scholarly journals Clinical Characteristics and Outcome of Patients with Wild-Type Transthyretin and AL Cardiac Amyloidosis Confirmed By Mass Spectrometry

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3126-3126
Author(s):  
Stephen Parkin ◽  
Michael A. Seidman ◽  
Margot Davis ◽  
Kevin Song
Keyword(s):  
Mass Spectrometry ◽  
Bone Marrow ◽  
Light Chain ◽  
Nyha Class ◽  
Complete Response ◽  
Al Amyloidosis ◽  
Cell Percentage ◽  
Bone Marrow Plasma ◽  
Kappa Light Chains ◽  
Al Amyloid

Abstract INTRODUCTION: Cardiac involvement is common in both wild-type transthyretin (wATTR) and AL amyloidosis and these entities can have overlapping clinical features (Banypersad et al, JAHA 2012). Accurate diagnosis is vital given differences in spectrum of disease, management, and prognosis. We examined the presenting clinical features and survival outcome of patients diagnosed with cardiac wATTR and AL amyloidosis confirmed by mass spectrometry. MATERIALS & METHODS: Patients diagnosed between January 2014 and September 2017 with biopsy proven wATTR or AL amyloidosis and cardiac involvement by consensus criteria (Gertz et al, Amyloid 2010) were included. Mass spectrometry testing was performed at the Mayo Clinic Laboratories to confirm amyloid subtype in all cases. Patient records were retrospectively reviewed to identify clinical characteristics as well as details regarding treatment and survival. RESULTS: Forty-three patients were identified (wATTR n=27, AL n=16) with site of biopsy: 41 cardiac (95%); 1 gastric (2%); 1 skin (2%). Two (13%) patients with AL amyloid had coexisting multiple myeloma. Thirty-five (81%) patients were male, with a strong male predominance in wATTR patients (100% vs 50% for AL patients, p=<0.01). Median age at diagnosis was 73 years (range 45-86), with a trend towards older age in wATTR patients (median 75 vs 62 years for AL patients, p=0.09). No difference was seen in presenting NYHA class or levels of troponin and ntProBNP between amyloid subtypes. BNP trended towards higher values in AL patients (median 514 vs 249 ng/L for wATTR, p=0.09). wATTR amyloid patients had lower median presenting left ventricular ejection fraction (43 vs 53%, p=0.05). Two (7%) patients with wATTR amyloid had an M-protein on SPEP compared to 7 (44%) with AL amyloid. Only 2 patients with AL amyloid had M-protein greater than 5 g/L while both wATTR patients had less than 5 g/L. In those with serum free light chain testing available (wATTR n=24, AL n=16), median lambda light chain level was higher in AL patients (176.0 vs 16.9 mg/L for wtATTR, p=<0.01). No difference was seen in kappa light chains (16.5 vs 23.8 mg/L for wATTR, p=0.60), though the only patient with kappa AL amyloid had kappa light chains significantly elevated at 1640 mg/L. The kappa/lambda ratio was abnormal in 15% of wATTR patients (all kappa predominant) compared to 100% in AL amyloid patients (94% lambda predominant) (p=<0.01). The median difference between involved and uninvolved light chain (dFLC) was 22 mg/L for wtATTR patients compared to 249 mg/L for AL patients. In patients with bone marrow biopsy results available (AL n=15, wATTR n=7), bone marrow plasma cell percentage was higher in patients with AL amyloid (median 7% vs 2%, p=0.01). No monoclonal plasma cells were seen on bone marrow in wATTR patients by immunophenotype. Treatment for patients with AL amyloid was: bortezomib, cyclophosphamide, and dexamethasone (VCD) in 11 (69%); VCD followed by melphalan 200 mg/m2 autologous transplantation in 1 (6%); melphalan/dexamethasone in 1 (6%); no treatment in 2 (13%); unknown in 1 (6%). In evaluable patients, hematologic response rate was 54% (complete response n=4, very good partial response n=2, partial response n=1, no response n=6). With a median follow-up of 1.8 years for surviving patients, 1 year overall survival (OS) was 76% for the entire cohort. Patients with AL amyloidosis had significantly poorer 1 year OS (41% vs 92% for wATTR patients, p=<0.01). Patients with NYHA class 3-4 had significantly worse 1 year OS (54% vs 96% for those 1-2, p=<0.01), and this held true for both AL and wATTR patients. In AL patients, revised Mayo stage (Kumar et al, JCO 2012) of III-IV predicted for poor 1 year OS (19% vs 75% for stages I-II, p=0.03), as did not achieving complete response to primary treatment (1 year OS 33% vs 67% for CR patients, p=0.06). DISCUSSION & CONCLUSIONS: Male sex, older age, and lower LVEF were more common in patients with wATTR compared to AL amyloidosis. Higher levels of BNP, larger dFLC with lambda predilection, and higher bone marrow plasma cell percentage were more common in AL amyloid patients. Overall survival was significantly worse for patients with AL amyloidosis, particularly those with high NHYA class, advanced revised Mayo stage, and suboptimal response to primary therapy. These results highlight the importance of accurate amyloid sub-typing in patients with suspected cardiac amyloidosis. Disclosures No relevant conflicts of interest to declare.

Clinical presentation and outcome of patients with AL amyloidosis requiring salvage therapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20043-e20043
Author(s):  
Chen Wang ◽  
Yumeng Zhang ◽  
Lauren Duncanson ◽  
Jason B. Brayer ◽  
Doris K. Hansen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Light Chain ◽  
Salvage Therapy ◽  
Plasma Cells ◽  
Al Amyloidosis ◽  
Comparison Results ◽  
Bone Marrow Plasma ◽  
Organ Response ◽  
Upfront Therapy

e20043 Background: The diagnosis and upfront management of immunoglobulin light chain (AL) amyloidosis have greatly improved in recent years. However, little is known about the presentation, treatment, and outcome of these patients at first relapse/progression (R/P). Methods: All patients with AL amyloidosis who received salvage therapy for first R/P disease at Moffitt Cancer Center between 2008 and 2020 were included in this retrospective review. Definitions of hematologic and organ R/P were based on 2012 consensus. Overall survival was measured from the time of salvage to last follow up/death. Survival was assessed by Kaplan-Meier with log-rank comparison. Results: Sixty-nine patients were included. The median age at diagnosis was 62 years and 61% were male. Upfront therapy included high dose melphalan with autologous transplant in 36% and bortezomib in 52%. At salvage, 19% had disease refractory to upfront therapy and 40% had not achieved an organ response. The median time from upfront to salvage therapy was 22 months. Salvage regimens included proteasome inhibitors, daratumumab and immunomodulatory drugs in 55%, 13% and 22%, respectively. At least a very good partial response and organ response were achieved in 35% (22/62) and 39% (21/54) with measurable disease. The median overall survival was 60 months. Based on salvage indication, patients were classified into hematologic (n = 29) and organ R/P (n = 40), and the latter showed more frequent lambda-light chain disease (59% vs. 83%, p = 0.028) and low difference of involved-uninvolved free light chain at diagnosis (< 50 mg/L, 8% vs. 44%, p = 0.002). Negative prognostic markers for survival included bone marrow plasma cells ≥20% at diagnosis (median 17 months vs. not reached; p < 0.001) and organ, particularly cardiac R/P (median, 31 months vs. not reached; p = 0.003). Salvage ( p = 0.48) or prior regimens ( p = 0.11) did not impact post-salvage survival. Conclusions: Our study highlights the unmet need of salvage in R/P AL amyloidosis in a real-world setting, given the low rate of deep responses regardless of current salvage options. Patients with bone marrow plasma cells ≥20% at diagnosis and organ R/P at salvage had inferior survival, supporting use of intensive upfront regimens for the former and adjustment of therapy if deep response is not achieved.[Table: see text]

