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Abstract Abstract 2797 Poster Board II-773 Background: Primary systemic amyloidosis (AL) is characterized by deposition of light chain derived amyloid fibrils in multiple organs leading to varying degree of dysfunction. Cardiac involvement is a common feature of AL, and when significant is highly predictive of poor outcome. The currently used prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro B-type Natriuretic peptide (NT-ProBNP) and is effective at predicting outcome in patients with AL. However, this is driven primarily by the degree of cardiac involvement and does not take into account the degree of plasma cell burden and its impact on the disease course. It is possible that some of the heterogeneity in outcome can be explained by the plasma cell characteristics rather than the degree of the end organ damage. Methods: We examined the baseline clinical and laboratory data from 2119 patients with AL who were seen at our institution with in 90 days of their diagnosis. The data were collected from a prospectively maintained data base, and additional testing was done for free light chain levels (FLC) on stored sera from patients seen before the routine introduction of FLC testing. Cox proportional hazards analysis was performed to estimate the prognostic values of different variables. Results: We first examined the impact of plasma cell clone related characteristics namely, difference between involved and uninvolved FLC (FLC-Diff), bone marrow plasma cell (BMPC) %, plasma cell labeling index (PCLI), beta 2 microglobulin (B2M), and presence of circulating plasma cells, on overall survival (OS) from diagnosis. All variables were dichotomized into high and low based on their median value (FLC-diff: 20 mg/dL, BMPC: 10%, PCLI as a continuous variable, B2M: 3 mg/dL and circulating cells: absent or present). While all were found to be prognostic for OS in univariate analysis; in a multivariate analysis incorporating a stepwise selection only B2M and FLC-diff were significant. We then used these two variables along with the cTnT and NT-ProBNP that are used in the current model to develop a staging system. The median values for all four variables were used for developing the scores. Patients were assigned a score of 1 for presence of each characteristic (FLC difference > 20 mg/dL, troponin-T > 0.02, NT-ProBNP > 1000, and B2M > 3) or 0 if the value was at or below the cutoff. The scores were added to obtain a composite prognostic score that grouped the 370 patients (who had all the variables available for analysis) into 5 groups with very different OS (4.4, 9.3, 24.4, 43, and not reached for stages 4, 3, 2, 1, and 0 respectively; Figure A). However, since the NT-ProBNP did not have independent impact on survival in a multivariable model incorporating all the four variables, we also examined a system that only included FLC-diff, cTnT and B2M. This system again allowed grouping of patients (n=450 with all three variables available) into four distinct groups with divergent outcome with OS of 4.6, 10.5, 36.8, and not reached for stages 3, 2, 1, and 0 respectively; (Figure B). Conclusion: Incorporation of plasma cell related measurements into the existing staging system using cardiac biomarkers allows better risk stratification of patients with AL amyloidosis. The system using FLC, B2M and troponin has the advantage of easily available laboratory values and can be widely adopted. Addition of NT-ProBNP into the system allows better refinement of the intermediate risk groups. This system will allow upfront risk stratification and development of risk-adapted therapies for patients with AL. Disclosures: Gertz: Genzyme: Research Funding.

