scholarly journals Biomarkers in AL Amyloidosis

2021 ◽  
Vol 22 (20) ◽  
pp. 10916
Author(s):  
Despina Fotiou ◽  
Foteini Theodorakakou ◽  
Efstathios Kastritis

Systemic AL amyloidosis is a rare complex hematological disorder caused by clonal plasma cells which produce amyloidogenic immunoglobulins. Outcome and prognosis is the combinatory result of the extent and pattern of organ involvement secondary to amyloid fibril deposition and the biology and burden of the underlying plasma cell clone. Prognosis, as assessed by overall survival, and early outcomes is determined by degree of cardiac dysfunction and current staging systems are based on biomarkers that reflect the degree of cardiac damage. The risk of progression to end-stage renal disease requiring dialysis is assessed by renal staging systems. Longer-term survival and response to treatment is affected by markers of the underlying plasma cell clone; the genetic background of the clonal disease as evaluated by interphase fluorescence in situ hybridization in particular has predictive value and may guide treatment selection. Free light chain assessment forms the basis of hematological response criteria and minimal residual disease as assessed by sensitive methods is gradually being incorporated into clinical practice. However, sensitive biomarkers that could aid in the early diagnosis and that could reflect all aspects of organ damage and disease biology are needed and efforts to identify them are continuous.

Blood ◽  
2016 ◽  
Vol 128 (2) ◽  
pp. 159-168 ◽  
Author(s):  
Giovanni Palladini ◽  
Giampaolo Merlini

Abstract Light chain (AL) amyloidosis is caused by a usually small plasma cell clone producing a misfolded light chain that deposits in tissues. Survival is mostly determined by the severity of heart involvement. Recent studies are clarifying the mechanisms of cardiac damage, pointing to a toxic effect of amyloidogenic light chains and offering new potential therapeutic targets. The diagnosis requires adequate technology, available at referral centers, for amyloid typing. Late diagnosis results in approximately 30% of patients presenting with advanced, irreversible organ involvement and dying in a few months despite modern treatments. The availability of accurate biomarkers of clonal and organ disease is reshaping the approach to patients with AL amyloidosis. Screening of early organ damage based on biomarkers can help identify patients with monoclonal gammopathy of undetermined significance who are developing AL amyloidosis before they become symptomatic. Staging systems and response assessment based on biomarkers facilitate the design and conduction of clinical trials, guide the therapeutic strategy, and allow the timely identification of refractory patients to be switched to rescue therapy. Treatment should be risk-adapted. Recent studies are linking specific characteristics of the plasma cell clone to response to different types of treatment, moving toward patient-tailored therapy. In addition, novel anti-amyloid treatments are being developed that might be combined with anti-plasma cell chemotherapy.


Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 595-603 ◽  
Author(s):  
Giampaolo Merlini ◽  
Giovanni Palladini

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic plasma cell disorder occurring in 4.2% of adults > 50 years of age, which can progress into symptomatic diseases either through proliferation of the plasma cell clone, giving rise to multiple myeloma and other lymphoplasmacellular neoplasms, or through organ damage caused by the monoclonal protein, as seen in light-chain amyloidosis and related conditions. Differential diagnosis of asymptomatic and symptomatic monoclonal gammopathies is the determinant for starting therapy. The criteria for determining end-organ damage should include markers of organ injury caused by the monoclonal protein. Patient assessment and optimal follow-up are now performed using risk stratification models that should also take into account the risk of developing AL amyloidosis. Patients with low-risk MGUS (approximately 40% of all MGUS patients) need limited assessment and very infrequent follow-up. The ongoing development of novel molecular biomarkers and advanced imaging techniques will improve the identification of high-risk patients who may benefit from early therapeutic intervention through innovative clinical trials.


2016 ◽  
Vol 135 (3) ◽  
pp. 172-190 ◽  
Author(s):  
Eli Muchtar ◽  
Francis K. Buadi ◽  
Angela Dispenzieri ◽  
Morie A. Gertz

Immunoglobulin amyloid light-chain (AL) amyloidosis is the most common form of systemic amyloidosis, where the culprit amyloidogenic protein is immunoglobulin light chains produced by marrow clonal plasma cells. AL amyloidosis is an infrequent disease, and since presentation is variable and often nonspecific, diagnosis is often delayed. This results in cumulative organ damage and has a negative prognostic effect. AL amyloidosis can also be challenging on the diagnostic level, especially when demonstration of Congo red-positive tissue is not readily obtained. Since as many as 31 known amyloidogenic proteins have been identified to date, determination of the amyloid type is required. While several typing methods are available, mass spectrometry has become the gold standard for amyloid typing. Upon confirming the diagnosis of amyloidosis, a pursuit for organ involvement is essential, with a focus on heart involvement, even in the absence of suggestive symptoms for involvement, as this has both prognostic and treatment implications. Details regarding initial treatment options, including stem cell transplantation, are provided in this review. AL amyloidosis management requires a multidisciplinary approach with careful patient monitoring, as organ impairment has a major effect on morbidity and treatment tolerability until a response to treatment is achieved and recovery emerges.


2021 ◽  
Vol 8 (5) ◽  
Author(s):  
Hammad Z ◽  
◽  
Hernandez E ◽  
Tate S ◽  
◽  
...  

Monoclonal Gammopathy of Undetermined Significance (MGUS) is a condition in which M protein, an abnormal monoclonal immunoglobulin, is present in the blood at a nonmalignant level. Specifically, it is defined by: blood serum M protein concentration <3 g/dL (<30 g/L), <10% plasma cells in the bone marrow, and no evidence of end organ damage [1,2]. Evidence of end organ damage includes hypercalcemia, renal insufficiency, anemia, and bone lesions. These are indicative of MGUS progression and which can be attributed to the monoclonal plasma cell proliferative process [3]. MGUS occurs in 3% of the general population older than 50 years. Incidence increases with age and varies with sex with higher rates observered in males than females [1,4]. MGUS is the most common plasma cell disorder, with 60% of patients that present to the Mayo Clinic with a monoclonal gammopathy being diagnosed with MGUS [3]. While it is typically an asymptomatic condition, it is premalignant disorder to other monoclonal gammopathies. Multiple Myeloma (MM) is almost always preceded by MGUS and the majority of patients will have detectable levels of M protein for at least 5 years prior to MM diagnosis [5,6]. MGUS also precedes immunoglobulin light chain (AL) amyloidosis and Waldenstrom Macroglobulinemia (WM) and tends to progress to disorders at a fixed but unrelenting rate of 1% per year [4].


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5319-5319
Author(s):  
Daniela Lakomy ◽  
Stephanie Lemaire-Ewing ◽  
Cedric Rossi ◽  
Jessica Borgeot ◽  
Jean-Noël Bastie ◽  
...  

Abstract Introduction The evaluation of multiple myeloma response to treatment as defined by international guidelines is currently based on morphologic examination of bone marrow plasma cells, serum protein electrophoresis (SPEP), immunofixation electrophoresis (IFE) and serum free light chain assay. For several years new tools are available as bone marrow plasma cell immunophenotyping and the HevyliteTM assay. HevyliteTM IgA assay provides an automated evaluation of serum heavy/light chain ratio (HLC) of the involved and uninvolved immunoglobulin (Ig) (i.e. IgAΚ/IgAλ). This is particularly interesting in IgA myeloma where the use of SPEP is limited due to a frequent comigration of monoclonal IgA with other proteins. We therefore compared the IgA quantification by Hevylite™ assay and the bone marrow plasma cell immunophenotyping for response evaluation and residual disease characterisation in IgA myeloma. Methods Hevylite™ assay, SPEP, IFE were performed in eleven IgA myeloma patients at different times: after induction chemotherapy, after the consolidation phase and after autologous stem-cell transplantation (ASCT). In the same time, minimal residual disease (MRD) assessment was performed on bone marrrow by multiparameter flow cytometry (MFC). Hevylite™ assay was performed on a Binding Site SPAplus analyser (Hevylite, Binding Site, Birmingham, UK) following the manufacturer recommendations. SPE and IFE were realized on Sebia Hydrasys analyser (Sebia, Evry, France) and results were read by two experienced biologists. Results 1. We found a perfect agreement between the IFE and immunophenotyping results at each time of evaluation, for positive results as for negative results. 2. The SPEP was contributive only in two patients and in these cases it was less sensitive than IFE. In the other patients, the monoclonal IgA migrated in beta region and/or as multiple bands, making the quantitative estimation difficult. 3. In all patients, when MRD by MFC was undetectable and IFE was negative, the HLC ratio was normal. 4. In 3 patients, HLC ratio was consistent with the IFE and MRD by MFC at each time of evaluation. Nevertheless, in 8 patients out of 11, while HLC ratio became normal, MRD by MFC and IFE were still positive. In all cases, the normalization of HLC ratio was followed, at the next step of evaluation, by the normalization of MFC and IFE. 5. In 5 patients, the normalization of HLC ratio occurred before ASCT, while IFE and MRD by MFC were still positive. Nevertheless, after ASCT, IFE and MRD by MFC became also negative, in accordance with the HLC ratio (Table 1). Conclusions During the evaluation of response to treatment of IgA myeloma, we observed a normalization of HLC ratio (Hevylite™ IgA assay) preceding the normalization of MRD by MFC and IFE. This could be explained by the fact that IFE and immunophenotyping provide very sensitive information but only on the monoclonal component. HLC ratio reflects the balance between the monoclonal and polyclonal Igs of involved and uninvolved isotype. A normalization of HLC ratio can be interpreted as an increasing polyclonal Ig proportion parallel with a decreasing monoclonal Ig proportion and may reflect the reconstitution of polyclonal plasma cells. If confirmed by other studies and long term follow-up, HLC ratio could be a non-invasive predictive marker of a good response in IgA myeloma. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4353-4353 ◽  
Author(s):  
Shayna Sarosiek ◽  
Vaishali Sanchorawala ◽  
Mariateresa Fulcinti ◽  
Allison P. Jacob ◽  
Nikhil C. Munshi ◽  
...  

Background: AL amyloidosis is a bone marrow disorder in which clonal plasma cells produce light chains that misfold and deposit in vital organs, such as the kidneys and heart, leading to organ failure and eventual death. Treatment is directed towards the clonal plasma cell population in an effort to halt the production of toxic light chains and recuperate organ function. Pallidini et al. demonstrated that almost 50% of patients with AL amyloidosis who achieved a complete hematologic response to prior therapy had minimal residual disease (MRD) detectable in their bone marrow by multiparametric flow cytometry (MPF).1. Next generation gene sequencing (NGS) has been a successful tool in measuring MRD among patients with multiple myeloma2 though the data regarding its use in AL amyloidosis are limited. AL amyloidosis is a disease with a much smaller plasma cell burden at baseline (typically 5-10%), making the task of isolating an initial clonal sequence even more challenging. We sought to evaluate NGS as a method of isolating a clonal population of plasma cells among patients with systemic AL amyloidosis in a first-ever feasibility study. Methods: Patients were eligible if they had systemic AL amyloidosis and no clinical evidence of concurrent active multiple myeloma. In this study, feasibility was deemed successful if discovery of a clone could be achieved in 3 out of 10 of patients. Approximately five cc's of peripheral blood and bone marrow aspirate were collected from each patient and processed for CD138 selection and DNA isolation/purification. De-identified samples were sent to Adaptive Biotech Inc. (Seattle, WA) for initial clonal identification using the ClonoSEQ immunoglobulin heavy chain (IGH) assay. Genomic DNA was amplified by implementing consensus primers targeting the IGH complete (IGH-VDJH) locus, IGH incomplete (IGH-DJH) locus, immunoglobulin κ locus (IGK) and immunoglobulin l locus (IGL). The amplified product was sequenced and a clone identified based on frequency. After proof of feasibility in the first 10 patients an additional 27 patients had initial clonal identification via the same process mentioned above. Results: In total, 37 patient samples underwent NGS via the ClonoSEQ IGH assay method. The median patient age was 66 years old (range: 44 to 83), 24% of which were female. All 37 patients had measurable disease based on serum electrophoresis and immunofixation and/or serum free light chain assay (Table 1). Four patients had no monoclonal protein detected on SIFE or UIFE and 13 patients had a normal sFLC ratio. Of the 33 patients with monoclonal disease on immunofixation, 12 patients had only a free lambda monoclonal protein and the remaining 21 patients had a clonal heavy chain with an associated light chain. Bone marrow biopsies demonstrated clonal plasmacytosis of 40% or lower. ClonoSEQ IGH assay identified trackable clones in 31 of 37 patients (84%) (see Table 1). Four patients had at least one trackable sequence (range: 1 to 5 sequences) in the peripheral blood and 29 patients had at least one trackable sequence in the bone marrow aspirate (range: 1 to 7 sequences). No correlation was seen between the detection of a clone and standard measures of plasma cell tumor burden (SIFE, SPEP, UIFE, UPEP, and sFLCs). Conclusion: NGS was successful in identifying an initial clone in 29 of 37 patients with systemic AL amyloidosis, four of which were detectable in the peripheral blood. Due to the low clonal burden in patients with AL amyloidosis, it is often difficult to assess disease status, especially post-treatment. These encouraging results may enhance disease monitoring and improve patient care in this rare disease. We are currently tracking MRD in the patients with identifiable clones as they receive systemic treatment, the results of which will be available for presentation in December 2019. REFERENCES 1. Palladini G, Massa M, Basset M, Russo F, Milani P, Foli A, et al. Persistence of Minimal Residual Disease By Multiparameter Flow Cytometry Can Hinder Recovery of Organ Damage in Patients with AL Amyloidosis Otherwise in Complete Response. Abstr 3261. 2016; 2. Ladetto M, Brüggemann M, Monitillo L, Ferrero S, Pepin F, Drandi D, et al. Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. Leukemia. 2014;28:1299-307. Table 1 Disclosures Sarosiek: Acrotech: Research Funding. Sanchorawala:Proclara: Consultancy, Honoraria; Takeda: Research Funding; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Celgene: Research Funding. Jacob:Adaptive Biotechnologies: Employment, Other: shareholder. Munshi:Amgen: Consultancy; Adaptive: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Oncopep: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; Adaptive: Consultancy.


2018 ◽  
Vol 10 (1) ◽  
pp. e2018022 ◽  
Author(s):  
Paolo Milani ◽  
Giampaolo Merlini ◽  
Giovanni Palladini

Light chain (AL) amyloidosis is caused by a usually small plasma-cell clone that is able to produce the amyloidogenic lights chains. They are able to misfold and aggregate, deposit in tissues in the form of amyloid fibrils and lead to irreversible organ dysfunction and eventually death if treatment is late or ineffective. Cardiac damage is the most important prognostic determinant. The risk of dialysis is predicted by the severity of renal involvement, defined by the baseline proteinuria and glomerular filtration rate, and by response to therapy. The specific treatment is chemotherapy targeting the underlying plasma-cell clone. This needs be risk adapted, according to the severity of cardiac and/or multi-organ involvement. Autologous stem cell transplant (preceded by induction and/or followed by consolidation with bortezomib-based regimens) can be considered for low-risk patients (~20%). Bortezomib combined with alkylators is used in the majority of intermediate-risk patients, and with possible dose escalation in high-risk subjects. Novel, powerful anti-plasma cell agents were investigated in the relapsed/refractory setting, and are being moved to upfront therapy in clinical trials. In addition, the use of novel approaches based on antibodies targeting the amyloid deposits or small molecules interfering with the amyloidogenic process gave promising results in preliminary studies. Some of them are under evaluation in controlled trials. These molecules will probably add powerful complements to standard chemotherapy. The understanding of the specific molecular mechanisms of cardiac damage and the characteristics of the amyloidogenic clone are unveiling novel potential treatment approaches, moving towards a cure for this dreadful disease.


2020 ◽  
Vol 143 (4) ◽  
pp. 373-380
Author(s):  
Layla Van Doren ◽  
Suzanne Lentzsch

Immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare, life-threatening disease characterized by the deposition of misfolded proteins in vital organs such as the heart, the lungs, the kidneys, the peripheral nervous system, and the gastrointestinal tract. This causes a direct toxic effect, eventually leading to organ failure. The underlying B-cell lymphoproliferative disorder is almost always a clonal plasma cell disorder, most often a small plasma cell clone of <10%. Current therapy is directed toward elimination of the plasma cell clone with the goal of preventing further organ damage and reversal of the existing organ damage. Autologous stem cell transplantation has been shown to be a very effective treatment in patients with AL amyloidosis, although it cannot be widely applied as patients are often frail at presentation, making them ineligible for transplantation. Treatment with cyclophosphamide, bortezomib, and dexamethasone has emerged as the standard of care for the treatment of AL amyloidosis. Novel anti-plasma cell therapies, such as second generation proteasome inhibitors, immunomodulators, monoclonal antibodies targeting a surface protein on the plasma cell (daratumumab, elotuzumab), and the small molecular inhibitor venetoclax, have continued to emerge and are being evaluated in combination with the standard of care. However, there is still a need for therapies that directly target the amyloid fibrils and reverse organ damage. In this review, we will discuss current and emerging nonchemotherapy treatments of AL amyloidosis, including antifibril directed therapies under current investigation.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2068-2068
Author(s):  
Stefan Schönland ◽  
Ute Hegenbart ◽  
Christoph Kimmich ◽  
Katarina Lisenko ◽  
Dirk Hose ◽  
...  

Abstract Introduction: AL amyloidosis is a rare and life-threatening protein-deposition disorder caused by a small B cell (mostly plasma cell) clone which produces amyloidogenic light chains. The goal of therapy is to target this clone and halt the uncontrolled release of free light chain, which might subsequently lead to improvement of organ function. In routine diagnostic some of these B cell clones are missed as they might be extremely small. However, specific treatment can only be applied if the clone is well characterized. Hardly any data on the characteristics of these cells using flow cytometry have been reported. (e.g. Paiva et al., Blood 2011). Study design: We performed a retrospective analysis of consecutive patients who were referred to our amyloidosis center (March to July 2014) and have been thoroughly studied (immunhistology of amyloid, free light chain assay, immunofixation, bone marrow diagnostic: cytology, flow cytometry and interphase-FISH cytogenetics (iFISH)). Patients and Methods: Twenty-two patients were included (all untreated, 21 AL patients, one pt with monoclonal gammopathy of renal significance (MGRS)). Plasma cells were detected by their co-expression of CD38 and CD138 antigens. Differentiation between malignant and normal plasma cells was achieved by analysis of aberrant CD45 and CD19 expressions and proof of intracellular light chain restriction (see Figure 1). To evaluate potential targets for an antibody-based immunotherapy, we stained CD20, CD22, CD30, CD52 and CS-1 on these plasma cells. Overall, positivity was defined as >20% expression of the antigen. iFISH was done after CD138 selection as previously described (Bochtler et al., Blood 2011). Results: Main characteristics and results are shown in Table 1. Median dFLC was 304 mg/l, three patients had a dFLC of less than 50 mg/l. Median plasma cell count in cytology was 10%, 3 patients had less than 5%. Median plasma cell count by flow was 3.8%, three patients had less than 1%. Correlation between dFLC, plasma cell count in cytology and flow was low (FLC vs. flow: spearman=0.25, p=0.26; FLC vs. cytology: spearman=0.49, p=0.02; flow vs. cytology, spearman=0.36, p=0.1). Detection of the amyloidogenic clone by flow was possible in all but one patient (95%). In this patient we were not able to show a light chain restriction although we detected a relevant aberrant plasma cell clone (CD45low, CD19low). In one patient we found a B cell lymphoma as underlying disease for MGRS type IgG lambda (CD19+, CD20+, lambda+, CD5-, CD22+, FMC7-, CD23-, CD25+, CD103-, CD38+ typical for marginal zone lymphoma). In all 21 patients the light chain restriction demonstrated by flow was confirmed by immunofixation, FLC, and immunohistology of the amyloid. All patients analyzed for the expression of CS-1 were positive. 25% were also positive for CD20 and none was positive for CD22, CD30 and CD52. Detection of the plasma cell clone by iFISH was possible in all 21 patients (see Table 1). Conclusion: Flow cytometric analysis of the bone marrow is a very sensitive method to detect and characterize the amyloidogenic clone in AL amyloidosis. B cell lymphomas can easily be distinguished from pure plasma cell clones. Secondly, flow provides useful information to specify immune-chemotherapy in AL amyloidosis and related disorders. Table 1: Patients (n=22) Characteristics and Results Age in yrs (median / range) 67 (41 – 77) Sex: female / male 9 / 13 Type of light chain: kappa / lambda 4 / 18 Median dFLC in mg/l (range) 304 (22 - 6621) Median % of plasma cells in BM cytology (range) 10 (0 – 68) Underlying disease leading to AL amyloidosis“MG” / MM III / B-NHL 20 / 1 / 1 Median % of PC by flow (range) 3.8 (0.2 - 34) Detection of the amyloidogenic clone by flow 21 / 22 Flow analysis of clonal plasma cells (% of pts)CD20+ / CD22+ / CD30+ / CD52+ / CD56+ / CS-1+ 25 / 0 / 0 / 0 / 75 / 100 Detection of a clone by iFISH 21/21 % of pts with t(11;14) / Gain of 1q21 / Hyperdiploidy / High-risk cytogenetic (del 17p13, t(4;14)) 52 / 10 / 14 / 10 Figure 1: Representative flow analysis of one pt. with a lambda+, CD38+, CD138+ plasma cell clone (green). Polyclonal CD19+ B cells in red. Figure 1:. Representative flow analysis of one pt. with a lambda+, CD38+, CD138+ plasma cell clone (green). Polyclonal CD19+ B cells in red. Disclosures Schönland: Janssen: Honoraria; Celgene: Honoraria. Hegenbart:Janssen: Honoraria; Celgene: Honoraria. Hose:Novartis: Research Funding. Hundemer:Celgene: Honoraria, Research Funding.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3261-3261 ◽  
Author(s):  
Giovanni Palladini ◽  
Margherita Massa ◽  
Marco Basset ◽  
Francesca Russo ◽  
Paolo Milani ◽  
...  

Abstract Introduction. In multiple myeloma, Minimal Residual Disease (MRD) demonstrated by multiparameter flow cytometry (MFC) identifies subjects with significantly shorter survival among those who attain complete response (CR). Patients with AL amyloidosis generally have a lower clonal burden than subjects with multiple myeloma, and, despite a higher rate of early death due to advanced organ damage, if they respond to therapy they have a better long term outcome and are less likely to relapse. The role of MRD in AL amyloidosis has not been assessed so far. In the present proof-of-concept study, we assessed the MRD by MFC in patients with AL amyloidosis who attained CR. Methods. Complete response was defined as per current criteria (negative serum and urine immunofixation and normal free light chain ratio). Immunofixation was performed with both a commercial semi-automated method (Hydragel, Sebia, Lisses, France) and our home-made high-resolution method in all cases and had to be negative by both techniques. Circulating free light chains were measured by the Freelite assay. For flow cytometry studies bone marrow samples were processed following the Euro Flow Bulk Lysis Standard Operating Protocol and stained with the EuroFlow-IMF MM MRD panel (Tube 1: CD138BV421 / CD27BV510 / CD38FITC / CD56PE / CD45PerCP-Cy5.5 / CD19PE-Cy7 / CD117APC / CD81APC-C750, and Tube 2: identical to Tube 1 except for CyKappaAPC / CyLambdaAPC-C750). At least 5x106 events were measured using a FACSCanto II (BD Biosciences, San Jose, USA) instrument. Data were analyzed using the Infinicyt software (version 1.7; Cytognos SL, Salamanca, Spain). Patients were identified as having residual disease if a discreet population of clonal plasma cells comprising ≥ 50 events was identified (0.001% limit of detection). Patients exposed to different treatment types, to different numbers of treatment lines, and at different points in time after achievement of CR were tested, in order to assess the possible impact of these variables on MRD. Differences in variables between patients with and without MRD were tested for significance by mid p Fisher exact test. Results. Seventeen patients were tested. Six subjects were found to have relapsed at the time of MRD assessment with monoclonal components detectable at immunofixation and/or abnormal FLC ratio. All of them also had detectable MRD. Eleven patients satisfied current criteria for CR. All of them had renal and 6 (54%) had cardiac involvement at diagnosis. Two and 3 lines of therapy were required to achieve CR in 3 and 1 subjects, respectively. Median time to CR was 8 months (range 3-23 months). Two patients underwent autologous stem cell transplant and 9 received bortezomib. Three patients (50%) had achieved cardiac response and 5 (45%) renal response at the time of attainment of CR. The median time from CR to MRD evaluation was 20 months (range 6-36 months). Flow cytometry identified MRD in 5 patients (45%). A median of 1089 (range 600-2500) corresponding to 0.03% (range 0.02-0.15%) plasma cells with abnormal phenotype were detected in patients with MRD. No differences in organ involvement, cardiac and renal stage, type of therapy (with 1 transplanted patient in each group), number of treatments, and organ response at the time of CR was found between patients with and without MRD. However, a further improvement of cardiac function compared to the time of CR attainment was observed in all 4 evaluable patients without MRD and in none of the 2 patients with MRD, with borderline statistical significance (P=0.067). Compared to the time of CR achievement, renal response was obtained in 5 subjects without MRD (83%) and in 1 (20%) with MRD (P=0.069). Overall, further improvement of cardiac or renal function after CR was significantly associated with absence of MRD (P=0.002). Interestingly, 1 patient with MRD had otherwise unexplained increase in proteinuria while still in CR, and anti-clone therapy was started based on MRD results. Conclusion. This proof-of-concept study indicates that almost 50% of patients with AL amyloidosis satisfying current criteria for CR have MRD detectable by MFC. MRD makes further organ improvement less likely and can explain organ progression. A validation study in a larger sample is ongoing at our center. The possible impact of MRD should be considered in trials aiming at increasing organ response rate in patients achieving CR. Disclosures Palladini: Prothena: Honoraria. Merlini:Takeda and Janssen-Cilag: Honoraria.


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