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Introduction Although several previous studies addressed the role of radiation in treating localized diffuse large B-cell lymphoma (DLBCL), chemotherapy alone has shown promising efficacy with the emergence of Rituximab. Thus, we evaluated the clinical efficacy outcomes and failure patterns of patients with localized DLBCL according to two different treatment strategies, either 6 or more cycles of R-CHOP chemotherapy alone or 3 or 4 cycles of R-CHOP followed by involved field radiotherapy (IFRT). Methods A prospectively collected database from 21 tertiary centers participating the Consortium for Improving Survival of Lymphoma (CISL), built up for PROCESS study (NCT01202448) for secondary central nervous system involvement in DLBCL, was recruited for current study in addition to the Asan Medical Center (AMC) Lymphoma Registry. CISL database and AMC lymphoma registry consisted of data from patients with newly diagnosed DLBCL between August 2010 and August 2012, and between February 2004 and February 2012, respectively. Inclusion criteria were localized (stage I or II), non-bulky ( Results A total of 357 patients (CISL prospective cohort: 161 patients, AMC registry: 196 patients) were eligible for the analyses. Two hundred ninety nine patients (83.5%) received 6 or more cycles of R-CHOP chemotherapy alone, and 58 patients (16.2%) underwent 3 or 4 cycles of R-CHOP followed by IFRT. Median age was 54 years (range, 16-87). During the median follow-up of 24 months (range, 4-116 months), 35 patients (9.8%) experienced relapse, and 22 patients (6.1%) died. Two-year OS and EFS rate was 94.7% and 89.9%, respectively, and 345 out of 357 patients (96.6%) achieved CR. Comparing R-CHOP alone to R-CHOP plus RT group, there was no significant difference in clinicopathologic parameters. R-CHOP alone could achieve significantly higher CR rate of 97.7 % than 91.4% of R-CHOP plus RT group (p = 0.030). Two-year OS and EFS were significantly longer in R-CHOP alone group than R-CHOP plus RT group (96.1 vs 89.9 %, p = 0.029 and 91.7% vs 81.8%, p= 0.028) (Figure 1). Relapse rate was significantly lower in R-CHOP alone group compared with R-CHOP plus RT group than group (7.4% vs 22.4%, p=0.001), and distant relapses were also significantly lower (15.5% vs 2.7%, p Conclusion In our cohort, R-CHOP alone for six to eight cycles without IFRT could achieve significantly higher 2-year OS and EFS rate as well as CR compared with R-CHOP plus RT group. In addition, the rate of relapse and systemic failure were significantly lower in R-CHOP alone group, which altogether warrant further validation in prospective trial. Table 1. Explorative comparison of overall clinical outcomes and patterns of relapse between two subgroups: patients who underwent six or more cycles of R-CHOP chemotherapy alone and who underwent 3 or 4 cycles of R-CHOP followed by IFRT Total (%) R-CHOP alone group (%) R-CHOP plus RT group (%) P -value Number of patients 357 (100) 299 (83.5) 58 (16.2) Treatment response Complete response 345 (96.6) 292 (97.7) 53 (91.4) 0.030 Overall response 351 (98.3) 294 (98.3) 57 (98.3) 1.000 Rate of relapse 35 (9.8%) 14 (7.4) 11 (22.4) < 0.001 Median time to relapse (95% CI) 11 (7-15) 11 (8-14) 10 (5-14) 0.346 Pattern of relapse < 0.001 (0.062) Locoregional 14 (4.7) (63.6) 4 (6.9) (30.8) Distant 8 (2.7) (36.4) 9 (15.5) (69.2) Figure 1. Comparison of overall survival and event-free survival in two subgroups: patients who underwent six or more cycles of R-CHOP chemotherapy alone and who underwent 3 or 4 cycles of R-CHOP followed by IFRT Figure 1. Comparison of overall survival and event-free survival in two subgroups: patients who underwent six or more cycles of R-CHOP chemotherapy alone and who underwent 3 or 4 cycles of R-CHOP followed by IFRT Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract 3106 Background: Induction therapy followed by ASCT is the standard therapy for the newly diagnosed younger patients with MM. Recently, new drugs such as lenalidomide or bortezomib have shown the promising results as an induction treatment. However, these drugs are not available in many countries as a front line treatment and many different type of induction treatment regimens including old regimens are used. We evaluate the efficacy and safety of the brief course of high dose dexamethasone (HD) and the response adapted PAD (Bortezomib, Adriamycin, Dexamethasone) or VAD (Vincristine, Adriamycin, Dexamethasone) induction chemotherapy in the newly diagnosed younger patients with MM. Methods: One hundred fifty five newly diagnosed patients with MM from 23 institutions received 2 cycles of HD followed by PAD or VAD chemotherapy according to the response to the HD. PAD 4 cycles were given to nonresponsders and VAD 2 cycles were given to who achieved more than PR to HD. The primary endpoint was CR + nCR rate after ASCT. Among 155 patents enrolled this study from November 2009, 29 patients (19%) have been dropped out. This trial will be continued until total 210 patients will be enrolled. The trial is registered on National Cancer Institute website, number NCT01255514. Results: One hundred fifty five patients (88 male, 69 female) were enrolled (median age; 57). 34 (22%) patients had ISS stage I, 64 (41%) stage II and 55 (35%) stage III. Thirty six (26%) patients had abnormal cytogenetics. In FISH analysis, there were 25% del13, 9% del17, 21% t (4; 14), 13% t (14; 16) and 26% t (11; 14). Among the 115 evaluable patients, CR + PR rate was 53% (61/115) after 2 cycles of HD. 61 patients (53%) received subsequent VAD chemotherapy and 54 patients (47%) received PAD chemotherapy. Among the evaluable patients, CR + PR rate after induction therapy was 83% (79%, 48/61 in VAD group vs. 89%, 48/54 in PAD group). 95 patients finished ASCT. CR + nCR rate after ASCT were 74% (74% in VAD group vs 73% in PAD group). Mortality rate of this trial was 15% (17/115). The cause of death was disease progression (n=5), bleeding (n=1) and infections (n=11). Among 115 patients in whom VAD or PAD chemotherapy was actually performed, 1 year OS was 88.1%. (VAD arm 90.7% versus PAD arm 86.1% (P=0.105): median follow-up; 16.6 months). Conclusion: Risk adapted approach using initial HD response showed good response results after ASCT compared with previous trial (CR + nCR rate of IFM 2005-01 trial-Bortezomib+dexa induction & ASCT was 35%, J Clin Oncol. 2010;28:4621–9) The MM patients who showed poor response to HD also showed similar good response rate after ASCT compared with the patients who had good response to HD in this trial. PAD re-induction therapy after failure of initial steroid induction treatment might overcome the inferior results in the high risk MM patients. Our data shows that almost half of the patients who responded to HD can be saved of novel agents during induction treatment, and PAD can successfully rescue the other half who are not sensitive to HD. Therefore, initial steroid response adapted strategy might be the more cost-effective approach in the newly diagnosed ASCT eligible MM patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 2683 Background Secondary central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL) includes CNS relapse or CNS involvement with systemic disease progression. Although many publications have provided information regarding the incidence and risk factors for CNS involvement in DLBCL, its incidence reported across those studies varies widely. It might be related with that the majority of data were from retrospective analyses. Furthermore, the role of CNS prophylaxis for DLBCL has been challenged, especially in the era of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). As a result, this rare but fatal clinical problem still remains a therapeutic dilemma in the management of DLBCL. In this study, we prospectively explored the risk factors of CNS involvement and the clinical impact of screening evaluation for CNS involvement. Methods We analyzed the incidence of secondary CNS involvement in pathologically confirmed DLBCL patients enrolled in the Prospective Cohort Study with Risk-adapted Central Nervous System Evaluation in Diffuse Large B-cell Lymphoma (PROCESS study, NCT01202448). Patients should be treated with at least one cycle of R-CHOP, and provide written informed consents. We assessed the risk of CNS involvement based on previously reported risk factors: serum LDH elevation, the number of extranodal involvements, serum albumin, bone marrow invasion, HIV positivity, the involvement of testis, breast, paranasal sinus, bone, retroperitoneal lymph nodes, orbit, and epidural space. If patients had any of these risk factors, they underwent CSF study to screen the CNS involvement at diagnosis. If the results were abnormal, additional studies including brain MRI could be done depending on physicians' decision. CNS prophylaxis was done with intrathecal chemotherapy with methotrexate for patients who had positive findings of screening evaluation or were determined to have a risk of CNS involvement based on physicians' decision. Results 564 patients were enrolled between 2010 and 2012 from 26 institutions belonged to the Consortium for Improving Survival of Lymphoma (CISL). They were prospectively monitored with the median follow-up duration of 10.5 months. The median age was 59.5 years old (range 20–89 years), and approximately a half of patients had Ann Arbor stage III/IV (n = 276, 48.9%) and 193 patients involved two or more than two extranodal sites (34.2%). Based on the International Prognostic Index (IPI) risk, 192 patients belonged to high or high-intermediate risk (34%). Among patients (n = 368) who had at least one of risk factors for CNS involvement, 243 patients underwent CNS evaluation, and the evidence of CNS involvement was found in16 patients including positive cytology (n = 11), and brain parenchyma lesion (n = 5). The other 78 patients showed equivocal results of CSF analysis including the presence of atypical cells (n = 17). Intrathecal prophylaxis was done for 51 patients whereas high dose methotrexate chemotherapy was combined with R-CHOP for patients with brain lesion. During follow-up, 14 cases of additional CNS involvement including brain parenchyma (n = 8), leptomeningeal (n = 5), and ocular invasion (n = 1) were observed. The median time to CNS event in these 14 patients was 7.5 months (range 1.2 – 15.9 months). Thus, 30 cases of secondary CNS involvement were documented in our study population at the time of analysis (5.3%) including 16 cases at diagnosis and 14 cases during follow-up. The univariate analysis for evaluation of risk factors demonstrated serum LDH, the number of extranodal involvements, bone marrow invasion, and the involvement of retroperitoneal lymph nodes, breast, paranasal sinus and orbit were significantly associated with CNS involvement. The high/high-intermediate risk of IPI was also predictive of CNS involvement (P < 0.05). However, in the multivariate analysis, bone marrow invasion and the involvement of breast, paranasal sinus and orbit were independently predictive for CNS involvement. Conclusions The incidence of secondary CNS involvement in DLBCL patients treated with R-CHOP was around 5%, and a half of cases had the evidence of CNS involvement at diagnosis. Considering a particular risk of CNS involvement of disease-related factors, risk-adapted active screening against CNS involvement may help to improve treatment outcome of patients with DLBCL. Disclosures: No relevant conflicts of interest to declare.

Abstract 1990 Introduction: Autologous stem cell transplantation (ASCT) is a standard of care for younger multiple myeloma patients (pts). However, nearly all pts undergoing ASCT will relapse and require salvage therapy. Several investigators have reported 2nd ASCT might be a feasible and effective treatment modality in some pts. However, these studies contained small number of pts with 2nd ASCT and did not compare with outcomes of salvage therapy using novel agents. Thus, the aims of this study are to investigate outcomes of 2nd ASCT in pts relapsed after front-line ASCT and identify the impact of 2nd ASCT compared to modern systemic therapy in the novel agent era. To minimize the heterogeneity between the 2 groups, matched-pair design was chosen. Methods: The data of 48 pts between 1998 and 2010 with 2nd ASCT after relapse of front-line ASCT identified from web-based registry (www.myeloma.or.kr) were analyzed. Pts with tandem ASCT or salvage allo-SCT were excluded. The goal of this study was to perform a matched-pair analysis, each patient with 2nd ASCT was matched to three pts from a cohort of 517 pts treated with systemic chemotherapy after relapse of prior ASCT. The pts were matched for 9 potential prognostic factors: age at relapse (MEL140), response to front-line ASCT (≥VGPR vs Results: The median age at relapse was 55.5 (range, 33.4–68.5) years and 106 pts (55%) were male. The ISS was I(54, 28%)/II(84, 44%)/III(54, 28%). Serum LDH level was elevated in 133 (69%) and sCr ≥2mg/dL was in 35 (18%). The data of conventional cytogenetic analysis was available in 156 pts (79%). Thirty-three (21%) were abnormal. Of these, 26 pts (79%) had complex chromosomal abnormalities, 15 (45%) del(13q), and 6 (18%) hypodiploidy. One hundred sixty (83%) received VAD as induction therapy for first ASCT. Conditioning regimen for first ASCT was MEL 140–200 mg/m2 in 187 (97%). Fifty-six (29%) received maintenance therapy after first ASCT. Response to front-line ASCT was 67 CR (35%), 39 VGPR (20%), 68 PR (35%), 13 MR/SD (7%), 5 PD (3%). The median TTP after first ASCT was 12.0 (range, 1.1–83.8) months, and pts with ≥18 months of TTP after first ASCT were 57 (30%). After matching process, we identified it was successful because the distribution of 9 matching variables and unmatched other variables (ECOG performance status, hypercalcemia, bone lesions) was balanced between 2 groups. 2nd ASCT conditioning consisted of MEL alone in 45 (94%), the remaining 3 had MEL with busulfan or bortezomib. Only one transplant-related death occurred following 2nd ASCT. Novel agents used as salvage therapy in their course of disease were bortezomib in 151 (79%), thalidomide in 138 (72%), and lenalidomide in 6 (3%). Thalidomide was less frequently used in the 2nd ASCT group than the systemic chemotherapy group (58% vs 80%, p=0.016). With a median follow-up of 55.3 (range, 3.4–140.0) months, the 2nd ASCT group revealed significantly better progression-free survival (median, 18.0 [95% CI, 15.2–20.8] months vs 9.1 [6.7-11.5] months, p=0.017, respectively) and overall survival (OS; median, 55.5 [46.2-64.8] months vs 25.4 [16.7-34.1] months, p=0.035, respectively) than the systemic chemotherapy group. In multivariate analysis for OS, Conclusion: The outcomes of salvage 2nd ASCT appear superior to those of systemic chemotherapy, even fewer pts in the 2nd ASCT group received thalidomide. Additionally, 2nd ASCT was an independent prognostic factor for better OS. Considering current low mortality of 2nd ASCT, our results might provide a substantial evidence for performing 2nd ASCT in relapsed myeloma pts and suggest the value of performing a prospective randomized trial comparing 2nd ASCT and systemic chemotherapy in pts relapsed after front-line ASCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 2021 Background: High dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become the standard approach for relapsed or high risk non-Hodgkin's lymphoma (NHL). Several different high dose therapy (HDT) conditioning regimens have been used for non-Hodgkin's lymphoma (NHL), such as BEAM (carmustine, etoposide, cytosine arabinoside, melphalan), BEAC (carmustine, etoposide, cytosine arabinoside, cyclophosphamide), and CBV (cyclophosphamide, carmustine, etoposide). Carmustine is an active drug in the HDT of NHL but the supply of carmustine is limited in some countries including Korea. Intravenous busulfan containing regimens as conditioining regimen have been used for both allogeneic and autologous stem cell transplantation in patients with hematologic and non –hematologic malignancies. The purpose of this prospective multicenter phase II study was evaluate the efficacy and safety of iv busulfan/melphalan/etoposide regimen as a conditioining regimen for high dose chemotherapy in the patients with relapsed or high risk NHL. Methods: Patients with relapsed or primary refractory NHL or chemosensitive high risk NHL underwent high dose chemotherapy followed by ASCT at 13 centers in Korea. The conditioning regimen consisted of iv busulfan 3.2mg/kg/day i.v. on days −8, −7 and −6, etoposide 400mg/m2/day i.v. on days −5 and −4 and melphalan 50mg/m2/day i.v. on days −3 and −2. Results: Fifty one patients were enrolled onto the study. Main subgroups were DLBCL (n=25, 49%) and T cell lymphoma (n=19, 37%). At the time of ASCT, the disease status of patients was as follows: 13 patients were high risk in remission, 16 were primarily refractory to inducton therapy, 15 patients were in chemosensitive relapse. All patients had successful stem cell engraftment with a median time to neutrophil recovery of more than 500/mm3 of 10 days (range, 2 to 30 days). Platelet recovery of more than 20,000/mm3 was seen after a median of 10 days (range, 2 to 51 days) with delayed recovery in one patient. Treatment related toxicities included nausea/vomiting in 28 patients (55%), diarrhea in 28 patients (55%) and mucositis in 33 patients (65%), which were grade I or II in the majority of cases. Grade I/II hepatic toxicities occurred in 24% (n=12) and grade III in 6% (n=3). There were no VOD and treatment related death. The median duration of hospitalization for ASCT was 30 days (range, 12 to 80 days). Forty one patients (80%) achieved a complete response 1 month after ASCT, while three patients showed progressive disease. At a median follow up of 14.7 months, 21(41%) patients exhibited a relapse or progression, while 11 patients had died of disease and one patient had died of heart failure. The estimated 2-year overall and progression free survival for all patients was 64% and 40%, respectively. Conclusion: This preliminary analysis suggests that conditioning regimen of i.v. busulfan/melphalan/etoposide would be well tolerated and effective in patients with relapsed or high risk NHL. Accordingly, this regimen may be regarded as an important treatment option to substitute for BEAM regimen. Disclosures: Lee: Novartis: Research Funding.

Abstract 2044 Background: Induction treatment followed by autologous stem cell transplantation (ASCT) is the standard therapy for the newly diagnosed younger patients with multiple myeloma (MM). Although new drugs such as lenalidomide or bortezomib have been shown the promising results as induction treatment, many different type of induction treatment regimens still have been used. We evaluate the efficacy and safety of the short course of high dose dexamethasone (HD dexa) and the response adapted PAD (Bortezomib, Adriamycin, Dexamethasone) or VAD (Vincristine, Adriamycin, Dexamethasone) induction chemotherapy in the newly diagnosed younger patients with MM. Methods: 107 newly diagnosed patients with MM from 21 institutions received 2nd cycles of HD dexa followed by PAD or VAD chemotherapy according to the response to the initial high dose dexamethasone. The primary endpoint was complete response (CR) + near CR rate after ASCT. Among 107 patents enrolled this study from November 2009, 25 patients (23%) have been dropped out. This trial will be continued until total 210 patients will be enrolled. The trial is registered on National Cancer Institute website, number NCT01255514. Results: One hundred seven patients (58 male, 49 female) were enrolled (median age; 56). 26 (24%) light chain disease were included. 31 (29%) patients were D-S stage II and 67 (63%) were stage III. According to the ISS, 23 (22%) patients had stage I, 51 (48%) had stage II and 33 (31%) had stage III. 26 (24%) patients had abnormal cytogenetics. There were 31% del13, 7% del17, 19% t(4;14), 15% t(14;16) and 28% t(11;14) in FISH analysis. Among the 82 evaluable patients, CR + PR rate was 48% (39/82) after 2nd cycles of HD dexa therapy. 39 patients (48%) received subsequent VAD chemotherapy and 43 patients (52%) received PAD chemotherapy. Among the 64 patients finished VAD or PAD chemotherapy, CR + PR rate was 83% (79%, 26/33 in VAD group vs. 87%, 27/31 in PAD group). 56 patients were finished ASCT until now. CR + near CR rate after ASCT were 61% (58% in VAD group vs 63% in PAD group). Mortality rate of this trial was 13% (11/82). The cause of death was disease progression (n=3), bleeding (n=1) and infections (n=7). Among 82 patients in whom VAD or PAD chemotherapy was actually performed, 1 year overall survival (OS) rate was 84.7%. 1 year survival rate was 93.8% versus 77.2% (P=0.049) with VAD versus PAD (median follow-up; 9.1 months). Conclusion: Risk adapted approach using initial steroid response showed good response results after ASCT compared with previous trial (CR + near CR rate of IFM 2005-01trial-Bortezomib+dexa induction & ASCT was 35%, J Clin Oncol. 2010;28:4621–9) The MM patients who had poor response to HD dexa also showed similar good response rate after ASCT compared with the patients who had good response to HD dexa treatment in this trial. PAD re-induction therapy after failure of initial steroid induction treatment might overcome the inferior results in the high risk MM patients. Therefore, initial steroid response adapted strategy might be the more cost-effective approach in the newly diagnosed ASCT eligible MM patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 1010 Background: Numerous studies have been reported non-HLA genetic associations with acute graft vs host disease (aGVHD) developing after allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, however, relatively few genes have been examined in each cohort. Meanwhile, aGVHD represents one of the most attractive targets to study the effect of normally silent genetic polymorphisms. We intended to elucidate genetic determinants predicting aGVHD in patients undergoing allo-HSCT by genome-wide screening of genetic polymorphisms, and develop a SNP model to predict development of aGVHD. Methods: Genetic polymorphisms predicting development of aGVHD were determined through successive 5 stages in a total of 429 patients who underwent allo-HSCT. Firstly, we screened genomic determinants predicting aGVHD using 109K SNP chip (Sentrix Human-1 GT Bead Chip, Illumina) in 15 patients (7 patients with aGVHD and 8 without aGVHD). At stage 2 and 3, low-density Immumina chips comprising 768 candidate SNPs and 96 SNPs, respectively, were manufactured and tested in independent cohorts of 91 patients (34 patients with aGVHD and 57 without aGVHD) and 84 patients (35 patients with aGVHD and 49 without aGVHD), respectively. At stage 4, 76 SNP chips comprising 33 SNPs discovered from the previous studies and also 43 SNPs reported to be associated with aGVHD in the literature were manufactured and evaluated in 36 patients (13 patients with aGVHD and 23 without aGVHD) undergoing allo-HSCT. Finally, 7 SNPs were chosen and validated in an independent cohort of 203 patients (50 patients with aGVHD and 153 without aGVHD) using TaqMan assay. Results: At stage 1, 955 SNPs were identified to be significantly associated with development of aGVHD by whole genome assay. At stage 2, candidate genetic determinants were narrowed down to 74 SNPs. Through stage 3 and 4, 7 SNPs including the two selected from the literature review (transforming growth factor beta receptor II (TGFBR2) and interleukin-18) were finally determined as predictive markers for aGVHD. The 7 SNP model was found to be effective in predicting the development of aGVHD after allo-HSCT. When decision tree model was applied, the sensitivity, specificity, accuracy, and area under ROC (AUR) of the 7 SNP model to predict aGVHD were 80.5%, 80.4%, 80.4% and 91.6%, respectively. Conclusion: A genome-wide association study approach was successful in elucidation of genetic determinants associated with development of aGVHD in patients undergoing allo-HSCT. The 7 SNP model was effective in predicting the development of aGVHD after allo-HSCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 2272 To test the correlation of trough plasma Imatinib Mesylate (IM) levels and pharmacogenomic variation with cytogenetic or molecular responses, we measured trough plasma IM levels and analyzed various genetic polymorphisms in newly diagnosed CML patients at 6 months of IM treatment and compared them with the likelihood of achieving cytogenetic complete response (CyCR) or major molecular response to standard dose of IM. Newly diagnosed 94 CML patients were prospectively enrolled in the current study. CyCR was achieved in 71 patients (75.5%). Eighty-four patients (89.4%) showed optimal response (CyCR + cytogenetic partial response CyPR) at 6 months. Trough plasma IM levels were highly variable ranging from 203 to 4980 ng/ml: mean (±SD) was 1392±78.8 ng/ml. Among 47 patients with trough plasma IM level of The impact of single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2B6, CYP2C8, CYP1A2) and transporter genes (hOCT1, hOCT2, hOCT3, ABCG2, ABCC2, SLCO1B1, ABCB1) potentially associated with IM trough level was also investigated. The AA genotype in CYP2C19*2 (681G>A) was significantly associated with higher IM trough level than dominant genotype (p=0.021), whereas transporter genes did not show any significant results. The CC genotype of ABCG2 (421C>A) gene was related with CCyR (OR 3.47, 95% CI 1.09–11.05; p=0.030). In conclusion, the incidence of optimal responses in newly diagnosed CML patients who had been treated with standard dose of IM for 6 months was significantly higher in the patient group with trough plasma IM level of ≥1320 ng/ml than the group with Disclosures: No relevant conflicts of interest to declare.

Abstract 3874 Poster Board III-810 Introduction Myelomatous pleural effusion (MPE) in multiple myeloma (MM) is rare ( Patients and Methods Multicenter retrospective data of MM patients presenting MPE, who were diagnosed from January 1998 to June 2009 were analyzed. Diagnosis of MPE was based on positive cytology or biopsy in conjunction with M protein by protein electrophoresis or immunofixation in pleural effusion. Results The median age was 53 (range 21-78). Twenty patients were male and 10 were female. The myeloma isotype was IgG in 8, IgA in 7, IgD in 5, light chain in 9 and non-secretory myeloma in 1 patient. Most patients had high-risk disease based on initial D-S stage IIIA or IIIB (83%). Thirteen of 19 patients, who had available BM chromosomal analysis or FISH result, showed various karyotypic abnormalities including deletion of chromosome-13 (n=8). MPE was the first manifestation of MM in 11 patients (early-onset group). In the other 19 patients (late-onset group), MPE developed at a median of 20 months (range 1 – 75) from diagnosis of MM. The effusions were left-sided in 6, right-sided in 9 and bilateral in 15 patients. In more than half of the cases, a thoracic skeletal lesion, lung parenchymal lesion, pleural involvement or mediastinal lymphadenopathy was concomitantly present. Before the development of MPE, median 2 lines of chemotherapy (range 1 – 9) were applied in late-onset group. Seven patients of this group received high-dose chemotherapy with stem cell transplantation (6 autologous and 1 allogeneic stem cell). After onset of MPE, the median number of chemo-regimen was 1 (range 0 -3) in both groups and 3 patients got high-dose chemotherapy with autologous stem cell transplantation (1 in early-onset and 2 in late-onset group). After onset of MPE, total 27 chemo-regimens were applied to 19 patients and the regimens were based on VAD (vincristine, adriamycin, dexamethasone) in 12, thalidomide in 5, bortezomib in 4 and other regimen in 6. Pleurodesis was done in 2 patients. MPE disappeared in 11 patients and median response duration, defined as days from disappearance to relapse of MPE or death of any cause, was 123 days (95% confidence interval (CI): 10 – 236). Median survival was 66 days (95% CI: 29 – 103) from onset of MPE and 16 months (95% CI: 5 – 28) from initial diagnosis of MM. From onset of MPE, median survival was 84 (95% CI: 57 – 111) and 55 days (95% CI: 0 – 113, p=1.0) in early and late-onset group, respectively. From initial diagnosis of MM, median overall survival was 2.8 (95% CI: 2.4 – 3.2) and 26 months (95% CI: 12 – 40, p Conclusions Base on this analysis, MPE is a poor prognostic indicator, irrespective of the time of onset. When pleural effusions develop in a patient with MM, clinicians should perform prompt and appropriate diagnostic work-up. In the case of MPE, aggressive treatment including novel agents or autologous stem cell transplantation should be considered, especially if MPE is the initially presenting manifestation of MM. Further evaluation of the utility of various novel chemotherapeutic agents in the setting of MPE is needed to improve treatment outcome. Disclosures: No relevant conflicts of interest to declare.

Abstract 4956 Introduction Osteonecrosis of the Jaw (ONJ) is a potentially serious complication of bisphosphonate (BP) therapy in multiple myeloma (MM). Despite of current update about bisphosphonate related ONJ (BRONJ), only a few Asian BRONJ cases were reported and incidence of BRONJ in Asian MM patients has not yet been definitively estimated. The purpose of this study was to determine incidence and characteristics of BRONJ in Korean MM patients who were receiving BP therapy. Patients and Methods We invited 9 hospitals of Korean Multiple Myeloma Working Group (KMMWP) to participate in a retrospective multicenter study on BRONJ in MM patients. To defined BRONJ incidence, we reviewed the data from 130 MM patients treated with BP in one hospital. We also reviewed the medical records of MM patients with BRONJ treated in 9 hospitals to know the patterns of disease. We analyzed patient and disease characteristics, type and number of BP infusions, previous history of dental procedures, locations of osteonecrosis, clinical symptoms, treatment and outcome. ONJ was defined as clinical evidence of exposed bone in the jaw, which has been present for more than 8 weeks. Results Nine of 130 MM patients (6.9%) treated with BP developed BRONJ in the hospital. Twenty-two patients with MM developed BRONJ after a median number of 17 BP infusions (range 6 - 50) in all 9 hospitals. None of the patients had been irradiated to the jaw. There were 14 male and 8 female patients. The median age was 62 years (range 46 – 75). Median time from MM diagnosis to BRONJ was 2.8 years (range 0.6 – 15.6). The MM isotype was IgG in 9, IgA in 8, IgM in 1, light chain in 3 and non-secretory myeloma in 1 patient. BP therapy included zoledronate (n = 2) or pamidronate (n = 4) and both drugs as sequential treatment (n = 16). Fifteen patients had recent problems in oral cavity (72.7%) and 14 had prior dental procedures (63.6%). The mandible was involved in 14 patients (63.6%), the maxilla in 7 (31.8%), and both the maxilla and mandible in 1 (4.5%). Patients usually presented with pain and soft tissue swelling. ONJ staging (Khan et al. Canadian consensus practice guidelines of Bisphosphonate associated ONJ. J Rheumatol 2008;35:1391-7) was used to define the severity, there were 5 patients in stage I, 14 in stage II and 1 in stage III. Because of the limitation of retrospective study, the stage of 2 patients could not be confirmed. Management of these established cases were discontinuation of BP and medical treatment including antibiotics and pain killer. Surgical debridement of necrotic bone was performed in 12 patients. From onset of exposed bone in jaw, patients were followed for median 11 months (range 4.2 - 42). Wounds of 10 patients were healed at median 175 days (range 60 – 404) after bone exposure. In 8 patients, lesions had persisted over 154 days (range 66 – 425). Evaluation was impossible for 4 patients due to loss of follow up. Four patients were dead because of disease progression (n = 3) or concomitant infection. BRONJ was healed in 2 of them. Conclusions To the best of our knowledge, this is the largest retrospective study ever reported about BRONJ in Asian MM patients. The incidence of BRONJ in Korean MM patients was 6.9% and this is similar with data in western countries. Clinical manifestations and outcome of BRONJ in Korean patients were not different from previously reported data, but no risk factors could be definitively identified with our retrospective analysis. In the name of KMMWP, prospective trials are ongoing to define incidence and risk factors of BRONJ in Korean MM patients. Disclosures No relevant conflicts of interest to declare.

Introduction: The junctional adhesion molecule 2 (JAM2) gene plays a key role in tight junction formation in epithelial and endothelial cell. We studied JAM2 polymorphism in GVHD and non-GVHD patients after allogeneic stem cell transplantation. Methods: We tested 3 sites of JAM2 gene - rs2276220 (G/A), rs963103 (T/C), rs974680 (G/A) - and studied the possible link between the JAM2 polymorphism and the risk of GVHD. We studied 251 patients who had treated with allogeneic stem cell transplantation. The three-SNP block study was performed with rs2276220-rs963103-rs974680 haplotypes. The JAM2 gene was screened for polymorphisms by SNaPShot method. We used SAS version 8.1 (SAS Institute Inc., Cary, NC, USA) for statistic analysis. The odds ratio and p-value was adjusted with multiple logistic regression analysis about age, gender, stem cell source, disease status at the time of transplantation, and conditioning regimen. Results: The minor allele C of rs963103 (T/C) was dominant in patients with acute GVHD (Odds ratio (OR) 2.918, 95% confidence interval (CI) 1.178~7.233; p=0.0207). This phenomenon was distinct in gut GVHD (OR 1.684, 1.019~2.784; p=0.0419). The minor allele A of rs2276220 (G/A) was dominant in patients with infection after allogeneic stem cell transplantation (OR 6.058, 1.266~28.979; p=0.0241). The overall survival (OS) was associated with rs2276220 (hazard ratio (HR) 0.887, 95% CI 0.633~1.242; p=0.0346) and rs974680 (HR 0.969, 0.763~1.23; p=0.0193). The progression-free survival (PFS) was associated with rs2276220 (HR 0.761, 0.544~1.064; p=0.0095) and rs974680 (HR 0.551, 0.274~1.108; p=0.0382). In three-SNP block study which was performed with rs2276220- rs963103-rs974680 haplotypes, ATA (HR 0.844, 0.645~1.105; p=0.0016) and GTA (HR 5.568, 1.686~18.384; p=0.0048) was associated with OS. ATA (HR 0.796, 0.559~1.133; p=0.0039) and GTG (HR 1.339, 0.834~2.149; p=0.0353) was associated with PFS. Conclusions: The JAM2 gene polymorphism rs963103 was associated with acute GVHD especially with gut GVHD after allogeneic stem cell transplantation; with higher risk in carriers of the C allele. The JAM2 gene polymorphism rs2276220 was associated with infection, OS, and PFS after allogeneic stem cell transplantation; with higher risk in carriers of the A allele.

Chronic graft-versus-host disease (GVHD) is one of the most serious long-term complications following allogeneic hematopoietic stem cell transplantation. The pathophysiology of chronic GVHD is poorly understood. Certain genes may affect the outcome by modulating tissue injury with the alloimmune reaction. We assessed the gene profiles of 21 transplant recipients with oligonucleotide microarray (CodeLink®) containing 20,142 probes. All patients received hematopoietic stem cells from HLA-matched sibling donors except one who’s HLA was mismatched in one A locus. All patients were in complete remission and in complete chimerism state. Among the 21 patients, 11 had chronic GVHD and 10 not. RNAs were extracted from peripheral blood mononuclear cells of the transplant recipients. Sample-wise hierarchical clustering of the whole gene expression profile showed tendency of GVHD patients aggregating in the dendrogram. In GVHD patients, 141 genes were revealed up-regulated by SAM method. Gene ontology annotation of these genes indicated that up-regulated genes were related with proteolysis, lipid biosynthesis, phosphate metabolism and tissue development. A total of 461 pathways were examined to find the pathways showing differential expression patterns between GVHD and non-GVHD patients. The results showed that 227 pathways were statistically significant. These pathways included many immune-related processes, including T cell receptor signaling pathway, T helper cell surface molecules pathway, and HIV induced T cell apoptosis. With the 17 selected classifier genes, prediction accuracy of PAM algorithm was 86%. We could identify differentially expressed genes and pathways in chronic GVHD patients using oligonucleotide microarrays. We also found that extracted classifier genes showed relatively high prediction accuracy. Gene expression profile data may provide new insights into biological mechanism underlying GVHD and reveal disease-associated biomarkers of potential therapeutic targets.