication in patients treated with chemotherapy for lymphoid malignancies. Although several guidelines recommend antiviral prophylaxis and/or monitoring for HBV-DNA, there is no consensus over what time period these should occur. Clinically, we have encountered delayed reactivation of HBV infections and have reported 12 cases of reactivation in patients. Among them, five patients developed HBV reactivation more than a year after they completed their chemotherapy. This means there can be a delayed HBV reactivation and prolonged monitoring of more than a year after cessation of chemotherapy may be needed. Hence, the current recommendation of stopping antiviral prophylaxis 6-12 months after the cessation of chemotherapy may not fully protect all patients from HBV reactivation. The optimal duration of follow-up needs to be determined, and until better guidelines are set, there is no choice but to keep monitoring patients for reactivation for as long as practicable.

A humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, mogamulizumab (MOG), has been shown to be safe and effective in the treatment of relapsed/refractory adult T-cell leukemia/lymphoma (ATLL). MOG depletes ATLL cells as well as regulatory T cells (Tregs), as CCR4 is expressed on these cells as well. In this context, pretransplant treatment with MOG may induce severe graft-versus-host disease (GVHD) in allogeneic hematopoietic stem-cell transplantation (HSCT). However, the influence of MOG on allogeneic HSCT, including its induction of GVHD, is unclear. In this report, we describe two patients treated with MOG who subsequently underwent allogeneic HSCT. They did not develop severe GVHD or treatment-related complications. In addition, we examined the kinetics of Tregs in the second case. Finally, we suggest that the detrimental effects of MOG can be avoided, which should be prospectively evaluated in future studies.

The acronym CRAB summarizes the most typical clinical manifestations of multiple myeloma, these being hypercalcemia, renal failure, anemia, and bone disease. CRAB can be used to distinguish between active, symptomatic multiple myeloma and monoclonal gammopathy of undermined significance or smoldering myeloma. The distinction is relevant not only for classification and diagnosis but also for therapy. CRAB factors influence the prognosis of multiple myeloma. However, it is unclear whether the presence of CRAB factors has an influence on the prognosis of myeloma treated with novel agents. In the current study, patients with hypercalcemia and bone disease showed a significantly worse prognosis, whereas anemia and renal failure showed no difference in survival. Novel agents used for treatment of patients with renal failure suggested a favorable outcome compared with conventional therapy. Bone disease was the most common factor and may have the strongest prognostic value in symptomatic myeloma patients using novel agents.

Dasatinib is currently approved for clinical use as a first-line treatment agent for newly diagnosed chronic myeloid leukemia (CML). However, only a few clinical trials have been performed to evaluate dasatinibinduced PE following first-line therapy. We investigated the incidence and clinical features of dasatinib-induced PE following first-line therapy in Japanese CML patients of real world clinical practice settings. Among 22 patients, the median age of PEpositive patients was higher than that of PEnegative patients. Major molecular response was achieved in 75% of PE-positive patients and 50% of PE-negative patients. Most patients developed PE more than 1 year after treatment. Appearance of PE is associated with better clinical response during dasatinib treatment, however it is developed at any time. Elderly and high-risk patients tend to develop PE. The clinical features of dasatinib-induced PE following first-line therapy might be late onset and might not immediately follow the increasing of large granular lymphocyte.

Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication of organ transplantation. Progress has recently been made in the pathological classification of PTLD. However, the clinical course has not been clarified because of the rarity of this disease. We experienced a case of PTLD with a fulminant clinical course. The patient had been under longterm immunosuppressive treatment for aplastic anemia. He received related allogeneic hematopoietic stem cell transplantation. Soon after transplantation, he developed PTLD. According to the guidelines, we reduced immunosuppression. However, the disease course was so fulminant that there was no time for the patient to respond, and he died of multi-organ failure. There may be various clinical types of PTLD, which may include some fulminant cases. In such a case, it is not sufficient to reduce immunosuppression. The patient should be carefully observed and an appropriate individual treatment should be chosen.

The correlation between human T-cell leukemia virus type І (HTLV-І) infection and malignant neoplasms other than adult T-cell lymphoma (ATL) remains unknown. We analyzed the frequency of primary malignant neoplasm in HTLV-І-seropositive patients. From January 2006 to December 2016, 203 patients were diagnosed as HTLV-І-seropositive at Kansai Medical University Hospital. Among them, 32 developed a primary malignant neoplasm. Their median age was 64 years old, 63% of them were male, and 69% of them were HTLV-I carriers. This group had the following distribution of ATL subtypes: 31% smoldering type, 0% chronic type, 3% acute type, and 3% lymphoma type. Among them, 53% was hematology malignancy, and solid tumor was 47%. The most frequent type of hematological malignancy was T-cell lymphoma (23%), followed B-cell lymphoma (16%), and myelodysplastic syndromes (6%). The most frequent primary solid tumor locations were the lung (15%), followed by the colon (9%), prostate (6%), kidney (6%), cervix (2%), breast (2%), liver (2%), pancreas (2%), and oral cavity (2%). Our results suggest that HTLV-Іinfection is often associated with the development of other malignant neoplasms. Therefore, HTLV-І-positive patients should be made aware of their increased risk for the onset of a malignant neoplasm and undergo increased surveillance.

To evaluate the National Comprehensive Cancer Network (NCCN) International Prognostic Index (IPI), we analyzed 284 patients treated with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in our institution in Japan. Their 5-year overall survival (OS) by risk level was 80.7%, 74.8%, 55.4% and 67.5% (P=0.005); and their 5-year progression-free survival (PFS) was 76.8%, 78.6%, 63.7% and 58.3% (P=0.0722). The NCCN-IPI is a simple scale that uses conventional clinical factors, but did not reflect survival in our cohort. The NCCN-IPI may require further evaluation for different regions and ethnicities before adopting it for routine clinical use., Highlights • The NCCN-IPI is developed to predict survival in the rituximab era. • The NCCN-IPI failed to predict survival in our cohort. • The NCCN-IPI may require further evaluation before routine clinical use.

A 69-year-old man with chronic-phase chronic myeloid leukemia was initially treated with 100 mg dasatinib once a day. Despite a major molecular response within 9 months, he developed hemorrhagic colitis 32 months after starting dasatinib. Colonoscopy identified multiple hemorrhagic ulcers in the transverse colon. The pathological findings indicated cytomegalovirus infection. Dasatinib was stopped and he was started on ganciclovir. Three months later, colonoscopy confirmed the disappearance of the hemorrhagic ulcers. Dasatinib is a second-generation tyrosine kinase inhibitor used to treat chronic myeloid leukemia. As a multi-kinase inhibitor that acts on SRC-family kinases, its broader off-target kinase-inhibitory activity may account for the adverse events of dasatinib. Although gastrointestinal bleeding is common in patients taking dasatinib, the combination of cytomegalovirus infection and hemorrhagic colitis in the absence of systemic immunodeficiency is rare. Based on this case of dasatinibinduced hemorrhagic colitis with cytomegalovirus infection, we describe a possible mechanism and effective treatment.

Background There is an unmet need to identify markers that predict the response to nivolumab in patients with non-small-cell lung cancer (NSCLC). The neutrophil-to-lymphocyte ratio (NLR) was recently recognized as an indicator of a poor prognosis in patients with various cancers. In the present study, we quantified the predictive impact of NLR in patients with NSCLC treated with nivolumab. Methods We retrospectively analyzed 101 patients with advanced NSCLC treated with nivolumab at Kansai Medical University Hospital from December 2015 to December 2016. Patients were administered nivolumab at a dose of 3 mg/kg every 2 weeks. The predictive value of NLR for disease progression before treatment and 2 and 4 weeks after nivolumab treatment was assessed. Results The median progression-free survival (PFS) of patients with an NLR of

Determinants of the efficacy and safety of pomalidomide (POM) monotherapy or POM plus dexamethasone (DEX) (POM/DEX) for relapsed and refractory multiple myeloma (RRMM) were examined retrospectively in a real-world clinical practice setting in Japan. The subjects were 108 patients registered with the Kansai Myeloma Forum, who were treated with either POM or POM/DEX. Of these, 79 (73%), 73 (68%), and 58 (54%) were resistant to bortezomib (BTZ), lenalidomide (LEN), and both BTZ and LEN, respectively. The median overall survival (OS) was not reached. The median time to treatment failure (TTF) was 4.4 months. The best response was recorded in 96 patients, with a 31% overall response rate (ORR) and a 79% rate of achieving at least stable disease. Number of pre-POM regimens ≥ 5, non-IgG-type M-protein, and time from initial therapy to POM or POM/DEX therapy 2 years were associated with shorter TTF and OS. Frequent ( 10%) severe adverse events included neutropenia (55.1%), thrombocytopenia (33.7%), anemia (30.6%), febrile neutropenia (12.2%), fatigue (11.2%), and anorexia (10.2%). In conclusion, POM and POM/DEX showed substantial efficacy against RRMM, but new combination therapies with POM are needed to improve efficacy further without causing hematologic toxicities.

Background: Lenalidomide (LEN), as a backbone drug for multiple myeloma (MM), has both direct tumoricidal and immunomodulatory effects in MM. LEN displays immunopotentiating activity, including augmentation of T and natural killer cell function and to induce selective reduction of regulatory T cells. Thus, the immune-based cancer treatments are currently important in MM therapy. Since myeloma cells together with immune cells are immersed in the pathogenic micro-environment, understanding the influence of micro-environment against myeloma cells and immune system may lead to the development of novel treatment strategies for MM. Series of analyses have clarified a functional plasticity of dendritic cells (DCs) to induce Th1 or Th2 response and DCs are pivotal in orchestrating both innate and acquire immune responses also in the anti-tumor immunity. Here, we focused on the effects of myeloma environment to modulate the human myeloid DCs (mDCs), which are the major regulators to induce Th1 or Th2 responses. Soluble form of SLAMF7 (sSLAMF7) is a pivotal environmental component of MM and functions as a self-ligand of myeloma cells. sSLAMF7 has been detected in the serum of patients with MM at higher levels than healthy individuals and therefore may presumably play some roles in pathophysiological condition of MM. To evaluate the functions of soluble factors/components derived from myeloma cells, we analyzed whether supernatants of myeloma cell lines could modulate mDC functions. Methods: Using cell sorting, blood human CD11+ mDCs were isolated from healthy adult volunteers. The DC functions were analyzed after culture for 24 h with supernatant of myeloma cell lines, NCI-H929 (H929) or MM.1R. This study was approved by the Institutional Review Board of Kansai Medical University.Results: We here found that both supernatants of myeloma cell lines, H929 and MM.1R did not affect CD86 expression on mDCs in response to toll-like receptor (TLR)-ligand (R848), but upregulated their CD86 expression in response to Th2-inducing cytokine, thymic stromal lymphopoietin (TSLP). Of note, the supernatants inhibited mDC-derived IL-12 production in response to R848 (p < 0.05: H929; 25-30% of cont. and MM1.R; less than 50 % of cont.), while in response to TSLP, dose-dependently enhanced the Th2-recruiting chemokine CCL17/TARC production (p < 0.05: H929; 130- 210 % of cont. and MM1.R; 120-185 % of cont.), which functions as chemoattractant for memory Th2 cells and contribute to promote humoral response. In addition, we revealed that these capacities were further enhanced by the addition of LEN at clinical in vivo plasma concentration of 1 µM. Thus, MM micro-environment could have the potential to shift DC-mediated response from Th1 to Th2. To clarify whether sSLAMF7 in the supernatant of myeloma cell lines play a role in the Th1/Th2-modulating effect, we calculated the sSLAMF7 concentration in the supernatants and analyzed an inhibitory effect of elotuzumab for the DC function induced by the supernatants. sSLAMF7 could not be detected at all in the supernatants of both myeloma cell lines, even in any concentration of cells. Furthermore, addition of 30 to 100 ug/ml (clinical trough serum concentration) elotuzumab into the culture of mDCs and the supernatants did not affect the CD86 expression and IL-12/CCL17 production. Hence, factors other than sSLAMF7 from myeloma cells can trigger DCs to suppress Th1 response and to promote Th2 response.Conclusion: Our data suggest that the MM micro-environment, while suppress the Th1-inducing capacity, rather lead to enhance Th2 response at DC phase. As sSLAMF7 is detected in the serum of patients with MM but not in the supernatants of MM cell lines in the experimental setting, there is a limitation that our data does not consider the action of sSLAMF7. However, the present result provides an important clue for understanding the biological basis for the MM micro-environment against host immune defense at onset. Disclosures Ito: Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria; Novartis Pharma: Honoraria; Pfizer: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria.

