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Abstract Background: Waldenström macroglobulinemia (WM) is an indolent B-cell lymphoma with a heterogeneous disease course. For nearly a decade, the International Prognostic Scoring system (IPSS), requiring 5 variables (platelet count, hemoglobin, age, Beta 2 microglobulin and immunoglobulin M size) has been used to prognosticate patients with active WM. In this study, we attempt to propose a simplified prognostic model for patients with active/symptomatic WM. Methods: All patients with active WM diagnosed between 01/01/1996 and 12/31/2017 and evaluated consecutively at Mayo Clinic, Rochester were included in the study after Institutional Review Board approval. Active WM was defined as ≥10% marrow infiltration with lymphoplasmacytic cells plus monoclonal IgM of any size requiring systemic therapy. The follow up and overall survival (OS) were calculated from the time of active WM until date of last follow up or death. Baseline parameters at active disease were used to assess prognostic factors for OS using a univariate followed by a multivariate (MV) Cox regression analysis. Independent variables on the MV analysis were given a score proportional to their risk ratios (RR). All time-to-event analyses were performed using the Kaplan-Meier method and the survival curves were compared using log-rank test. Discriminatory ability of the IPSS and the currently proposed prognostic system was assessed using Harrell's concordance index wherein a higher c-statistic is associated with a better discriminatory ability. Results: We identified 889 patients with active WM. The median follow up was 8.2 years (95% CI: 7.5-9 years). The baseline characteristics of the patients are shown in Table 1. At the time of diagnosis of WM, 16% of patients had previously documented MGUS and 16% patients had smoldering (asymptomatic) WM. The course of WM was complicated by systemic amyloidosis in 8% (n=69), transformation to high-grade lymphoma in 4% (n=38), symptomatic hyperviscosity in 13% (n=118), myelodysplastic syndrome in 2% (n=17) and Bing-Neel syndrome in 1.4% (n=12) of patients. Of the patients tested, cryoglobulinemia was present in 17% (n=48), cold agglutinin disease in 34% (n=43) and Coombs positive hemolytic anemia in 9% (n=34) patients. The median OS was 10.6 years (95% CI: 9.7-11.4 years). The factors affecting OS are shown in Table 2. While the patients' MYD88L265P mutation status was not found to be prognostic for OS, age >65 years [RR 1.8 (95% CI: 1.2-2.8); p=0.01], LDH > upper limit of normal [RR 2.5 (95% CI: 1.3-4.6); p=0.003] and serum albumin <3.5 g/dL [RR 1.6 (95% CI: 1.1-2.5); p=0.02] were independently prognostic. Owing to comparable RRs, each of these were assigned a score of 1 point and a prognostic model with a minimum score of 0 and maximum score of 3 was constructed. A score of 0 was considered as low risk WM and 1 as intermediate risk WM. The patients with scores of 2 and 3 were analyzed together to form the high risk cohort due to comparable OS for these two groups. The patient outcomes based on this prognostic model are depicted in Figure 1. Using the new prognostic model (n-=341), the median OS for the low risk group (n=71, 21%) was 14.6 years (95% CI: 9 years- not reached) compared to 11 years (95% CI: 8.1-14.7 years) for intermediate risk (n=140, 41% ) and 7.2 years (95 % CI: 5.4-10 years) for the high risk group (n=130, 38%), p<0.0001. The data for the IPSS-WM were available in 319 patients in the entire cohort. The OS for low risk IPSS (n=56) was 14.6 years (95% CI: 12.1 years-NR), 15.6 years (95% CI: 8.3-18.5 years) for intermediate risk IPSS (n=131) and 9.1 years (95% CI: 6.8-11.2 yeas) for the high risk IPSS group (n=132; p=0.009). Among the 220 patients having data for IPSS-WM as well as our proposed model, the current three variable model held its prognostic significance (p=0.0004). The Harrell's c-index was 0.647 (95% CI 0.592-0.702) for our prognostic model and 0.58 (95%CI: 0.521-0.638) for IPSS-WM. Common frontline treatment comprised of rituximab monotherapy (n=277, 33%), rituximab with alkylator or purine analog combination (n=255, 30.5%) and other therapies, including alkylators/purine analog monotherapy, ibrutinib, proteasome inhibitors, etc., in 37% patients. Conclusion: A simpler, clinically useful, risk stratification model based on age, serum albumin and serum LDH with a potentially higher discriminatory value than IPSS-WM may be used to prognosticate patients with WM. This model requires external validation. Disclosures Ansell: Pfizer: Research Funding; Affimed: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Merck & Co: Research Funding; Regeneron: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Abbvie: Consultancy; Prothena: Honoraria; Medscape: Consultancy; annexon: Consultancy; Amgen: Consultancy; Alnylam: Honoraria; Teva: Consultancy; janssen: Consultancy; Physicians Education Resource: Consultancy; Ionis: Honoraria; spectrum: Consultancy, Honoraria; celgene: Consultancy; Research to Practice: Consultancy; Apellis: Consultancy. Witzig:Celgene: Consultancy, 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. Kumar:Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: 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; 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; KITE: 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. Kapoor:Takeda: Research Funding; Celgene: Research Funding.

Abstract Introduction Waldenstrom macroglobulinemia (WM) is a rare disease accounting for only 1-2% of all hematologic malignancies and with an overall annual, age-adjusted incidence of approximately 3.5 to 5.5 cases per million-person years. With approximately 13,000 active hematologist/oncologists in the US, most of who are in the community oncology setting, it's estimated that a hematologist/oncologist will only diagnose a WM case approximately every 8 years. Therefore, the clinical experience of a general hematologist/oncologist in the management of WM is likely very limited compared to more prevalent malignances. Previous studies in the setting of rare cancers suggest a correlation between higher volume of care and improved outcomes. Therefore, we explored the volume-outcome relationship in WM using the National Cancer Data Base (NCDB). Methods Patient-level data from the NCDB, a nationwide, facility-based, database covering approximately 70% of all newly diagnosed cancer cases in the US, was queried for all new WM cases diagnosed between 2004 and 2014. Only patients requiring treatment were included. Treatment facilities were divided into quartiles based on the average annual volume of newly diagnosed cases of WM seen. Cox regression was used to analyze the association between facility WM volume and survival, adjusted by demographics (sex, age, race), socioeconomic status (income, education, insurance type), geography (area of residence, treatment facility type, travel distance), comorbidity factors (Charlson-Deyo score), and year of diagnosis. Time-to-event analysis was calculated from frontline therapy initiation date using the Kaplan-Meier method and the log-rank test. Results A total of 3,732 patients with WM treated in 831 facilities were included. The median age at diagnosis was 70 years and 75% of the patients were treated within 20 miles from their residency zip code. Patient characteristics per treatment facility volume quartile are shown in table 1. The median annual facility volume was 1 new WM patient/year (range 0.1 to 21). The median follow-up from frontline treatment was 5 years. The unadjusted median OS by facility volume was: Q1: 6.5 years (95% CI: 5.7-7.4), Q2: 7 years (95% CI: 6.3-8.2), Q3: 8.2 years (95% CI: 7.1-8.9), and Q4: NR (95% CI: 8.5-NR), p<0.0001 (figure 1). The estimated 5-year OS by facility volume was: Q1: 56%, Q2: 61%, Q3: 64%, Q4: 71%, p<0.0001. Multivariate analysis including all variables showed in Table 1 demonstrated that facility volume was independently associated with all-cause mortality. Compared to patients treated at Q4 facilities, patients treated at lower-quartiles facilities had a higher incremental risk of death (Q3 hazard ratio [HR], 1.07 [95% CI: 0.88 to 1.29] p=0.46; Q2 HR, 1.34 [95% CI: 1.11 to 1.63] p=0.002; Q1 HR, 1.52 [95% CI: 1.23 to 1.88] p=<0.0001). Conclusion Our results suggest that a volume-outcome relationship exits in WM as patients treated initially at higher-volume facilities had a lower risk of mortality. Although differences in the underlying disease biology, referral patterns after initial therapy, or cumulative treating-physician experience could not be assessed, these potential biases would only underestimate the magnitude of the volume-outcome relationship reported. Disclosures Ansell: Celldex: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Regeneron: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding. Gertz:Medscape: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Ionis: Honoraria; Physicians Education Resource: Consultancy; Prothena: Honoraria; Teva: Consultancy; Research to Practice: Consultancy; spectrum: Consultancy, Honoraria; celgene: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; annexon: Consultancy; Apellis: Consultancy. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Ailawadhi:Amgen: Consultancy; Janssen: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy; Takeda: Consultancy. Reeder:Affimed: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Kumar: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; 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.

Abstract Background The survival of patients with multiple myeloma (MM) has improved significantly over the past two decades with the introduction of novel treatment agents. However, MM is still largely considered an incurable malignancy with a relapsing-remitting course. A follow-up of at least 10 years from active disease is required to determine whether a plateau in progression-free survival has been attained. Prior literature has used 10 years as a cutoff for "long-term survivorship". In this study, we have assessed the biological disease characteristics and outcomes of long-term survivors with MM (≥10 years from active disease). Methods All patients with active MM evaluated at the Mayo Clinic, Rochester between January 1, 1999 and July 1, 2008 were included in the study after approval of the Institutional Review Board. Patients with smoldering multiple myeloma were excluded. The overall survival (OS) was calculated from the time of symptomatic disease requiring treatment. Patients were then divided into two cohorts: (1) long-term survivors, which included patients who had an overall survival of at least 10 years; and (2) short-term survivors, which included patients who had an overall survival of less than 5 years from the diagnosis of active MM. The baseline characteristics between these two groups were compared using Wilcoxon, chi-square, and Fisher's exact test as applicable. All time-to-event analyses were performed using the Kaplan-Meier method and the survival curves were compared using Log-Rank test. Results During the time frame of the study, 2,125 patients were identified who fulfilled the diagnostic criteria for active MM. The median follow-up for the entire cohort was 12.6 years (95% CI: 12.5-13.4).The median OS for the entire cohort was 4.4 years (95% CI: 4.2-4.7 years). Three-hundred and ninety nine (18.7%) patients survived at least 10 years whereas 872 patients (41%) survived less than 5 years from the date of initial diagnosis. The median OS was 14.1 years for the long-term survivors (95% CI: 13.9-14.6 years) and 2.1 years for the short-term survivors (95% CI: 1.8-2.2 years). The clinical features at diagnosis comparing long-term survivors and short-term survivors are shown in Table 1. Among long-term survivors (n=399), based on the available data regarding remission and ongoing treatment status, 331 patients were categorized into 6 cohorts (Table 2). The MM specific survival data of these 6 cohorts is depicted in Table 2.Figure 1 shows survival outcomes from the 10-year landmark. Of the 6 cohorts, 38 patients in Cohort 1 and 19 patients in Cohort 2 (total 57; 17% of long term survivors, ~3% of the entire cohort ) have been off therapy for at least 5 years and remain in remission, representing a distinct group of patients with 100% 15-year survival. Conclusion In our large database with prolonged follow-up, long-term survivors appear to have distinct baseline characteristics, but also constitute a heterogenous group of patients with disparate outcomes. A small subset (17% of long-term survivors) was identified that may represent patients closest to being considered as 'operationally cured'. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Teva: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; Apellis: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; janssen: Consultancy; celgene: Consultancy; Prothena: Honoraria; annexon: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Merck: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; 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; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding.

