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ObjectivesIn AL amyloidosis, organ response assessment is based on surrogates (eg, cardiac biomarkers). An objective functional test, such as the 6 min walk test (6MWT), capturing overall clinical improvement, is required. We aimed to evaluate the prognostic impact of the 6MWT at baseline and change following chemotherapy.MethodsThis study evaluated the outcomes of patients who enrolled in a prospective observational study at the UK National Amyloidosis Centre (2012–2017). Patients underwent comprehensive assessments inclusive of blood testing, echocardiogram and 6MWT at baseline and annually thereafter.ResultsIn total, 799 patients were included within the study. Median baseline 6 min walk distance (6MWD) was 362 m (IQR: 231 m). 6MWD progressively decreased with worsening cardiac disease stage (458 m, 404 m, 331 m and 168 m for cardiac Mayo stages I, II, IIIa and IIIb, respectively (pConclusionThe 6MWT is prognostic in AL amyloidosis. A baseline distance of ≥350 m independently predicts better survival. These data suggest that 6MWT has utility in AL amyloidosis for baseline prognosis and assessing response.

Purpose:Immune dysregulation is described in multiple myeloma. While preclinical models suggest a role for altered T-cell immunity in disease progression, the contribution of immune dysfunction to clinical outcomes remains unclear. We aimed to characterize marrow-infiltrating T cells in newly diagnosed patients and explore associations with outcomes of first-line therapy.Experimental Design:We undertook detailed characterization of T cells from bone marrow (BM) samples, focusing on immune checkpoints and features of immune dysfunction, correlating with clinical features and progression-free survival.Results:We found that patients with multiple myeloma had greater abundance of BM regulatory T cells (Tregs) which, in turn, expressed higher levels of the activation marker CD25 compared with healthy donors. Patients with higher frequencies of Tregs had shorter PFS and a distinct Treg immune checkpoint profile (increased PD-1, LAG-3) compared with patients with lower frequencies of Tregs. Analysis of CD4 and CD8 effectors revealed that low CD4effector (CD4eff):Treg ratio and increased frequency of PD-1–expressing CD4eff cells were independent predictors of early relapse over and above conventional risk factors, such as genetic risk and depth of response. Ex vivo functional analysis and RNA sequencing revealed that CD4 and CD8 cells from patients with greater abundance of CD4effPD-1+ cells displayed transcriptional and secretory features of dysfunction.Conclusions:BM-infiltrating T-cell subsets, specifically Tregs and PD-1–expressing CD4 effectors, negatively influence clinical outcomes in newly diagnosed patients. Pending confirmation in larger cohorts and further mechanistic work, these immune parameters may inform new risk models, and present potential targets for immunotherapeutic strategies.

Supplementary tables and figures

Systemic immunoglobulin light chain amyloidosis (AL) is an incurable disorder, and the natural history is incompletely understood. In this study, we describe its natural history based on an analysis of real-world longitudinal data. All patients seen at the National Amyloidosis Centre, UK, between February 2010 and August 2019 and treated with up-front bortezomib are included. In all, 1 276 patients received the first-line treatment; 259, 85, and 32 patients received second, third, and fourth treatment lines, respectively. Among patients requiring further treatment after the first line, 77·2% started the second line within two years of the first line; 50·5%, 50·6%, 40·1% and 40·6% of patients had achieved at least very good partial response after the first, second, third and fourth treatment lines. Median overall survival (OS) from first, second, third and fourth lines was 45 months, 56 months, 37 months and not reached, respectively (P = 0·109). In summary, although relapses occur in AL amyloidosis, the outcomes and responses do not worsen with each subsequent relapse, making it attractive to design therapeutics with curative intent.

ObjectivesWild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is a progressive and fatal condition. Although prognosis can be determined at the time of diagnosis according to National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage, the clinical course varies substantially between individuals. There are currently no established measures of rate of disease progression. Through systematic analysis of functional, biochemical and echocardiographic disease-related variables we aimed to identify prognostic markers of disease progression in wtATTR-CM.MethodsThis is a retrospective observational study of 432 patients with wtATTR-CM diagnosed at the UK NAC, none of whom received disease-modifying therapy. The association between mortality from the 12-month timepoint and change from diagnosis to 12 months in a variety of disease-related variables was explored using Cox regression.ResultsChange in N-terminal pro-B-type natriuretic peptide concentration (∆ NT-proBNP) at 12 months from diagnosis was the strongest predictor of ongoing mortality and was independent of both change in other disease-related variables (HR 1.04 per 500 ng/L increase (95% CI 1.01 to 1.07); p=0.003) and a range of known prognostic variables at the time of diagnosis (HR 1.07 per 500 ng/L increase (95% CI 1.02 to 1.13); p=0.007). An increase in NT-proBNP of >500 ng/L, >1000 ng/L and >2000 ng/L during the first year of follow-up occurred in 45%, 35% and 16% of patients, respectively.ConclusionChange in NT-proBNP concentration during the first year of follow-up is a powerful independent predictor of mortality in wtATTR-CM.

Objectives The benefit of autologous stem cell transplantation (ASCT) in the treatment of light chain (AL) amyloidosis requires re-evaluation in the modern era. This retrospective case-matched study compares ASCT to bortezomib for the treatment of patients with AL amyloidosis. Methods Newly diagnosed patients with AL amyloidosis treated with ASCT or bortezomib between 2001 and 2018 were identified. Patients were excluded if the time from diagnosis to treatment exceeded 12 months. Patients were matched on a 1:1 basis, using a propensity-matched scoring approach. Results A total of 136 propensity score-matched patients were included (ASCT n = 68, bortezomib n = 68). There was no significant difference in overall survival at two years (P = .908, HR: 0.95, CI: 0.41-2.20). For ASCT vs bortezomib: overall haematological response rate at 6 months was 90.6% vs 92.5%; organ response at 12 months: cardiac (70.0% vs 54%, P > .999), renal (74% vs 24%, P = .463) liver (21% vs 22%, P = .048); median progression-free survival (50 vs 42 months P = .058, HR: 0.61, CI: 0.37-1.02) and time to next treatment (68 vs 45 months, P = .145, HR: 0.61, CI: 0.31-1.19). More patients required treatment in the bortezomib group compared to ASCT group at 24 months (41 vs 23, Chi-squared P = .004) and 48 months (57 vs 41, Chi-squared P = .004). Conclusions This small retrospective study suggests that there is no clear survival advantage of ASCT over bortezomib therapy. A prospective randomised controlled trial evaluating ASCT in AL amyloidosis is critically needed.

BackgroundOutcomes after renal transplantation have traditionally been poor in systemic amyloid A (AA) amyloidosis and systemic light chain (AL) amyloidosis, with high mortality and frequent recurrent disease. We sought to compare outcomes with matched transplant recipients with autosomal dominant polycystic kidney disease (ADPKD) and diabetic nephropathy (DN), and identify factors predictive of outcomes.MethodsWe performed a retrospective cohort study of 51 systemic AL and 48 systemic AA amyloidosis patients undergoing renal transplantation. Matched groups were generated by propensity score matching. Patient and death-censored allograft survival were compared via Kaplan–Meier survival analyses, and assessment of clinicopathological features predicting outcomes via Cox proportional hazard analyses.ResultsOne-, 5- and 10-year death-censored unadjusted graft survival was, respectively, 94, 91 and 78% for AA amyloidosis, and 98, 93 and 93% for AL amyloidosis; median patient survival was 13.1 and 7.9 years, respectively. Patient survival in AL and AA amyloidosis was comparable to DN, but poorer than ADPKD [hazard ratio (HR) = 3.12 and 3.09, respectively; P 12 mm (HR = 26.58; P = 0.03), while survival was predicted by haematologic response (very good partial or complete response; HR = 0.07; P = 0.018). In AA amyloidosis, recurrent amyloid was associated with elevated serum amyloid A concentration but not with outcomes.ConclusionsRenal transplantation outcomes for selected patients with AA and AL amyloidosis are comparable to those with DN. In AL amyloidosis, IVSd thickness and achievement of deep haematologic response pre-transplant profoundly impact patient survival.

Hereditary apolipoprotein A-I (AApoAI) amyloidosis is a rare heterogeneous disease with variable age of onset and organ involvement. There are few series detailing the natural history and outcomes of solid organ transplantation across a range of causative APOA1 gene mutations.We identified all patients with AApoAI amyloidosis who presented to the National Amyloidosis Centre (NAC) between 1986 and 2019.In total, 57 patients with 14 different APOA1 mutations were identified including 18 patients who underwent renal transplantation (5 combined liver-kidney (LKT) and 2 combined heart-kidney (HKT) transplants). Median age of presentation was 43 years and median time from presentation to referral was 3 (0-31 years). Involvement of the kidneys, liver and heart by amyloid was detected in 81%, 67% and 28% of patients, respectively. Renal amyloidosis was universal in association with the most commonly identified variant (Gly26Arg,AApoAI amyloidosis is a slowly progressive disease that is challenging to diagnose. The outcomes of transplantation are encouraging and graft survival is excellent.

INTRODUCTION Whilst excision biopsy is traditionally preferred, advances in radiological and histological techniques warrant a re-look at core biopsy as a viable primary diagnostic method. METHOD Over a 3-year period, all patients who underwent core biopsy to investigate lymphoma at our centre were included. RESULTS 554 consecutive patients were included (40.1% prior lymphoma and 59.4% new presentations). Three or more cores were taken in 420 (75.8%) cases. Median time from request to biopsy and biopsy to histology report was 2 (0-40) days and 7 (1-24) days, respectively. 510/544 (93.8%) biopsies were diagnostic. There was no difference in whether the biopsy was diagnostic based on indication (new vs. relapsed lymphoma) (P = .445), whether biopsy was PET-directed (P = .507), for T-cell lymphoma (P = .468) or nodal vs. extra-nodal (P = .693). Thirty-eight patients (6.9%) required a second biopsy due to inadequate tissue. In a patient experience survey, only 13.9% reported any complications (1 self-limiting minor bleeding, 4 bruising) whilst 16.7% reported any discomfort beyond 12 hours. CONCLUSION Core biopsy performed by experienced radiologists and analysed by expert haemato-pathologists is a reliable, well-tolerated method for diagnosing lymphoma and confirming relapse. Multiple cores can be obtained under local anaesthetic yielding sufficient material in the majority of cases.

Aims Cardiac transthyretin amyloidosis (ATTR‐CM) is a progressive and fatal condition. Prognosis can be determined at diagnosis according to the National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage. We sought to examine how NAC ATTR stage changes during follow‐up and whether it maintains its prognostic value throughout the disease course. Methods and results We performed a retrospective study of 945 patients with wild‐type ATTR‐CM (wtATTR‐CM) or hereditary ATTR‐CM associated with the V122I variant (V122I‐hATTR‐CM) who were diagnosed and serially evaluated at the UK NAC. Patients who commenced any disease‐modifying therapy for amyloidosis were censored at the time of doing so. Landmark Kaplan–Meier survival analyses were performed at diagnosis (n = 945) and at 6 ± 1 (n = 432), 12 ± 3 (n = 562), and 24 ± 3 (n = 316) months and stratified by recalculated NAC ATTR stage at the relevant time point. Cox regression analyses were performed to assess the prognostic significance during follow‐up of an increase in NAC ATTR stage from Stage I at diagnosis. Mortality in ATTR‐CM was predicted by NAC ATTR stage at each time point [Stage II vs. I, hazard ratios (HRs) 1.95–2.67; P

Purpose: Immune dysregulation is described in multiple myeloma. While preclinical models suggest a role for altered T-cell immunity in disease progression, the contribution of immune dysfunction to clinical outcomes remains unclear. We aimed to characterize marrow-infiltrating T cells in newly diagnosed patients and explore associations with outcomes of first-line therapy. Experimental Design: We undertook detailed characterization of T cells from bone marrow (BM) samples, focusing on immune checkpoints and features of immune dysfunction, correlating with clinical features and progression-free survival. Results: We found that patients with multiple myeloma had greater abundance of BM regulatory T cells (Tregs) which, in turn, expressed higher levels of the activation marker CD25 compared with healthy donors. Patients with higher frequencies of Tregs had shorter PFS and a distinct Treg immune checkpoint profile (increased PD-1, LAG-3) compared with patients with lower frequencies of Tregs. Analysis of CD4 and CD8 effectors revealed that low CD4effector (CD4eff):Treg ratio and increased frequency of PD-1–expressing CD4eff cells were independent predictors of early relapse over and above conventional risk factors, such as genetic risk and depth of response. Ex vivo functional analysis and RNA sequencing revealed that CD4 and CD8 cells from patients with greater abundance of CD4effPD-1+ cells displayed transcriptional and secretory features of dysfunction. Conclusions: BM-infiltrating T-cell subsets, specifically Tregs and PD-1–expressing CD4 effectors, negatively influence clinical outcomes in newly diagnosed patients. Pending confirmation in larger cohorts and further mechanistic work, these immune parameters may inform new risk models, and present potential targets for immunotherapeutic strategies.

Background: Daratumumab is a monoclonal antibody, which targets CD38; an antigen expressed on malignant plasma cells in AL amyloidosis thus providing a rationale for its use.Method: Patients treated with daratumumab monotherapy (2016-2019) for relapsed/refractory systemic AL amyloidosis were identified from the database at the UK National Amyloidosis Centre.Results: Of 50 evaluable patients, haematological responses at 3 months were: CR - 19 (38%), VGPR - 14 (28%), PR - 9 (18%) and no response - 8 (16%). Median time to response was 1 (1-6) month. Of assessable patients, cardiac, renal and hepatic responses were seen in 43.8%, 25.0% and 0% of patients whilst progression occurred in 25.0%, 12.5% and 37.5% respectively. Patients achieving a CR had longer median OS (not reached vs. 22.7 months [95% CI 17.0-28.4 months]) (p = .036). Furthermore, patients achieving a rapid response (at 1 month) had a longer median PFS (not reached vs. 9 months [95% CI 5.8-12.2 months]) (p = .013).Conclusion: Daratumumab monotherapy is effective in multiply-relapsed systemic AL amyloidosis and should be considered, if available, in patients who have not received prior daratumumab therapy. Responses are achieved rapidly and overall response rate was 84%. CR predicts overall survival whilst speed of response is predictive of a longer PFS.

Systemic amyloidosis is a rare but increasingly recognised disease that is heterogeneous in presentation. Early diagnosis, whilst imperative, remains challenging but can improve prognosis and limit organ dysfunction. An increased repertoire of diagnostic imaging and histological techniques are becoming mainstream and promise to aid early diagnosis. Better risk stratification, via biomarkers and cytogenetics, has improved multidisciplinary treatment decisions. The use of novel agents has improved treatment efficacy, which translates into survival benefit. Newer strategies targeting pre-deposited amyloidogenic protein are under investigation. The current paper reviews available data relating to the most recent advances in the field of systemic amyloidosis.

With improving outcomes in amyloid light-chain (AL) amyloidosis, there is a need to study novel agents in this setting. We report outcomes of 40 patients with relapsed AL amyloidosis treated with ixazomib + lenalidomide + dexamethasone (IRd). Haematological responses were assessed on an intention-to-treat basis at three months: complete response (CR) - 8 (20·5%), very good partial response (VGPR) - 8 (20·5%), partial response (PR) - 7 (17·9%) and no response (NR) - 16 (41·0%). One patient had missing data. Six patients subsequently improved response. Best responses were: CR - 10 (25·6%), VGPR - 8 (20·5%), PR - 7 (17·9%), NR - 14 (35·9%). Cardiac and renal organ responses occurred in 5·6% and 13·3% respectively. Median progession-free survival (PFS) was 17·0 months (95% CI 7·3-20·7 months), improving to 28·8 months (95% CI 20·6-37·0 months) in those achieving CR/VGPR. Median overall survival was 29·1 months (95% CI 24-33 months). Serious adverse events were seen in 14 (35·0%) patients inclusive of 15 admissions due to: infection (6/15, 40·0%), fluid overload (5/15, 33·3%), cardiac arrhythmia (2/15, 13·3%), renal dysfunction (1/15, 6·6%) and anaemia (1/15, 6·6%). In summary, IRd is an oral treatment option with a manageable toxicity profile leading to deep responses in 47% of patients with relapsed AL amyloidosis.

Aims Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly diagnosed at an early stage of the disease natural history, defined as National Amyloidosis Centre (NAC) ATTR Stage I. The natural history of early-stage ATTR-CM remains poorly characterized. Methods and results A retrospective multi-centre observational study of 879 patients with ATTR-CM, either wild-type TTR genotype or carrying the p.V142I TTR variant, and NAC ATTR Stage I biomarkers at the time of diagnosis who did not receive disease-modifying therapy for amyloidosis. Disease characteristics at diagnosis that were independently associated with mortality by Cox regression analysis were N-terminal pro-B-type natriuretic peptide (NT-proBNP), TTR genotype, and troponin T. Patients were categorized into NAC ATTR Stage Ia, defined as a furosemide equivalent diuretic requirement of 100 months in the 12% with Stage Ia disease [hazard ratio for death 5.06 (95% confidence interval 1.23–20.87); P = 0.025] despite significant cardiovascular morbidity at the time of diagnosis which increased during follow-up, including among patients diagnosed in NAC ATTR Stage Ia. Estimated survival among UK NAC ATTR Stage Ia patients was comparable to UK general population controls (P = 0.297). Conclusion Patients with NAC ATTR Stage I ATTR-CM can be further stratified according to NT-proBNP concentration and diuretic requirement at diagnosis. Patients with Stage Ia ATTR-CM have significant cardiovascular morbidity despite good short- and mid-term survival.

Bortezomib is a standard therapy in light-chain amyloidosis (AL), but little is known about response duration. A difference in involved amyloidogenic and uninvolved serum-free light chains (dFLC)10 mg/L (low dFLC response) predicts survival in AL patients with low presenting dFLC (20-50 mg/L). We report outcomes in the largest AL cohort treated with upfront bortezomib and explore the impact of posttreatment dFLC10 mg/L ("stringent dFLC response"). A total of 915 newly diagnosed AL patients treated with bortezomib and assessed at our center were included. Hematologic responses, 6-month dFLC, organ responses, overall survival (OS), and time-to-next-treatment (TNT) (excluded patients who died without starting second-line treatment) were evaluated. Overall response rate (intent-to-treat) was 65%, with 49% complete response (CR)/very good partial response/low dFLC response and with a stringent dFLC response, dFLC 10-40 mg/L, and dFLC40 mg/L was 30%, 22%, and 48%, respectively. Median OS was 72 months. A total of 289 patients died without progressing to second-line treatment. Median TNT was not reached, and 55% had not progressed to further treatment at 7 years. Patients with stringent dFLC responses had significantly better OS and TNT than did those with lesser responses. A total of 72% of CR patients did not progress to further treatment at 3 years compared with 84% with stringent dFLC responses. Cardiac responses were better in those with stringent dFLC responses (61%) compared with lesser responses (45%; P = .005). Upfront bortezomib confers durable hematologic responses. A stringent dFLC response predicts prolonged TNT and impressive organ responses.

The outcomes in systemic AL amyloidosis are dependent on the depth of haematologic response. However, there is limited data on the impact of the speed of response on outcomes. Here we report the impact of speed of response in a cohort of AL patients treated with upfront Bortezomib. Patients seen from February 2010 until August 2019 are included in the present analysis. 1194 & 1133 patients comprised the ITT and 1-month landmark cohorts. In the landmark cohort, 137 (11.5%), 270 (22.6%), 252 (21.1%) and 352 (31.1%) patients had a CR, VGPR, PR and NR at 1-month. Patients with ≥ VGPR at 1-month had significantly better survival (median not reached; at the end of 1, 2, 5,10 years, 87%/92%, 83%/87%, 68%/72% and 63%/58% of patients in CR/VGPR, respectively, were alive) compared to those with a PR (median OS 60 months) or NR (median OS 32 months) (p 20 mg/l (p = 0.005). Reaching ≥ VGPR at 1-month significantly improved survival in all Mayo disease stages. In conclusion, patients achieving an early deep haematologic response have a significantly superior survival irrespective of cardiac involvement.

Background: Systemic amyloidosis is characterized by amyloid deposition that can involve virtually any organ. Splenic and hepatic amyloidosis occurs in certain types, in some patients but not others, and may influence prognosis and treatment. SAP (serum amyloid P component) scintigraphy is uniquely able to identify and quantify amyloid in the liver and spleen, thus informing clinical management, but it is only available in 2 centers globally. The aims of this study were to examine the potential for extracellular volume (ECV) mapping performed during routine cardiac magnetic resonance to: (1) detect amyloid in the liver and spleen and (2) estimate amyloid load in these sites using SAP scintigraphy as the reference standard. Methods: Five hundred thirty-three patients referred to the National Amyloidosis Centre, London, between 2015 and 2017 with suspected systemic amyloidosis who underwent SAP scintigraphy and cardiac magnetic resonance with T1 mapping were studied. Results: The diagnostic performance of ECV to detect splenic and hepatic amyloidosis was high for both organs (liver: area under the curve, −0.917 [95% CI, 0.880–0.954]; liver ECV cutoff, 0.395; sensitivity, 90.7%; specificity, 77.7%; P P P P P P Conclusions: Our study demonstrates that ECV measurements obtained during routine cardiac magnetic resonance scans in patients with suspected amyloidosis can identify and measure the magnitude of amyloid infiltration in the liver and spleen, providing important clues to amyloid type and offering a noninvasive measure of visceral amyloid burden that can help guide and track treatment.

Background Renal light chain (AL) amyloidosis manifests as proteinuria with or without renal failure and is associated with a risk of progression to renal replacement therapy (RRT). A significant reduction in circulating amyloidogenic light chain is needed to achieve a renal response. Current renal response criteria are binary defining a renal response as >30% reduction in 24-h proteinuria without worsening estimated glomerular filtration rate (eGFR). Several studies suggest that greater reduction in proteinuria following successful therapy improves renal and overall survival. Methods AL amyloidosis patients diagnosed between 2010 to 2015, achieving at least hematological partial response to therapy and with renal involvement were included. Four renal response categories were formulated based on reduction level in pretreatment 24-h proteinuria in the absence of renal progression: renal complete response (renCR, 24-h proteinuria ≤200 mg/24-h); renal very good partial response (renVGPR, >60% reduction in 24-h proteinuria); renal partial response (renPR, 31-60% reduction in 24-proteinuria); and renal no response (renNR, 30% or less reduction). Renal response was assessed at landmark (6-, 12-, and 24 months from treatment initiation) and as best renal response. Graded renal responses were assessed as predictors for time from diagnosis to RRT and overall survival. Results Seven hundred and thirty-seven patients were included. The median age was 63. Renal stage I, II and III were assigned to 34%, 52% and 14% of patients, respectively. Reduction in 24-h proteinuria from baseline improved over time with a median reduction of 34%, 50% and 71%, at 6-month, 12-month and 24-months, respectively. At best response, renCR, renVGPR, renPR and renNR were achieved in 27%, 34%, 15% and 24% of patients, respectively. A renal response as early as 6 months after therapy initiation was able to predict time to RRT with an increase in RRT risk with lower level of renal response at that time point (5-year RRT 0%, 3%, 9% and 16% for renCR, renVGPR, renPR and renNR, respectively, P Conclusions We validated new graded renal response criteria based on reduction in 24-h proteinuria. These 4-level renal response criteria highlight the importance of achieving a deep renal response to improve renal and overall survival. These findings will allow clinicians to make decision on therapy changes or augmentation based on response depth as early as 6-month before irreversible renal failure has developed.

Background Binary cardiac response assessment using NT-proBNP is prognostic in light chain (AL) amyloidosis. Previous studies suggested that refining the criteria to multi-level cardiac responses improves prognostic prediction. We aimed to validate a graded cardiac response assessment tool in AL amyloidosis using NT-proBNP or BNP. Methods In this retrospective, multicenter study AL amyloidosis patients who were diagnosed between 2010 and 2015, achieved at least a hematological partial response (PR) within 12 months of diagnosis and were evaluable for cardiac response (defined as baseline NT-proBNP >650 pg/mL or BNP >150 pg/mL) were included. The following response criteria were tested: cardiac complete response (carCR, nadir NT-proBNP≤350 pg/mL or BNP≤80 pg/mL); cardiac very good partial response (carVGPR, >60% reduction in NT-proBNP/BNP); Cardiac PR (carPR 31-60% reduction); and cardiac non response (carNR, ≤30% reduction). Response was assessed at fixed time points (6, 12 and 24 months from therapy initiation) and at best response. The primary outcome was overall survival based on depth of cardiac response. Results Six hundred and fifty-one patients were included. Mayo 2004 cardiac stage II, IIIA and IIIB was present in 47.5%, 38% and 14.5% of patients, respectively (by definition, patients with Mayo stage 1 do not have cardiac amyloidosis evaluable for response). Hematological CR, hematological VGPR and hematological PR was achieved in 38%, 39% and 23% of patients, respectively. Cardiac response improved over time with a median percentage reduction in NT-proBNP/BNP compared to baseline of 15%, 37% and 54%, at 6, 12 and 24 months respectively. At best cardiac response, carCR, carVGPR, carPR and carNR were achieved in 16%, 26%, 23% and 35% of patients, respectively. Patients achieving a carCR were more likely to be in cardiac stage II compared to carVGPR or carPR patients (65% vs 47% each, P30% rise in NT-proBNP/BNP) in multivariate analysis that included age, type of first line therapy, light chain burden, cardiac stage and hematological response. Conclusions We validated the prognostic value of graded cardiac response. These response criteria allow better discrimination of patient populations and assessment of treatment effectiveness in an era of improved therapies for AL amyloidosis. The study emphasizes the importance of early diagnosis which increases the likelihood of deep and durable cardiac responses.

Introduction Cardiovascular events in patients with inherited bleeding disorders are challenging to manage. The risk of bleeding secondary to antithrombotic treatment must be balanced against the risk of thrombosis secondary to haemostatic therapy. Methods Patients with inherited bleeding disorders with coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI) or atrial fibrillation (AF) from a single centre (2010-2018) are included. Results A total of 11 patients undergoing CABG (n = 3), PCI (n = 5) or with AF (n = 3) and a diagnosis of haemophilia A (n = 8), haemophilia B (n = 1), factor XI deficiency (n = 1) and von Willebrand disease (n = 1) managed by a multidisciplinary team are reported. In patients undergoing CABG, factor levels were normalized for 7-10 days with trough levels of 70-80% with severe patients continuing high-dose factor prophylaxis (trough 20-30%) three weeks post-operatively with daily aspirin. In a patient with mild haemophilia A and an inhibitor, recombinant factor VIIa dosing was monitored with thromboelastometry. For PCI, a 3rd-generation drug-eluting stent with one month of dual antiplatelet therapy in addition to high-dose prophylaxis as needed was preferred. Patients with AF and severe haemophilia did not receive antithrombotic treatment, and a thrombin generation assay was used to guide heparin dosing in mild haemophilia. Conclusion Our experience demonstrates the importance of interdisciplinary communication to identify strategies that decrease the risk of bleeding and thrombosis. The use of extended, increased intensity prophylaxis facilitated antiplatelet therapy. Global assays may help balance the intensity of haemostatic and antithrombotic treatment.

Aims Cardiac involvement, a major determinant of prognosis in AL (light-chain immunoglobulin) amyloidosis, is characterized by an impairment of longitudinal strain (LS%). We sought to evaluate the utility of LS% in a prospectively observed series of patients. Methods and results A total of 915 serial newly diagnosed AL patients with comprehensive baseline assessments, inclusive of echocardiography, were included. A total of 628/915 (68.6%) patients had cardiac involvement. The LS% worsened with advancing cardiac stage with mean −21.1%, −17.1%, −12.9%, and −12.1% for stages I, II, IIIa, and IIIb, respectively (P < 0.0001). There was a highly significant worsening of overall survival (OS) with worsening LS% quartile: LS% ≤−16.2%: 80 months, −16.1% to −12.2%: 36 [95% confidence interval (CI) 20.9–51.1] months, −12.1% to −9.1%: 22 (95% CI 9.1–34.9) months, and ≥−9.0%: 5 (95% CI 3.2–6.8) months (P < 0.0001). Improvement in LS% was seen at 12 months in patients achieving a haematological complete response (CR) (median improvement from −13.8% to −14.9% in those with CR and difference between involved and uninvolved light chain Conclusion Baseline LS% is a functional marker that correlates with worsening cardiac involvement and is predictive of survival. Baseline LS% and an absolute improvement in LS% are useful additional measures of prognosis and response to therapy in cardiac AL amyloidosis, respectively.

INTRODUCTION Systemic amyloidosis is a histological diagnosis, often achieved via critical organ biopsy. Screening biopsies represent a low-risk approach to diagnosis. OBJECTIVES AND METHODS All patients with systemic AL and ATTR amyloidosis who underwent abdominal fat aspiration (AFA) and either a bone marrow (BM) or gastrointestinal (GI) biopsy at the UK National Amyloidosis Centre (2006-2019) were identified. We sought to determine diagnostic sensitivity in relation to whole body amyloid burden, amyloid type and organ involvement. RESULTS Diagnostic sensitivity established in 471 patients with AL (n = 321) and ATTR (n = 150) amyloidosis, respectively, was 73.2% and 27.3% for AFA (P

Introduction: Renal light chain (AL) amyloidosis typically manifests as proteinuria with or without renal failure and is associated with a risk of progression to renal replacement therapy (RRT). A significant reduction in circulating amyloidogenic light chain is needed to achieve a renal response. Current renal response criteria are binary defining a renal response as >30% reduction in 24-h proteinuria without worsening estimated glomerular filtration rate (eGFR). Several studies suggest that greater reduction in proteinuria following successful therapy improves renal and overall survival. Methods: AL amyloidosis patients diagnosed between 2010 to 2015, achieving at least hematological partial response (hemPR) to therapy and with renal involvement (defined as 24-h non-selective proteinuria >0.5 g/24-h) were included. Four predefined renal response categories were formulated based on reduction level in pretreatment 24-h proteinuria in the absence of renal progression (≥25% decrease in eGFR): renal complete response (renCR, 24-h proteinuria ≤200 mg/24-h); renal very good partial response (renVGPR, >60% reduction in 24-h proteinuria); renal partial response (renPR, 31-60% reduction in 24-proteinuria); and renal no response (renNR, 30% or less reduction). Renal response was assessed at landmark (6-, 12-, and 24 months from treatment initiation) and as best renal response. Graded renal responses were assessed as predictors for time from diagnosis to RRT and overall survival. Results: Seven hundred and thirty-seven patients were included. The median age was 63. The breakdown of renal stage was: I, 34%; II, 52%; and III, 14%. Eighty percent of patients received 1 line of therapy within 12 months of their diagnosis. Bortezomib-based therapy was given to 60% of the patients; 28% received autologous stem cell transplantation (ASCT) as their first line therapy. Hematological CR was achieved in 44% of patients, followed by hematological very good partial response (38%) and hemPR (18%). RRT was required during follow-up in 15% of patients (n=108) with a median time from diagnosis to RRT of 18 (IQR 6-43) months. Twenty-eight percent of the patients died. The median follow-up of the surviving patients was 69 months (IQR 56-86). Reduction in 24-h proteinuria from baseline improved over time with a median reduction of 34%, 50% and 71% at 6-month, 12-month, and 24-months, respectively. At best response, renCR, renVGPR, renPR and renNR were achieved in 27% (n=199), 34% (n=247), 15% (n=112) and 24% (n=179) of patients, respectively. The median time to best renal response among renal responders was 17 (IQR 8-31) months, longer for renCR (23 months, IQR 10-40) compared to renVGPR (16 months, IQR 9-27) or renPR (11 months, IQR 6-19). A renal response as early as 6 months after therapy initiation was able to predict time to RRT with an increase in RRT risk with lower level of renal response at that time point (5-year RRT risk 0%, 3%, 9% and 16% for renCR, renVGPR, renPR and renNR, respectively, P Conclusions: We validated new graded renal response criteria based on reduction in 24-h proteinuria. These 4-level renal response criteria highlight the importance of achieving a deep renal response to improve renal and overall survival. These findings will allow clinicians to make decisions on therapy changes or augmentation based on response depth as early as 6-months, before irreversible renal failure develops. Figure 1 Figure 1. Disclosures Palladini: Janssen Global Services: Honoraria, Other: advisory board fees; Siemens: Honoraria; Pfizer: Honoraria. Milani: Celgene: Other: Travel support; Janssen-Cilag: Honoraria. Schönland: Sanofi: Research Funding; Prothena: Honoraria, Other: Travel grants; Janssen: Honoraria, Other: Travel grants, Research Funding; Takeda: Honoraria, Other: Travel grants; Pfizer: Honoraria. Hegenbart: Akcea: Honoraria; Alnylam: Honoraria; Janssen: Consultancy, Research Funding; Prothena: Research Funding; Pfizer: Consultancy, Honoraria. Dispenzieri: Oncopeptides: Consultancy; Alnylam: Research Funding; Sorrento Therapeutics: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. Kumar: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Carsgen: Research Funding; Beigene: Consultancy; Novartis: Research Funding; Bluebird Bio: Consultancy; Amgen: Consultancy, Research Funding; Roche-Genentech: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Antengene: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding. Dimopoulos: Takeda: Honoraria; Janssen: Honoraria; Beigene: Honoraria; BMS: Honoraria; Amgen: Honoraria. Liedtke: Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Alnylam: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Witteles: Pfizer: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding; Eidos: Research Funding. Sanchorawala: Pfizer: Honoraria; Takeda: Research Funding; Celgene: Research Funding; Prothena: 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; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding. Landau: Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genzyme: Honoraria. Cibeira: Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akcea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wechalekar: Caelum Biosciences: Other: Clinical Trial Funding; Amgen: Research Funding; Janssen: Consultancy; Celgene: Honoraria; Takeda: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy. Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria.

Background The six-minute walk test (6MWT) is an easy-to-implement objective measure of functional capacity. This standardised reproducible measure of individual function may have value in systemic AL amyloidosis to provide an additional objective measure of fitness for chemotherapy, impact of chemotherapy and, within the clinical trial setting, both as a potential clinical endpoint and exclusion criteria. We aim to validate its prognostic value in AL amyloidosis. Methods All patients from a prospective observational study of newly diagnosed AL amyloidosis, (ALchemy) over a 5-year period, were studied. Six-minute walk testing was performed at baseline and 6, 12, 18, 24, 36 and 48-month follow up. Both the median 6MWT and percentage predicted for age, sex, height and weight were analysed. Results In total, 799 evaluable patients were included of whom 564 (70.6%) had cardiac involvement. Baseline 6MWT distance was 418.5 metres (m) / 80.5% predicted, and diminished with increasing cardiac Mayo stage (p Patients were followed up for a median of 32 (1-90) months following diagnosis. Median overall survival (OS) was 70.0 (56.8-83.2) months. The median OS of patients achieving ≥300m on baseline 6MWT was not reached whilst those achieving The 6MWT fell significantly by 6 months (391.0m/73.5%, p=0.0002) then rose again by 12 months (median 415.0m/78.0%, p=0.02). There was no significant change in 6MWT thereafter. When stratified by haematological response and censoring deaths before 12 months, only patients in a complete response (CR) improved at 12 months (431.0m/83.0% vs. 437.0m/85%, p=0.001) whilst those with a lesser haematological response got worse (Very good partial response [VGPR]: 403.5m/75.0% to 395.5m/76.5%, p=0.02; Partial Response [PR]: 413.0m/79.0% to 362.5m/74.0%, p=0.0007; Nil response [NR]: 437.0m/83.0% to 355.0m/70%, p=0.0002). A 33m improvement in 6MWT, a value reported to be clinically meaningful in cardiopulmonary disorders, was independent of haematological response in predicting survival (CR [reference], VGPR: HR 2.02 [1.08-3.80], p=0.03; PR: HR 3.51 [1.83-6.73], p Patients in whom 6MWT improved by ≥33m at 12 months survived longer although median OS was not reached in either category (p=0.01). In patients who achieved a baseline 6MWT of Conclusion The 6MWT is prognostic in AL amyloidosis at multiple time points and a baseline distance of ≥300m is independent of current Mayo stage criteria in predicting survival. Inability to undertake a 6MWT at baseline is an extremely poor prognostic indicator. At 12 months, improvement in 6MWT of ≥33m predicts survival independent of haematological response. The 6MWT is a useful prognostic indicator in systemic AL amyloidosis and could be used as an inclusion/exclusion criterion in the clinical trial setting. Disclosures Wechalekar: Celgene: Honoraria; Takeda: Honoraria, Other: Travel; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory.

Immune dysregulation is described in multiple myeloma. While preclinical models suggest a role for altered T-cell immunity in disease progression, the contribution of immune dysfunction to clinical outcomes remains unclear. We aimed to characterize marrow-infiltrating T cells in newly diagnosed patients and explore associations with outcomes of first-line therapy.We undertook detailed characterization of T cells from bone marrow (BM) samples, focusing on immune checkpoints and features of immune dysfunction, correlating with clinical features and progression-free survival.We found that patients with multiple myeloma had greater abundance of BM regulatory T cells (Tregs) which, in turn, expressed higher levels of the activation marker CD25 compared with healthy donors. Patients with higher frequencies of Tregs had shorter PFS and a distinct Treg immune checkpoint profile (increased PD-1, LAG-3) compared with patients with lower frequencies of Tregs. Analysis of CD4 and CD8 effectors revealed that low CD4effector (CD4BM-infiltrating T-cell subsets, specifically Tregs and PD-1-expressing CD4 effectors, negatively influence clinical outcomes in newly diagnosed patients. Pending confirmation in larger cohorts and further mechanistic work, these immune parameters may inform new risk models, and present potential targets for immunotherapeutic strategies.

Background: Cardiac involvement is the major determinant of prognosis in systemic AL amyloidosis. The extent is assessed by cardiac biomarker-based staging system using N-terminal pro-brain natriuretic peptide (NT-proBNP) and Troponin T. Longitudinal strain evaluates the global and regional function of the left ventricle (LV) and may be preferable to both LV ejection fraction and NT-proBNP, which is limited by its sensitivity to changes in fluid balance, in determining prognosis. This is the first report of a large cohort of uniformly treated prospectively followed patients assessing the utility of changes in longitudinal function by 2-D strain (LS%), impairment of which is a hallmark of amyloidosis. Methods: 915 newly diagnosed patients seen at the UK National Amyloidosis Centre (February 2010 - August 2017) were studied. All patients underwent comprehensive assessments including echo-cardiogram at baseline and each follow up visit. Results: 628/915 (68.6%) patients had cardiac involvement. Mayo stage I, II, IIIa and IIIb in 144 (15.7%), 302 (33.0%) 344 (37.6%) and 125 (13.7%) respectively. Impairment of LS% correlated significantly with increasing Mayo stage (p Conclusion: Longitudinal strain is an informative functional marker that is independent of Mayo staging in predicting outcomes in patients with cardiac AL amyloidosis which can be incorporated in prognostic staging for these patients. Improvement in LS% was observed in patients who achieved a CR, and a value of 1.5% was associated with superior outcomes over and above achieving a cardiac response by international consensus criteria. An absolute improvement in LS% should be considered a criterion for cardiac response in AL amyloidosis. Disclosures Wechalekar: Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel; Celgene: Honoraria.

Introduction: High dose therapy and autologous stem cell transplant (ASCT) remain standard first line therapy for young fit patients with multiple myeloma (MM). Beyond cytoreduction, ASCT may also alter the bone marrow (BM) immune environment to augment anti-tumour immune responses. A more precise understanding of the immune microenvironment post ASCT and its relationship with clinical outcomes may identify biomarkers to refine prognostication and provide opportunity for therapeutic intervention. Aim: We aimed to define T cell subsets and expression of co-activating and co-inhibitory proteins in the BM early post ASCT, and explore associations with clinical outcomes. Methods: BM samples were obtained at 100 days (D100) post ASCT from 61 MM patients, and 15 healthy donors (HD). BM mononuclear cells (MNCs) were stained for surface (CD3, CD4, CD8, PD-1, LAG-3, and ICOS) and intracellular markers (GzmB, Ki-67, CTLA-4, and FoxP3). Data were acquired on a BD LSR Fortessa and analysed using FlowJo. Progression free survival (PFS) was defined from ASCT as per IMWG criteria, and patient groups were compared using Mann-Whitney U test. Adverse risk genetics was defined as t(4;14), t(14;16) or del(17p). Results: Median age of patients at ASCT was 58yrs (36-71), 70.5% were male. Median follow up was 17 months (3-54). At diagnosis, 36.1% were ISS stage I, 8.2% had extramedullary disease, and 14.7% had adverse risk genetics. As induction therapy, 96.7% received a proteasome inhibitor, 45.9% an immunomodulatory drug, 54.1% both, and 21.3% received post ASCT maintenance/consolidation. Median PFS was 24 months. At D100, 24.6% had achieved CR, 47.5% VGPR, 21.3% PR, 4.9% SD and none had PD. Improved PFS was found in patients with deeper response (CR/VGPR vs. rest, p=0.003), and with ISS stage I vs II/III (p=0.013). There was a trend for improved PFS with standard risk genetics (p=0.088 cf high risk). MM BM contained lower frequencies of CD3 and CD4 T cells compared to HD (CD3, 28% of live MNCs, vs 41.2%, p=0.012; CD4, 4.1% vs 14.0%, p Immune checkpoint proteins were highly expressed on BM T cell subsets in post ASCT compared to HD. CD4eff in MM patients expressed higher frequency of PD-1, LAG-3, ICOS, CTLA-4, GzmB, and Ki-67 (p Clinical outcomes were not influenced by T cell subsets (CD3, CD4eff, CD8, and Treg) but there was an inverse association with co-inhibitory receptor expression. High frequency (>median) of LAG-3 on CD4eff and CD8, and Tregs was associated with shorter PFS (median 18mo vs 53, p=0.0028; 20mo vs 53, p=0.0057; 20mo vs 53, p=0.046 respectively). Further, patients with high frequency of PD-1 on CD4eff and Ki-67 on CD8 T cells had shorter PFS (median 18mo vs 36, p=0.042 and 18mo vs unreached, p=0.019 respectively). A multivariate Cox regression model was built to include ISS stage, depth of response at D100, and the immune phenotypes identified to correlate with PFS. In this model, high frequency of PD-1 on CD4eff retained independent prognostic value, along with ISS stage and CD8 Ki67+ T cells. Conclusion: We present data indicating that high frequency of PD-1+ CD4eff and Ki67+ CD8 T cells post ASCT associate with shorter PFS in MM patients. Pending confirmation in larger cohorts, these data reveal potential immune biomarkers for poor outcomes, and prompt deeper phenotypic analysis and mechanistic studies to uncover the immune drivers of sustained remissions post ASCT. Disclosures Lee: Autolus Therapeutics: Equity Ownership, Research Funding. Yong:Takeda: Research Funding, Speakers Bureau; Autolus: Consultancy; Amgen: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Sanofi: Speakers Bureau.

Systemic AL amyloidosis, caused by monoclonal light chain depositing as amyloid fibril protein, commonly presents with renal involvement. A third of patients with renal involvement have or develop significant renal dysfunction leading to end-stage renal failure (ESRF). In an era of improving life expectancy for patients with AL amyloidosis, renal transplantation, with its marked impact on improving quality of life and reducing the cost burden, is increasingly considered. We report the outcomes of fifty patients who had received a renal allograft between 2004-2019, seen at the UK National Amyloidosis Centre Patient characteristics were: 60% male; median age at diagnosis was 53.5 years (38-69 years); median ECOG performance status 1 (0-3); median presenting creatinine, eGFR and proteinuria were 199μmol/L (69-756 μmol/L), 27ml/min and 8.95g/24h (0.4-19.7g/24h) respectively. Involved light chains were - lambda - 36 (72%) and kappa - 14 (28%). 40 patients were evaluable (5 transplanted for non-amyloid conditions prior to diagnosis, 4 lost to follow up, 1 transplanted for amyloidosis overseas prior to referral). Thirteen (32.5%) had isolated renal involvement whilst 35 (87.5%) patients had other multi-organ involvement including 13/40 (32.5%) with cardiac involvement. Median time from diagnosis to ESRF was 15 months (0-115 months) and from renal replacement therapy to renal allograft was 28 months (3-83 months). Four (10%) received a pre-emptive renal allograft. At time of renal transplantation, patients had a median of 2 prior lines of chemotherapy (range 1-4) whilst 10/40 patients (25%) had a prior autologous stem cell transplant. At transplant, haematological responses (HR) were: complete response (CR) - 22 (55%), very good partial response (VGPR) - 12 (30%), partial response (PR) - 4 (10%) and stable disease - 2 (5%). Median time from HR to renal transplant was 29 months (0-93 months). From renal transplant, haematological PFS was 82.7 months (95% CI 61.2-104.2). Patients achieving a CR achieved a markedly higher PFS of 102.5 months (95% CI 68.8-136.3 months) (p=0.023) as did those with a dFLC At a median follow up of 107 months (26-231 months), 14 (35%) patients died, of whom only one had graft failure at the time of death. One patient (with stage 3 cardiac AL) died within 2 days of a renal allograft after a post-operative hypotensive episode. Nine (22.5%) patients had post-transplant chemotherapy for relapse. Median OS from renal transplantation was 106.6 months (95% CI 85.0-128.3 months); significantly better in patients achieving a CR (133.0 months, p=0.005) or dFLC In conclusion, the outcomes of carefully selected patients with AL amyloidosis undergoing renal transplantation is promising and justifies careful consideration. There was only 1 peri-operative death. Patients in a complete response or who have a dFLC Disclosures No relevant conflicts of interest to declare.

Introduction Lymph node excision has historically been preferred to core biopsy in diagnosing lymphoma given reported higher diagnostic yield and concerns that core biopsies yielded insufficient material. However, core biopsy is associated with lower morbidity and has been reported to be more cost effective. Consequently, advances in radiological and histological techniques in extracting and processing material warrants a re-look at the efficacy of core biopsy as a viable primary diagnostic method. Method Over a three year period (January 2016 - December 2018), all patients who underwent core biopsy at our centre for investigation of possible lymphoma or relapse, were identified from a local database. Argon medical BioPinceTM needles were used for the majority of procedures. Data collected included: indication and final diagnosis, number of cores taken, waiting times from referral to histological diagnosis, diagnostic rates and any histological request for extra tissue due to sample inadequacy. A patient telephone survey was undertaken to document patient experience and record complications. Results 554 consecutive patients were included. 225 (40.1%) patients had a prior lymphoma diagnosis whilst 329 (59.4%) were new presentations. 78 (14.1%) biopsies were guided by prior PET imaging of which 69/78 (88.5%) were to assess relapsed disease. Biopsies sites were: 326 (58.8%) cervical, 71 (12.8%) axilla, 96 (17.3%) inguinal and 61 (11.0%) extra nodal. Three or more cores were taken in 420 (75.8%) cases. The median time from request to biopsy was 2 days (range 0-40 days) whilst median time from biopsy to histology report was 7 days (range 1-24 days). Final diagnoses were: 195 (35.2%) reactive/non-malignant, 346 (62.5%) lymphoma [88 (15.9%) Diffuse large B cell lymphoma, 76 (13.7%) Follicular lymphoma, 56 (10.1%) Hodgkin lymphoma, 37 (6.7%) T-cell lymphoma, 28 (5.1%) Chronic lymphocytic leukaemia, 61 (11.0%) other B cell lymphoma], 12 (2.2%) other malignancy and 1 (0.18%) inadequate for interpretation. 510/544 (93.8%) biopsies were diagnostic inclusive of 74/78 (94.9%) PET-directed biopsies. 35/37 (94.6%) biopsies confirming T-cell lymphoma were diagnostic whilst in 2 cases repeat biopsy was required. There was no significant difference in whether the biopsy was diagnostic based on whether it was indicated for new or relapsed lymphoma (p=0.445), PET-directed (p=0.507), for a diagnosis of T-cell lymphoma (p=0.468) or nodal vs. extra nodal (p=0.693). The histologist requested additional tissue in 64 (11.6%) cases. Of these, 38/64 (59.4%) patients were adjudged by the clinician to require a second biopsy. 3/195 (1.5%) reactive cases went on to be diagnosed with lymphoma within 6 months. 2/3 had inadequate biopsies and the histology report advised repeat. A third patient was diagnosed with DLBCL based on a repeat biopsy done for clinical suspicion. Of 35 consecutive patients, 31 agreed to participate in the patient experience survey. Only 5/31 (16.1%) reported any complications (1 self-limiting minor bleeding, 4 minor bruising). 6/31 (19.4%) reported any discomfort beyond 12 hours. Median waiting time in department pre-biopsy was 10 minutes (range 5-60 minutes) and all patients left the department within 20 minutes of the procedure. Conclusion Core biopsy performed by experienced interventional radiologists and analysed by expert haemato-pathologists is a reliable and convenient method for diagnosing lymphoma and confirming relapse inclusive of T-cell lymphoma (which is typically harder to diagnose). Multiple cores can be obtained under local anaesthetic and this yields sufficient material without need for further biopsy in the majority of cases (88.4%) including where samples are also required for trials purposes. Using PET to direct biopsy is highly effective in confirming relapse. Core biopsy is well tolerated and can be performed safely and effectively in the outpatient setting with a median time from referral to biopsy of only 2 days in our centre. Disclosures Ardeshna: Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria.

Background: Consolidation after high dose therapy and autologous stem cell transplant (ASCT) for multiple myeloma (MM) can improve response depth and prolong progression free survival (PFS), but it is important to ensure good quality of life (QoL) and responsiveness to further salvage therapy. We conducted a single-arm Phase II weekly bortezomib consolidation trial (BCT) to assess outcomes in MM patients receiving upfront ASCT. Methods: Bortezomib-na•ve patients with at least stable disease at 3-4 months post-high dose melphalan 200mg/m2 with ASCT received up to 8 cycles of bortezomib (1.3mg/m2 days 1,8,15,22 in a 4-week cycle), 17 intravenously (IV) and 23 subcutaneously (SC). The primary endpoint was disease response (IMWG) at 6 and 12 months post-ASCT. Other endpoints were MRD by multiparametric flow cytometry (patient 15 onwards) at 6 and 12 months post-ASCT, toxicity, PFS, overall survival, osteoblast function and Qol (EORT-QLQ-C30). Serum basic alkaline phosphatase (bALP) and ostocalcin (OC) were measured by ELISA. Results: The study recruited 40 patients between December 2009 and March 2014 at a median of 3.4 months post-ASCT. The median age was 61 years (range 43-69); 55% male; isotypes were: 22 (59%) IgG, 9 (24%) IgA, 1 (3%) IgD, 5 (14%) light chain only, 1 non-secretory and 2 unknown. Induction regimens pre-ASCT were thalidomide (33, 87%), idarubicin and dexamethasone (5, 13%). and unknown in 2. One patient was withdrawn prior to commencement (unfit for treatment) and 3 patients stopped trial treatment after 1 cycle (2 toxicity, 1 disease progression). Of 36 patients who completed >1 cycle of bortezomib, 10 stopped treatment early (5 toxicity, 4 patient choice, 1 disease progression); median number of cycles received was 8. Eleven (28%) patients experienced a total of 15 grade 3 adverse events (AE); 6 (neuropathy, 3 in IV group, 18% cf 3 in SC group, 13%), 4 (infection), 1 (fatigue), 2 (haematological), 2 other. One patient had a grade 4 infection (cycle 1, treatment discontinued) and 1 grade 4 back pain. EORTC-QLQ-C30 scores for global health status and physical, emotional and social functioning did not change significantly throughout treatment. After a median follow up of 44.4 months, 18 (45%) are alive without progression, 20 (50%) are alive with progression and 2 (5%) died after progression. BCT improved response depth in assessable patients who completed >1 cycle (n=34). Disease response at trial entry: 4 (12%) sCR/CR, 19 (56%) VGPR, 10 (29%) PR, 1(3%) SD, cf. response at 12 months post-ASCT: 7 (21%) sCR/CR, 22 (65%) VGPR, 4 (12%) PR, 1(3%) PD. Biochemical response depth improved in 12 patients. 19 patients had MRD testing at 3 (where available) or 6 months post-ASCT and again at 12 months, 10 were MRD+ at the earlier time point, of whom 4 converted to MRD- at 12 months. Of the 9 MRD- patients, all remained negative at 12 months. 15 patients (44%) had improvement in biochemical and/or MRD response at 12 months. Median PFS was 38.5 months (95%CI 29.1-47.9)(Figure). Patients who were MRD- at 12 months had median PFS of 49.2 months (95%CI 35.3-63.2) compared with 22.0 months (95%CI 21.5-22.6) in MRD+ patients (p=0.03). Of the 22 patients who relapsed, 12 received bortezomib-based salvage regimens, 5 received carfilzomib-based regimens and 5 have not started second-line therapy. Disease responses in patients receiving bortezomib salvage was 8 (67%) VGPR, 4 (33%) PR. Four patients went on to have a 2nd ASCT. In the 17 patients receiving salvage, median 2nd PFS from start of second line was 14.8 months (95%CI 8.2-18.0). At 3 months post-ASCT, levels of the osteoblast markers bALP and OC were significantly higher in CR/VGPR patients, compared to patients with PR or less (p=0.04 and 0.03, respectively). Neither marker changed significantly following BCT. Conclusions: For patients with MM, consolidation with weekly bortezomib post-ASCT is well tolerated and deepens disease response and MRD negativity without compromising the response to subsequent bortezomib-based salvage therapy. Patients who are MRD- at 12 months enjoy a median PFS of 4 years. This low intensity post-ASCT strategy deserves further study in the context of current and evolving protocols for newly diagnosed patients. Figure Figure. Disclosures Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.