Abstract: Background: We recently reported that the International Prognostic Scoring System for Waldenström macroglobulinemia (ISSWM), which is widely used to predict the prognosis of WM patients, might not be applicable to Japanese patients, and evidence of pleural effusion might be a novel adverse prognostic factor for symptomatic WM in the rituximab era. Further studies with a large number of patients are deemed to be conducted. Methods: We retrospectively analyzed the clinical data of 498 patients with WM diagnosed between January 2001 and December 2015 from 44 institutes involved with the Japanese Society of Myeloma. The overall survival (OS) was analyzed using Kaplan-Meier methods and compared using log-rank test. Several clinical characteristics at the diagnosis were assessed by Cox regression for univariate and multivariate analyses of the OS. Results: We included 420 cases diagnosed with symptomatic (n=314) and asymptomatic WM (n=106) in accordance with the classification of the Second International Workshop on WM. The median age at the diagnosis was 69 (range, 32-91) years, with 75.5% male, and 16.0% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2-4. Oral alkylating agents, purine analogs, cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or CHOP-like regimens ± rituximab, rituximab monotherapy, or dexamethasone, rituximab and cyclophosphamide (DRC) were mainly administered as initial treatment. Rituximab-containing therapy was administered in 76.8% of all patients. The median follow-up was 45 months. The 5-year OS rate for all patients was 77.9%, while the rates for those with symptomatic and asymptomatic WM were 72.9% and 92.2%, respectively. Significant differences in the survival were seen between risk groups of ISSWM in symptomatic WM patients (5-year OS: high, 55.4%; intermediate, 81.2%; low, 90.2%; p 〈 0.0001) (Figure 1). A univariate analysis showed that age 〉 65 years, platelet count ≤10×104/µL, serum β2-microglobulin (β2-MG) 〉 3 mg/L, ECOG PS 2-4, abnormal karyotype, pleural involvement, WBC 〈 4000/µL, amyloidosis, fluid retention, pleural effusion, ascites, serum albumin ≤3.5 g/dL, serum creatinine 〉 1.5 mg/dL, CRP 〉 2.0 mg/dL and sIL-2R 〉 4000 U/mL were significant adverse prognostic factors for the OS. A multivariate analysis revealed that a platelet count ≤10×104/µL (hazard ratio [HR] 5.942; 95% confidence interval [CI] 2.265-14.761), serum β2-MG 〉 3 mg/L (HR 2.748; 95% CI 1.091-7.655), ECOG PS 2-4 (HR 2.899; 95% CI 1.219-6.290), and pleural involvement (HR 11.066; 95% CI 3.672-29.829) were adverse independent risk factors for symptomatic WM. We constructed a prognostic model by combining these prognostic variables as follows: patients with good risk (n=219), no adverse factors or only serum β2-MG 〉 3 mg/L or ECOG PS 2-4; patients with poor risk (n=81), ≥1 adverse factors with a platelet count ≤10×104/µL, pleural involvement, or both serum β2-MG 〉 3 mg/L and ECOG PS 2-4. The 5-year OS rates were 82.3% for good risk and 44.4% for poor risk, and this prognostic model significantly stratified symptomatic WM patients separately by the survival (p 〈 0.0001) (Figure 2). The survival of patients with both poor risk in our model and high risk in ISSWM were extremely poor (5-year OS: poor and high [n=57], 24.7%; poor and intermediate [n=14] , 80.0%; poor and low [n=2], not available; p=0.0031). In contrast, no significant differences were observed for the survival for the ISSWM risk groups in patients with good risk in our model (5-year OS: good and high [n=69] , 76.0%; good and intermediate [n=83], 81.6%; good and low [n=42] , 89.5%; p=0.2045). Conclusion: Although ISSWM may be useful for survival risk stratification in Japanese patients, we found that intermediate- and high-risk patients seemed to have a better prognosis than those in Western studies in the rituximab era (Dimopoulos MA, et al. Haematologica. 2008; 93: 1420-22). Thrombocytopenia and pleural involvement were found to be strong adverse prognostic factors in symptomatic WM, and our new prognostic index including them was easy to use in daily clinical practice and superior to ISSWM for detecting high-risk patients. Further studies are warranted to validate our prognostic index, especially in the era of novel agents. Disclosures Yamamoto: Bristol-Myers Squibb: Honoraria. Hagiwara:Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Sunami:Celgene: Honoraria, Research Funding; Sanofi: Research Funding; Janssen: Research Funding; Daiichi-Sankyo: Research Funding; Ono: Honoraria, Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; AbbVie: Research Funding; Takeda: Research Funding; MSD: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding. Kurokawa:Teijin Pharma: Research Funding; Eizai: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Pfizer: Research Funding; Takeda Pharmaceutical: Research Funding; MSD: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Nippon Sinyaku: Honoraria, Research Funding; Astellas Pharma: Research Funding; Otsuka Pharmaceutical: Research Funding. Takamatsu:Janssen: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Ono: Research Funding. Ito:Bristol-Myers Squibb, Celgene: Honoraria. Tamura:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria.

Abstract: Rituximab has dramatically improved the clinical outcomes of mature B cell lymphoma. It has been reported that women show more favorable survival than men with rituximab-containing treatment. A multicenter, retrospective study was conducted to assess the role of sex in survival with rituximab treatment. Patients and Methods Patients with newly diagnosed mature B cell lymphoma treated at 20 National Hospital Organization hospitals in Japan from January 2000 to December 2004 were consecutively registered. Rituximab was approved in September 2002 for indolent B cell lymphoma and in September 2003 for aggressive B cell lymphoma in Japan. The patients were divided into two groups depending on whether they received induction therapy containing rituximab. The target population of this study was all mature B cell lymphoma patients who received first remission induction therapy containing rituximab. The patients treated without rituximab were used as controls. The endpoint was to compare 2-year progression-free survival (PFS) and overall survival (OS) between men and women. Survivals were assessed using the Kaplan-Meier method, and the groups were compared using the log-rank test. Results A total of 1126 patients received systemic chemotherapies during this study period. Of these, 348 (men 185, women 163), including 184 diffuse large B cell lymphomas (DLBCLs) and 111 follicular lymphomas (FLs), were treated by rituximab-containing regimens as front-line therapy. The 2-year PFS was better in women than in men (75.8% vs. 64.2%, p=0.048). This difference was not seen in the control group (men 396, women 382), which was treated by chemotherapeutic regimens without rituximab (48.7% vs. 50.6%, p=0.994). The 2-year OS was not statistically different between men and women (81.9% vs. 88.6%, p=0.115). When this population was broken down into DLBCL and FL, the women’s benefit in 2 year PFS was not statistically significant in both subtypes. Multivariate analysis both with forced entry and stepwise method could not show that sex was an independent prognostic factor in mature B cell lymphoma treated by rituximab containing induction regimen. Conclusions In mature B cell lymphoma, women would have better PFS than men when treated with rituximab containing therapy. These data suggest that the sex-based rituximab dose modification might be considered. Disclosures: No relevant conflicts of interest to declare.

Abstract: Introduction: Survival outcome of patients with multiple myeloma (MM) is heterogeneous because of different disease- and patient-related prognostic factors as well as in treatment-related factors. A survival benefit of continuous and maintenance (C/M) therapies after induction therapy in both transplant-eligible and -ineligible patients has been demonstrated in clinical trials. However, its usefulness is still to be clarified in the patients treated in routine clinical practice. Here, we report survival outcome of patients who received C/M therapy after induction therapy by analyzing the data of a multicenter retrospective study of the Japanese Society of Myeloma. Methods: Compiled clinical data of the patients diagnosed with MM and treated between 2013 and 2016 were analyzed retrospectively. Treatment decision whether or not to implement autologous stem cell transplantation (ASCT) was made at the discretion of a physician-in-charge. Treatment response was assessed by the investigators according to the International Myeloma Working Group uniform response criteria. Treatment decision to implement maintenance therapy after ASCT or to continue frontline treatment in non-transplanted patients was made based on the response to frontline treatment by the physician-in-charge. Patients were bifurcated using the propensity score methods in terms of age, gender, R-ISS stage, and commencement of ASCT to those who received C/M therapy and others without. Results: A total of 771 patients were enrolled. Among them, 216 patients received frontline C/M therapy, while the remaining 555 patients did not. In 720 patients who have achieved at least stable disease after induction therapy with or without ASCT, 161 patients of C/M group and another 161 patients of non-C/M group were matched according to the baseline covariates. Patient demographics and disease characteristics were well balanced between the matched set of patients (C/M vs non-C/M) in terms of median age (years, 65 vs 65), gender (male, 52% vs 53%), and R-ISS (stage I, 19% vs 20%; stage II, 70% vs 69%; and stage III, 11% vs 11%), respectively. ASCT were performed in 54% vs 54% in either group. C/M regimens included lenalidomide (n=73), bortezomib (n=35), ixazomib (n=9), elotuzumab (n=6), thalidomide (n=5), carfilzomib (n=2), combination of proteasome inhibitors and IMiDs (n=28), and others (n=3). Median PFS was significantly prolonged in the C/M group compared with the non-C/M group (37.7 vs 21.6 months, p=0.00017, Figure A). Median PFS in each of the two groups of the transplanted and non-transplanted patients were 40.5 vs 29.5 months (p=0.0063) and 24.6 vs 11.2 months (p=0.0013), respectively. For patients who have attained a CR after the frontline therapy, there was no significant difference in median PFS between the C/M and non-C/M groups (not reached vs 37.5 months, p=0.39). However, there was a significant prolongation of median PFS in the C/M group among those who did not achieve a CR (33.0 vs 19.2 months, p=0.006). Median OS was not reached in either groups, but it appeared to be longer in the C/M group than in the non-C/M group (p=0.061, Figure B). Although median OS of both groups were similar in the transplanted patients (p=0.56), there was a significant prolongation in the non-transplanted patients (58.1 months vs not reached, p=0.024). For those who have attained a CR, there was no significant difference in median OS between the C/M and non-C/M groups (p=0.29), but for those who did not achieve a CR, there was a significant prolongation of median OS in the C/M group (58.1 months vs not reached, p=0.048). A significant beneficial impact of C/M therapy on PFS and OS was observed in the R-ISS stage II and III patients but not in the stage I patients. In multivariate analysis, R-ISS stage, CR response after frontline therapy, ASCT, and C/M therapy were significant prognostic factors for PFS, whereas R-ISS and C/M therapy were associated with prolonged OS. Conclusions: C/M therapy had a beneficial impact on PFS and OS especially in patients with non-transplanted, non-CR response, and R-ISS stage II and III cohorts, but exerted less impact on standard-risk patients in our current clinical practice. Thus, C/M therapy is a key strategy for high-risk patients, but clarification of patients other than risk status who benefit from C/M therapy might be needed to further improve the prognosis of high-risk patients with MM. Disclosures Handa: Ono: Research Funding. Sunami:MSD: Research Funding; GSK: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Alexion-pharma: Research Funding; Janssen: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Research Funding; Daiichi Sankyo: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Iida:Takeda: Honoraria, Research Funding; Sanofi: Research Funding; Gilead: Research Funding; Celgene: Honoraria, Research Funding; Daichi Sankyo: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Abbvie: Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; MSD: Research Funding; Chugai: Research Funding; Janssen: Honoraria, Research Funding; Astellas: Research Funding; Teijin Pharma: Research Funding. Nishimura:Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy; Celgene K.K.: Honoraria. Shimizu:Amgen: Consultancy; Fujimoto: Consultancy; Daiichi: Consultancy; Medical Biological Laboratory: Consultancy; Takeda: Speakers Bureau.

Abstract: Posttransplant cyclophosphamide (PTCy) is an effective prophylaxis for both acute and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Recent studies reported that PTCy has been associated with low incidence of viral infections and EB-LPD, suggesting PTCy-based immune modulation leads the favorable immune reconstitution after transplant. However, the immune reconstitution dynamics of each subset after HSCT using PTCy remains poorly understood. To address this issue, we explored the impact and role of PTCy on the early lymphocyte reconstitution by using murine BMT model. Irradiated B6D2F1 mice were transplanted with 5x106 spleen cells from the CD45.1 B6 mice together with 5x106 TCD-BM from CD45.2 B6 donors. Cyclophosphamide 100mg/kg or control vehicle was administered at day 3 after transplant. Peripheral blood mononuclear cells (PBMCs) and splenic cells were sequentially obtained at day7, 14 and 21.The chimeric balances among host-residual H-2kd+ cells, donor graft-derived cells and donor BM-derived cells in CD8+ T cells, CD4+ Tcons, Tregs, B cells and NK cells were monitored separately. To evaluate the homeostatic stability of each lymphocyte subset at various time points, proliferation marker Ki-67 and anti-apoptotic BCL-2 were also quantitatively examined in each subset. To evaluate the clonal diversity of T and B cells, we performed the TCR- and BCR- repertoire analysis at day 21. Between day 0, transplanted recipients were developed severe acute GVHD, however, recipients received PTCy at day 3 promptly showed the recovery of the weight and improvement of the clinical GVHD score after day 5, whereas control continue to lose weight, suggesting the effect of PTCy to ameliorate acute GVHD. At day 7, all T cell subsets were critically depleted from both peripheral blood and spleen. The number of T cells was markedly lower in PTCy group than in control group (CD8 T+ cells; 5.1 vs 155.1/mm2, P 〈 0.01: CD4 Tcons; 5.2 vs 61.2/mm2, P 〈 0.01: Treg; 0.02 vs 0.52/mm2, P 〈 0.01, respectively). Especially, Ki-67+ proliferating cells, including Tcons and Tregs, were completely depleted, indicating these activated cells are very sensitive to cyclophosphamide intervention. However, interestingly, surviving T cells in recipients just after cyclophosphamide intervention showed significantly high-levels of BCL-2 expression than control recipients (MFI: CD8 T cells; 2.8 vs 10.0: CD4 Tcns; 2.9 vs 9.9: Treg; 1.8 vs 5.3, respectively). Based on the elevated anti-apoptotic elements, T cell in PTCy-treated recipients undergo aggressive homeostatic proliferation and the number of CD4 T cell subset, especially Tregs, took over that of control recipient by day 14. CD8+ T cell proliferation after PTCy was less aggressive than CD4 T cells, resulting Treg ratio to CD8 T cells in PTCy recipents was greatly higher than in control (Treg/CD8: 0.061 vs 0.031, P 〈 0.05). During 3 weeks, T cell recovery was basically maintained by donor graft-derived cell, though PTCy recipents involved averagely 10% of host-residual T cells. In comparison to T cells, main reconstitution of B cells was maintained by donor stem cell-derived cell. In PTCy recipients, CD23+CD24+ Transitional-2 naïve B cell and CD21-CD24+ mature follicular B cell overwhelmingly increased by Day 21(Follicular B cells in PTCy group and control; 1.22e6 vs 1.31e5, P 〈 0.0001). BCR-repertoire diversity analysis demostrated that PTCy resulted in the broad diversity of B cell repertoire (Inverse Simpson Index; 40.5 vs 13.9). Our data clearly indicated that PTCy contributes the favorable immune reconstitution by modulating coordinate T and B cell recovery. These findings might provide important information to promote immune tolerance after PTCy-based transplant. Disclosures Maeda: Mundipharma KK: Research Funding.

Abstract: Acute myeloid leukemia (AML) is a heterogenous malignancy characterized by distinct lineage subtypes and various genetic/epigenetic alterations. As with other neoplasms, AML cells have well-known aerobic glycolysis, but metabolic variations depending on cellular lineages also exist. Lysine-specific demethylase-1 (LSD1) has been reported to be crucial for human leukemogenesis, which is currently one of the emerging therapeutic targets. However, metabolic roles of LSD1 and lineage-dependent factors remain to be elucidated in AML cells. Here, we show that LSD1 directs a hematopoietic lineage-specific metabolic program in AML subtypes. Erythroid leukemia (EL) cells particularly showed activated glycolysis and high expression of LSD1 in both AML cell lines and clinical samples. Transcriptome, chromatin immunoprecipitation–sequencing, and metabolomic analyses revealed that LSD1 was essential not only for glycolysis but also for heme synthesis, the most characteristic metabolic pathway of erythroid origin. Notably, LSD1 stabilized the erythroid transcription factor GATA1, which directly enhanced the expression of glycolysis and heme synthesis genes. In contrast, LSD1 epigenetically downregulated the granulo-monocytic transcription factor C/EBPα. Thus, the use of LSD1 knockdown or chemical inhibitor dominated C/EBPα instead of GATA1 in EL cells, resulting in metabolic shifts and growth arrest. Furthermore, GATA1 suppressed the gene encoding C/EBPα that then acted as a repressor of GATA1 target genes. Collectively, we conclude that LSD1 shapes metabolic phenotypes in EL cells by balancing these lineage-specific transcription factors and that LSD1 inhibitors pharmacologically cause lineage-dependent metabolic remodeling.

Abstract: Introduction : In the past decade, the combination of high-dose melphalan (MEL) and auto-hematopoietic stem cell transplantation (auto-HCT) with novel agents substantially improved the outcomes in younger patients with multiple myeloma. However, the safety and efficacy of auto-HCT in patients aged ≥65 years remain uncertain. Large clinical trials evaluating the role of auto-HCT in multiple myeloma mostly included patients aged 〈 65 years even in the era of novel agents. Here, we examined the safety and efficacy of auto-HCT in patients with multiple myeloma who were aged ≥65 years. Methods: We examined 2,056 patients aged ≥16 years who underwent auto-HCT for multiple myeloma from 2007 to 2014; they were selected based on the following criteria: (1) first auto-HCT with peripheral blood stem cells; (2) use of MEL alone (100, 140, and 200 mg/m2) as a conditioning regimen; and (3) without planned tandem transplantation. A total of 2,056 patients met these criteria, and 287 of them were aged ≥65 years. The era of novel agents was defined as the date of transplantation after December 2006 because bortezomib was approved for public administration in Japan in December 2006. The primary end-point was 100-day treatment-related mortality (TRM), i.e., not myeloma-related or accidental deaths within 100 days after the first auto-HCT, and the secondary end-point was overall survival (OS). To adjust for a selection bias, the 100-day TRM was compared between two age groups ( 〈 65 vs. ≥65 years) by a propensity score analysis with the following factors: sex, immunoglobulin subtype, Durie-Salmon staging system and international staging system (ISS) stages at diagnosis, renal impairment at diagnosis, cytogenetic abnormalities, disease status at transplantation, conditioning regimen, and performance status (PS) at transplantation. Finally, 1:1 matched pairs were extracted. The probability of 100-day TRM was calculated using the Gray test and assessed by cumulative incidence analysis. The probability of OS was estimated using the Kaplan-Meier method and compared between groups using the log-rank test. Multivariate analysis for OS was performed using the Cox proportional hazards model. Results: The median age at transplantation was 66 (range, 65-76) and 57 (range, 18-64) years in the elderly and younger groups, respectively. The number of patients who used 100, 140, and 200 mg/m2 MEL were 17 (1.0%), 71 (4.0%), and 1,681 (95.0%), respectively, in the younger group and 19 (6.6%), 51 (17.8%), and 217 (75.6%), respectively, in the elderly group, with a significant difference (p 〈 0.001). The number of 100-day TRM and deaths due to disease relapse or progression were 13 (0.7%) and 5 (0.3%), respectively, in the younger group and 3 (1.0%) and 1 (0.3%), respectively, in the elderly group. A matched-pair analysis was performed based on the propensity score, and 263 patients were extracted from each group. The 100-day TRM probability was 0.4% (95% confidence interval [CI] : 0.0-2.0%) and 1.2% (95% CI: 0.3-3.1%) in the younger and elderly groups, respectively, without significant difference (p=0.315, Figure 1) in the propensity score-matched pair analysis. The probabilities of 5-year OS after transplantation were 62.5% (95% CI: 58.6-66.1%) and 63.5% (95% CI: 52.2-72.7%) in the younger and elderly groups, respectively, without significant difference (p=0.561, Figure 2). In the multivariate analysis, except age at transplantation ( 〈 65 or ≥65 years), gender, immunoglobulin subtype, ISS stage, unfavorable cytogenetic abnormalities, disease status at transplantation, and PS were significantly associated with OS. Conclusion: The 100-day TRM and OS were not significantly different between the younger and elderly patients who underwent auto-HCT for multiple myeloma in 2007-2014. We showed that auto-HCT is safe and effective for treating multiple myeloma in elderly patients, particularly in the era of novel agents. A comparable benefit was observed in elderly patients who underwent auto-HCT for multiple myeloma, highlighting the fact that chronologic age alone should not be used to determine transplantation eligibility. Disclosures Hanamura: CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Hakko Kirin Company, Limited: Research Funding; Bristol-Myers Squibb: Other: Lecture fee, Research Funding; Celgene: Other: Lecture fee; Takeda Pharmaceutical Company Limited.: Other: Lecture fee; Fujimoto Pharmaceutical Corporation: Research Funding. Sunami:Sanofi: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Research Funding; MSD: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Research Funding; Janssen: Research Funding. Mori:Janssen: Honoraria; Eisai: Honoraria; Japan Blood Products Organization: Honoraria; Shire Japan: Honoraria; Kyowa Hakko Kirin: Honoraria; Ono: Honoraria; Celgene: Honoraria; MSD: Honoraria; Taisho Toyama Pharmaceutical Co: Honoraria; Pfizer: Honoraria; Novartis Pharma: Research Funding; Asahi Kasei: Research Funding; Astella Pharma: Honoraria; CHUGAI: Honoraria; SHIONOGI: Honoraria; Novartis Pharma: Honoraria; MSD: Research Funding. Iida:MSD: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Kyowa-Hakko Kirin: Research Funding; Gilead: Research Funding; Sanofi: Consultancy; Teijin Pharma: Research Funding; Toyama Chemical: Research Funding; Astellas: Research Funding; Chugai: Research Funding. Kako:Takeda Pharmaceutical Company Limited.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Celgene K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Sawa:Celgene Corporation: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis International AG: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Mundipharma K.K.: Honoraria. Kanda:Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Nippon-Shinyaku: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Pfizer: Research Funding; MSD: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; CSL Behring: Research Funding; Tanabe-Mitsubishi: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria. Ichinohe:Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Alexion Pharmaceuticals: Honoraria; Zenyaku Kogyo Co.: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; MSD: Research Funding; Nippon Shinyaku Co.: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Eisai Co.: Research Funding; CSL Behring: Research Funding; Chugai Pharmaceutical Co.: Research Funding; Astellas Pharma: Research Funding; Novartis.: Honoraria. Takamatsu:Bristol-Myers Squibb: Research Funding; Ono: Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Takami:Chugai: Research Funding; Bristol-Myers Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding.

Abstract: Background: Autologous stem cell transplantation (ASCT) combined with novel therapeutic drugs, including proteasome inhibitors (PIs)/immunomodulatory agents (IMiDs), can substantially improve the prognosis of patients with multiple myeloma (MM). Because MM patients survive longer, the incidence of secondary primary malignancies (SPMs) in long-term survivors is increasing. To date, only few studies have evaluated SPMs in real-world patients, particularly in those with MM in Asia. Aims: To analyze the risk factors of SPMs in MM patients after ASCT before and after the introduction of PIs/IMiDs. Methods: In this retrospective observational study, data from the Registry of the Japan Society for Hematopoietic Cell Transplantation were collected and analyzed. A total of 2340 newly diagnosed MM patients who underwent ASCT between 1993 and 2016 were enrolled in this study. Median age 58 at ASCT (range 22-72); males 1329 (56.8%), females 1011 (43.2%); IgG 1340 (57.3%), IgA 452 (19.3%), IgD 63 (2.7%), IgE 3 (0.1%), IgM 6 (0.3%), BJP 416 (17.8%), non-secreting 38 (1.6%), unknown 22 (0.9%); ISS1 774 (33.1%), ISS2 825 (35.3%), ISS3 455 (19.4%), not assessed 286 (12.2%). 1908 (81.5%) and 432 (18.5%) patients received single melphalan 200 mg/sqm (Mel200) and double Mel200, respectively as conditioning regimen before ASCT. Moreover, 771 (32.9%) and 1569 (67.1%) patients underwent ASCT from 1993 to 2006 and from 2007 to 2016, respectively. 659 (28.2%) patients received PIs, 73 (3.1%) IMiDs and 903 (38.6%) both PIs and IMiDs. Meanwhile, 38 (1.6%) patients received radiation treatment. The disease status at ASCT was as follows: 690 (29.5%), sCR/CR; 580 (24.8%), VGPR; 831 (35.5%), PR; 144 (6.2%), SD; 50 (2.1%), PD; and 45 (1.9%), unknown. Results: The median follow-up from ASCT was 24 (range: 0-218) months. A total of 38 patients in this cohort developed SPMs, with a cumulative incidence of 0.8% [95% confidence interval (CI): 0.4%-1.2%] and 2.4% (95% CI: 1.6%-3.5%) at 24 and 60 months, respec tively. Twenty-four solid (4, stomach; 3, breast; 5, lung; 2, liver; 2, pancreas; 2, colon; 1, uterus; 1, thyroid gland; 1, bladder; 2, sarcoma; and 1, basal cell carcinoma), 11 hematologic (7, myelodysplastic syndrome; 1, acute leukemia; 2, lymphoma; and 1, unknown), and 3 unknown tumors were observed. The cumulative incidence of hematologic and solid SPMs at 60 months was 0.8% and 1.7%, respectively. OS at 60 months after ASCT was 62.9%, and OS after the diagnosis of SPMs at 24 months was 70.7% for hematologic and 64.6% for solid SPMs (median follow-up of 23 months). Next, the risk factors affecting the incidence of SPMs were analyzed, which included age at ASCT (≤65 or 〉 65 years), sex, PI/IMiD treatment, use of radiation, single/double ASCT, and period of ASCT (1993-2006 or 2007-2016). Because bortezomib, thalidomide, and lenalidomide were released for relapse/refractory MM treatment in Japan in December 2006, February 2009, and July 2010, respectively, we categorized the patients into two treatment cohorts: pre-novel agent era (1993-2006) and novel agent era (2007-2016). Univariate analysis showed that the novel agent era (1.7% vs 4.3% at 60 months; P = 0.013; Fig. 1) and use of radiation (2.3% vs 9.5% at 60 months; P = 0.027) were significant independent risk factors for SPMs. Multivariate analysis revealed that the use of radiation [hazard ratio (HR): 3.895; 95% CI: 1.163-13.050; P = 0.027] was a significant, independent risk factor for SPMs. The novel agent era (HR: 1.716; 95% CI: 0.857-3.438; P = 0.13) and IMiD without PI treatment (HR: 2.206; 95% CI: 0.787-6.189; P = 0.13) were likely high-risk factors for SPMs. In contrast, PI without IMiD treatment (P = 0.79) was not a risk factor for SPMs. The probabilities of developing SPMs and death due to other causes (mainly MM) at 60 months were 2.4% and 36.5% (Fig. 1), respectively, indicating that the risk for SPMs was lower than that for death from MM. Furthermore, OS between the pre-novel and novel agent era groups significantly improved (59.2% vs. 69.5%, P 〈 0.0001) at 60 months after ASCT. Conclusions: The incidence of SPMs in patients with MM in Japan was consistent with that reported recently (Sahebi et al. BBMT, 2018). Although the risk for SPMs increased in the novel agent era group, the mortality rate of SPMs was lower than that of other causes (primarily MM). Considering the increase in the number of long-term survivors with MM, the early occurrence of SPMs should be cautiously monitored. Disclosures Takamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; Ono pharmaceutical: Honoraria, Research Funding; CSL Behring: Research Funding; SRL: Consultancy, Research Funding; Daiichi-Sankyo Company: Honoraria; Becton, Dickinson and Company: Honoraria; Sanofi: Consultancy, Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Fujimoto Pharmaceutical: Honoraria; Janssen Pharmaceutical: Consultancy, Honoraria; Abbvie: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Mizuno:Takeda Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb Corporation: Honoraria; Celgene Corporation: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Fuchida:Japan Blood Products Organization: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Daiichi-Sankyo Company: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Ono pharmaceutical: Honoraria; Kyowa Kirin: Honoraria; SEKISUI MEDICAL CO., LTD.: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria. Hanamura:Asai Clinic: Research Funding; Yamada Yohojo: Research Funding; AbbVie: Honoraria; Chugai: Research Funding; Eli Lilly: Research Funding; Taiho: Research Funding; Sanofi: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Pfizer: Honoraria, Research Funding; Eisai: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Fukuyu Hospital: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Nihon Shinyaku: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Shionogi: Honoraria, Research Funding; Fujimoto: Research Funding; MSD: Research Funding; Zenyaku: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Mundi: Honoraria. Nakamura:Astellas Pharma Inc.: Honoraria; Takeda Pharmaceutical Company Limited: Research Funding; Eisai Co. Ltd.: Honoraria; Kyowa Kirin: Research Funding. Mori:Celgene: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Ono Pharmaceutical: Honoraria; Novartis Pharma K.K: Honoraria. Tsukada:Chugai Pharmaceutical Co.,Ltd: Honoraria; Kyowa Kirin: Honoraria; Celgene: Honoraria; Ono Pharmaceutical: Honoraria; Sanofi: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; MOCHIDA PHARMACEUTICAL CO., LTD.: Honoraria; Asahi Kasei Pharma Corporation: Honoraria; Ohtsuka Pharmaceutical: Honoraria; Fujimoto Pharmaceutical: Honoraria. Ichinohe:Astellas Pharma: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Nippon Shinyaku Co.: Research Funding; MSD: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria. Kanda:Pfizer: Research Funding; Novartis: Research Funding; Mochida: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Nippon-Shinyaku: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Tanabe Mitsubishi: Research Funding; Novartis: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria; Tanabe Mitsubishi: Research Funding; Asahi-Kasei: Research Funding; MSD: Research Funding; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Mochida: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Research Funding; CSL Behring: Research Funding; MSD: Research Funding; Otsuka: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Sanofi: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Sanofi: Research Funding; Taiho: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; Celgene: Consultancy, Research Funding; Taiho: Research Funding. Atsuta:CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria. Sunami:Takeda: Honoraria, Research Funding; GSK: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding; Ono: Honoraria, Research Funding; Alexion-pharma: Research Funding; Daiichi Sankyo: Research Funding; MSD: Research Funding; Abbvie: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Research Funding.

Abstract: Introduction:Central nervous system invasion in multiple myeloma (CNS-MM) is extremely rare (approximately 1% of MM). Prognosis of patients with CNS-MM is generally poor, and the median overall survival (OS) time from its diagnosis (Dx) has been reported to be 2 to 7 months. However, because of its rareness, most available data concerning CNS-MM are based on anecdotal reports on small case series. In this study, we retrospectively collected clinical data of Japanese patients with CNS-MM and analyzed them to reveal clinical features and prognosis of this disease entity. Methods:We conducted a nationwide multicenter retrospective study involving 107 centers that consist of educational facilities authorized by Japanese Society of Hematology and its related hospitals. CNS-MM was defined based on the previously reported criteria (Br J Haematol 2013;162:483-48). Univariate and multivariate analyses were performed to explore prognostic factors and the suitable treatment of CNS-MM. Results:From December 1978 to February 2016, 75 patients with CNS-MM were identified. The median age was 58 (range: 32-77 years). CNS invasion was detected at initial Dx of MM in 4% and at relapse in 96%. The median time from Dx of MM to that of the secondary CNS-MM was 1.8 years. Concomitant plasma cell leukemia (18%), skull plasmacytoma (12%), and myeloma cells in the cerebrospinal fluid (63%) were observed at the Dx of CNS-MM. Common symptoms of CNS-MM included consciousness disturbance (37%), cranial nerve palsy (25%), diplopia (18%), headache (16%), spinal nerve disorder (13%), and nausea/vomiting (12%). Intrathecal chemotherapy (IT) was used in 37%, cranial and/or spinal irradiation therapies (RTx) in 45% in addition to various systemic therapies, which included immunomodulatory drugs (IMiDs) (21%), bortezomib (19%), alkylators (21%), dexamethasone alone (6%), autologous stem cell transplant (auto-SCT, 4%), and allogeneic stem cell transplant (allo-SCT, 3%). With a median follow-up of 3.4 months from Dx of CNS-MM and of 31.5 months from that of MM, the median OS time from Dx of CNS-MM was only 3.7 months. The median OS times for the 12 untreated and 61 treated patients were 0.2 and 5.1 months, respectively (P 〈 0.01), suggesting that the patients who did not receive any treatments (Txs) were in a severe condition and their prognoses were extremely poor. In univariate analyses for the entire group, absence of both atypical lymphocytes and plasma cells in the peripheral blood at Dx of MM and no Tx for MM before Dx of CNS-MM were significantly favorable prognostic factors (P = 0.008 and P 〈 0.0001, respectively). Regarding Tx for CNS-MM patients who received any Txs (conventional chemotherapies, bortezomib, IMiDs, IT, and RTx), only RTx was correlated with longer OS time (P = 0.047). In multivariate analyses, RTx and IT had a significant impact on longer OS time ( 〉 6 months, OR = 3.80, 3.97, P = 0.002, 0.01, respectively). Although the prognosis of CNS-MM in this study cohort was very poor, seven patients could survive for 〉 1 year from Dx of CNS-MM. Among them, RTx, IMiDs, IT, bortezomib, auto-SCT, and allo-SCT were given to 5, 4, 5, 3, 1, and 1 patients, respectively. Conclusions:Prognosis of CNS-MM is extremely poor in general. Although there must be a selection bias that patients who received various salvage Txs for CNS-MM were in a better condition, the results of our study suggest that multi-modality Txs with RTx, IT, and IMiDs/bortezomib may prolong the survival time in some cases. Prospective studies are needed to confirm our preliminary observations. Disclosures Takamatsu: Celgene: Honoraria; Janssen Pharmaceuticals: Honoraria. Sunami:Janssen Pharmaceutical: Research Funding; Sanofi: Research Funding; Daiichi Sankyo: Research Funding; Bristol-Myers Squibb K.K.: Research Funding; Novartis: Research Funding; Celgene: Honoraria, Research Funding; Takeda: Research Funding; Ono Pharmaceutical: Research Funding. Hagiwara:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Kuroda:Janssen: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Astra Zeneca: Research Funding; Celgene: Honoraria, Research Funding. Murakami:Bristol Meyers Squibb: Honoraria; Astellas: Honoraria; Mochida: Honoraria; Eisai: Honoraria; Takeda: Honoraria; MSD: Honoraria; Chugai: Honoraria; Celgene: Honoraria. Nakao:Alexion Pharmaceuticals: Honoraria, Research Funding. Tobinai:Celgene: Research Funding; Mundipharma KK: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SERVIER: Research Funding; HUYA Bioscience: Honoraria; Kyowa Hakko Kirin: Research Funding; Zenyaku Kogyo: Honoraria; Chugai Pharma: Research Funding; Abbvie: Research Funding; GlaxoSmithKline: Research Funding; Ono Pharmaceutical: Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy; Janssen Pharmaceuticals: Honoraria, Research Funding. Iida:Celgene: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding.