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Abstract Introduction: Outcomes in multiple myeloma have significantly improved in recent times owing to the availability of newer more effective therapies. Autologous stem cell transplantation (ASCT) has been used for over three decades to treat multiple myeloma. We aimed to evaluate the outcome of patients receiving ASCT at our institution between 1990 and 2015. Patients and Methods: A total of 2025 patients received ASCT at Mayo Clinic Rochester between 1st January 1990 and 31st December 2015. The patients were divided in to three cohorts of approximately equal time period, Cohort 1 (1990-1999, n=144), Cohort 2 (2000-2009, n=909) and Cohort 3 (2010-2015, n=972). Outcomes of interest were early mortality, progression free survival (PFS) and overall survival (OS). Disease characteristics were documented from time of diagnosis and PFS and OS were calculated from date of ASCT unless otherwise stated. Results: Median age for the whole cohort was 60 years (range 24-77) and increased over time (55 Cohort 1 vs 59 Cohort 2 vs 61 Cohort 3, p<0.0001). The proportion of males (60% for whole cohort) was not significantly different between the 3 time periods. Almost all patients (99%, n=2018) received chemotherapy prior to transplantation (median lines of therapy 1, range 0-6). The number of patients receiving >1 line of therapy prior to transplantation decreased over time (67% Cohort 1 vs 27% Cohort 2 vs 34% Cohort 3, p<0.0001). The use of novel agents was congruous with their availability and increased over time (0% Cohort 1 vs 59% Cohort 2 vs 100% Cohort 3, p<0.000). After a median follow up of 84 months (95% CI, 78-91 months), median PFS and OS for the whole cohort were 24 and 66 months respectively. Both PFS and OS improved significantly over time (median PFS: 12 months Cohort 1vs 18 months Cohort 2 vs 33 months Cohort 3, p<0.0001; median OS: 26 months Cohort 1vs 63 months Cohort 2 vs 83 months Cohort 3, p<0.0001), Figure 1. The improvement in PFS and OS over the 3 time periods was seen in patients receiving early (≤ 12 months from diagnosis) and delayed (>12 months) ASCT, Table 2. OS from diagnosis was no different for early versus delayed transplant in Cohort 1 and Cohort 2 (Cohort 1: median OS 57 months for early vs 56 months for delayed, p=0.24 and Cohort 2: median OS 81 months for early vs 82 months for delayed, p=0.70) and showed a trend towards a marginal benefit for delayed transplant in Cohort 3 (median OS 105 months for early vs 109 months for delayed, p=0.046).Treatment related mortality (100 days post transplant) improved over time (7.6% Cohort 1 vs 1.8% Cohort 2 vs 0.7% Cohort 3, p<0.0001), Figure 2A. Mortality within 12 months of ASCT also improved over time (24% Cohort 1vs 8% Cohort 2 vs 6% Cohort 3, p<0.0001). A landmark analysis of OS from 12 months post ASCT continued to reveal improved survival over time(median OS 26 months Cohort 1vs 63 months Cohort 2 vs 83 month Cohort 3, p<0.0001), Figure 2B. Conclusion: ASCT remains an important therapeutic option for eligible patients with multiple myeloma. There has been a marked improvement over time in PFS and OS and reduction in treatment related mortality and early mortality in myeloma patients receiving ASCT. This is likely to reflect the addition of novel agents to induction regimens and improved post transplant therapies. Despite these improvements myeloma remains incurable with patients continuing to relapse and die many years after ASCT. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Research to Practice: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; spectrum: Consultancy, Honoraria; celgene: Consultancy; annexon: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; Ionis: Honoraria; Teva: Consultancy; Apellis: Consultancy; Medscape: Consultancy; Prothena: Honoraria.

Abstract Background: The introduction of several novel agents has led to an improvement in response rates and survival outcomes in patients with newly diagnosed multiple myeloma. Despite significant therapeutic advances a subset of patients with multiple myeloma do not achieve a deep response to first-line treatment and biomarkers are needed to identify those at risk. Methods: We studied 472 patients with newly diagnosed multiple myeloma who were treated in clinical practice (n = 280, training cohort) or on prospective clinical trials (n = 192, validation cohort) at Mayo Clinic between 12/2003 and 12/2015. All patients had measurable disease (M-spike ≥ 1.0 g/dL) and received treatment with novel agents. Serum M-spike and free light chains (FLC) were measured before and after the first treatment cycle. The outcome of interest was the best response to first-line treatment (evaluated using the International Myeloma Working Group Uniform Response Criteria). Failure to achieve a deep response was defined as not achieving a very good partial response or better. The serum parameters of interest were the relative decrease in M-spike and absolute free light chain difference (ΔFLC). The Wilcoxon signed-rank test was used to compare the serum parameters before and after the first treatment cycle. Logistic regression models were used to assess the associations between the change in serum parameters after the first treatment cycle and best response to first-line treatment. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis in the training and the validation cohort were 67 (32 - 94) and 66 years (41 - 86), respectively. One hundred eighty one (65%) and 103 patients (54%) were male, respectively. The three most common regimens in the training cohort were lenalidomide + dexamethasone, lenalidomide + cyclophosphamide + dexamethasone, and bortezomib + lenalidomide + dexamethasone. In the validation cohort, the three most common regimens were carfilzomib + thalidomide + cyclophosphamide, lenalidomide + cyclophosphamide + dexamethasone, and ixazomib + cyclophosphamide + dexamethasone. In the two cohorts, the median baseline M-spike decreased from 3.1 g/dL (1.0 - 10.0) to 1.7 g/dL (0.0 - 6.6) and 3.2 g/dL (1.0 - 8.5) to 1.4 g/dL (0.0 - 4.5) after the first treatment cycle, respectively (p < 0.001 for both comparisons). The median baseline ΔFLC decreased from 31.1 mg/dL (0.0 - 2269.7) to 5.4 mg/dL (0.0 - 785.8) and from 23.3 mg/dL (0.1 - 3579.6) to 4.3 mg/dL (0.0 - 1139.3) after the first treatment cycle, respectively (p < 0.001 for both comparisons). M-spike reduction < 50% during the first treatment cycle was associated with failure to achieve a deep response: OR 4.54 (95% CI 2.72 - 7.58, p < 0.001) in the training cohort and OR 6.68 (95% CI 3.42 - 13.03, p < 0.001) in the validation cohort. Patients with reduction in M-spike < 10% during the first treatment cycle experienced failure to achieve a deep response in 86% (25/29) and 100% (10/10), respectively. ΔFLC reduction < 50% during the first treatment cycle was associated with treatment failure to achieve a deep response: OR 4.83 (95% CI 2.83 - 8.25, p < 0.001) in the training cohort and OR 5.09 (95% CI 2.37 - 10.92, p < 0.001) in the validation cohort. Patients with reduction in ΔFLC < 10% during the first treatment cycle experienced failure to achieve a deep response in 83% (34/41) and 91% (19/21), respectively. Conclusions: Early changes in M-spike and ΔFLC are strong predictors of response to treatment. We established and prospectively validated two readily available biomarkers that can identify patients at risk for treatment failure and may inform treatment decisions in newly diagnosed multiple myeloma. Disclosures Lacy: Celgene: Research Funding. Gertz:Physicians Education Resource: Consultancy; janssen: Consultancy; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Apellis: Consultancy; Medscape: Consultancy; annexon: Consultancy; Abbvie: Consultancy; celgene: Consultancy; Prothena: Honoraria; Ionis: Honoraria; Amgen: Consultancy; spectrum: Consultancy, Honoraria. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background: It is well known that the staging stratification at diagnosis predicts survival in immunoglobulin light chain (AL) amyloidosis, but there is a paucity of literature delineating the prognostic value of these systems at the time of 2nd-line therapy. Methods: We conducted a retrospective study to evaluate the prognostic value of AL staging among 563 patients with staging data, who initiated a 2nd-line therapy between 2000 and 2015. Both the Revised Mayo 2012 staging system and the European revision of the Mayo 2004 staging system were used. Results: The median time from initial treatment to 2nd-line therapy was 11.6 months. Median follow-up from institution of 2nd-line therapy was 54.1 months. The 1st-line therapy for patients was autologous stem cell transplant (ASCT) in 216 (38%) patients; and 2) non-ASCT therapies in 347 patients. Both staging systems were prognostic with a risk ratio of 9.4 (95%CI: 6.0, 15.1; p<0.0001) between stage IIIb and I, and of 12.2(8.1, 18.5; p<0.0001) between IV and I. At the time of 2nd-line therapy the staging systems' predictive values were independent of what the patients' 1st-line therapies had been despite the fact that the median time from initial treatment to 2nd-line therapy was 19.4 months in ASCT group and 8.0 months in non-ASCT group. Among the patients receiving 2nd-line therapy after ASCT, the 5-year overall survival (OS) from 2nd-line therapy for those with ≤ stage II versus >stage II was 65% and 31% (Mayo 2004) and 70% and 23% (Mayo 2012). The respective numbers for patients relapsing from a non-ASCT therapy were 57% and 26% (Mayo 2004) and 60% and 23% (Mayo 2012). Conclusions: This study indicates that the Mayo staging systems work well at the time of instituting 2nd-line therapy and is independent of whether 1st-line therapy was ASCT based. Figure. Figure. Disclosures Gertz: annexon: Consultancy; Medscape: Consultancy; Apellis: Consultancy; celgene: Consultancy; Prothena: Honoraria; Abbvie: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; spectrum: Consultancy, Honoraria; Ionis: Honoraria; Research to Practice: Consultancy; Teva: Consultancy; janssen: Consultancy; Alnylam: Honoraria. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lacy:Celgene: Research Funding. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Russell:Vyriad: Equity Ownership. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

Abstract Background The management of extramedullary relapse (EM) of acute myeloid leukemia (AML) after allogeneic stem cell transplant (allo-SCT) is not standardized. We present a single institution experience, describing the risk factors, outcomes and management of EM leukemia relapse in AML patients who underwent allo-SCT. Methods After due IRB approval, 351 patients with AML who underwent allo-SCT at Mayo Clinic, Rochester, from 1985 through 2012, were evaluated for EM relapse. All patients had BM biopsies and cytogenetic studies at diagnosis and at relapse. Extramedullary relapse was identified by clinical exams and radiological methods and confirmed where possible by biopsies and cerebrospinal analysis (CSF). Clinical, pathological and transplant related data was retrospectively abstracted. Results Of 351 patients, 26 (7%) had EM involvement at initial diagnosis (17 CNS, 9 non-CNS, 3 both). Forty-four (13%) patients had CNS disease detected prior to allo-SCT. Of these, 17 (39%) were detected at AML diagnosis due to clinical signs/symptoms, 11 (25%) were detected to have CNS involvement at the time of AML relapse and 16 (36%) were asymptomatic; diagnosed on routine pre transplant CSF studies. All patients with pretransplant EM disease received appropriate therapy prior to undergoing transplantation. After allo-SCT, 21 (6%; 12 male) of 351 patients sustained an EM relapse (11 CNS alone, 9 non-CNS, 1 both). The non-CNS EM relapse sites were cutaneous, skeletal, renal, breast, testicular, gastrointestinal tract and soft tissue. In 12 patients with CNS relapse, 8 (68%) presented with localizing signs and symptoms and 4 were asymptomatic. The median age at EM relapse was 42 years (range; 2 - 61 years) and the median time to EM relapse was 443 days (range; 90- 6069 days). Salvage therapy offered in 18 patients included, intrathecal chemotherapy (IT) alone in 2, IT + systemic chemotherapy (CTX) in 2, allo-SCT in 1, CTX alone in 6, IT + radiation therapy (XRT) in 1, CTX, IT and XRT in 1, and CTX + XRT in 5 patients, respectively. Three patients were ineligible for further therapy. Median survival after EM relapse was 136 days (18 – 819, days), with 4 patients alive at last followup. At the time of AML diagnosis; 6 (29%) of 21 patients had EM involvement (2 breast, 1 lymph node, 1 CNS and lymph node, 1 cutaneous), 8 (38%) patients had a monocytic differentiation (AML-M4/M5) and 6 of 9 tested, had CD56 expression. Three (14%), 8 (38%) and 10 (48%) patients were risk stratified based on cytogenetic and molecular status (FLT3/NPM1) into favorable, intermediate and high risk, respectively. Subsequently, all 21 patients underwent allo-SCT with 14 patients undergoing matched related donor (MRD) transplants. The transplant conditioning was myeloablative in 16 (76%) patients, of which 11 (69%) received total body irradiation (TBI). Grade II-IV acute graft versus host disease (GVHD) was noted in 11 (52%) patients, while chronic GVHD was noted in 8 (38). On univariate analysis, factors associated with shortened survival after EM relapse included; high risk karyotype at diagnosis (p=0.009), concurrent bone marrow involvement with EM relapse (p=0.01) and reduced intensity conditioning (RIC) (p=0.04). Importantly, CD56 expression (p=0.27), CNS involvement at diagnosis (p=0.76), and chronic GVHD (p=0.383) were not prognostic. On a multivariate analysis, high risk karyotype (p=0.04) and concurrent bone marrow involvement (p=0.04) retained their negative prognostic value. Conclusions Although uncommon, EM relapse after allo-SCT for AML is associated with poor outcomes. Pretransplant CSF screening identifies a significant number of asymptomatic patients with CNS disease. High risk karyotype at diagnosis and concurrent BM involvement with EM relapse are poor prognosticators. Disclosures: No relevant conflicts of interest to declare.

Abstract Background The presence of circulating plasma cells (PCs) in multiple myeloma (MM) is a known poor prognostic marker. Prior studies have utilized a technically challenging slide-based immunofluorescence technique to detect and quantify the presence of circulating PCs which was not widely adapted in clinical practice. More recently, the routine use of flow cytometry has provided the opportunity to quantitatively assess circulating PCs in MM patients with relative ease. We report the prognostic value of quantifying circulating clonal PCs using multiparametric flow cytometry in MM patients with relapsed disease. Methods We evaluated all MM patients seen at the Mayo Clinic, Rochester from 2009 to 2011 with previous or ongoing relapsed disease and who had their peripheral blood samples evaluated by flow cytometry. Each blood sample had its peripheral blood mononuclear cells isolated by ficoll gradient and stained with antibodies to CD45, CD19, CD38, CD138 and cytoplasmic Kappa and Lambda Ig light chains. A six-color multi-parameter flow cytometer (Becton Dickinson FacsCantos II) was used to examine each sample with a target of detecting 150,000 events (cells) that was then analyzed using the Facs Diva Software. Plasma cells were selectively analyzed through combinatorial gating using light scatter properties and CD38, CD138, CD19, and CD45. Normal PC's were then separated from clonal plasma cells based on the differential expression of CD45, CD19 and polytypic Ig light chains. The clonal plasma cells detected were reported out as the number of clonal events/150,000 collected total events. For those samples where less than 150,000 events were gated or examined, the number of final clonal events was adjusted to 150,000 events. Survival analysis was performed by the Kaplan-Meier method and differences in survival assessed using the log rank test. Results There were 647 consecutive patients with a history of treated MM who had a peripheral blood flow cytometry as part of their routine clinical evaluation. The median patient age was 62 years (29-88) and 55% were male. The median time since diagnosis was 12 months (range: 1-363) and the median number of lines of treatment received was 2 (1-11). There were 81 (13%) patients with clonal circulating PCs with a median of 368 cells (4 – 133,464). The 2-year overall survival (OS) for the 81 (13%) patients with any circulating PCs was 17% compared with 65% for those with none (P<0.001). The presence of circulating clonal PCs was associated with high-risk disease by FISH (P <0.001) as well as higher PCLI (P <0.001). We then correlated the presence of circulating clonal PCs with the disease status at flow cytometry assessment. Among the study patients, only 145 (22%) had actively relapsing disease with the remaining 502 (78%) in a plateau including patients in CR. Circulating clonal PCs were more likely to be detected in patients with actively relapsing disease compared with plateau phase (43% vs. 4%, P < 0.001); none of the CR patients and <5% of the remaining plateau phase patients had any detectable circulating clonal PCs. We then restricted the analysis to the actively relapsing patients; the best cutoff predicting 1-year mortality by ROC analysis was 100 events. Based on this, we defined >=100 events as a cutoff for defining the prognostic role of circulating clonal PCs in actively relapsing patients. The median OS for those with >=100 clonal PC events was 12 months compared with not reached for those with <100 events (p<0.001; Figure 1 ). Among patients with actively relapsing disease, >= 100 circulating PCs was associated with a higher ISS stage, plasma cell labeling index and bone marrow PC% compared with those with <100 circulating PCs. In a multivariable model, only LDH > 222 (HR: 2.08, P = 0.045) and >= 100 circulating PCs (HR: 2.48, P = 0.048) were found to adversely affect OS in actively relapsing patients. Conclusion The utilization of flow cytometry to quantify circulating clonal PCs in patients with relapsed MM appears to have significant prognostic relevance. In patients with actively relapsing disease, >= 100 circulating PCs predicted for worse OS with a median of 12 months. Future studies are needed to determine if this would allow an opportunity to develop a more risk adapted approach for patients with relapsed disease. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

Abstract Introduction: Localized immunoglobulin light chain amyloidosis (LAL) is a rare disease. Systematic data regarding its presentation, management and patient outcomes are limited to small case series. Our objective was to systematically describe the Mayo clinic experience of patients with LAL. Methods: We retrospectively reviewed clinical records of 403 patients with biopsy proven localized amyloidosis seen at the Mayo Clinic between 1969-2014. Median follow-up for survival and progression were 72 months and 39 months, respectively Results: OF 5551 patients with light chain amyloidosis seen at the Mayo clinic during the study period, 403 (7%) had LAL. Median age at diagnosis was 60 years (range, 13-93) and 51% of them were male. Sites involved included: urothelial (bladder, ureter, renal pelvis), 75 (19%), larynx, 51 (13%), lung parenchyma, 42 (11%), skin, 44 (11%), synovial tissue 36 (9%), tracheobronchial, 31 (8%), gastrointestinal tract, 30 (8%), seminal vesicles, 22 (6%), eyes, 23 (6%), pharynx 22 (6%) and other 24 (6%). Typing was performed in 178 (45%) cases. A monoclonal protein was detected in 23 of 351 (7%) evaluated cases, 5 of which had different light restriction from that of LAL. Thirty one (8%) patients had a co-existent autoimmune disease. No patients progressed to systemic AL. Of 403, 109 (27%) were observed or received supportive care only and 241 (60%) underwent local removal of the amyloid deposits. Sixty-four (16%) patients required repeated interventions (median 1, range 1-4, upper decile requiring 4 interventions) for progressive disease. The most common sites requiring repeated interventions were: urothelial (33%), laryngeal (19%) and tracheobronchial (8%). Ten year overall survival (OS) and progression free survival were 79% and 61%, respectively and there was no difference according to site of involvement. Of the 70 patients that died during the follow-up period, cause of death was known for 29 and death was attributed to LAL in only 2 cases. Conclusions: In the largest series of patients with LAL reported so far we demonstrated that LAL has an excellent prognosis but can sometimes be associated with significant morbidity. Although our study was limited by incomplete typing in 55% of cases, it appears that true LAL does not "progress" to systemic amyloidosis. However, systemic amyloidosis can frequently involve organs typical involved only in LAL;, therefore a complete work-up for systemic disease should be performed in all patients with LAL. Treatment usually involves local excision for symptom palliation. In 16% of cases, repeated interventions for relapse/progression were required and as a result, follow-up is recommended, especially for cases involving the urothelial and upper respiratory tract. Disclosures Kumar: Skyline, Noxxon: Honoraria; Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy.

Abstract Background Waldenström macroglobulinemia (WM) is a rare, indolent immunoglobulin M- associated lymphoplasmacytic lymphoma characterized by the alternation in the MYD88 locus in 90-95% of the cases. MYD88L265P is the most common alteration in WM patients and is considered a key molecular signature with a pathophysiological role in WM. Because of extremely low prevalence of WM with MYD88 wild type (WT) genotype there is a paucity of clinical and outcome data in this unique patient population. A recent study (Treon et al, Blood May, 2014), in an analysis based on the patients' MYD88 status, reported on the clinical features including older age at presentation and an unexpectedly higher mortality (38%) in the MYD88WTcohort compared to MYD88L265P patients (mortality 6%, P < .0001). However, the sample size of the MYD88WT WM cohort was small (n=15), with a few events during the short follow-up (median 4.84 years). Herein, we report on larger cohort of WM patients with this rare genotype. Methods This study included patients evaluated at Mayo Clinic, Rochester in whom the diagnosis of WM was established based on their clinicopathologic features and the MYD88 mutation status was determined through AS-PCR (assay sensitivity 1% mutant allele) performed on archived bone marrow samples obtained between 2007-2014. Patients with MYD88WT status were the focus of this study. Clinical data were collected from the patients' medical records. The Kaplan-Meir method was utilized for the survival analysis calculated from the time of diagnosis of WM. Outcomes of MYD88WT patients were compared with those harboring the MYD88L265Pmutation. Results Our cohort of 171 patients with an established diagnosis of WM and known MYD88 mutation status was found to be enriched for MYD88WT (n=40) patients. All patients required therapy. At diagnosis, the median age of the patients with MYD88 WT was 63 years (range 37.5-83.5 years; comparable to that of the MYD88L265P cohort, median 65 years, range: 32-92 years, p=0.16). Familial WM was identified in 10% of patients. Sixty four percent of patients presented with constitutional symptoms at diagnosis. These symptoms included fatigue (45%), weight loss (17%), night sweats (8%) dizziness (10%), dyspnea (23%), bleeding (10%), headache (10%) and hyper viscosity syndrome (5%). Splenomegaly and lymphadenopathy was observed in 20% and 27% of patients, respectively. Thirteen percent of patients had concomitant AL amyloidosis. Additional baseline characteristics are reported in Table 1. Transformation to a higher grade lymphoma was noted in 9 (23%) of patients, four of whom had received a purine analog and /or chlorambucil previously. The estimated median follow of MYD88WT patients was 8.1years (95% CI: 6.4-8.9) and their median overall survival (OS) was 8.5 years (95% CI: 6.4-29.4). No OS difference was evident between this cohort and the remainder of the patients with the MYD88L265Pmutation (n=131, median OS 11.7 years, 95% CI: 10-18, p=0.7; median follow-up 7.7 years 95% CI: 6.4-9.1, Figure 1). Conclusion In this relatively large cohort of WM MYD88WT patients with a prolonged follow-up, the MYD88mutation status was not found to be a determinant of patients' outcomes. Our findings contradict the results of a seminal previous study and require external validation, preferably through prospective studies. Disclosures Kapoor: Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Kumar:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Millennium: Consultancy, Research Funding; AbbVie: Research Funding; Kesios: Consultancy.

Abstract Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for primary myelofibrosis (PMF). Reduced intensity conditioning (RIC) allows otherwise ineligible patients to proceed with HSCT. Host factors in PMF such as bone marrow (BM) fibrosis, massive splenomegaly, and transfusion related allo-immunization increase the risk of engraftment failure, especially with RIC. Spleen directed therapy (SDT) is often used in PMF patients with splenomegaly to help with engraftment, however little data exists supporting this practice. This study was carried out to investigate the role for SDT and the predictors of outcomes with RIC HSCT for PMF. Methods :After IRB approval, the Mayo Clinic HSCT registry was queried for patients with PMF that underwent RIC allo-HSCT from 2005-2014. Disease and transplant related data were retrospectively abstracted and analyzed for HSCT related outcomes. SDT was defined as a therapeutic strategy with specific intent to overcome an enlarged spleen prior to HSCT and included splenectomy, splenic artery embolization, splenic irradiation, or JAK inhibitor therapy that was stopped <30 days before HSCT. Survival estimates were calculated using the Kaplan-Meier method and means were compared using the log-rank test. Univariate and multivariate analyses were performed using Cox regression modeling. Results :51 patients (67% males) with WHO defined PMF with palpable splenomegaly that underwent RIC allo-HSCT were included in the study; median age 57 years (range, 35-68). The median follow-up was 12.2 months, and at last follow up, 19 deaths (37%) and 4 relapses (8%) were documented. The median OS for the group was not reached (mean 34.2 months); 88% at 100 days and 60% at 2 years. 17 deaths were attributed to non-relapse mortality (NRM). There were 3 engraftment failures (6%). 32 patients (63%) developed acute GVHD (grades II-IV) and 24 patients (47%) developed chronic GVHD (all grades). Twenty-one patients (41%) received SDT; 10 (48%) splenectomy, 2 (9%) splenic irradiation, and 9 (43%) JAK inhibitor therapy (ruxolitinib). The SDT group had a median spleen size of 14.5 cm (range, 1-29 cm) below the left costal margin (LCM) and 13 patients (62%) with spleen size >10 cm below LCM, while the no SDT group had a median spleen size of 7 cm (range, 1-19 cm) and 12 patients (40%) with spleen size >10 cm below LCM; p = 0.01. Seven (64%) of 11 patients receiving splenic irradiation (n = 1) or JAK inhibitor therapy (n = 6) were eligible for IWG-MRT spleen response, and 2 (29%) responded (both in JAK inhibitor group). Of the remaining 5 patients, 2 had a response not meeting IWG-MRT criteria. There were no differences in age (p = 0.09), gender (p = 1.0), DIPSS + score (p = 0.35), or HCT-CI (p = 0.61) between the two groups. There was a statistically significant difference in engraftment failure, with all 3 engraftment failures occurring in the SDT group (2 splenectomy patients, 1 splenic irradiation patient; p = 0.02). Engraftment failures were not attributable to insufficient cell dose, donor specific antibodies, or identifiable host factors. The patient with engraftment failure who underwent splenic irradiation had persistent massive splenomegaly. There were similar outcomes with regards to relapse rates, NRM, and acute and chronic GVHD. In the SDT group, the median OS was 13.3 months; 81% at 100 days and 33% at 2 years. In the no SDT group, the median OS was not reached; 94% at 100 days and 68% at 2 years; p=0.13. In a univariate survival analysis that included age, gender, SDT, DIPSS+ score, HCT-CI, CMV status, ABO status, HLA matching, donor source, graft source, engraftment status, and acute and chronic GVHD, predictors of survival were engraftment failure (p = 0.02) and major/bidirectional ABO incompatibility (p = 0.02). Similar results were obtained when JAK inhibitor therapy was considered separately from other forms of SDT. In a multivariate analysis, engraftment failure (HR 8.2, 1.8-27.2; p = 0.01) and major/bidirectional ABO incompatibility (HR 4.1, 1.4-10.9; p = 0.009) retained independent prognostic significance. Discussion:In patients with PMF and splenomegaly, there was no demonstrable benefit from SDT. Predictors of post-HSCT survival included engraftment failure and major/bidirectional ABO incompatibility. These findings need validation in a larger cohort of patients. Disclosures Al-Kali: Celgene: Research Funding. Mesa:Gilead: Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding.

Abstract Background WM remains an incurable cancer despite recent advances. While a phase II trial has demonstrated efficacy of dexamethasone, rituximab and cyclophosphamide (DRC) in the treatment-naïve (TN) patients, this regimen has not been studied systematically in the relapsed/refractory (R/R) setting. Recent data has suggested the MYD88mutation status in WM patients can serve as a predictive marker with therapies such as ibrutinib. We examined the efficacy and tolerability of up to 6 cycles of DRC, with focus on R/R population and activity of this regimen with respect to the patients' MYD88L265Pstatus. Methods Records of WM patients seen consecutively at Mayo Clinic campuses in Rochester, Arizona and Florida from 01/2007 to 12/2014 were reviewed. MYD88L265P status, as assessed by AS-PCR, was recorded when available. Data obtained from symptomatic patients treated with DRC (dexamethasone 20 mg intravenously followed by rituximab 375 mg/m2 intravenously on day 1 and cyclophosphamide 100 mg/m2 orally bid on days 1 to 5) were analyzed. Time-to-event analyses were performed from DRC therapy using the Kaplan-Meier method. We used the Consensus response criteria (6th International Workshop). Results Of 100 symptomatic patients who received DRC, 50 had R/R WM (40% refractory) and 50 were TN. Table 1 shows the patients' baseline characteristics. In the R/R population, DRC was 2nd line (range 2-8) therapy in 58% of patients. The median IgM levels declined from 3,870 mg/dL to 1,846 mg/dL (p=0.0001) at best response. Median follow-up from DRC was 51 months (95% CI: 38-55). The median time-to-best response was 6.8 (0.5-28) months. Overall response rate (ORR) was 87% [VGPR 4%, PR 64%, MR 19%]. Four patients (9%) achieved SD and 2 patients (4%) had PD. Of the sixteen deaths (32%) noted at time of analysis, 11 were related to progressive disease. The median disease-specific survival (DSS) from DRC was not reached (NR) (95% CI: NR-NR). The median progression-free survival (PFS) and time-to-next-therapy (TTNT) were 32 months (95% CI: 15-51) and 50 months (95% CI: 35-60), respectively. In contrast, in the TN patients the median IgM levels declined from 4,130 mg/dL to 1,250 mg/dL (p=0.0001) at best response; median time to best response was 11 (0.6-47) months; median follow-up from DRC was 30 months (95% CI: 21-36). ORR was 96% [VGPR 17% (n=8), PR 70% (n=32), MR 9% (n=4)]. Of the 7 deaths (14%) at time of analysis, 4 were related to WM progression. Median DSS from DRC was NR (95% CI: NR-NR); median PFS and TTNT were 34 months (95% CI: 23-NR) and NR (95% CI: 37-NR), respectively. Among 29 genotyped patients in whom MYD88 mutation status was available, MYD88L265P was present in 25 patients (8 of 10 TN and 17 of 19 R/R patients). The response rates and the time-to-event outcomes were similar in the MYD88L265P and wild-type patients. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Conclusions Similar to the frontline setting, DRC is an active and well-tolerated salvage regimen. In contrast to ibrutinib, DRC offers a less expensive, limited-duration treatment option, with preliminary data suggesting activity independent of patients' MYD88 mutation status. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Kumar:Glycomimetics: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Kesios: Consultancy; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy. Dispenzieri:Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Celgene: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Kapoor:Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding.

Abstract Background Waldenstrom macroglobulinemia (WM) is an IgM-associated lymphoplasmacytic lymphoma, first described over seven decades ago. Although WM is typically a disease of the elderly, with a median age at diagnosis of ~ 67 years, approximately 10% of patients are ≤50 years (y) of age at diagnosis. Data for young patients are sparse and the few available studies demonstrate inconsistent findings, with potential overestimation of survival owing to inclusion of patients with smoldering WM. In this case-control study, we evaluate outcomes, prognostic features and impact of changing therapies in a large cohort of young symptomatic WM patients compared to matched older patients seen over the course of the past five decades. Methods The medical records of all WM patients seen consecutively at Mayo Clinic from 01/1960 to 10/2013 were reviewed. Of 1181 patients, 140 (11.8%) were ≤ 50 y of age at diagnosis. A cohort of patients 65 y or older at diagnosis, matched 1:1 by the time of diagnosis, served as the control population. The patients were divided into 3 groups based on the timing of initiation of therapy: Group 1 (1960-1977), Group 2 (1978-1995) and Group 3 (1996-2013). The baseline characteristics were compared. Initiation of frontline therapy was used for all time-to-event analysis using the Kaplan Meier method. Results Younger patients were more likely to present with adenopathy and splenomegaly, have higher IgM levels and hyperviscosity symptoms (Table 1). The median follow-up from the frontline therapy was similar (10.7 y vs. 10 y for the control population). At the time of analysis, 91% of the deaths for the younger cases were WM-related compared to 58% in the control arm (p=0.0001). Younger patients had a better OS with a median disease-specific survival (DSS) of 15.6 y (95% CI: 13-21; 10-y OS of 77%) vs. 11 y (95% CI: 7.8-12; 10-y OS of 51%) for the older patient (p=0.0003). Among the young patients, there was no difference in the median DSS across the 3 groups (p=0.42). However, the median DSS for the control group incrementally improved (p=0.02) over the 3 time periods (Table 1). In the younger patients, no improvement in DSS was noted with the use of either frontline rituximab-based therapy compared to non-rituximab based regimens [median NR (95% CI: 7.6-NR) vs. 15.8 y (95% CI: 13-22) with other regimens, p=0.30], or frontline chlorambucil-based compared to non-chlorambucil based regimens [median 16 y (95% CI: 12-22) vs 15.6 y (95% CI: 12-NR) with other regimens, p=0.73]. In the control group, however, there was significant difference in DSS among patients who received frontline rituximab-based compared to non-rituximab based regimens [median NR (95% CI: 8.3-NR) vs 9.1 y (95% CI: 5.6-12) with other regimens, p=0.04], or frontline chlorambucil-based vs non-chlorambucil based regimens [8 y (95% CI: 5-12) vs 12.3 y (95% CI: 11-NR) in other regimens; p=0.001]. Conclusion Striking differences in presentation are evident in young WM patients compared to their older counterparts. The incorporation of rituximab to the previously existing anti-WM regimens and the transition to non-chlorambucil based regimens has resulted in substantial survival gains in the older WM population over the past five decades. However, such improvement in outcome has not yet been observed in the young patients. The majority of younger patients, despite a protracted disease course, succumb to their disease. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Reeder:Novartis: Research Funding; Celgene: Research Funding; BMS: Research Funding; Millennium: Research Funding. Kumar:Kesios: Consultancy; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; AbbVie: Research Funding; BMS: Consultancy; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.