Background: Analogs of thalidomide, lenalidomide (LEN) and pomalidomide (POM), are novel anti-multiple myeloma (MM) drugs (so-called Immunomodulatory Drugs; IMiDs). LEN has been reported to enhance function of effector immune cells such as T cells and NK cells and to induce selective reduction of regulatory T cells. Meanwhile, LEN and POM treatments lead to relatively high rate onset of itchy skin with rash like allergic reaction. However, cellular and molecular mechanisms underlying their immunomodulatory effects still remain largely unclear. Although there is evidence indicating the immunomodulatory actions of LEN on mouse conventional dendritic cells (DCs), there are few reports showing their effects on human DC subsets. DCs are pivotal in orchestrating both innate and acquire immunity as the center of the immune regulatory system, and series of analyses have clarified a functional plasticity of DCs to induce Th1 or Th2 response. Therefore, we focused on the effects of LEN and POM on the function of human myeloid DCs (mDCs), which are the major regulators to induce Th1 or Th2 responses and play a pathogenic role in allergy by their dysregulated Th2-inducing function (Ito T. J Exp Med 2005; 202: 1213). Methods: Using cell sorting, flow cytometry, real-time PCR, and ELISA methods, function and signaling were analyzed in blood human CD11+ mDCs from healthy adult volunteers. Sera were obtained from 24 MM patients with before and after LEN therapy. Written informed consent was obtained for all patients. This study was approved by the Institutional Review Board of Kansai Medical University. Results: We found that both agents at clinical in vivo plasma concentration of 0.1 µM to 1 µM did not affect the mDC survival and their CD86 and OX40-ligand expression in response to toll-like receptor (TLR)-ligands (LPS, poly IC, or R848) and Th2-inducing cytokine, thymic stromal lymphopoietin (TSLP) for 24 h culture. Either LEN or POM inhibited dose-dependently mDC-derived Th1-associated cytokines, IL-12 in response to R848 (1 µM LEN; 5.2 % of cont. and 0.3 µM POM; 12 % of cont.), IFN-λ in response to poly IC (1 µM LEN; 5.4 % of cont. and 0.3 µM POM; 10 % of cont.), and TNFα in response to R848 (1 µM LEN; 36 % of cont. and 0.3 µM POM; 17 % of cont.), but enhanced IL-10 production in response to R848 (1 µM LEN; 4.8-fold increase and 0.3 µM POM; 7.5-fold increase). When mDCs were stimulated with TSLP, both agents significantly enhanced the production of Th2-recruiting chemokine CCL17/TARC (1 µM LEN; 2.4 fold increase and 0.3 µM POM; 3.9 fold increase), which functions as chemoattractant for memory Th2 cells and contribute to aggravation of allergic inflammation. These capacities of POM were stronger than those of LEN. In addition, we revealed that, in response to LPS or R848, both LEN and POM downregulated not only IRF4 mRNA in human mDCs as in LEN-treated myeloma cells, but also STAT4 mRNA, which is important for DC-mediated Th1 response and IL-12 production. In mDCs treated with TSLP, both agents were found to upregulate STAT6 mRNA, which is responsible for TSLP-mediated CCL17 secretion (Arima K. Sci Signal2010;3:ra4). Clinically, serum CCL17/TARC levels are associated with the disease activity of atopic dermatitis and sensitively reflect short-term changes in skin conditions. We also found, in MM patients, serum CCL17 levels at the onset of LEN-associated rash during 4 weeks (n=9; 1271 ± 376 pg/ml) were significantly higher (p Conclusion: Our data suggest that the IMiDs, while suppress the Th1-inducing capacity of DCs, rather lead to enhance allergic response at DC phase through modulation of signaling pathways in this stream of action. Thus, IMiDs could have the potential to shift DC-mediated response from Th1 to Th2, and our findings provide a plausible explanation for pathogenesis of IMiD-associated rash in the treatment for MM. Disclosures Ito: Celgene corporation: Honoraria; GSK: Patents & Royalties.

Constitutive activation of NF-κB and STAT3 plays an important role in the cellular proliferation and survival of multiple myeloma cells. We first found that auranofin (AF), a coordinated gold compound, induced a significant level of cell cycle arrest at G1 phase and subsequent apoptosis of myeloma cells. Further, AF inhibited constitutive and IL-6-induced activation of JAK2 and phosphorylation of STAT3 followed by the decreased expression of Mcl-1. AF down-regulated the activation of NF-κB, and the combination of AF and a specific NF-κB inhibitor resulted in a marked decrease of Mcl-1 expression. These results suggest that AF inhibits both IL-6 induced-JAK/STAT pathway and NF-κB activation in myeloma cells.

Abstract 1993 Background: Recent advance in allogeneic hematopoietic stem cell transplantation (HSCT) has led to an increasing use of transplantation for older, having comorbidities, and more heavily pretreated patients. Thus, the evaluation of comorbidity is of increasing importance in order to estimate precisely benefits and risks of transplant procedure. The HCT-CI scoring system has been proposed, and has been confirmed as a useful tool to predict the probability of post-transplant non-relapse mortality (NRM) and overall survival (OS) while taking into account any pre-transplant comorbidity. However, HCT-CI has not been fully validated by prospective studies in multicenter setting, and its predictive value remains to be elucidated in Japanese population. Objectives: The aim of this cohort study is to prospectively evaluate whether HCT-CI score could be predictive for transplant outcomes Japanese patients in multicenter transplant setting. Patients and Methods: 244 consecutive patients (median age 45.3 years; range 16 to 74) with a variety of hematological disorders who had received myeloablative (MA, n= 167) or reduced-intensity (RIST, n= 77) conditioning followed by the first HSCT were enrolled in this study from 2007 to 2009 in 14 facilities of the KSGCT in Japan. The stem cell sources included bone marrow (BM, n=156), peripheral blood (PB, n=30) and cord blood (CB, n=58). The commonest diagnosis was myeloid malignancies (AML/MDS; 58.2 %) followed by ALL (18.4%), and NHL (10.7%). Pre-transplant co-morbidities were scored according to original HCT-CI scoring system in all patients. Patients were followed for 2 years or until relapse/death before two years after transplantation. Results: The most frequent comorbidity observed was mild & severe pulmonary comorbidities (51.9%), followed by mild hepatic comorbidity (14.6%) and active infections (9.3%). The other comorbidities observed in this cohort included psychiatric problems (4.8%), diabetes (3.6%), moderate to severe hepatic (2.8%), and solid tumors (2.8%). The OS and NRM of all patients were 59.2% and 20.4% at 2 years, respectively. The proportion of patients with HCT-CI score 0, 1–2, 3≤ was 32%, 30%, 38%, respectively. The original HCT-CI score failed to predict for OS and NRM (Fig 1). Furthermore, it was not correlated with KS score at 2Y and specific causes of death. We then applied flexible HCT-CI risk scoring system (re-stratified as low-risk; 0–3, and high-risk; 4≤). The distribution of flexible HCT-CI score did not differ significantly in terms of age at the time of transplant (51≤ vs. ≤50), sources of stem cells (BM vs. PB vs. CB), and conditioning (MA vs. RIST). The better predictive capacity for NRM and OS at 2Y of the flexible HCT-CI than original HCT-CI was confirmed (p=0.003) (fig 2). Multivariate analysis identified age (≥50) (p=0.010, HR=1.80), PS (≥90%) (p=0.010, HR=2.57), donor type (HLA-mismatched/unrelated donor) (p=0.020, HR=1.82), and flexible HCT-CI score (4≤) (p=0.019,HR=1.82) as significant predictors of worse OS at 2Y. However, flexible HCT-CI score did not remain as significant predictor of NRM at 2Y while age (p=0.017, HR=2.17), PS (p=0.0001, HR =4.60)and donor type (p =0.019, HR=2.80) remained as significant predictors. Conclusion: Our multicenter prospective study suggests that the modified 2-group scoring HCT-CI, not the original scoring HCT-CI, is a useful predictor of 2 -year OS but not NRM in Japanese. Reconsidering the scoring weight of comorbidity and incorporation of other risk factors (age, PS and donor type) may further improve the predictive capacity of flexible HCT-CI scoring system. Disclosures: Nannya: Otsuka Seiyaku Koujyou: Research Funding.

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.

Recent advances in allogeneic hematopoietic stem cell transplantation have led to increasing use of this modality in older patients who tend to have been more heavily pretreated and have more comorbidities. Thus, the evaluation of comorbidity is of increasing importance to more precisely assess the benefits and risks of the transplantation procedure. Researchers from Seattle developed the hematopoietic cell transplantation–specific comorbidity index (HCT-CI), which was associated with the risk of mortality in several retrospective studies. However, its clinical utility has not been extensively documented in prospective studies. The aim of the present study was to evaluate the utility of the HCT-CI prospectively in a multicenter setting. Overall survival (OS) and nonrelapse mortality (NRM) at 2 years were 59% and 20%, respectively (n = 243). We found that the HCT-CI in its original scale failed to predict OS and NRM in this set of patients. Thus, we applied a flexible HCT-CI risk scoring system (restratifying scores from 0 to 3 to indicate low risk, and scores of 4 or higher as high-risk). The flexible HCT-CI was found to predict 2-year NRM and OS better than the original HCT-CI (NRM: P = .01, OS: P = .003). In subgroup analysis, we evaluated the usefulness of the original HCT-CI for patients excluding those who received cord blood transplantation (n = 186). Both 2-year OS and 2-year NRM were not significantly different according to the original HCT-CI (P = .304, P = .996), but with the flexible HCT-CI, there were significant differences in 2-year OS and 2-year NRM (P = .005 and P = .005, respectively). Multivariate analysis identified age >50, performance status (PS)