Serum Free Lambda Light Chain Research Articles

AL–AMYLOIDOSIS RELATED ADVANCED HEART FAILURE DIAGNOSED THROUGH F–18–FLUTEMETANOL PET SCAN

Abstract Background Systemic amyloidosis (SA) is a group of rare diseases in which abnormal misfolded proteins, amyloid fibrils, accumulate in tissue. The gold standard for diagnosis is tissue biopsy of the affected organ, but it is invasive and needs specific proteomic or immunohistochemistry analyses to characterize the involved protein. We report a case of a complex diagnosis of SA in an advanced heart failure (HF) patient. Methods and Results A 68–year–old woman with history of recurrent uveitis started to complain dyspnea in 2022, after Covid19. Since her symptoms worsened, in June 2023 she was diagnosed in another center with restrictive cardiomyopathy with preserved left ventricular (LV) ejection fraction. She underwent coronary angiography (unremarkable), cardiac MRI (aspecific fibrosis), and a FDG–PET scan which showed non–homogeneous LV fixation. The patient was treated with steroids for the suspicion of an immunologic–inflammatory disease, without benefit. Fourteen months after the initial presentation, she was admitted to our centre for advanced inotrope–dependent HF. She had mildly increased LV hypertrophy and severe systolic dysfunction with restrictive physiology and, notably, peri–orbital subcutaneous hemorrhages (Figure 1). Hematological screening for amyloidosis showed elevated serum free lambda light chains. Repeated cardiac MRI scan was consistent with infiltrative disease. A total–body PET scan with dual tracer was performed. The control session with F–18–FDG showed mild aspecific cardiac uptake in the basal septum and lateral wall (Figure 2), while off–label use of F–18–Flutemetanol, an Alzheimer‘s disease approved experimental tracer that binds to amyloid fibrils beta sheets with very high sensitivity and specificity, showed intense cardiac, hepatic, pulmonary and muscular uptake, with wash–out–timing diagnostic for AL–SA (Figure 3). Periumbilical fat biopsy confirmed the clinical suspicion of SA. Hematological investigations led to the diagnosis of stage I–A lambda micromolecular multiple myeloma, with systemic amyloidosis and a IIIb cardiac prognostic score. Conclusions Endomyocardial biopsy is an invasive procedure and periumbilical fat biopsy discriminates the amyloid protein type only by proteomic analysis, which is available in very few Italian centres. The off–label use of Alzheimers’ PET tracers could reduce the delay of cardiac AL–SA diagnosis, allowing early disease identification and prompting timely hematological therapy.

Cardiac Tamponade in Idiopathic Capillary Leak Syndrome: Philippines’ First

Background: Clarkson’s disease, more known as idiopathic systemic capillary leak syndrome (SCLS) is a rare condition characterized by hypotensive episodes due to capillary hyperpermeability, which may be manifested by fluid accumulation in any organ or potential space, causing range of complications: respiratory failure (from pulmonary edema or pleural effusion), mesenteric hypoperfusion (from hepatic congestion and severe intestinal edema), compartment syndrome and rhabdomyolysis, and even shock from hypovolemia or cardiac tamponade. Very few cases of cardiac tamponade have been reported and certainly a serious and life-threatening complication. Case Summary: A 44-year-old female, reported to have intermittent episodes of angioedema aggravated by menstruation and infection, came in due to persistent hypotension. Patient presented with flu-like symptoms and tested positive for COVID – 19 infection. Initial laboratories revealed hemoconcentration, slightly elevated creatinine and hypoalbuminemia. Electrolytes and urinalysis were normal. 2D echocardiography showed large pericardial effusion with right atrial and ventricular collapse suggestive of cardiac tamponade, hence patient underwent emergency pericardial windowing. Initial chest X-ray was normal but repeat study showed pleural effusion on the 4th day of admission which was drained surgically. Additional diagnostic tests revealed negative for hepatitis, Mycoplasmal and Epstein-Barr virus. Direct and indirect Coomb’s test were also negative and Lupus panel was unremarkable. Serum free light chain panel showed suspicious for low level monotypic serum free lambda light chains (based only on the free light ratio). Immunopathology results showed no overt evidence of monoclonal bands. Protein electrophoresis pattern showed decreased albumin fraction and increased alpha, beta, and gamma fractions. C1 inhibitor was slightly elevated while serum tryptase was within normal values. Patient was managed as a case of idiopathic systemic capillary leak syndrome or Clarkson’s disease. Aside from judicious fluid resuscitation and vasopressors assist Methylprednisolone pulse therapy (MPPT) and intravenous immunoglobulin (IVIg) were administered. Patient was discharged with tapering doses of oral steroids and scheduled monthly IV immunoglobulin infusion. Conclusion: Cardiac tamponade, an uncommon yet severe and life-threatening complication of systemic capillary leak syndrome (SCLS) or Clarkson’s disease, requires immediate intervention. While the exact cause remains unclear, research suggests that during acute SCLS episodes and hyperinflammatory states, fluid accumulation in the pericardial space can impede ventricular filling, leading to hemodynamic compromise.

Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin abnormalities (POEMS) Syndrome in a Filipino Nurse Returning to Work Following Bortezomib Treatment: A Case Report

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) also known as Crow-Fukase syndrome or Takatsuki syndrome is a rare and disabling paraneoplastic syndrome that frequently occurs in the fifth or sixth decade of life without a known standard first-line therapy. A 34-year-old Filipino male nurse, who presented with gradually progressive distal lower extremity weakness and sharp shooting pain in bilateral legs accompanied by mild joint effusion on the left knee, hypertrichosis, bilateral conjunctival injection, and gynecomastia underwent extensive workup and was diagnosed with POEMS syndrome. Complete blood count revealed erythrocytosis and thrombocytosis with elevated serum VEGF (vascular endothelial growth factor) and elevated monoclonal serum free lambda light chains. The electrophysiologic studies revealed chronic demyelinating sensorimotor polyneuropathy while bone marrow core biopsy and bone marrow aspirate smear immunohistochemical staining showed it to be positive for lambda and CD138. He had an initial unsuccessful treatment course with melphalan and prednisone. Hence, bortezomib and dexamethasone were given which gave significant improvement in symptoms from the overall neuropathy limitation score of 5 to 1.

Successful management of a severe factor X deficiency patient with amyloidosis undergoing renal biopsy

Introduction: Systemic amyloidosis is a disease with a high risk of bleeding. The mechanism of bleeding is complex and involves multiple factors including amyloid-relating coagulopathy, platelet dysfunction and abnormal structural changes of arterioles. Among these, acquired coagulation factor X deficiency is the most common coagulopathy. Fatal bleeding may be associated with severe factor X deficiency particularly in the perioperative setting following invasive procedures. For the diagnosis of systemic amyloidosis, an invasive tissue biopsy is indispensable, and this procedure also requires close monitoring to prevent bleeding complications associated with factor X deficiency. Patient concerns: A 38-year-old Chinese man who developed nephrotic syndrome with both obviously prolonged prothrombin and activated partial thromboplastin time was admitted for further investigation. He also complained mild gingival hamorrhage intermittently for nearly 1 year. Diagnosis: The patient was diagnosed with a severe deficiency of coagulation factor X with factor X levels at 12.9%. The serum free lambda light chain was slightly elevated. A diagnosis of systemic amyloidosis was suspected. But no myocardial hypertrophy was observed. There was neither hepatomegaly nor splenomegaly. No signs of amyloidosis and plasma cells abnormality were found by routine analysis of bone marrow and abdominal fat pad biopsy samples. Interventions: After administration of low-dose prothrombin complex concentrates which lead rise to 27.4% in factor X level, the patient underwent kidney biopsy successfully without the occurrence of major bleeding and thrombotic events. The final pathological diagnosis was renal lambda light chain amyloidosis. Outcomes: No gross hemoturia, perirenal hematoma, and a thrombotic event occurred during his hospital stay after the kidney biopsy. For further management, the patient has been advised for autologous stem cell transplantation. Conclusion: This case report presents a rare occurrence of severe factor X deficiency in a patient diagnosed with amyloidosis. Overall coagulation state assessment before invasive procedure is helpful for bleeding-risk stratification and hemostatic-dose formulation. Proper dosage of prothrombin complex concentrates can be safe and effective in preventing factor X-related bleeding complications.

MON-469 Rapidly Expanding Thyroid Goiter as the First Manifestation of Systemic Amyloidosis

INTRODUCTIONAmyloidosis is a condition manifesting with extracellular tissue deposition of fibrils of low molecular weight proteins. In Ig light chain amyloidosis (AL), the deposition of Ig light chains can cause organ dysfunction, and patients can have involvement of a range of organs including kidney (70%), liver (70%), heart (60%), peripheral nerves (20%), the tongue, skin, and the coagulation system (1). We describe a unique case of AL amyloidosis, which first presented with thyroid involvement.CLINICAL CASEA 78 year old female patient with hx of small lymphocytic lymphoma and normal thyroid function presented with an expanding symptomatic goiter and compressive symptoms (positive Pemberton sign) for which a total thyroidectomy was performed. Pathology showed Congo red-birefringent amyloid deposition. SPEP showed a small amount of M protein, with circulating monoclonal free lambda light chain on immunofixation. The free kappa lambda light chain ratio was low (0.04) with an elevated serum free lambda light chain (283.93). Mass spectrometry confirmed AL light chain amyloidosis - lambda type. A work up was initiated to assess other organ involvement. Echocardiogram showed mild thickening of left ventricle with a preserved EF and EKG showed low voltage in limb leads. Creatinine (1.05) was minimally elevated from baseline with minimal proteinuria (396 mg/24 hours). Alkaline phosphatase, APTT, and PT were normal. The patient described tongue enlargement and scalloping of the tongue from tooth impingement was seen. Biopsies of tongue and bone marrow also showed amyloidosis thereby securing the diagnosis of systemic amyloidosis, and chemotherapy was initiated.CONCLUSIONThis case illustrates the importance of considering amyloid goiter in the differential for a rapidly enlarging thyroid, even when there is no history of amyloidosis. Although extremely uncommon, a few case reports have described amyloid goiter. In our case, thyroid AL was the initial presentation of systemic amyloidosis. Because disease can be localized or systemic, work up should include an assessment for the presence of a monoclonal gammopathy and an assessment for amyloid mediated organ dysfunction. Tissue should be sent for amyloid typing – there are 35 different proteins known to form amyloid fibrils and prognosis and treatment depends on amyloid type (2). Typing using Liquid Chromatography-Tandem Mass Spectrometry, is the most sensitive and specific methodology, though, in experienced hands, typing by immune histochemistry is an option.REFERENCES1. Rajkumar, S.V., Dispenzieri, A. Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis. Uptodate. 2019.2. Winter, M., Tholey, A., Kristen, A., Röcken, C. MALDI Mass Spectrometry Imaging: A Novel Tool for the Identification and Classification of Amyloidosis. Proteomics 2017, 17, 1700236.

PB2138 LIGHT CHAIN (AL) AMYLOIDOSIS: A SINGLE CENTRE EXPERIENCE AND THE EFFECTIVENESS OF BORTEZOMIB BASED THERAPY AS FIRST LINE THERAPY

Background:Amyloidosis is a heterogenous disease characterised by deposition of amyloid fibrils in soft tissue. Light chain (AL) amyloidosis is the most common form of systemic amyloidosis and is a complication of plasma cell dyscrasia. It can affect a wide range of organs including kidneys, heart, nervous system, liver, gastrointestinal tract and spleen which make the diagnosis difficult. Kidneys are the most commonly affected organ in AL amyloidosis and most patients present with nephrotic range proteinuria.In light chain amyloidosis, clonal plasma cells use proteasome to cope with misfolded light chain induced proteotoxicity, and the proteasome inhibitor bortezomib is a potential targeted therapy. Studies have demonstrated that Cyclophosphamide, Bortezomib, Dexamethasone (CyBorD) is a useful, highly effective upfront option.Aims:A retrospective study to evaluate the experience of a single centre, Waitemata District Health Board on the source of referral, biopsy source and the effectiveness of Bortezomib‐based therapy with long term follow up.MethodsDatabase at Waitemata District Health Board was searched for newly diagnosed patients with amyloidosis between 2001 and 2018. 55 out of 70 cases reported to New Zealand Cancer Registry were included. The source of referral, light chain subtype, disease association and biopsy source were analysed.43 patients who received Bortezomib based therapy as first line had been identified. The haematological response was assessed according to the International Society of Amyloidosis criteria. The duration to complete remission and relapse rates were also analysed.Results:55 patients were diagnosed with AL amyloidosis between 2001 and 2018. Half of the patients were referred by renal service (49%) and 11/55 (20%) were from cardiology service. Two third (38/55) of the patients had lambda light chains. Vast majority (87%) had either MGUS or smouldering myeloma.Half of the patients were diagnosed from renal biopsy. Other sites of diagnostic biopsy sample include bone marrow, lymph node, cardiac, GI tract, liver and tongue. Congo red stain was done on 39/50 bone marrow trephine samples and 16 of them (41%) were positive (8 muscular layer, 1 cortical bone, 7 marrow interstitium). Rectal biopsies were done on 10 patients with 7 positive result (70%).Of the 43 patients who received Bortezomib based therapy as first line treatment, 14 (32.6%) achieved complete response within 30 days of commencing treatment. Three patients (21.4%) relapsed with median time to relapse of 3.6 years. 15 patients (34.9%) achieved complete response after 30 days of commencing therapy and 5 patients (33.3%) relapsed with median time of 2 years. Five patients achieved very good partial response (VGPR), six patients with limited or no response.Summary/Conclusion:Renal disease is the most common presentation of AL amyloidosis followed by cardiac involvement. 2/3 of patients have elevated serum free lambda light chain and most of them have either MGUS or smouldering myeloma on bone marrow biopsy. Diagnoses are mostly made on renal biopsy but rectal biopsy seems to be sensitive for diagnosis of amyloidosis infiltration as well. Bortezomib based therapy appeared to be effective treatment as first line therapy with 79% achieving good haematological response with sustainable remission status. Ongoing follow up and larger cohort will be required for more conclusive results.

Detection of Extramedullary Multiple Myeloma in Liver by FDG-PET/CT.

We present the case of a 42-year-old man with a painful mass lesion in the right shoulder that was detected by contrast-enhanced computed tomography (CT) and 18F-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET)/CT (Fig. 1). Excisional biopsy revealed infiltration of plasma cells with anaplastic features, consistent with solitary plasmacytoma (PC). Serum analysis showed elevation of serum free lambda light chain levels (27.78 mg/l), with an abnormally high kappa:lambda ratio (2.33) and high total proteins (10.4 g/dl). Serum protein electrophoresis revealed an M spike in the gamma-globulin region (56.1 % = 5.8 g/dl).

Elevation of clonal serum free light chains in patients with HIV-negative primary effusion lymphoma (PEL) and PEL-like lymphoma

Elevation of clonal serum free light chains in patients with HIV-negative primary effusion lymphoma (PEL) and PEL-like lymphoma

Evaluation of Serum Free Light Chains and Outcome in Multiple Myeloma Patients with an Intact Monoclonal Immunoglobulin Treated with Autologous Stem Cell Transplantation.

Introduction: The serum free light chain (FLC) assay is a useful tool in diagnosing and monitoring multiple myeloma (MM) patients (pts) with non-secretory and light chain only disease. In addition, the detection of an abnormal serum FLC ratio is an adverse prognostic factor in pts with monoclonal gammopathy of undetermined significance. However, the relationship of the FLC assay to the outcome of patients with an intact monoclonal immunoglobulin following a single autologous stem cell transplantation (ASCT) has not been studied. Thus, the objective of this single centre, retrospective review study was to evaluate the usefulness of the FLC assay as a predictor for response rate and progression free survival (PFS) in this category of pts.Patients & Methods: We identified in our Princess Margaret Hospital MM database a total of 290 pts who underwent a single ASCT between June 2003 and May 2006. Of these, 65 had an intact monoclonal immunoglobulin (IgG in 47, IgA in 16 and IgD in 2) detected at diagnosis plus FLCs measured at referral. Normal range for FLC measurements is as follows: kappa 3.3–13.1 mg/L, lambda 5.7–26.3 mg/L, and kappa/lambda ratio of 0.26–1.65.Results: The median age at diagnosis was 59 years (range, 34–73); 33 (51%) were male. The median time from diagnosis to ASCT was 9.0 months (range, 5.0–29), with a median follow-up time of 27 months (range, 1.0–58.0). Assessment of best response following ASCT revealed that 20 (31%) pts achieved CR/nCR, 21 (32%) VGPR, 21 (32%) PR, 2 (3%) MR, and 1 (2%) was not evaluable for response. No prognostic factors for response were identified. To date, only 9 pts have died and the median overall survival is not yet reached. The median PFS is 25.4 months, with 36 patients progressing after ASCT. An elevated kappa and lambda light chain was detected in 30 (46%) and 22 (34%) of the 65 pts, respectively. Additionally, 52 (82%) of the 65 pts were found to have an abnormal kappa/lambda ratio. There was no significant difference in the PFS of patients with abnormal vs. normal free kappa light chains or FLC ratio. However, a decreased PFS was associated with elevated levels of serum free lambda light chains (p=0.01), β-2 microglobulin (p=0.007) and LDH (p=0.01).Conclusions:The majority of pts with an intact monoclonal immunoglobulin also have an abnormally high level of the corresponding serum FLC and an abnormal FLC ratio;an elevated serum free lambda level as well as increased β-2 microglobulin and LDH levels, as previously described, were identified as adverse prognostic factors for PFS in this population;we continue to routinely assess serum FLC for all pts at referral; however, longer follow-up is needed to further evaluate the prognostic significance of this parameter on the clinical outcome of pts.