Abstract Abstract 1892 Background: Primary or light chain amyloidosis (AL) is a clonal plasma cell disorder characterized by a relatively low plasma cell burden and multi-organ deposition of immunoglobulin light chain derived amyloid fibrils. The survival of patients with amyloidosis is quite variable with median survival of 12–18 months in different series, and largely dependent on the number and severity of organs involved. In addition to new drugs, the combination of melphalan and dexamethasone is an effective regimen for AL and risk adapted approaches to SCT has decreased treatment related mortality. It is not clear if the recent progress in risk stratification and treatment approaches have translated into improved survival for these patients. Methods: We studied two separate cohorts of patients; the first cohort consisting of 2118 patients with AL seen at Mayo Clinic over a 40-year period between November 1967 and August 2006 was used to examine the trends in overall survival from diagnosis during this time period. The second cohort of 443 patients seen between September 2006 and August 2009 were examined only for the changes in early mortality and for validation of a model for predicting early mortality developed using the first cohort of patients. Results: The estimated median follow up for the entire group was 7.8 years (95% CI; 7.1, 8.5). The patients were divided into 4 cohorts based on date of diagnosis; 1966–1976 (n=121), 1977–1986 (n=343), 1987–1996 (n=636) and 1997–2006 (n=1017). The median OS from diagnosis for the four cohorts were 0.9, 1.2, 1.2 and 1.5 years respectively, P < 0.001 (Figure 1). More importantly there was steady improvement in the long-term survival among these patients with 4-year survival estimates of 16%, 21%, 24% and 33% respectively. Next, we specifically looked at the survival trends within the last cohort (1996-2006), dividing the patients into three time periods; 1996–1999 (n=263), 2000–2003 (n=291) and 2003–2006 (n=463). While the OS from diagnosis was relatively unchanged between the first and second time periods (28 vs. 30% 4 year survival), there was significant improvement in the last three year period (42% survival at 4 years); P =0.02. Given the high early mortality in this disease, we specifically examined the one-year mortality among the entire patient cohort and found no clear improvement in terms of one-year mortality. Using logistic regression analysis, we identified cTnT > 0.01, NT-ProBNP > 4200 and Uric Acid > 8.0 mg/dL to be the best predictors of death within one year of diagnosis. The probability of death within one year for those with none, 1, 2, and 3 risk factors was 19, 38, 61, and 78% respectively, P < 0.01 (Figure 2). This model was further validated among patients seen during the most recent three years, September 2006 and August 2009. Conclusion: Survival in AL amyloidosis has improved over time, particularly in the recent years and likely reflects the recent improvements in therapy. However, early mortality remains a problem and baseline factors can be used to identify patients at risk for early mortality, who then can be targeted for risk adapted therapy approaches in clinical trials. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Abstract Abstract 2574 Rasburicase is a recombinant urate oxidase approved for the prevention of tumor lysis syndrome (TLS). In adults, the recommended dose is 0.2 mg/kg intravenously daily up to 5 days. For a 75 kg person, the cost is over $5100. Given the vast reduction of uric acid seen with this dose, it may be possible to use a reduce dose. The aim of this study is to evaluate the effectiveness of 0.1 mg/kg dose vs the recommended dose in the prevention of TLS. Between October of 2003 and February of 2009, all patients with a hematologic or oncologic diagnosis who received rasburicase were reviewed. Rasburicase had been dosed at either 0.1 mg/kg (low dose) or 0.2 mg/kg (standard dose) due to variations in practice among the practitioners. Rasburicase was given on the first day of chemotherapy and repeated as necessary. Renal insufficiency was defined by 0.5 mg/dl rise in serum creatinine (Scr) within 7 days of chemotherapy initiation. The need for dialysis was recorded separately. Labs were performed pretreatment and usually daily after chemotherapy until electrolytes stabilized. A multivariate analysis using pretreatment labs was performed to determine risk factors for renal insufficiency or failure. During the study period, 125 patients received rasburicase. Fifty-five patients