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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 Introduction Autologous stem cell transplantation (ASCT) plays a central role in the treatment of multiple myeloma (MM), even in the era of novel therapies (Gonsalves et al, 2018). Given the efficacy of the latter, as well as for logistical reasons, many patients opt to store their stem cells and delay ASCT until the time of progression. Delayed transplant does not appear to affect overall survival (OS) (Attal et al, 2017). However, in the "salvage" setting, the impact of treatment with additional chemotherapy prior to ASCT is unknown. One study, albeit in the front-line, suggested that in patients achieving less than a partial response (PR), additional induction prior to ASCT did not improve survival (Vij et al, 2015). The present study investigates the role of induction therapy prior to salvage ASCT. Methods We identified 380 patients who underwent ASCT >12 months after being diagnosed with MM from January 1, 2006 to July 1, 2017 at Mayo Clinic Rochester. 121 had a delayed ASCT, but no International Myeloma Working Group (IMWG) progression prior to ASCT and were excluded. Another 17 patients achieved less than PR prior to ASCT, thus were deemed primary refractory and excluded. Finally, 8 patients were excluded because they received a planned tandem ASCT. Thus, 234 patients were included in the present study, which was approved by the Mayo Clinic Institutional Review Board, in accordance with the Declaration of Helsinki. We refer to the time of progression prior to ASCT, after which we examined the use of pre-ASCT therapy, as T0 to avoid confusion. Time to next therapy (TNT) was defined as the time from ASCT (stem cell infusion, Day +0) to the initiation of a new therapy, not including planned consolidation or maintenance. Patients who were alive and had not received any new therapies, or died before receiving another therapy were censored at the time of last follow up, as of May 15, 2018. OS was defined as the time from Day +0 to death from any cause, with living patients censored at the time of last follow-up. TNT and OS were estimated using the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazard model was used for univariate and multivariate analysis. High-risk cytogenetics were defined as del(17/17p), t(4;14), t(14;16), and t(14;20). The Mann-Whitney U test and Fisher's Exact test were used to compare continuous and categorical variables, respectively. Statistical analysis was completed using JMP 13.0 (SAS Institute Inc., Cary, NC, USA). Results Of the 234 patients who underwent salvage ASCT, 188 were treated with additional chemotherapy after T0 (hereafter referred to as "pre-ASCT induction"), whereas 46 patients went directly to ASCT. Baseline characteristics were comparable, however more patients in the pre-ASCT induction group had >1 progression prior to ASCT (28% vs. 9%, p= .0065) and had a trend towards a shorter duration of response (DOR) prior to T0 (14.7 vs. 18.5 months, p= .12). Intuitively, the pre-ASCT induction group had a longer time from T0 to ASCT (5.3 vs. 2.3 months, p< .0001). The median TNT for the entire cohort of 234 patients from Day +0 was 17.2 months (95% CI, 14.8-19.7); median OS was 50.4 months (95% CI, 43.3-60.7). TNT and OS were comparable between the two treatment groups (Figure 1). After adjusting for other significant prognostic factors, such as DOR prior to T0 and the presence of high risk cytogenetics, treatment with pre-ASCT induction did not significantly affect TNT or OS (Table 1). However, among the 188 patients treated with pre-ASCT induction, the subsequent depth of response prior to ASCT significantly affected TNT (Figure 2A) and OS (Figure 2B). TNT at 1-year post ASCT was 79.2% for patients achieving a ≥VGPR, 62.1% in those who achieved a PR or stable disease, and 45.7% for patients who had relapsed/refractory MM at the time of ASCT or received >2 lines of pre-ASCT therapy (p= .0003). Interestingly, the time from diagnosis to T0 was comparable between these 3 groups (27 vs. 28 vs. 26 months, respectively, p= .26). Conclusions Many patients with MM do not undergo ASCT until disease progression. In our cohort of 234 patients who underwent salvage ASCT, outcomes were similar whether patients received pre-ASCT induction or not. However, among the 188 patients treated with pre-ASCT induction, deeper responses correlated with significantly longer TNT and OS after ASCT. Further research into the role of chemotherapy prior to delayed ASCT in the era of novel agents is warranted. Disclosures Gertz: annexon: Consultancy; Apellis: Consultancy; Medscape: Consultancy; Teva: Consultancy; janssen: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Ionis: Honoraria; spectrum: Consultancy, Honoraria; celgene: Consultancy; Prothena: Honoraria; Abbvie: Consultancy. Lacy:Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: 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:Celgene: Research Funding; Takeda: 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; 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.

Abstract Background Limited data exist with respect to outcome and optimal therapeutic strategies in patients with central nervous system (CNS) involvement in multiple myeloma (MM). We present a single center experience of patients with myelomatous CNS involvement in newly diagnosed and relapsed / refractory MM. Methods Of 4060 patients with MM seen at Mayo Clinic, Rochester, MN between January, 1st 1998 and December, 31st 2012, 26 patients had identifiable CNS involvement confirmed by biopsy / presence of plasma cells in the cerebrospinal fluid (CSF) and/or identification of intraparenchymal or meningeal involvement by imaging (MRI/CT). Patients were risk stratified by mSMART (Mayo Stratification for Myeloma And Risk-adapted Therapy) criteria. Overall survival (OS) from diagnosis and the time of CNS involvement was calculated using the Kaplan-Meier method. Results Myelomatous CNS involvement occurred in 26 (0.6%) patients with MM of whom 3 were newly diagnosed. The median time to detection of CNS involvement was 24 months (range: 0-125) from diagnosis of MM. Median age at CNS myeloma diagnosis was 58 years (range 37-80) and 73% were male. Abnormally high LDH was observed in 11 out of 22 patients at the time of CNS involvement. Lumbar puncture was performed on 16 patients, 13 (81%) of whom had plasma cells in the CSF detected by cytology/flow-cytometry. Two patients, without evidence of plasma cells, had abnormally high CSF protein and 1 had normal CSF analysis. Of the 25 patients who underwent MRI, 16 (64%) had at least one of the following significant abnormalities; intraparenchymal disease (37%), leptomeningeal enhancement (68%) or direct extension of MM (31%). The neurological symptoms at or after diagnosis of CNS myeloma included headache (38%), cranial nerve palsy (38%), visual disturbance (38%), gait disturbance (35%), paresthesias (35%), limb weakness (31%), confusion (30%), nausea/vomiting (15%), dysarthria (12%), seizures (8%) and urinary incontinence (4%). Fluorescent in-situ hybridization (FISH n=7), cytogenetics (n=8) and/or plasma cell labeling index (PCLI n=12) were available in 18 patients prior to the diagnosis of CNS disease. Ten (56%) out of those 18 patients had high-risk features at least by one criterion. At the time of CNS involvement, six additional patients demonstrated high risk features [5 by PCLI (≥ 3%) and 1 by FISH]. Overall, 16 out of 26 (62%) patients were classified as high risk by mSMART criteria prior to or at the time of CNS involvement. Four (27%) out of 15 had a deletion p53 or monosomy 17 chromosomal abnormality. Median OS was 42 (95% CI, 19-55) months from the diagnosis of MM and 3 months (95% CI: 1-7.9) from the time of CNS involvement (Figure). OS of patients with high risk features was significantly worse (27 months) compared to standard risk disease (67 months, p=0.02) from diagnosis of MM. Eighteen patients received radiation therapy for CNS myeloma. Five of those patients also received intrathecal (MTX and ARA-C) therapy. One patient received intrathecal and systemic chemotherapy. Four patients did not receive any treatment. Novel agents, including bortezomib (23%), thalidomide (15%), and pomalidomide (4%) were administered to the patients post diagnosis of CNS disease. Six (23%) patients underwent autologous stem cell transplant post diagnosis of CNS disease with a median OS of 19 months (95% CI: 10-122 months) from the time of CNS involvement. Conclusion CNS involvement is a rare complication of MM that portends a poor survival outcome. It is likely that the rates in this study are an underestimate of the true incidence due the perceived futility of CNS directed therapy in this disease. Among those recognized, high-risk genetic and markers of increased proliferative activity, including deletion p53 / monosomy 17 and elevated PCLI (≥ 3%) appear to cluster in this cohort. Current therapeutic approaches are largely ineffective in managing this aggressive subset of myeloma patients. Disclosures: No relevant conflicts of interest to declare.

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 Background: Hereditary transthyretin amyloidosis (hATTR) is a rare, systemic, progressive, and fatal condition in which misfolded proteins, mainly produced in the liver, deposit in muscle and organ tissues leading to symptoms of peripheral neuropathy, and possible cardiomyopathy and autonomic neuropathy. The Norfolk Quality of Life (QOL)-Diabetic Neuropathy (DN) Questionnaire is a patient-reported measure that has been validated for capturing neuropathic-specific QOL in patients with hATTR amyloidosis. Examination of patients' responses to the items of the Norfolk-QOL-DN can provide important insights into the impact of hATTR amyloidosis, and its treatment, on concrete aspects of patients' daily activities and physical functioning. Objective: To provide a descriptive analysis of item-level responses to the Norfolk-QOL-DN by patients with hATTR amyloidosis with polyneuropathy, who participated in the NEURO-TTR trial, in order to identify the impact of treatment with inotersen versus placebo on concrete aspects of patients' functioning and daily activities. Methods: Data come from the NEURO-TTR trial, a multicenter, multinational, double-blind trial (NCT01737398) of 172 adults with hATTR amyloidosis with polyneuropathy who received 65 weeks of either treatment with the investigational drug inotersen, an antisense oligonucleotide, or a matching placebo. The Norfolk QOL-DN was administered to patients at baseline, week 35, and week 66. The Norfolk QOL-DN is a 35-item measure which captures neuropathic-related QOL. Nineteen items from the scale were determined to elicit concrete information about functioning and daily activities. Each of these 19 items used five response choices: "no problems", "very mild problems", "mild problems", "moderate problems", and "severe problems". Response options were dichotomized such that the latter two options were coded as indicating substantial impairment in functioning or activities. Descriptive analyses compared, for each item, the proportion of patients in the inotersen and placebo arms at baseline and week 66 (and change from baseline to week 66) who indicated substantial impairment. Results: At baseline, there were no differences for any Norfolk QOL-DN items in the proportions of patients who indicated substantial impairment. However, at week 66, patients receiving inotersen were less likely than those receiving placebo to indicate that they had a substantial impairment on several aspects of functioning and daily activities. Patients in the inotersen arm were half as likely as those receiving placebo to indicate a problem of pain keeping them awake at night (15% vs. 37%) and being moderately or severely bothered by the touch of bedsheets (12% vs. 27%). A noticeably smaller percentage of patients receiving inotersen than placebo reported problems with their symptoms affecting their usual activities (37% vs. 50%); having difficulty moving their fingers (47% vs 64%); feeling unsteady on their feet (49% vs 67%); having difficulty getting out of a chair (51% vs. 62%) or walking down stairs (42% vs. 58%); and having difficulty bathing (24% vs. 35%), dressing (21% vs 35%), walking (41% vs 60%), getting on/off the toilet (22% vs. 37%), and utensil use (19% vs. 31%). Percentages of change in patients from baseline to week 66 show larger increases in having substantial impairment in these functions and activities for patients receiving placebo than inotersen, with those receiving inotersen generally showing small increases, and even decreases in substantial impairment over the course of treatment. Conclusion: Following 66 weeks of treatment, hATTR amyloidosis patients receiving inotersen were less likely than those receiving placebo to report substantial impairment in many aspects of functioning and activities of daily living, including moving fingers, balance while standing, getting out of a chair, walking down stairs, bathing, dressing, walking, getting on/off the toilet, and using utensils. Ability to engage in these functions and activities was better preserved in patients treated with inotersen than placebo. These findings present a context for understanding the concrete impact of inotersen treatment on the day-to-day lives of patients with hATTR amyloidosis with polyneuropathy. Disclosures Yarlas: Optum: Employment; Akcea: Research Funding. Merlini:Millenium: Consultancy; Pfizer: Consultancy; Janssen: Consultancy; Prothena: Consultancy; Ionis: Consultancy; Akcea: Consultancy. White:Optum: Employment; Akcea: Research Funding. Sikora Kessler:Optum: Employment; Akcea: Research Funding. Lovley:Optum: Employment; Akcea: Research Funding. Guthrie:Akcea: Employment, Other: Stock Ownership. Pollock:Akcea: Employment. Gertz:Apellis: Consultancy; Amgen: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Prothena: Honoraria; annexon: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria; Teva: Consultancy; Ionis: Honoraria; Medscape: Consultancy; Physicians Education Resource: Consultancy; Research to Practice: Consultancy; celgene: Consultancy.