Abstract Background: Limited data exist regarding histological transformation in patients with Waldenström macroglobulinemia (WM). In this study, we present the disease characteristics, outcomes and risk factors for histological transformation in WM. Methods: Patients with WM seen at Mayo Clinic, Rochester, MN between January 1996 and December 2017 were included. Patients with aggressive non-Hodgkin lymphoma in the setting of WM were considered to have transformation. Univariate analysis for comparing baseline characteristics of transformed versus non-transformed WM was performed using Wilcoxon, Fisher's exact and Chi square tests, as appropriate. Multivariate analysis was performed using logistic regression analysis. Cox proportional hazard method was used to assess the impact on time-to-transformation. All time-to-event analyses were calculated by the Kaplan-Meier method. Results: Of 1014 patients with WM, 42 patients (4.1%) developed histological transformation. The median follow-up for the entire cohort was 9.5 years (95% CI: 8.8-10.5 years). The cumulative probability of transformation was 2.3% at 5 years, 5.3% at 10 years and 8.5% at 15 years from diagnosis of WM, respectively. There was no difference in the 5-year cumulative probability of transformation in patients with WM diagnosed between 1996-2000 (2.1%), 2001-2005 (2.9%), 2006-2010 (2.7%) and 2011-2015 (3.8%), p=0.61.The disease characteristics, laboratory parameters and histology at transformation are outlined in Table 1. In patients with DLBCL histology (n=39), Revised-International Prognostic Index was calculable in 28 patients, with 50% (n=14), 46% (n=13) and 4% (n=1) of DLBCL belonging to poor, good and very good risk groups, respectively. For DLBCL histology, 18 patients were classifiable using Hans algorithm into germinal center B-cell (GCB) type (n=3, 17%) and non-GCB type histology (n=15, 83%). The median lines of therapy received prior to transformation for the entire cohort was 2 (range 0-9), with 5 (11%) patients not having received any therapy for WM before transformation. Number of lines of alkylator-based therapy used prior to transformation [median 1 line (range 0-4)] was comparable to that used in patients in whom WM did not occur [median 1, (range 0-6); p=0.78]. The median time-to-transformation from diagnosis of WM was 4.8 years (95% CI: 2.6- 6.8 years). Overall survival (OS) from transformed disease was 3.2 years (95% CI 1.1-3.9 years). The 10-year OS of patients with WM who transformed was lower (46%) compared to patients without transformation (60%) with a trend towards statistical significance (p=0.08), Figure 1. The MYD88L265P mutation status was available in 333 patients in the entire cohort (22/42 pts in the transformed cohort and 311/972 in the non-transformed cohort. Of the 22 patients in the transformed WM cohort, 13 (59%) exhibited MYD88WT genotype and 9 (41%) exhibited MYD88L265P genotype. The risk of transformation was higher in patients with MYD88WT status [Odds ratio 6.3 (95% CI: 2.6-15.5); p<0.0001]. Additionally, serum lactate dehydrogenase (LDH) was higher at diagnosis of WM in patients who transformed, Table 2. On multivariate analysis, MYD88WT status remained an independent predictor of disease transformation [p=0.003; odds ratio 10 (95% CI: 2.1-48)]. On univariate Cox proportional hazard analysis for identifying predictors of time-to-transformation, only MYD88WT mutational status was associated with shorter time-to-transformation with a 5-year transformation rate of 15.5 % for MYD88WT versus 2.6 % with MYDL265P mutated patients [risk ratio 6.2 (95% CI: 2.5-16.4); p<0.0001]. Treatment-related details in the transformed cases were available for 37 (90%) patients; R-CHOP was the most common (41%) frontline therapy for transformation; 33% patients underwent autologous stem cell transplantation for transformed disease during their disease course. Conclusion: Histological transformation is an uncommon event in WM but confers poorer survival. MYD88WT genotype is independently associated with histological transformation a shorter time-to- transformation in patients with WM. Disclosures Ansell: Trillium: Research Funding; Pfizer: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Takeda: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Gertz:Apellis: Consultancy; Alnylam: Honoraria; spectrum: Consultancy, Honoraria; janssen: Consultancy; annexon: Consultancy; Prothena: Honoraria; Abbvie: Consultancy; Amgen: Consultancy; celgene: Consultancy; Teva: Consultancy; Medscape: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy. Dingli: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.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Kumar:Merck: 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; AbbVie: 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; KITE: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding.

Abstract Introduction Recent advances in the understanding of the WM pathobiology led to the expansion of our therapeutic options in this disease. A number of targeted drugs are either available or under investigation and are poised to change the chemo-immunotherapy paradigm in the treatment of WM. Now more than ever, an individualized treatment approach for patients with WM is possible, where patient characteristics and preferences can be matched by different treatment goals and side effect profiles. While deep responses have been associated with longer disease-free survival in other hematologic malignancies, data on patients with WM are sparse. We report the impact of depth of response in disease-free and overall survival (OS) in WM. Methods WM patients consecutively seen at Mayo Clinic between 01/1998 and 12/2016 were reviewed for response to therapy and disease burden. The best response achieved after the treatment of interest (TOI) was classified using the IWWM-7 Response Criteria. The included TOI were: BR, DRC, BDR and high-dose chemotherapy followed by ASCT. All time-to-event analyses were performed from the TOI initiation date using the Kaplan-Meier method and the log-rank test. A landmark analysis from the date-of-best response was also performed for OS to prevent immortal-time bias. Univariate and multivariate analyses of progression-free survival (PFS) and time-to-next therapy (TTNT) were performed using the Cox regression method. Results A total of 181 patients had disease response assessed after the TOI. Baseline characteristics at time of diagnosis are summarized in table 1. The median follow up from TOI was 3.8 years (95% CI: 3-4), the majority of patients received TOI as salvage therapy [n=112 (63%); median 2nd line (rage 1-11)]. Best response rates with the corresponding 5-year PFS and TTNT are summarized in table 2. The median OS from TOI was longer in patients who achieved at least a PR [median 7.2 years (95% CI: 5-NR) vs 3.7 years (95% CI: 1.6-NR), p=0.01]. A trend towards a longer OS was also seen with deeper responses (PR or better) achieved with frontline therapy [median 5.8 years (95% CI: 5.8-NR) vs 3.4 years (95% CI: 1.6-NR), p=0.24]. Figure 1 shows the correlation between deeper responses with PFS and TTNT. Among patients achieving a PR or VGPR, those with a normal FLC ratio post TOI demonstrated a longer PFS and TTNT [PFS: median NR (95% CI: 3.4-NR) vs 4.9 years (95% CI: 2.8-8.7), p=0.01; TTNT: median NR (95% CI: 3.5-NR) vs 5.2 years (95% CI: 4.2-9.4), p=0.04], figure 2. In a multivariate analysis including normal FLC ratio, normal IgM level and minimal BM involvement (<5%) post TOI, normal FLC ratio remained an independent prognostic factor for longer PFS and TTNT. Similar trends were seen when considering treatment naïve and relapsed/refractory patients independently (data not shown). Discussion Our results not only suggest an association between depth of response with PFS and TTNT, but also with OS in patients with WM. A normal FLC ratio (not part of the IWWM-7 response criteria) seems to predict a longer disease-free interval in patients achieving a PR or VGPR. Disclosures Gertz: Ionis: Honoraria; Apellis: Consultancy; annexon: Consultancy; Prothena: Honoraria; janssen: Consultancy; Physicians Education Resource: Consultancy; Alnylam: Honoraria; Teva: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; celgene: Consultancy; Research to Practice: Consultancy; Amgen: Consultancy; Abbvie: Consultancy. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Ailawadhi:Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy. Reeder:Affimed: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy: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; KITE: 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. Ansell:Seattle Genetics: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Regeneron: Research Funding.

Abstract Background : Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor was approved for the treatment of Waldenstrom Macroglobulinemia (WM) in January, 2015 based on the results of a clinical trial of 63 previously-treated patients with WM. Data on outcomes with ibrutinib outside of clinical trials are limited. Methods : Medical records of patients with WM seen consecutively between 02/01/2015 and 06/01/2018 at Mayo Clinic, MN, FL and AZ were reviewed and those treated with ibrutinib at any point during their disease were included. Refractoriness to prior therapy was defined as disease progression on therapy or within 2 months of stopping treatment. The response rates were assessed by WM VI International Workshop Criteria. Adverse events were graded using National Cancer Institute Common Toxicity Criteria for Adverse Events (AEs) v4.03. All time-to-event analyses were performed from the time of initiation of ibrutinib. Results : Eighty patients [previously treated, n=67 (84%), treatment-naïve, n=13 (16%)] received ibrutinib for active WM. Median follow-up was 18 months (95% CI: 12-19) and the median overall survival (OS) was not reached (NR) (95% CI: 27-NR) for the entire cohort at the date of last follow-up. The median age was 67 years (range: 50-88) and the median ECOG performance score was 1 (range: 0-3) at the time of ibrutinib initiation. Median lines of therapies prior to ibrutinib for the previously-treated patients was 2 (range: 1-9) and 35 patients (44%) had received ≥3 prior lines of therapy. Of the 80 patients, 52 patients (43 previously treated, 9 treatment-naïve) had data for response assessment. The baseline characteristics and laboratory parameters at initiation of ibrutinib are outlined in Table 1a and prior therapies are mentioned in Table 1b. Overall response rate (ORR) was 90% (100% in patients with ibrutinib as primary therapy and 88% in salvage therapy setting); major-response rate (MRR) was 77%. Median time to first and best response was 2.1 months (95% CI: 1.5-3.5) and 5.4 months (95% CI: 3.5-13), respectively. Other clinically relevant endpoints and AEs related to ibrutinib therapy are outlined in Table 2 and 3, respectively. The median time-to-next therapy was 33 months (95% CI: 28-NR). At last follow-up, 25 (32%) patients had discontinued ibrutinib therapy. The reasons for discontinuation was progression (n=8), elevated liver enzymes (n=4), cognitive changes (n=1), inability to achieve better than MR (n=1), atrial fibrillation (n=3), consolidation with autologous stem cell transplantation after PR with ibrutinib (n=1), transition to hospice care due to progressive head and neck cancer (n=1), infection in lower extremity (n=1), transformation to DLBCL (n=1), blistering rash which resolved after ibrutinib discontinuation (n=1), obscure GI bleed that resolved after ibrutinib discontinuation (n=1), fatigue (n=1) and for unclear reasons recorded as treatment intolerance (n=1). Following discontinuation of ibrutinib, 21 patients received salvage therapy. Of these, data regarding the response to salvage therapy was available in 9 (43%) patients (VGPR=2, PR=3, SD=3 and progressive disease=1); median PFS from the salvage therapy following ibrutinib discontinuation was 18 months (95% CI: 2-25). Of the 4 patients who were not treated following ibrutinib discontinuation; 1 elected hospice care due to concurrent head and neck cancer progression, and the other 3 patients elected to be monitored off therapy (one had achieved SD and two had PR from ibrutinib). Fourteen patients were evaluable for IgM rebound following ibrutinib discontinuation. Of those, 5 (36%) had sudden increase in IgM level [median: 158% from the IgM level after ibrutinib discontinuation (range: 22%-1368%)] within a median of 2 months (range: 1-3 months) and 1 patient required plasmapheresis for symptomatic hyperviscosity. Four of 5 patients received salvage therapy between 0-15 months. At last follow-up, 11 patients (14%) had died of whom 3 were on ibrutinib at the time of death [CNS involvement, (n=1), causes unrelated to WM, (n=2)]. Conclusions : Ibrutinib is an effective agent in WM patients with MYD88L265Pmutation. Our data regarding outcomes in non-trial setting appear comparable to the results observed in the pivotal clinical trial. Hematologists should be aware of unique ibrutinib associated toxicities and clinically relevant IgM rebound phenomenon following abrupt discontinuation of ibrutinib. Disclosures Ailawadhi: Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy. Gertz:janssen: Consultancy; Prothena: Honoraria; Medscape: Consultancy; Teva: Consultancy; celgene: Consultancy; annexon: Consultancy; Alnylam: Honoraria; Physicians Education Resource: Consultancy; spectrum: Consultancy, Honoraria; Apellis: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy. Kumar:Novartis: 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; Roche: Research Funding; AbbVie: 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; 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lacy:Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, 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:Celgene: Research Funding; Takeda: Research Funding.

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 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 Bendamustine/rituximab (BR) and dexamethasone/rituximab/cyclophosphamide (DRC) combination therapy are acceptable options for the treatment of WM, both in the frontline or salvage setting. Prospective data, however, are only available in treatment-naïve (TN) WM patients, and no direct comparison between BR and DRC has been reported. We compared outcomes of BR and DRC in relapsed/refractory (R/R) and TN WM patients seen at a single institution. Methods Records of WM patients seen consecutively at Mayo Clinic from 01/2007 to 12/2014 were reviewed. The MYD88L265P status, as assessed by AS-PCR, was recorded when available. The data obtained from symptomatic patients treated with DRC or BR were analyzed. The time-to-event analyses were performed from DRC or BR therapy using the Kaplan-Meier method. We used the Consensus criteria (6th International Workshop) for response assessment. Results Of 160 WM patients, 60 patients received BR (73% in R/R setting) and 100 patients received DRC (50% in R/R setting). In the R/R population, BR was the 2nd line (range 2-11) therapy in 47% of patients, while DRC was 2nd line (range 2-8) in 58% of patients. Rituximab monotherapy was the only prior line of therapy in 8 (20%) patients in the BR group and 20 (40%) in the DRC group (p=0.66). Baseline characteristics were similar in patients treated with BR or DRC (Table 1). Six patients received both BR and DRC during their disease course and overlapped between the 2 cohorts. Among the previous untreated patients, the median IgM levels decreased from 3,785 mg/dL to 724 mg/dL (p=0.0001) at best response with BR, while it decreased from 4,130 mg/dL to 1,250 mg/dL (p=0.001) with DRC. The median time to best response was 6.1 (1-25) months in the BR group and 11 (0.5-47) months in the DRC group (p=0.13). For patients treated with BR, the overall response rate (ORR) was 93% [VGPR 29% (n=4), PR 57% (n=8), MR 7% (n=1)]. One patient (7%) had progressive disease. For patients treated with DRC, ORR was 96% [VGPR 17% (n=8), PR 70% (n=32), MR 9% (n=4)]. One patient (4%) achieved SD. Median follow up in the BR and DRC groups were similar (30 months). The 2-year progression-free survival (PFS) was 88% and 61% in the BR and DRC groups, respectively (p=0.08). The 2-year time-to-next therapy (TTNT) was 88% and 76% in the BR and DRC groups, respectively (p=0.35). Median PFS, TTNT and disease specific survival (DSS) were not reached with either regimen. In the R/R setting, the median IgM levels decreased from 3,880 mg/dL to 659 mg/dL (p=0.0001) at best response with BR, and from 3,870 mg/dL to 1,846 mg/dL (p=0.001) with DRC. The median time to best response was similar [7 (1-39) months with BR and 7 (0.5-28) months with DRC (p=0.77)]. For patients treated with BR, ORR was 95% [CR 3% (n=1), VGPR 38% (n=14), PR 41% (n=15), MR 13% (n=5)]. Two patients (5%) had progressive disease. With DRC, the ORR was 87% [VGPR 4% (n=2), PR 64% (n=30), MR 19% (n=9)]. Four patients (9%) achieved SD and 2 patients (4%) had progressive disease. Median follow up from BR was 32 months and 51 months from DRC (p=0.24). The 2-year PFS was 66% and 53% in the BR and DRC groups, respectively (p=0.08). The 2-year TTNT was 75% and 68% in the BR and DRC groups, respectively (p=0.24). The median DSS in the BR group was 69 months (95% CI: 65-69) and NR (95% CI: NR-NR) in the DRC group (p=0.57). The proportion of patients with R/R disease was significantly higher in the BR cohort (Table 1). In a bivariate analysis of the entire cohort for PFS, incorporating the setting (TN vs. RR) and the regimen involved (BR vs. DRC), the latter emerged as a significant factor (hazard ratio 0.52, p=0.019) in favor of BR. Time-to-event outcomes and response rates were similar in the MYD88L265P and MYD88WT patients. Grade ≥ 3 adverse events were neutropenia (12%), infections (7%) and nausea/vomiting (2%) with BR, and neutropenia (20%), thrombocytopenia (7%) and infections (3%) with DRC. Conclusions Although both DRC and BR regimens show activity and comparable toxicities, BR regimen shows a trend for superior PFS in WM patients, both in the TN and R/R setting. No difference was seen in TTNT. MYD88 L265P mutation status does not appear to impact activity of BR or DRC. Randomized controlled trial(s) are needed to confirm our findings. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Reeder:Millennium: Research Funding; BMS: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Dispenzieri:Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Kumar:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy; Glycomimetics: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

Abstract BACKGROUND Light-chain amyloidosis (AL) is the most common form of systemic amyloidosis, with an incidence of approximately 1 case/100,000 person-years. Clinically relevant data with regard to the very young (≤ 40 years) patients (pts) are scant. We present a case-control study of very young pts with AL seen at a single institution. METHODS We reviewed the medical records of all pts with AL who were consecutively evaluated at Mayo Clinic, Rochester, MN between 01/01/1995 and 12/31/2015. The clinical characteristics and survival outcomes of very young pts at the time of AL diagnosis (cases) were compared to a 2:1 matched cohort of pts (controls) with AL who were 65 years or older and matched by the time of diagnosis. Upfront autologous stem cell transplantation (ASCT) was defined as transplantation within 6 months of the diagnosis of AL. The Kaplan-Meier method was used to all time-to-event analyses. The average years of life lost was computed by subtracting the mean survival from diagnosis observed in the cohort from the mean survival expected in the population based on life-tables. RESULTS Of 3433 pts with AL, 50 (1.5%) pts were ≤ 40 years of age at diagnosis (cases). Fatigue, peripheral edema, dyspnea and bleeding were less common at presentation in cases compared to controls (table A). The cases were also more likely to have liver or GI involvement (OR= 3.45, 95% CI: 1.6-7.2). Unusual initial clinical features in the cases included unprovoked splenic rupture (2%) and erectile dysfunction (4%) observed 6-15 months prior to the diagnosis of AL in cases; no such features were observed in the control group. The median time between the onset of symptoms and definitive diagnosis was 0.4 years (95% CI: 0.3-0.7) for the cases and 1 year (95% CI: 0.8-1.2) for controls (p<0.0001). The ECOG performance score at diagnosis was ≥2 in 51% of cases compared to 78% of the controls (OR= 0.29, 95% CI: 0.14-0.63). The involvement by 3 or more organs at diagnosis was comparable [24 (48%) cases compared to 34 (34%) controls (p=0.11)]. Concomitant myelomatous (AL-CRAB) features were evident in 12% of each group and 27 (54%) cases and 37 (41%) controls had >10% BMPCs without active myeloma (AL-PCMM) (p=0.16). Monoclonal light chain involvement without involvement of heavy chain was seen in 23 cases (50%) and 31 controls (32%), (OR= 2.1, 95% CI: 1.04-4.37). The median follow-up was similar for cases and controls, [10.9 years (95% CI: 7.6-12) vs 9.9 years (95% CI 8-14)], respectively. The estimated average years-of-life lost was 8.6 years over 20 years of follow-up in cases, (Figure 1a). In cases, 1 and 10-year overall survival (OS) from diagnosis was 73% and 51%, respectively (median OS 12.7 years; 95% CI: 4.0-NR) while, in controls, 1 year and 10 year OS was 62% and 15% respectively (median OS 2.1 years; 95% CI (1.0-3.6), p<0.001), (Figure 1b). Cardiac involvement was associated with a worse OS in both cohorts, (cases: median OS was 3.2 years with cardiac involvement (95% CI: 0.6-8.7) vs NR (95% CI: 8.0-NR) in those without; p=0.003; controls: median OS was 1.1 years with cardiac involvement (95% CI: 0.53-1.6) vs 4.8 years (95% CI: 3.7-8.1) in those without; p=0.02. Thirty one of 47 (66%) cases were eligible and 20 of 79 (25%) controls were eligible for upfront ASCT. In cases, upfront ASCT was associated with a longer OS. Median OS was NR (95% CI: NR-NR) in pts who underwent upfront ASCT (n=25) vs 4.0 years (95% CI: 0.5-8) in pts who did not, p≤0.0001. For controls, the median OS was 9 years (95% CI: 0.5-11) for pts who underwent upfront ASCT (n=7) vs 1.6 years (95% CI: 1.0-2.8) for pts who did not (n=93), p=0.26. In cases, six (12%) pts underwent solid organ transplantation (kidney 5, heart 1) and none in the control arm. CONCLUSIONS AL amyloidosis is infrequently encountered at the age of ≤40 years, but the loss of productive years of life and the disease burden are substantial in this cohort. A substantial delay in diagnosis from the onset of symptoms was noted in our study in the control population. Cardiac involvement remains a primary determinant of prognosis irrespective to age. Although over one-half of young pts are alive 10 years after the diagnosis (contrast ≈15% ≥ 65 years), early mortality remains substantial irrespective of age. An ASCT-based approach is associated with superior outcome in the young. A greater proportion of the young pts is fitter and ASCT-eligible at diagnosis, and should therefore be offered this approach. Disclosures Dispenzieri: Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding. Kumar:Array BioPharma: Consultancy, Research Funding; Kesios: Consultancy; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding.