ALBERT

Description: Introduction: Pomalidomide plus low-dose dexamethasone (POM + LoDEX) is approved for the treatment of patients with relapsed and refractory multiple myeloma (RRMM). In RRMM, POM + LoDEX significantly prolonged progression-free survival (PFS) compared with POM alone (MM-002; Richardson et al Blood, 2014) and significantly improved PFS and overall survival (OS) compared with high-dose DEX alone (MM-003; San Miguel et al Lancet Oncol, 2013), while demonstrating an acceptable safety profile. In Japanese patients with RRMM, a phase 1 study identified POM 4 mg/day as the tolerated dose (MM-004; Iida ASH 2014), consistent with observations in Caucasian patients. The study presented here, MM-011, was conducted to evaluate the efficacy and safety of POM + LoDEX in Japanese patients with RRMM. Methods: MM-011 was a multicenter, single-arm, open-label phase 2 study in patients with RRMM. Eligible patients had received ≥ 2 prior therapies, including ≥ 2 cycles of lenalidomide and ≥ 2 cycles of bortezomib (either separately or in combination) and had developed progressive disease on or within 60 days of the last prior therapy. Patients received POM 4 mg orally on days 1-21, and LoDEX orally on days 1, 8, 15, and 22 of each 28-day cycle. LoDEX was given at 40 or 20 mg in patients aged ≤ 75 or 〉 75 years, respectively. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was overall response rate (ORR; partial response rate [PR] or better) of POM + LoDEX according to the International Myeloma Working Group criteria. The required sample size was calculated using the expected response rate of 25%, the threshold response rate of 10% on 1-sided alpha of 0.05, and the statistical power of 80% based on the test for 1 sample proportion. Thirty-three pts were needed as a result of this calculation. Results: A total of 36 patients were enrolled. Median age was 64.5 years (range, 43-78 years), and 11% were aged 〉 75 years. Patients had a high tumor burden (81% had Durie-Salmon stage II or III disease) and were heavily pretreated (median of 6.5 prior anti-myeloma regimens; range, 2-15 regimens). All but 1 patient (97%) were refractory to lenalidomide and 58% were refractory to both lenalidomide and bortezomib. At the data cutoff (February 3, 2015), 16 patients (44%) remained on treatment. Disease progression was the most common reason for discontinuation (n = 14; 39%). All 36 patients enrolled were evaluable for efficacy. The ORR was 42% (n = 15 [95% CI, 26%-58%]), including complete response in 3% (n = 1) and PR in 39% (n = 14). Median PFS was 10.2 months (median follow-up, 4.6 months), and median OS was not reached (median follow-up, 7.7 months). In the 15 responders, median time to response was 1.9 months and median duration of response was not reached. The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (n = 23; 64%), anemia (n = 15; 42%), and thrombocytopenia (n = 11; 31%), and the most common grade 3/4 non-hematologic AEs were pneumonia (n = 3; 8%) and decreased appetite (n = 3; 8%). Peripheral neuropathy (any grade) occurred in 8% (n = 3). No deep vein thrombosis or pulmonary embolism was reported. Overall, AEs were similar to those in other POM studies, and no new significant AEs were reported in Japanese RRMM patients. Three patients (8%) had an AE that led to discontinuation. Three patients died on study (or within 28 days of the last dose of study drug). Two of these patients died due to multiple myeloma and 1 due to AE (asthma and pneumonia, suspected to be related to study drug). Conclusions: POM + LoDEX is an effective regimen in heavily pretreated Japanese patients with RRMM with acceptable safety profiles that are comparable with those of POM studies in RRMM in other regions. Disclosures Hagiwara: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Matsue:Celgene Corporation: Honoraria. Iida:Celgene Corporation: Honoraria, Research Funding; Janssen Pharmaceuticals Inc: Honoraria; Kyowa Hakko Kirin Inc: Research Funding; Ono Pharmaceutical Inc: Research Funding; Chugai Pharmaceutical Co: Research Funding; Eli Lilly Inc: Research Funding. Sunami:Ono Pharmaceutical Company, Limited: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding. Ando:Kyowa Hakko Kirin Co., Ltd: Research Funding. Tobinai:Gilead Sciences: Research Funding. Chou:Celgene Corporation: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Ono Pharmaceutical CO., LTD.: Consultancy, Honoraria. Kaneko:Celgene Corporation: Research Funding. Uemura:Celgene Corporation: Employment. Tamakoshi:Celgene Corporation: Employment. Zaki:Celgene Corporation: Employment, Equity Ownership. Doerr:Celgene Corporation: Employment.

Description: Introduction There has been dramatic evolution in multiple myeloma (MM) therapy in the last decade. The novel agents (Thal, Bor, and Len) have been reported to improve natural history of the cases with MM. In order to use optimal drugs for each patient, we should investigate the actual conditions of the clinical practice. However, we could not have the information regarding epidemiology, clinical features, treatment results, prognosis, and so on because there is no large-scale database demonstrating the clinical features of MM-related diseases in Japan. Therefore, we have founded the study group, named as Kansai Myeloma Forum (KMF), for the purpose of registering the cases with MM-related diseases in Kansai area of Japan on November, 2012. In this study, we analyzed the clinical characteristics and outcomes of MM-related diseases registered in KMF and evaluated the treatment strategies in the novel agent era. Patients & Results Among a total of 923 cases initially diagnosed since 2006 and registered to KMF database until March 31, 2013, we analyzed 434 symptomatic MM cases (213 females/221 males), who were treated since 2006. The median age was 69 (range: 32-96), and the OS rates at 3 and 5 years were 68.7% and 45.3%, respectively. The prognosis of the cases treated after 2010 became significantly better than that of the cases treated between 2006 and 2009 (log-rank test: P=0.019). The prognosis of the cases treated with the novel agents was significantly better than without them (p=0.005). Among the non-transplanted 339 cases, the effects of the novel drugs were shown more clearly (p=0.002). The best response during the course differentiated the prognosis; the hazard ratios of CR, VGPR, PR, SD and PD compared to sCR were 2.23, 3.19, 9.54, 16.84 and 432.01, respectively (P

Description: Abstract 4480 Introduction: Adult T-cell leukemia (ATL) endemic in southwestern Japan is an HTLV-I-induced mature T-cell neoplasm. It has a dismal prognosis when treated with conventional chemotherapy, mainly because ATL cells overexpress multidrug-resistance genes. Allogeneic hematopoietic stem cell transplantation (allo-SCT) has been reported to improve the prognosis. However, it is also known that allo-SCT shows high treatment-related mortality (TRM) because of disease characteristics of severely deteriorated cellular immunity. Therefore, we evaluated the outcome of reduced-intensity stem cell transplantation (RIST), compared to conventional stem cell transplantation (CST) for ATL patients (pts). Patients and methods: We retrospectively analyzed consecutive 20 pts with aggressive ATL (acute type, 16; lymphoma type, 4) who underwent allo-SCT between 2000 and 2010 in our institute. The age of pts who received RIST was significantly older than that of CST (P =

Description: Regenerative medicine and disease modeling are expanding rapidly, through the development of human-induced pluripotent stem cells (hiPSCs). Many exogeneous supplements are often used for the directed differentiation of hiPSCs to specific lineages, such as chemicals and hormones. Some of these are known to synchronize the circadian clock, like forskolin (Frk) and dexamethasone (Dex); however, the response to these stimulations has not been fully elucidated for hiPSCs. In this study, we examined the response of clock genes to synchronizing stimulation, and compared it with fully differentiated cells, U2OS, and fibroblasts. The expression of clock genes did not show circadian rhythms in hiPSCs with Frk and Dex, which could be due to the significantly low levels of BMAL1. On the other hand, a circadian-like rhythm of D-box binding protein (DBP) expression was observed in hiPSCs by culturing them in an environment with a simulated body temperature. However, the inhibition of temperature-inducible factors, which are involved in temperature rhythm-induced synchronization, could not repress the expression of such rhythms, while the inhibition of HIF-1α significantly repressed them. In summary, we suggest that clock genes do not respond to the synchronizing agents in hiPSCs; instead, a unique circadian-like rhythm is induced by the temperature rhythm.

Description: Chondrocytes proliferate and mature into hypertrophic chondrocytes. Vascular invasion into the cartilage occurs in the terminal hypertrophic chondrocyte layer, and terminal hypertrophic chondrocytes die by apoptosis or transdifferentiate into osteoblasts. Runx2 is essential for osteoblast differentiation and chondrocyte maturation. Runx2-deficient mice are composed of cartilaginous skeletons and lack the vascular invasion into the cartilage. However, the requirement of Runx2 in the vascular invasion into the cartilage, mechanism of chondrocyte transdifferentiation to osteoblasts, and its significance in bone development remain to be elucidated. To investigate these points, we generated Runx2fl/flCre mice, in which Runx2 was deleted in hypertrophic chondrocytes using Col10a1 Cre. Vascular invasion into the cartilage was similarly observed in Runx2fl/fl and Runx2fl/flCre mice. Vegfa expression was reduced in the terminal hypertrophic chondrocytes in Runx2fl/flCre mice, but Vegfa was strongly expressed in osteoblasts in the bone collar, suggesting that Vegfa expression in bone collar osteoblasts is sufficient for vascular invasion into the cartilage. The apoptosis of terminal hypertrophic chondrocytes was increased and their transdifferentiation was interrupted in Runx2fl/flCre mice, leading to lack of primary spongiosa and osteoblasts in the region at E16.5. The osteoblasts appeared in this region at E17.5 in the absence of transdifferentiation, and the number of osteoblasts and the formation of primary spongiosa, but not secondary spongiosa, reached to levels similar those in Runx2fl/fl mice at birth. The bone structure and volume and all bone histomophometric parameters were similar between Runx2fl/fl and Runx2fl/flCre mice after 6 weeks of age. These findings indicate that Runx2 expression in terminal hypertrophic chondrocytes is not required for vascular invasion into the cartilage, but is for their survival and transdifferentiation into osteoblasts, and that the transdifferentiation is necessary for trabecular bone formation in embryonic and neonatal stages, but not for acquiring normal bone structure and volume in young and adult mice.