received low dose rasburicase and 70 received the standard dose. The diagnoses are listed in Table 1. Lactate dehydrogenase (LDH) was similar between the two groups (604 U/l in low dose vs 665 U/l in standard dose, p = 0.69). Additional doses were required in 14.5% of the low dose patients vs 21.4% of the standard dose patients, p = 0.36. Renal insufficiency was noted only in the standard dose patients 7.4% vs 0%, p = 0.04. Rates of dialysis were similar between low dose patients 7.3% vs 17.4% in the standard dose patients, p = 0.10. Dialysis was often initiated for hyperkalemia and hyperphosphatemia. Only 12.5% were started for elevation in Scr. Uric acid reduction was higher in the standard dose patients (90.4 ± 15.8%) as compared with low dose patients (82.0 ± 19.0%, p = 0.01). Pretreatment Scr, uric acid and phosphorus levels were found to be significant variable for dialysis but only uric acid was found to be significant in the multivariate analysis. Pretreatment uric acid was a risk factor for dialysis (p < 0.001) but not for renal insufficiency (p = 0.24). Our results suggest that low dose rasburicase may be as effective as 0.2 mg/kg. While high dose rasburicase was more effective at reducing uric acid, it did not reduce the need for dialysis because dialysis was often needed for hyperkalemia and hyperphosphatemia which rasburicase did not affect. Despite bias, our results suggest low dose rasburicase may be a viable alternative and definitely support further study into its use. The potential savings could be enormous given that it would be $2550 per patient. Table 1. Baseline diagnosis of 125 patients with TLS Diagnosis Low dose Standard dose dose Diffuse large B-cell lymphoma 13 17 Chronic lymphocytic leukemia 3 12 Multiple myeloma 7 5 Non-Hodgkin's lymphoma 4 7 Acute myeloid leukemia 4 7 Burkitt's lymphoma 3 4 T-cell lymphoma 4 3 B-cell lymphoma 5 1 Solid Tumor 1 5 Myelofibrosis 3 2 Mantle cell lymphoma 3 1 Amyloidosis 0 2 Blast crisis in acute leukemia 1 1 B-cell lymphoproliferative disorder 0 1 Chronic myeloproliferative disorder 0 1 Follicular mixed lymphoma 0 1 Hodgkin's lymphoma 1 0 undifferentiated 1 0 Lymphoreticular myeloid malignancy 1 0 Post-transplant lymphoproliferative disorder 0 1 Splenic marginal cell lymphoma 1 0 Waldenstrom macroglobulinemia 1 0 Total 55 70 Disclosure: No relevant conflicts of interest to declare.

Abstract Background: High dose melphalan followed by autologous stem cell transplant (ASCT) is an effective treatment of immunoglobulin light chain amyloidosis (AL). However, the high treatment related mortality (TRM, death before day 100) remains a serious concern and is the major drawback of this therapy. A better understanding the risk factors contributing to TRM could help physicians choose the most appropriate therapy for these patients. We performed a retrospective study to identify risk factors that contribute to TRM after ASCT in AL patients. Methods: All patients who underwent ASCT for AL at our institution from 7/96 to 12/04 were studied. Data were collected on age, sex, septal thickness, glomerular filtration rate (GFR), B2M, CRP, proteinuria, albumin, cardiac troponin T (cTnT) and alkaline phosphate. Results: A total of 218 patients underwent ASCT for AL during this time period. One patient refused consent for this study. Pretransplant cTnT was available on 161 (73.9%) patients. The overall TRM rate for the 217 patients was 12.4%. By univariate analysis, septal thickness, GFR, albumin, alkaline phosphatase and cTnT were found to be associated with TRM. In the multivariate analysis, only albumin, alkaline phosphatase and cTnT remained independent predictors of TRM. Cutoffs were identified using receiver-operator characteristic (ROC) curve. The cutoff for albumin was 2.85 g/dL, 249 U/L for alkaline phosphatase and 0.02 ng/mL for cTnT. The percentage of patients with low albumin, elevated cTnT and alkaline phosphatase were 51.1%, 20.5% and 12.4% respectively. The TRM rate of patients with low albumin was 18.0%, 27.3% for elevated cTnT and 29.6% for high alkaline phosphatase. Risk of TRM increased significantly with each additional risk factor (Table). Discussion: In our AL population, low serum albumin, elevated alkaline phosphatase and cTnT were independent risk factors of TRM after ASCT. Patients with 2 or more risk factors are at significant risk of TRM during ASCT. In these high risk patients, alternative therapy should be considered in order to avoid excessively high incidence of TRM. Treatment Related Mortality by Number of Risk Factors Risk Factors 0 1 2 3 Rate of TRM 1.8% 8.4% 35.0% 66.0% Odds Ratio 5.0 29.1 108.0