Standard Oral Melphalan Chemotherapy for AL Amyloidosis Revisited Using the Serum Free Light Chain Assay.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3495-3495 ◽  
Author(s):  
Mark Offer ◽  
Ashutosh D. Wechalekar ◽  
Hugh J.B. Goodman ◽  
Julian D. Gillmore ◽  
Helen J. Lachmann ◽  
...  
Keyword(s):  
Partial Response ◽  
Light Chain ◽  
Nyha Class ◽  
Single Agent ◽  
Complete Response ◽  
Free Light Chain ◽  
Al Amyloidosis ◽  
Serum Free ◽  
Haematological Response ◽  
Serum Free Light Chain

Abstract Treatment of systemic AL amyloidosis (AL) remains difficult, especially in older and sicker patients in whom dose intensive therapies are often associated with unacceptable morbidity and mortality. Many such patients continue to be treated with oral melphalan ± prednisone (MP) despite early trials having shown only very modest clinical efficacy, presumably encouraged by its perceived low toxicity. The recent advent of the sensitive nephelometric serum free light chain (sFLC) assay has for the first time enabled the typically subtle underlying clonal disease to be monitored in an effective quantitative manner in the majority of patients with AL. We report here sFLC responses and clinical outcome of patients with AL who received MP first-line and underwent serial evaluations at the UK National Amyloidosis Centre. The 90 patients comprised 46 males and 44 females with a median age of 68yrs (range 43–83). Median number of organs involved was 3 (1–4), including kidneys in 72%, heart in 56%, and liver in 29%. 16 (17%) had ≥ NYHA class III heart failure. Median ECOG performance status was 1. Median follow-up was 2.3 yrs (0.3–14). 60 patients received oral melphalan with prednisone, and 30 received single agent melphalan. Patients received a median of 6 cycles of treatment (range 1– 26), and the sFLC assay was scheduled following each cycle after availability of the assay and retrospectively on stored sera for earlier patients. Haematological response data using sFLC assay were evaluable in 54 (60%). Responses were defined as complete response (CR) - sustained normalisation of sFLC ratio, partial response (PR) - sustained ≥50% reduction in pre-treatment clonal isotype. There was a haematological response in 22 (40%) of evaluable patients. 4 (7%) had a complete response, 18 (33%) had a partial response and 32 (59%) did not respond. 42% of patients treated with single agent melphalan responded compared with 39% of those treated with melphalan and prednisone (p=0.8). Responders received a median 6 cycles of treatment, and complete responders received a median of 14 cycles. Non-responders received a median of 5 cycles of treatment. The median time to commencing further chemotherapy was 5 months. The median overall survival (OS) was 5.8yrs, but most patients received further salvage treatments and the influence of MP treatment on OS could not be ascertained. Toxicities during MP were seen in 13 (14%) cases, including myelodysplasia in 2 patients. There were no treatment related deaths. In conclusion, use of the sFLC assay confirms that response of the underlying clonal plasma cell disease to standard oral melphalan and prednisone is poor in AL amyloidosis, and that response is usually very delayed even among patients who respond completely. Encouragingly however, toxicity was low among this relatively old and sick cohort of patients. These findings support frequent sFLC measurements in AL patients receiving MP to enable rational treatment decisions to be made at the earliest opportunity.

scholarly journals Coexistent Multiple Myeloma or Increased Bone Marrow Plasma Cells Define Equally High-Risk Populations in Patients With Immunoglobulin Light Chain Amyloidosis

2013 ◽  
Vol 31 (34) ◽  
pp. 4319-4324 ◽  
Author(s):  
Taxiarchis V. Kourelis ◽  
Shaji K. Kumar ◽  
Morie A. Gertz ◽  
Martha Q. Lacy ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Light Chain ◽  
Plasma Cells ◽  
Survival Rates ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Characteristic Analysis ◽  
Bone Marrow Plasma

Purpose There is consensus that patients with light chain (AL) amyloidosis with hypercalcemia, renal failure, anemia, and lytic bone lesions attributable to clonal expansion of plasma cells (CRAB criteria) also have multiple myeloma (MM). The aim of this study was to examine the spectrum of immunoglobulin AL amyloidosis with and without MM, with a goal of defining the optimal bone marrow plasma cell (BMPC) number to qualify as AL amyloidosis with MM. Patients and Methods We identified 1,255 patients with AL amyloidosis seen within 90 days of diagnosis between January 1, 2000, and December 31, 2010. We defined a population of patients with coexisting MM on the basis of the existence of CRAB criteria (AL-CRAB). Receiver operating characteristic analysis determined the optimal BMPC cut point to predict for 1-year mortality in patients with AL amyloidosis without CRAB to produce two additional groups: AL only (≤ 10% BMPCs) and AL plasma cell MM (AL-PCMM; > 10% BMPCs). Results Among the 1,255 patients, 100 (8%) had AL-CRAB, 476 (38%) had AL-PCMM, and 679 (54%) had AL only. Their respective median overall survival rates were 10.6, 16.2, and 46 months (P < .001). Because the outcomes of AL-CRAB and AL-PCMM were similar, they were pooled for univariate and multivariate analyses. On multivariate analysis, pooled AL-CRAB and AL-PCMM retained negative prognostic value independent of age, Mayo Clinic AL amyloidosis stage, prior autologous stem-cell transplantation, and difference between the involved and uninvolved free light chain. Conclusion Patients with AL amyloidosis who have more than 10% BMPCs have a poor prognosis, similar to that of patients with AL-CRAB, and should therefore be considered together as AL amyloidosis with MM.

scholarly journals Quantitative Immunoprecipitation Free Light Chain Mass Spectrometry (QIP-FLC-MS) Simplifies Monoclonal Protein Assessment and Provides Added Clinical Value in Systemic AL Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4375-4375 ◽  
Author(s):  
Faye Amelia Sharpley ◽  
Hannah Victoria Giles ◽  
Richa Manwani ◽  
Shameem Mahmood ◽  
Sajitha Sachchithanantham ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Light Chain ◽  
Residual Disease ◽  
Renal Involvement ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Free Light Chains ◽  
Accurate Identification ◽  
Monoclonal Protein ◽  
Serum And Urine

Introduction Early diagnosis, effective therapy and precise monitoring are central for improving clinical outcomes in systemic light chain (AL) amyloidosis. Diagnosis and disease response assessment is primarily based on the presence of monoclonal immunoglobulins and free light chains (FLC). The ideal goal of therapy associated with best outcomes is a complete responses (CR), defined by the absence of serological clonal markers. In both instances, detection of the monoclonal component (M-component) is based on serum FLC assessment together with traditional serum and urine electrophoretic approaches, which present inherent limitations and lack sensitivity particularly in AL where the levels are typically low. Novel mass spectrometry methods provide sensitive, accurate identification of the M-component and may prove instrumental in the timely management of patients with low-level amyloidogenic light chain production. Here we assess the performance of quantitative immunoprecipitation FLC mass spectrometry (QIP-FLC-MS) at diagnosis and during monitoring of AL amyloidosis patients treated with bortezomib-based regimens. Methods We included 46 serial patients with systemic AL amyloidosis diagnosed and treated at the UK National Amyloidosis Centre (UK-NAC). All patients had detailed baseline assessments of organ function and serum FLC measurements. Baseline, +6- and +12-month serum samples were retrospectively analysed by QIP-FLC-MS. Briefly, magnetic microparticles were covalently coated with modified polyclonal sheep antibodies monospecific for free kappa light chains (anti-free κ) and free lambda light chains (anti-free λ). The microparticles were incubated with patient sera, washed and treated with acetic acid (5% v/v) containing TCEP (20 mM) in order to elute FLC in monomeric form. Mass spectra were acquired on a MALDI-TOF-MS system (Bruker, GmbH). Results were compared to serum FLC measurements (Freelite®, The Binding Site Group Ltd), as well as electrophoretic assessment of serum and urine proteins (SPE, sIFE, UPE and uIFE). Results Cardiac (37(80%) patients) and renal (31(67%) patients) involvement were most common; 25(54%) patients presented with both. Other organs involved included liver (n=12), soft tissue (n=4), gastrointestinal tract (n=3) and peripheral nervous system (n=2). Baseline Freelite, SPE, sIFE and uIFE measurements identified a monoclonal protein in 42(91%), 22(48%), 34(74%) and 21(46%) patients, respectively. A panel consisting of Freelite + sIFE identified the M-component in 100% of the samples. QIP-FLC-MS alone also identified an M-component in 100% of the samples and was 100% concordant with Freelite for typing the monoclonal FLC (8 kappa, 34 lambda). In 4 patients, QIP-FLC-MS identified an additional M-protein that was not detected by the other techniques. In addition, 4/8(50%) kappa and 4/38(11%) lambda patients showed a glycosylation pattern of monoclonal FLCs at baseline by mass spectrometry. Interestingly, the frequency of renal involvement was significantly lower for patients with non-glycosylated forms (25% vs 76%, p=0.01), while no similar relationship was found for any other organs. During the 1-year follow-up period, 17 patients achieved a CR; QIP-FLC-MS identified serum residual disease in 13(76%) of these patients. Conclusion In our series, QIP-FLC-MS was concordant with current serum methods for identifying the amyloidogenic light chain type and provided, against all other individual tests, improved sensitivity for the detection of the monoclonal protein at diagnosis and during monitoring. The ability to measure the unique molecular mass of each monoclonal protein offers clone-specific tracking over time. Glycosylation of free light chains is over-represented in AL patients which may allow earlier diagnosis and better risk-assessment of organ involvement. Persistence of QIP-FLC-MS positive M component in patients otherwise in CR may allow targeted therapy. Overall, QIP-FLC-MS demonstrates potential to be exploited as a single serum test for precise serial assessment of monoclonal proteins in patients with AL amyloidosis. Disclosures Wechalekar: GSK: Honoraria; Janssen-Cilag: Honoraria; Amgen: Research Funding; Takeda: Honoraria; Celgene: Honoraria.

scholarly journals Systemic AL amyloidosis with high bone marrow plasma cells (BMPCs) infiltration: a case report and literature review

2019 ◽  
Vol 4 ◽  
pp. I 30-30
Author(s):  
Hui-Wen Wang ◽  
Rong Tang ◽  
Xiang-Cheng Xiao ◽  
Wei Liu ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Case Report ◽  
Literature Review ◽  
Plasma Cells ◽  
Al Amyloidosis ◽  
Bone Marrow Plasma ◽  
High Bone

scholarly journals Confocal Cornea Microscopy Detects Involvement of Corneal Nerve Fibers in a Patient with Light-Chain Amyloid Neuropathy Caused by Multiple Myeloma: A Case Report

2016 ◽  
Vol 8 (2) ◽  
pp. 134-139 ◽  
Author(s):  
Dietrich Sturm ◽  
Tobias Schmidt-Wilcke ◽  
Tineke Greiner ◽  
Christoph Maier ◽  
Marc Schargus ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Case Report ◽  
Light Chain ◽  
Nerve Fibers ◽  
Al Amyloidosis ◽  
Fiber Damage ◽  
Small Fiber ◽  
Corneal Nerve ◽  
Al Amyloid

Changes in the subbasal corneal plexus detected by confocal cornea microscopy (CCM) have been described for various types of neuropathy. An involvement of these nerves within light-chain (AL) amyloid neuropathy (a rare cause of polyneuropathy) has never been shown. Here, we report on a case of a patient suffering from neuropathy caused by AL amyloidosis and underlying multiple myeloma. Small-fiber damage was detected by CCM.

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