Abstract Background: Cardiac involvement is integral in staging and prognosis of immunoglobulin light chain (AL) amyloidosis. The N-terminal prohormone of brain natriuretic peptide (NT proBNP) is a cardiac biomarker used in screening for cardiac involvement and staging the disease. Transthoracic echocardiogram (TTE) and cardiac magnetic resonance (CMR) are the imaging modalities recommended to determine cardiac involvement and function. Methods: We conducted a retrospective review of all patients with biopsy proven systemic AL amyloidosis seen at the mayo clinic between Jan 1, 2006 and Dec 30, 2015. The aim of the study is to identify the nature of abnormalities in cardiac biomarkers and echocardiographic features in patients with AL amyloidosis and the ability of these investigations to diagnose cardiac involvement. We first identified all patients with AL amyloidosis that underwent endomyocardial biopsy for suspicion of cardiac involvement (Cohort 1). We then analyzed a cohort (Cohort 2) which consisted of patients who had serum NT proBNP and a comprehensive echocardiographic evaluation at time of diagnosis. Results: 179 patients with AL amyloidosis underwent endomyocardial biopsy (Cohort 1) of whom 173 had evidence of amyloid deposition. In this cohort, 159 patients had NT proBNP performed at the time of the procedure. The NT proBNP was elevated (>300) in all 159 patients with a median NT proBNP of 4917 (range 355-69541). The median left ventricular ejection fraction (LVEF), interventricular septal (IVS) thickness and strain rate were 54 (range 10-77), 15 (range 8-30) and -9 (range -21 to 0) respectively. CMR findings were consistent or suggestive of light chain amyloidosis in 38/42 patients, yielding a sensitivity of 90 percent. The LVEF, IVS thickness and strain rate were abnormal in 89/168 (53%), 102/64 (61%) and 92/95 (97%) respectively. 95 patients with biopsy proven cardiac amyloidosis had complete echocardiogram data available on LVEF, IVS thickness and strain rate, with 97% (n=92) presenting with an abnormality in at least one of these variables . CMR findings were consistent or suggestive of light chain amyloidosis in 38/42 patients, yielding a sensitivity of 90 percent. Patients with a normal NT proBNP and normal echocardiogram were considered disease free (true negative), based on our initial analysis of these investigations in Cohort 1. Cohort 2 consisted of 342 consecutive patients. The median NT pro BNP was 1878 (25-48214). The median LVEF, IVS thickness and strain rate were 63 (22-90), 14 (6-25) and -13 (-25 to -3) respectively. 259 (76%) patients had a positive NT proBNP (above 300), of whom 237 (92%) had an abnormality detected on TTE. 83 patients had a negative NT proBNP, of whom 27 (33%) had an abnormality in either LVEF, IVS thickness or strain rate. 19 of these 27 patients had a borderline reduced strain rate between -17 and -18, whilst the remaining 8 patients had a strain between -14 and -15. Only 6/27 patients were considered to have possible early cardiac involvement and none have any other diagnostic or classical features of amyloidosis on TTE. Conclusion: The combination of NT proBNP and comprehensive echocardiographic evaluation provides substantial information to diagnose cardiac amyloidosis in a significant portion of patients negating the need for endomyocardial biopsy. A negative NT proBNP rules out clinically meaningful cardiac involvement and may obviate the routine use of TTE in patients with a low clinical suspicion of cardiac amyloidosis. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Research to Practice: Consultancy; Physicians Education Resource: Consultancy; Ionis: Honoraria; celgene: Consultancy; spectrum: Consultancy, Honoraria; Teva: Consultancy; Amgen: Consultancy; Medscape: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; annexon: Consultancy; Apellis: Consultancy; Prothena: Honoraria. Lacy:Celgene: Research Funding. 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.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Research Funding; Celgene: 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; 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; 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.

Abstract Introduction: Immunoglobulin light chain (AL) amyloidosis is associated with significant morbidity and mortality. Several models were developed to allow survival prediction, but head-to-head model comparison is lacking. Patients and Methods: Five prognostic models were compared: Mayo 2004; Mayo 2012; 2013 European modification of Mayo 2004 (where Mayo 2004 stage 3 is subdivided into 3 subgroups based on NT-proBNP at 8500 ng/L and systolic blood pressure at 100 mmHg); 2015 European modification of Mayo 2004 (where Mayo 2004 stage 3 is subdivided into 2 subgroups based on NT-proBNP at 8500 ng/L); and organ model (a model based on number of involved organs). All patients with available baseline data for the 5 models were included in this study (n=1005). Improvements in predictive accuracy of the various models were determined by calculating a net improvement in survival prediction for each pair of prognostic models. Net improvement was considered as the proportion where model A outperforms model B minus the proportion where model B outperforms model A. Results: For all models, there was increasing risk for death with increasing stage. The organ model was the least powerful system with a hazard ratio of 2.8 for ≥4 organs compared to 1 involved organ. The organ model was consistently outperformed by the other 4 systems. In the cohort as a whole, the biomarker models (Mayo 2004; Mayo 2012; European 2013; European 2015) were comparable in ability to predict survival (Figure). However, a slightly superior performance of the European 2013 modification of the Mayo 2004 system was seen over the Mayo 2004 system in the group as a whole (net improvement 4.1%, P=0.023) and when restricted to non-ASCT population (net improvement 6.3% P=0.014). The European 2015 modification performed slightly better than the Mayo 2004 system in the ASCT population (net improvement 3.4%, P=0.025). 1-year mortality was better predicted by the European models (net improvement 11-14%, P<0.05), while the Mayo 2012 had better survival prediction to all other biomarker models in 3-year landmark comparison (net improvement 7-9%, P<0.05). Conclusion: Using biomarker based staging is a clear improvement over the organ staging system. The different biomarker staging systems' abilities to predict for survival were relatively comparable, solidifying the importance of soluble cardiac biomarkers and free light chain measurement as prognosticators in AL amyloidosis. Mayo 2004-based models better predict for early death while Mayo 2012 model has a better prediction for long-term survival. Figure. Figure. Disclosures Gertz: Ionis: Honoraria; celgene: Consultancy; spectrum: Consultancy, Honoraria; janssen: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Medscape: Consultancy; annexon: Consultancy; Teva: Consultancy; Research to Practice: Consultancy; Apellis: Consultancy; Alnylam: Honoraria; Prothena: Honoraria; Physicians Education Resource: Consultancy. Lacy:Celgene: Research Funding. 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.. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Russell:Vyriad: Equity Ownership. Kumar: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; 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. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

Abstract Introduction: Light chain burden in light chain (AL) amyloidosis is often low, making accurate response assessment challenging. Methods: AL amyloidosis patients achieving very good partial or complete response to first line therapy and had serial sFLC studies during and after completion of therapy were included (n=396). Involved free light chain (iFLC), difference in involved-to-uninvolved free light chains (dFLC) and sFLC ratio (sFLCR) were assessed at the end of first line therapy and at nadir iFLC. Survival analysis was done using the Kaplan-Meier method. Hematological progression-free survival (hemPFS) was defined as the time from diagnosis until hematological progression or death, where patients known to be alive and progression-free at the end of follow-up were censored. Hematological progression was defined according to consensus criteria or upon initiation of second line therapy, whichever came first. Results: The median iFLC and dFLC at the end of therapy was 1.7 mg/dL and 0.5 mg/dL, respectively. sFLCR normalization occurred in 70% of patients. iFLC ≤2 mg/dL and dFLC ≤0.5 mg/dL were associated with a longer hemPFS compared to their counterparts (Figure). Only iFLC ≤2 mg/dL was associated with a significantly longer overall survival (Figure). sFLCR normalization did not predict hemPFS or overall survival. Organ response was predicted by iFLC ≤2 mg/dL and dFLC ≤0.5 mg/dL (Table), with best discrimination seen with iFLC ≤2 mg/dL. Organ response was not predicted by sFLC normalization (Table). The median nadir iFLC was 1.4 mg/dL and was reached 3.9 months from the end of therapy, longer in transplanted patients compared to patients treated with non-transplant regimens (7.3 vs 1.8 months, respectively; P<0.001). iFLC ≤2 mg/dL at the completion of therapy and nadir iFLC reached >12 months from the end of therapy were favorable predictors of hemPFS/OS in a multivariate analysis. Conclusion: iFLC at the end of first line therapy better predicts for organ response and survival than dFLC among deep responders. Normalization of sFLCR does not predict for organ response or survival and should not be used as measure of therapeutic efficacy. Figure. Figure. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Dingli: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; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Russell:Vyriad: Equity Ownership. Kumar: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; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Alnylam: Honoraria; celgene: Consultancy; Ionis: Honoraria; Abbvie: Consultancy; annexon: Consultancy; janssen: Consultancy; spectrum: Consultancy, Honoraria; Research to Practice: Consultancy; Medscape: Consultancy; Apellis: Consultancy; Teva: Consultancy; Amgen: Consultancy; Prothena: Honoraria; Physicians Education Resource: Consultancy.

Abstract ATTRwt (formerly known as senile) amyloidosis and plasma cell disorders share a common demographic of occurrence with increasing prevalence with age. We aimed to identify the prevalence of plasma cell disorders in patients diagnosed with ATTRwt. We retrospectively reviewed all patients seen at Mayo Clinic Rochester between 1st January 2009 and 31st of December 2017 who were diagnosed with ATTRwt. The start date of the study was chosen to coincide with routine clinical availability of laser microdissection mass spectrometry (LCMS) for subtyping of amyloidosis. 492 patients with ATTRwt were evaluated during the study period. Serum immunofixation electrophoresis (SIFE), urine immunofixation electrophoresis (UIFE) and serum free light chain (FLC) assay testing was performed in 74% (n=362), 53% (n=261) and 79% (n=386) respectively. Of the 492 ATTRwt seen during this period, 139 (28%) had abnormal monoclonal protein studies, the vast majority (92%, n=128) of which were monoclonal gammopathy of undetermined significance (MGUS). Monoclonal protein testing in this cohort included SIFE, UIFE and FLC in 96% (n=134), 71% (n=99) and 99% (n=137) respectively. The non-MGUS diagnoses included smoldering multiple myeloma in <1%% (n=2), multiple myeloma (MM) in 6% (n=8), AL amyloidosis in 2% (n=3), and lymphoplasmacytic lymphoma (LPL) in 3% (n=4). MM and LPL developed after progression from MGUS in 2 and 3 patients respectively. Two patients with MGUS also had a diagnosis of low grade non Hodgkin lymphoma (chronic lymphocytic leukemia in one and marginal zone lymphoma in the other). The abnormal monoclonal protein studies included SIFE in 55%, UIFE in 26% and an abnormal serum free light chain ratio (FLCr) in 73%. The organ biopsied for the diagnosis of ATTRwt was heart in 43% (n=60), bone marrow in 24% (n=33), fat in 9% (n=12) and other sites in 5% (n=8, 3 lung, 2 lip, 2 bladder and 1 small bowel). LCMS confirmed the subtype of amyloidosis as ATTRwt in all patients with a biopsy positive for amyloidosis by congo red staining. 19% (n=26) of patients were diagnosed with ATTRwt based on clinical features and a strongly positive PYP scan. PYP scan was positive for ATTR in 55/56 patients in whom the test was performed. The most common monoclonal protein isotypes detected were light chain (45%) and IgG (28%). Light chain subtype was kappa in the majority of patients (80%). Plasma cell disorders are not uncommon in patients with ATTRwt amyloidosis. The diagnosis of a plasma cell disorder and ATTRwt are not mutually exclusive, and their coexistence can confuse the diagnosis if amyloid typing is not performed. Patients with ATTRwt may be misclassified as AL amyloidosis due to the presence of amyloid and a clonal plasma cell disorder with significant prognostic and therapeutic implications. Disclosures Kumar: Novartis: 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; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Merck: 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; 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; 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; 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. 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. Gertz:Ionis: Honoraria; Research to Practice: Consultancy; Amgen: Consultancy; Prothena: Honoraria; Alnylam: Honoraria; Medscape: Consultancy; celgene: Consultancy; Teva: Consultancy; Abbvie: Consultancy; janssen: Consultancy; spectrum: Consultancy, Honoraria; annexon: Consultancy; Apellis: Consultancy; Physicians Education Resource: Consultancy. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

Abstract Background: Peripheral blood biomarkers of tumor microenvironment and immune surveillance such as absolute lymphocyte (ALC) and monocyte (AMC) counts are independent prognostic factors in several hematologic malignancies including multiple myeloma. The timing and prognostic impact of immune reconstitution has been studied after autologous hematopoietic stem cell transplantation, less is known about its significance in newly diagnosed multiple myeloma prior to transplantation. Methods: We studied 771 patients with newly diagnosed multiple myeloma who were treated with novel agents at Mayo Clinic between 01/2004 and 12/2015. Peripheral blood absolute lymphocyte and monocyte counts were measured at the time of treatment initiation and one month thereafter in all patients (including data obtained between 14 and 42 days after treatment initiation). The outcome of interest was overall survival. The peripheral blood parameters of interest were abnormal ALC (reference range 800-2400/µL) and AMC (reference range 500-1500/µL) at baseline and at one month. Immune dysregulation was defined as both abnormal ALC and AMC. Immune reconstitution was defined as recovery of both normal ALC and AMC. The Wilcoxon signed-rank test was used to compare the peripheral blood parameters before and after the first month of treatment. Multivariable-adjusted proportional hazards regression models were used to assess the associations between changes in peripheral blood parameters and overall survival. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis was 65 years (27 - 90) and 459 patients were male (60%). The three most common first-line regimens were lenalidomide + dexamethasone, bortezomib + cyclophosphamide + dexamethasone, and bortezomib + lenalidomide + dexamethasone. Two hundred and eighty patients (36%) went on to undergo autologous hematopoietic stem cell transplantation as part of their first-line therapy. The median ALC decreased from 1100/µL (range 60 - 5590) at baseline to 850/µL (range 60 - 5590) at one month (p < 0.001). The median AMC increased from 330/µL (range 0 - 1840) at baseline to 420/µL (range 0 - 1840) at one month (p < 0.001). The median time between re-assessment of ALC and AMC was 25 days (range 15 - 42). Two hundred and thirty-four patients (31%) had evidence of immune dysregulation at baseline (both abnormal ALC and AMC). Eighty-seven of these 234 patients (37%) recovered normal ALC and AMC at one month (early immune reconstitution). One hundred and thirty-seven of the 537 patients with normal ALC and AMC at baseline (26%) developed new immune dysregulation at one month. The absence of immune dysregulation at baseline (compared to the presence thereof) was associated with better overall survival (HR 0.77, 95% CI 0.61 - 0.97, p = 0.025, n = 771). The absence of immune dysregulation at one month (compared to the persistence or development thereof) was associated with better overall survival (HR 0.63, 95% CI 0.50 - 0.80, p < 0.001, n = 771). Early immune reconstitution (compared to the persistence or development of immune dysregulation) was associated with better overall survival (HR 0.62, 95% CI 0.43 - 0.92, p = 0.016, n = 771). Both associations remained statistically significant after adjusting for age at diagnosis, sex, International Staging System stage, and eligibility for transplantation: HR 0.70 (95% CI 0.54 - 0.90, p = 0.006, n = 612) and HR 0.59 (95% CI 0.39 - 0.90, p = 0.014, n = 612), respectively. Conclusions: Peripheral blood biomarkers of immune dysregulation vary over time and have prognostic significance both at baseline and during follow-up. The presence or development of immune dysregulation in newly diagnosed multiple myeloma is an independent risk factor. The favorable impact of early immune reconstitution suggests that immune dysregulation is a potentially modifiable risk factor that may be exploited for therapeutic benefit. Figure. Figure. Disclosures Lacy: Celgene: Research Funding. Gertz:celgene: Consultancy; Medscape: Consultancy; janssen: Consultancy; Prothena: Honoraria; Apellis: Consultancy; Ionis: Honoraria; annexon: Consultancy; spectrum: Consultancy, Honoraria; Amgen: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; Alnylam: Honoraria. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar: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.