Abstract Introduction Refractory pleural effusions present a challenging management problem and are associated with a poor prognosis in patients with primary systemic amyloidosis (AL). Vascular endothelial growth factor (VEGF) has been implicated to play a role in both malignant and non-malignant pleural effusions through its ability to regulate vascular permeability. VEGF can induce morphologic changes in vascular endothelial cells, regulate gene expression, stimulate cell proliferation and migration, and inhibit apoptosis. We report a series of four patients with AL who presented with bilateral pleural effusions that were refractory to diuretic therapy. After treatment with bevacizumab, an anti-VEGF antibody, three of the four patients had improvement in their pleural effusions, peripheral edema, and functional status. Methods A retrospective chart review was conducted four patients with AL and refractory pleural effusions who received bevacizumab. Three of the patients had documented renal amyloid by biopsy and two had suspected cardiac involvement. Serum creatinine ranged from 1.3–3.8 mg/dL (mean=2.15 mg/dL), 24 hour urine protein ranged from 190 mg – 12.5 grams per 24 hours (mean=6.1 grams). Bevacizumab 5 mg/kg was administered for 1–4 cycles (mean=2). Results Three of the four patients had demonstrable improvement in their pleural effusions, peripheral edema and functional status after a single dose of bevacizumab. One patient had no objective response to treatment. The three responders experienced a 2–7 kg (mean= 4.6 kg) decrease in weight within two weeks after receiving bevacizumab. This effect was observed in patients who were re-treated. All three patients received concurrent diuretic therapy, however, they had not previously responded to diuretic therapy. Two weeks after the first dose of bevacizumab, the 24 hour urine protein of the patient who received four cycles of bevacizumab increased to 18.2 grams per 24 hours, however it returned to baseline (12.5 grams per 24 hours) one week later, and increased slightly to 13.3 grams per 24 hours after the fourth dose. A second patient also experienced an increase in 24 hour protein excretion (6.9 grams per 24 hours to 9.2 grams per 24 hours) after the first dose of bevacizumab. One patient experienced a deep vein thrombosis after the third cycle of bevacizumab. No hemorrhagic complications were observed. Conclusion Bevacizumab may represent a novel non-invasive management strategy for patients with systemic amyloidosis and diuretic-refractory pleural effusions, however, additional studies are needed to further define the role of bevacizumab in the management of this group of patients.

Abstract Background: Renal insufficiency of varying severity including end stage renal disease requiring dialysis is often a presenting manifestation of multiple myeloma (MM). While many patients (pts) improve following initiation of therapy for MM, a considerable number of pts proceed to stem cell transplant with less than optimal renal function. It is not clear whether the outcome of their transplants differs from pts with normal renal function. Methods: The MM transplant database was searched to identify pts with a Creatinine clearance (Crcl) of less than 50 ml/min/m2 (study cohort). These pts were then matched to two pts each with a clearance of ≥ 50 ml/min/m2 (control cohort), based on cytogenetic abnormalities (normal vs. abnormal), circulating plasma cells (yes vs. no), age at transplant, % of plasma cells at transplant, plasma cell labeling index, time to transplant from diagnosis and the disease status at transplant, the factors used in that order of importance. Results: Eighty pts with a Crcl < 50 ml/min were identified and matched to 160 pts with Crcl ≥ 50 ml/min. The pts were matched for the above factors and the two groups were similar in terms of their other baseline features except CRP and B2M, both of which were lower in the control group. Pts with reduced renal function were more likely to receive dose reduced melphalan for conditioning (32.5%) compared to the control group (2%; P < 0.0001). The outcomes from the stem cell transplant were similar in both the groups. 96% of pts obtained an objective response to stem cell transplant in each of the groups with no difference in the time to response; and a complete response was seen in 38.5% and 36.6% of the study and control cohorts respectively (P=NS). The median post transplant progression free survival was 18.2 months and 18.4 mos respectively for the study cohort and the control group (P=0.4). However, the median overall survival from transplant was shorter for the study cohort (30.7 mos vs. 60 mos for the controls; P = 0.007; Figure). The time to platelet and neutrophil engraftment was not different between the groups. In terms of transplant related toxicity, the median days hospitalized was higher in the study group (5 days vs. 9.5 days; P=0.003) as was the incidence of grade 3 and 4 mucositis (8% vs. 23%; P= 0.0008). Six pts (7.5%) had treatment related deaths in the study group compared to 3 pts (2%) among the controls (P=0.03), the majority of the deaths being infection related. Conclusion: Here we demonstrate that pts with MM and reduced renal function derive disease free survival comparable to those with normal renal function, despite the increased use of reduced dose Melphalan for conditioning. The toxicity is clearly increased in the presence of abnormal renal function. Interestingly, the overall survival was inferior among the pts with reduced renal function. One possible explanation for this observation is the decreased availability of novel therapies for salvage among pts with reduced renal function as many of them would not be eligible for clinical trials due to reduced renal function. Figure Figure

Abstract BACKGROUND: Complement-mediated thrombotic microangiopathies (TMAs) are a subset of TMAs in which the thrombocytopenia, microangiopathic hemolytic anemia, and end organ damage are caused by mutations in genes encoding the alternative complement pathway. Numerous complement genes have been implicated in complement-mediated TMAs including complement factor H (CFH), CD46 (MCP), complement factor I (CFI), complement component 3 (C3), complement factor B (CFB), factor H related 5 (CFHR5), and thrombomodulin (THBD) among others. Genetic analysis typically yields a mutation in 60% of patients whose TMA is presumed to be mediated by complement dysregulation. However, the description of novel disease-associated variants may increase this proportion. METHODS: A retrospective study of patients with TMAs diagnosed between 2000 and 2014 was performed. TMA diagnosis was made based on thrombocytopenia and evidence of microangiopathic hemolytic anemia. Analysis was performed with Alamut¨ software with additional in silico prediction tools (SIFT, MutationTaster, and Polyphen) for classification of gene variants. Variants of unknown significance (VUS) and likely pathogenic variants were further assessed using several mutation databases, including HGMD, ClinVar, and Factor H database RESULTS: Of patients diagnosed with a TMA, genetic analysis was performed in only a 10% of patients. Of the 29 patients with genetic studies performed, mutations were identified in 18 patients (62%). The majority of the mutations had been described previously in the literature, but four novel variants were identified: three missense and one splice-site. The table below summarizes these variants as well as laboratory findings on presentation. These were two variants of CFH, one variant of CFHR5, and one variant of CFI. In silico modeling of these variants revealed two polymorphisms likely to be pathogenic, one polymorphism likely benign given the lack of predicted splicing changes, and one VUS. Table 1. Protein Mutation Classification Age Sex Hemoglobin (g/dL) Platelets (thousands) Creatinine (mg/dL) CFH c.245-10_245-9dup Likely benign 61 F 11.6 51 6.7 CFH c.476G>A, p.Ser159Asn Likely pathogenic 43 F 9.1 101 9.1 CFHR5 c.1412G>A p.Gly471Glu Likely pathogenic 30 F 9.8 129 4.9 CFI c.1190T>A p.Val397Glu Unknown significance 51 M 9.4 125 6.1 DISCUSSION: With therapy available to target the alternative complement pathway, genetic analysis to identify genetic variants capable of causing complement mediated TMAs is an essential part of the evaluation. This genetic data must be interpreted and correlated with functional analysis and clinical phenotype. The reporting of novel variants in clinical databases, with inclusion of relevant clinical findings, is necessary to accurately classify and verify variants as pathologic mutations or benign polymorphisms. The full understanding of this diverse disease requires a more complete understanding of its genetics. While complement pathway-directed therapies are available, their rational use requires thorough interpretation of laboratory data, including genetic analysis. Disclosures Murray: Mayo Clinic: Patents & Royalties: Patent Application Filed.

Abstract Abstract 1858 Systemic light chain amyloidosis (AL amyloidosis) is a condition where clonal plasma cells produce misfolded insoluble immunoglobulin light chains that deposit in various organs causing progressive organ dysfunction. Chemotherapy and autologous stem cell transplant (ASCT) when eligible is the standard treatment options for patients with AL amyloidosis. There are several studies who report long term outcomes of patient post ASCT. However, there is a paucity of literature describing the outcomes of patients who have received ASCT but have relapsed. We performed a retrospective study to assess the outcomes and treatment regimens employed following relapse after ASCT. Between 1996 and 2009, 410 patients received ASCT at the Mayo Clinic as first line therapy. Of those 410 patients 42 patients died within 3 months of transplant, 64 patients died without documented relapse, 158 patients were alive without documented progression, and 146 patients had documented progression. Those 146 patients are the subject of our study. The median time to hematologic relapse was 2 years (range: 0.2–15.5 years). At relapse, 59 patients were treated with IMiD based therapy, 36 with alkylator based therapy, 24 with bortezomib, 15 with steroids, and 5 with second ASCT. The respective hematologic response rates were 58%, 33%, 50%, 53%, and 60%. The remaining six patients were not evaluable for response for one other following reasons: organ transplants; no further therapy; inevaluable disease. With a median post relapse follow up of 3.6 years, the median overall survival (OS) from the first post ASCT relapse was 4.6 years. The median post transplant follow up was 6.1 years, the median OS for these patients was 7.3 years from the time of transplant. These data provide novel information about outcomes after SCT relapse, which should be useful not only for patients and doctors but also for investigators designing studies for salvage therapies post-transplant. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Among patients with immunoglobulin light chain (AL) amyloidosis, there is little consensus on when reinstitution of chemotherapy should occur (Milani and Dispenzieri, International Society of Amyloidosis 2016). AL amyloidosis patients who are treated with high dose chemotherapy followed by autologous stem cell transplant (ASCT) are a relatively low-risk and homogenous population, making them an ideal group to study practice patterns. Methods: We conducted a retrospective study to evaluate the patterns of relapse or progression and the timing of re-initiation of therapy among 146 patients who were initially treated with ASCT at Mayo Clinic between 1996 and 2009 and who received second-line therapy between 7/9/1997 and 4/12/2012. Results: The median time from ASCT to second-line therapy was 23.6 months and the median follow up post ASCT was 57.5 months. The indications for second-line treatment were: 1) both hematologic and organ progression 24.7% (36 patients); 2) organ progression only 41.1% (60); 3) hematologic relapse only 34.2% (50). The median dFLC at the time of starting second-line therapy was 10.5 mg/dL (1.6 - 59.5 mg/dL), which was 44.9% (13.8-167.2%) of dFLC level at diagnosis. Increase in proteinuria by > 50% from nadir (that was also at least 1g/24 hours, i.e. renal progression) was present in 35.8%. Increase in NT proBNP by >30% from nadir and minimum of 300 pg/mL was present in 48.9% of patients. The respective 4 years overall survival rates from the time of ASCT were 87.8%, 63.9%, and 56.7% (p=0.0016) for patients who had hematologic relapse, organ progression only and both organ and hematologic progression. Comparisons of laboratory markers at diagnosis, nadir of post ASCT and initiation of second-line therapy are listed in the table. Conclusions: Our study investigated the patterns of relapse / progression following upfront ASCT. This provides some insights on practice patterns of when physicians re-initiate therapy. Table Table. Disclosures Gertz: NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Novartis: Research Funding; Prothena Therapeutics: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria; Ionis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Annexon Biosciences: Research Funding. Kumar:Millennium: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Kesios: Consultancy. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Celgene: Research Funding; Jannsen: Research Funding; pfizer: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Introduction High dose chemotherapy and autologous stem cell transplantation (ASCT) is an effective therapy for eligible patients with newly diagnosed systemic AL amyloidosis. Dose attenuated melphalan is used in patients with older age, renal dysfunction, and multi-organ involvement in an effort to limit treatment related mortality. Reducing the dose of melphalan compromises response rates and survival outcomes, but this is often contributed to frailty of these patients. The revised Mayo staging (MS) system improves risk stratification and helps develop risk-adapted therapies. We analyzed the outcomes of ASCT following standard [(200 mg/m2); SD group] versus risk adapted [(140-160 mg/m2); RD group] melphalan conditioning, in the context of the factors typically leading to dose modification. Methods Three hundred and twenty nine patients with newly diagnosed systemic AL amyloidosis who underwent conditioning with melphalan followed by ASCT at Mayo Clinic between 2006 and 2015 were identified using existing databases. The clinical and laboratory data, treatment and follow - up details were collected by chart review and analyzed retrospectively. Overall survival(OS) was defined as the time from start of initial therapy until death from any cause or last follow up. Progression free survival(PFS) was defined as the time to relapse or progression requiring change or reinstitution of treatment or death from any cause. The OS and PFS curves were estimated using Kaplan-Meier method while log rank test was used to estimate their difference. Multivariate survival analysis was performed using the Cox proportional hazards model. Results Among the 329 patients, 240 patients were in SD group and 89 patients were in RD group (1 patient received 120 mg/ m2, 2 received 160 mg/m2 and the rest received 140 mg / m2). In the SD group, median age was 58.5 years (25.6 - 72.3); 59.6% were males; 38.7% / 61.7 %/ 7.5% had cardiac / renal /hepatic involvement; and 47.1% / 35.7% / 8.8% / 8.4% had MS I/II/III/IV. In the RD group, median age was 60.8 years (40 - 73.7); 62.9% were males; 66.3% / 71.9 %/ 11.2% had cardiac / renal /hepatic involvement; and 26.2% / 32.5% / 21.2% / 20% had MS I/II/III/IV. The response rates for patients in the SD group [complete response (CR) - 53.7%, very good partial response (VGPR) - 19.6%, partial response (PR) - 12.5%, no response (NR) - 1.2%, progressive disease (PD) - 1.6%] were significantly higher than patients in the RD group (CR - 34.8%, VGPR - 20.2%, PR - 15.7%, NR - 10.1%, PD - 1.1%) (85.8 vs 70.7%; p < 0.002). The PFS and OS for both the groups according to Mayo stage are presented in Figure 1. Multivariate survival analysis for PFS and OS was performed using age (≤ vs > 70 years), serum creatinine (≤ vs > 2 mg/dL), number of major organs involved (heart, kidney, liver, gastrointestinal tract and autonomic neuropathy), MS (1 vs 2 vs 3 and 4) and dose of melphalan (SD vs RD). The dose of melphalan (p=0.0002), MS (p=0.03) and the number of organs involved (p=0.04) were significant for PFS while the dose of melphalan (p=0.0001) and the MS (p = 0.004) were significant for OS. Conclusion Reducing the dose of melphalan during conditioning for frontline ASCT in systemic AL amyloidosis renders more patients eligible for transplant but compromises on the response rates. There is no impact on PFS and OS in Mayo stage I patients. However the OS as well as PFS in Mayo stage II, III and IV were significantly lower in RD group as compared to SD group. These results suggest a suboptimal outcome with use of reduced dose melphalan, even after accounting for the pother prognostic factors, suggesting that high dose therapy should potentially be limited to those eligible to receive the full dose conditioning. Disclosures Dispenzieri: Jannsen: Research Funding; pfizer: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Takeda: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Kumar:Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; Kesios: Consultancy; Noxxon Pharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding.