Light Chain Deposition Disease Research Articles

Association of plasma neurofilament light chain with disease activity in chronic inflammatory demyelinating polyradiculoneuropathy.

This study was undertaken to explore associations between plasma neurofilament light chain (pNfL) concentration (pg/ml) and disease activity in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and examine the usefulness of pNfL concentrations in determining disease remission. We examined pNfL concentrations in treatment-naïve CIDP patients (n= 10) before and after intravenous immunoglobulin (IVIg) induction treatment, in pNfL concentrations in patients on maintenance IVIg treatment who had stable (n= 15) versus unstable disease (n= 9), and in clinically stable IVIg-treated patients (n= 10) in whom we suspended IVIg to determine disease activity and ongoing need for maintenance IVIg. pNfL concentrations in an age-matched healthy control group were measured for comparison. Among treatment-naïve patients, pNfL concentration was higher in patients before IVIg treatment than healthy controls and subsequently reduced to be comparable to control group values after IVIg induction. Among CIDP patients on IVIg treatment, pNfL concentration was significantly higher in unstable patients than stable patients. A pNFL concentration > 16.6pg/ml distinguished unstable treated CIDP from stable treated CIDP (sensitivity=86.7%, specificity=66.7%, area under receiver operating characteristic curve=0.73). Among the treatment withdrawal group, there was a statistically significant correlation between pNfL concentration at time of IVIg withdrawal and the likelihood of relapse (r= 0.72, p< 0.05), suggesting an association of higher pNfL concentration with active disease. pNfL concentrations may be a sensitive, clinically useful biomarker in assessing subclinical disease activity.

IgD-Lambda Multiple Myeloma without Renal Failure: An Unusual Presentation

Immunoglobulin D (IgD) multiple myeloma is a rare form of myeloma having often an aggressive course, affecting 2% of all cases. It shows frequentely renal failure, Bence Jones proteinuria and the difficulties of diagnosis. We report a case of a 59 years old man with IgD multiple myeloma associated with good renal function. The patient was hospitalized in the hematology department for bone pain and alteration of the general condition. A further evaluation for multiple myeloma revealed presence of a monoclonal protein band in Beta2 region in serum protein electrophoresis (SPE). Urine protein electrophoresis (UPE) showed presence of BenceJones proteinuria.The immunofixation electrophoresis (IE) of the serum reported as IgD-Lambda paraproteinaemia. Laboratory studies showed also an anemia , hypercalcemia, but fortunatuly, our patient did not have renal failure, as is common with myeloma. Bone marrow examination showed infiltration by plasma cells. Thus, the patient was put on chemotherapy and stem cell autotransplantation with a good clinical and biological improvement. This case is reported to emphasize the importance of performing IgD immunofixation routinely for all suspected multiple myeloma patients because many cases are erroneously diagnosed as light chain disease. And it describes a rare case of an even rarer and uncommon situation and highlights the fortunate situation of this patient's unfortunate disease.

A Cohort Study of Free Light Chain Ratio in Combination with Serum Protein Electrophoresis as a First-Line Test in General Practice.

Simple SummaryMultiple Myeloma (MM) can be a diagnostic challenge as it often presents with unspecific symptoms in patients in general practice. Serum-free light chain (sFLC) ratio is suggested to replace urine protein electrophoresis (UPE) in the diagnostic work-up of myeloma. We aimed to investigate the performance of the sFLC ratio in general practice (GP) compared to UPE in a low prevalence cohort of 13,210 patients from general practice. We found that sFLC ratio performs in line with UPE; however, we observed a pronounced number of false-positive tests. Therefore, local instrument-dependent adjustment of reference ranges/decision limits should be considered to avoid an unnecessarily high number of false-positive tests.Multiple Myeloma (MM) often present with unspecific symptoms, which can lead to diagnostic delay. Serum-free light chain (sFLC) ratio is suggested to replace urine protein electrophoresis (UPE) in the diagnostic work-up of myeloma. We aimed to investigate the performance of the sFLC-ratio in general practice (GP) compared to UPE, just as we explored different sFLC-ratio cut-offs’ influence on diagnostic values. In a cohort of 13,210 patients from GP measures of sFLC-ratio, serum protein electrophoresis (SPE), or UPE were compared to diagnoses of incident M-component related diseases acquired from Danish health registers. UPE and sFLC-ratio equally improved diagnostic values when combined with SPE (sensitivity: SPE and UPE: 95.6 (90.6–98.4); SPE and sFLC-ratio: 95.1 (90.2–98.0)). The addition of the sFLC-ratio to SPE resulted in the identification of 13 patients with MGUS, light chain disease and amyloidosis, which was in line with the addition of UPE to SPE. The number of false-positive tests was UPE and SPE: 364 (11%) and sFLC-ratio and SPE: 677(19%). Expanding sFLC-ratio reference range to 0.26–4.32 resulted in a significant reduction in false positives n = 226 (6%) without loss of patients with clinical plasma cell dyscrasias. sFLC-ratio improves the diagnostic value of SPE in GP. However, due to low specificity and a large number of false positives, expanded cut-off values should be considered.

Cardiac amyloidosis-interdisciplinary approach to diagnosis and therapy.

The vast majority of cardiac amyloidosis (CA) cases are caused by light chain (AL) or transthyretin (ATTR) amyloidosis. The latter is divided into hereditary (ATTRv) and wild-type forms (ATTRwt). The incidence of ATTRwt amyloidosis has significantly increased, particularly due to the improved diagnosis of cardiac manifestations, with relevant proportions in patient populations with heart failure (HF) and preserved ejection fraction (HFpEF). Cardiac amyloidosis should be suspected in HF with indicative clinical scenarios/"red flags" with typical signs of CA in echocardiography. Further noninvasive imaging (cardiovascular magnetic resonance imaging, scintigraphy) and specific laboratory diagnostics are important for the diagnosis and typing of CA into the underlying main forms of ATTR and AL amyloidosis. The histopathologic analysis of an endomyocardial biopsy is necessary if noninvasive diagnostic methods do not enable reliable typing of CA. This is crucial for initiating specific therapy. Therapy of HF in CA is largely limited to the use of diuretics in the absence of evidence on the benefit of classic HF therapy with neurohormonal modulators. Innovative therapies have been developed for amyloidosis with improvement in organ protection, prognosis, and quality of life. These include specific cytoreductive therapies for monoclonal light-chain disease in AL amyloidosis and pharmacologic stabilization or inhibition of transthyretin expression in ATTR amyloidosis. Since the CA underlying amyloidosis is asystemic disease also affecting other organ systems, close interdisciplinary cooperation is crucial for rapid and effective diagnosis and therapy.

Morphological pattern of non-diabetic nephropathy in type 2 diabetes mellitus patients

Abstract. The aim of this study was to evaluate the contribution of kidney biopsy performed with an appropriate indication to diagnosis and treatment in diabetic patients with nephropathy.
 Methods: In this retrospective study 32 type 2 diabetes patients who underwent kidney biopsy in a single center between 2012-2019 were included. Kidney biopsy indications were determined as patients with diabetes without diabetic retinopathy and with proteinuria above 1 g/day.
 Results: Diabetic (DN) and non-diabetic (NDN) nephropathies were diagnosed with renal biopsy. In 14 (43.7%) of 32 patients, NDN was reported in histopathological evaluation. Membranous nephropathy was detected in 4 of these patients, focal segmental glomerulosclerosis (FSGS) in the other 4 patients, light chain disease in 2 patients, IgA nephropathy in 2 of the patients, minimal change nephropathy in another patient, and finally AA amyloid in one patient. NDRD seen superimposed on DN (DN + interstitial nephritis and DN + FSGS) was observed in 2 patients. DN was detected in 16 (50%) of 32 type 2 diabetic patients.
 Conclusion: Kidney biopsy in patients with type 2 diabetes is an important tool for diagnosing NDN, choosing the right treatment tactics and determining kidney prognosis.

69-Year-Old Man With Dysuria and Right Lower Abdominal Pain

69-Year-Old Man With Dysuria and Right Lower Abdominal Pain

Clinicopathological characteristics of high-risk multiple myeloma in Hispanic versus non-Hispanic patients in central California.

8056 Background: Roughly 37% of Multiple Myeloma (MM) patients in the U.S. are non-white minorities. Advanced stage at diagnosis and specific cytogenetic abnormalities are associated with high-risk disease and poor prognosis. Few studies evaluated these risk factors in ethnic minorities. To further investigate, we analyzed ethnic variations in characteristics and outcomes of high-risk MM patients who were treated at our institution in Fresno, CA (49.6% Hispanic population). Methods: Patients diagnosed with high-risk MM at Community Medical Centers from 1-1-2011 to 12-31-2020 were included. High risk was defined by Mayo Clinic mSMART 3.0 classification. Demographic and disease-relevant information were collected. Cytogenetics, R ISS stage, 1st line treatment (doublet vs triplet), and treatment response (IMWG response criteria) were evaluated. Hispanic and non Hispanic comparisons were made by Fisher’s exact test where appropriate. Progression Free Survival (PFS) and Overall Survival (OS) were evaluated by Kaplan-Meier estimates and compared via log-rank test. Univariate cox proportional hazard model for survival was used to examine the association of variables with mortality risk after 1st line therapy. Results: 147 MM patients were screened. 42 high risk patients were identified: 11 (26%) Hispanic, 31 (74%) non Hispanic (22 white, 8 African American, 1 East Indian). Median age at diagnosis was 65. 26 (61%) were females. 25 (59%) were R ISS stage 3. Hispanic vs non Hispanic median income was $46119 vs $65080 (p=0.035). 6 Hispanics had Medi-Cal insurance vs 2 non-Hispanics (54.6% vs 6.5%, p=0.003). More Hispanics had Lambda light chain disease (73% vs 26%; p=0.01). 13 non Hispanics had del 17p vs 0 Hispanics (p=0.009). 40/42 patients (95%) received triplet therapy. 4 Hispanics received ASCT vs 9 non Hispanics (40% vs 33.3%, p=0.716). Hispanics and non Hispanics did not have significantly different treatment responses per IMWG criteria (p=0.799). No significant difference in PFS was seen between Hispanics and non Hispanics (805 vs 793 days; p=0.089); OS was better in Hispanics (1062 days vs 453 days; p=0.008). Per univariate cox proportional Hazard model, female sex (HR 4.34) and age (HR 1.05) were associated with higher mortality while Hispanic ethnicity was associated with lower mortality (HR 0.19). Conclusions: Hispanic and non Hispanic high risk MM patients differed significantly in median income, insurance, and del 17p incidence. These did not translate to a difference in 1st line therapy or treatment response. OS in our study is higher in Hispanic high-risk MM patients compared to other ethnicities and warrants further investigation. [Table: see text]

MO135: Efficacy and Safety of Bortezomib Combined with Autologous Stem Cell Transplantation in the Treatment of MGRS

Abstract BACKGROUND AND AIMS To evaluate the efficacy and safety of bortezomib combined with autologous stem cell transplantation (ASCT) in the treatment of monoclonal gammopathy of renal significance (MGRS). METHOD The clinicopathologic data of 16 patients with non-AL MGRS who received bortezomib combined with ASCT in Jinling Hospital of Nanjing University School of Medicine from February 2012 to June 2021 were retrospectively analysed. RESULTS Twelve patients were male and four were female, with a median age of 49 years, a median serum creatinine was 1.71 mg/ dL (1.45, 2.09) and a median eGFR wad 42.1 mL/min/1.73 m2 (29.0, 51.6). Renal pathological types included seven patients were light chain deposition disease, two patients were heavy chain deposition disease, one patient was light and heavy chain deposition disease, five patients were light chain proximal tubulopathy and one patient was proliferative glomerulonephritis with monoclonal immunoglobulin deposition. Sixteen patients received bortezomib-based induction therapy with a median three courses before transplantation. Stem cells were successfully collected from all patients and CD34 + cell counts were 4.4–13.55 × 106/kg (8.77 ± 3.29 × 106/kg). All patients had successful haematopoietic reconstitution, and a median time of achieving granulocyte count of 500/L was 10 (9, 10) days, and a median time of achieving platelet count of 20 000/L was 12 (11, 13) days. The major treatment complications during transplantation were mucositis (87.5%), diarrhoea (62.5%), fever (56.3%), and nausea and vomiting (18.8%); the other rare complications were acute kidney injury, skin rashes and liver function damage. Haematologic responses were achieved in 15 patients (93.8%), with 10 patients (62.5%) achieved complete responses, 3 patients (18.8%) achieved very good partial responses, 2 patients (12.5%) achieved partial responses, and 1 patient had no haematologic responses. Before treatment with ASCT, seven patients (43.8%) achieved partial response, of which four achieved complete response after ASCT, and one patient did not achieve hematologic response but achieved complete response after ASCT. A total of 12 patients (75%) achieved renal response before ASCT and 14 patients (87.5%) achieved renal response after ASCT. The median follow-up time was 43.5 months. One patient died during the follow-up due to infection, and one patient developed end-stage renal disease during the follow-up. Three patients relapsed, with a median time of 49 months. CONCLUSION Our data demonstrated that ASCT is a safe and effective treatment for rigorously selected non-AL MGRS patients, with few serious treatment complications and high haematological and organ response rates.

MO174: Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits: Rare Disease with Poor Prognosis?

Abstract BACKGROUND AND AIMS Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMIDs) is a recently described disease among the spectrum of monoclonal gammopathy of renal significance (MGRS). The disease is renal limited and manifests with chronic glomerular disease, altered renal function and albuminuria, sometimes in the nephrotic range. Kidney injury results from direct glomerular deposition of the monoclonal immunoglobulin. Of note, in approximately 70% of the cases of PGNMID, a clone cannot be detected. METHOD Clinical case of PGNMID. RESULTS A 36-year-old woman, with a past history of acute glomerulonephritis, was treated with mycophenolate mofetil 2 g and concomitant methylprednisolone 2 mg from January 2020 to September 2021 (kidney biopsy was not performed). After 3 months, she showed recurrence of nephrotic syndrome: peripheral edema, severe weakness, shortness of breath, decreased diuresis up to oliguria and increased blood pressure. Blood analysis has shown: GFR 127 mL/min/1.73 m2, total protein 44.4 g/L, albumin 16.2 g/L; autoimmune markers—negative; kappa free light chains 182 mg/L (3.3–19.4 mg/L); lambda free light chains 112 mg/L (5.71–26.3 mg/L), ratio of kappa/lambda 1.63 (0.26 to 1.65). Urine analysis has shown: total protein excretion rate 3.5 g/24 h; albuminuria 1000 mg/g; urine microscopy—normal; kappa free light chains ++++; lambda free light chains +++. A kidney biopsy has shown up to 12 glomerulies, which have different sizes, some are enlarged, as due to diffuse proliferation of mesangial cells, oedema and segmental proliferation of endothelial cells, as fibrinoid changes; some of the capillary loops are infiltrated with monocytes, an uneven increase in the mesangial matrix, there are small areas of segmental sclerosis that tend to be nodular in some glomerulies. Degenerative changes (granular, vacuolar, in some areas hyaline-droplet dystrophy), necrosis of epithelial cell groups, areas of epithelial atrophy with thickening of the tubular basement membrane (up to 10% of the biopsy volume) are sharply expressed in the tubules. In the tubules—protein masses, exfoliated epithelium, the lumen of the tubules is sharply reduced and/or absent due to pronounced degenerative changes in the epithelium. In the stroma—edema, areas of interstitial fibrosis, including perivascular (up to 10% of the biopsy volume), focal lymphohistiocytic cell infiltrates. By definition, there is evidence of monoclonal deposits by immunofluorescence: IgA (predominantly), IgG, IgM, С3 deposits; С1q, CD20 (В- lymphocytes), AA amyloidosis -negative expression; kappa free light chains (predominantly) +++; lambda free light chains ++ (Figure 1). Finally, we reached a clinical diagnosis of CKD G1, A3: PGNMIDs (IgM, IgA, IgG; LC Ķ˃λ). Nephrotic syndrome. Light Chain Deposition Disease. At that point (January 2021), we have started clone-targeted chemotherapy following the data sheet, with urinary and haematological response after 2 weeks, and normal kidney function with complete remission of nephrotic syndrome after 4 weeks, as well as a negativization of kappa and lambda free light chains deposits (Table 1). Three months after admission, the patient maintained haematological and kidney remission up to now. CONCLUSION MGRS is not an independent kidney disease, not ‘chronic glomerulonephritis’, but a condition in which kidney damage is secondary to clonal B-cell proliferation. In other words, MGRS is a precancerous disease combined with chronic kidney disease that requires immediate treatment. Renal prognosis is poor, with progression to ESKD in 25% of patients within 30 months and frequent early recurrence on the renal allograft. However, recent studies indicate that clone-targeted chemotherapy may significantly improve renal outcomes, opening future perspectives for the management of this rare disease.

Circulating Serum MiRNA-8074 as a Novel Prognostic Biomarker for Multiple Myeloma.

MiRNA-8074 is a molecule with the potential to regulate the expression of key genes related to the pathogenesis of multiple myeloma (MM), i.e., TP53, MYC, MAPK1, and KIAA. We analyzed the predictive and prognostic value of miRNA-8074 expression in MM patients. In total, 105 newly diagnosed MM patients treated with thalidomide (n = 27), bortezomib (n = 41) and bortezomib with thalidomide (n = 37) were studied. For miRNA analysis, the column method and the Real-Time PCR technique with specific TaqMan Fast Advanced Master Mix and TaqMan probes were used. Factors that were associated with a significant reduction in progression-free survival (PFS) included: ECOG > 1, ISS stage III, low hemoglobin, thrombocytopenia, hypoalbuminemia, abnormal renal function, elevated creatinine, GFR < 60 mL/min/1.73 m2, elevated LDH, del(17p), t(11;14), the use of a single drug regimen (thalidomide or bortezomib) and high miRNA-8074 expression (HR = 2.01, 95% CI: 1.16–3.49; p = 0.0233). In addition to the known prognostic factors, such as ECOG > 1, Durie–Salmon stage III, diagnosis of light chain disease or non-secreting MM, renal failure, hypoalbuminemia, hypercalcemia, high β2-microglobulin, elevated LDH, and t(14;16), a high expression of miRNA-8074 was significantly associated with a higher risk of death (HR = 4.12, 95% CI: 2.20–7.70; p = 0.0009). In summary, miRNA-8074 may be a useful diagnostic tool to assess the prognosis in MM patients.

POEMS Syndrome: a clinical challenge / Síndrome de POEMS: um desafio clínico

A 42-year-old male patient admitted to our service with a history of progressive and symmetrical weakness, paresthesia of the lower limbs, weight loss and urinary retention for about 8 months. Physical examination demonstrated poor general condition, lower limb edema, hepatomegaly and digital clubbing. Neurological examination showed a polyneuropathic pattern, with hypoesthesia and absence of deep reflexes of the lower limbs. Initial laboratory investigation demonstrated erythrocytosis and thyroid and adrenal dysfunction in addition to hypergammaglobulinemia. CSF analysis, due to the clinical suspicion of chronic inflammatory demyelinating polyneuropathy, resulted in protein-cytological dissociation. PIDC was hypothesized to be due to light-chain disease, but for this association we supplemented with bone marrow analysis and whole-body CT scan, which showed 4% atypia in plasma cells and osteolytic and osteoblastic lesions in the vertebro-costal region between the 8th and 9th vertebrae. Subsequent biopsy confirmed plasmacytoma. He performed autologous bone marrow transplantation, but evolved with infectious complications and died within 3 months.

Spectrum of Biopsy-proven Native Kidney Disease in Central India.

Spectrum of native renal biopsy reports varies geographically. Here, we tried to determine the prevalence of renal biopsy disorders and compare it with other studies. Retrospective study was performed at Saraswati Kidney Care Center, Nagpur and Jawaharlal Nehru Medical College, Sawangi, India. All the native kidney biopsies from January 2017 to March 2020 were included in the analysis. Demographic details of all the patients were recorded. Renal diseases were classified as glomerular, tubulo-interstitial, predominant vascular involvement and other disease categories. Total 347 native kidney biopsies were performed during the study period. Mean age of the patients at the time of biopsy was 41.41 ± 15.75 years. Majority of patients were males (58.5%). Most common indication for kidney biopsy was nephrotic syndrome (36.3%) followed by nephritic syndrome (19.9%). Among the glomerular diseases (GDs), 69% were primary glomerulopathies and 31% were secondary GDs. Immunoglobulin (IgA) nephropathy (30.85%) was the most common primary GD followed by membranous nephropathy (MN) (26.59%), focal segmental glomerulosclerosis (FSGS) (17.02 %) and minimal change disease (14.36 %). Among secondary glomerulopathies, lupus nephritis was the most common histopathological diagnosis (31.8%) followed by diabetic nephropathy (26.1%), amyloidosis (17%), infection related glomerulonephritis (11.3%), light chain deposition disease (4%) and anti-neutrophil cytoplasmic antibody associated vasculitis (3.4%). In tubulointerstitial disease, 33.3% had acute tubulointerstitial nephritis, whereas each 26.6% had acute tubular injury and cast nephropathy. The most prevalent diagnosis in our only study from central India was IgA nephropathy followed by MN and FSGS. Data analysis at regular intervals helps in understanding the changing trend of prevalence of native kidney disease and also gives understanding of geographical variations.

Acute kidney injury due to deposition disease

Acute kidney injury presenting without obvious cause is a diagnostic dilemma. One condition to be considered is monoclonal gammopathy. A case of light chain deposition disease was detected as a cause, involving kidney and extra renal site. It is a part of monoclonal immunoglobulin deposition disease, and may or may not be related to multiple myeloma. Delayed diagnosis can lead to end stage kidney disease, requiring long term dialysis, with its vascular access problems, preventing the treatment by autologous stem cell transplant. The case is presented with review of literature.

232 A multidisciplinary case of multiple myeloma with cardiac and renal involvement: a look beyond amyloidosis

Abstract Aims Multiple myeloma (MM) is a malignant neoplasm with a frequent cardiac involvement characterized by restrictive cardiomyopathy. Kidney and thromboembolic complications are also described. Methods and results A 52-year-old woman with a history of kidney disease was admitted to nephrology department due to worsening of renal function and refractory hypertension. A bone marrow biopsy revealed the diagnosis of MM. A renal and fat pad biopsy with Congo red staining was performed but amyloid deposition was not observed. Increased cardiac enzymes suggested a cardiac involvement. Indeed, two intracardiac right-sided masses and massive pulmonary embolism were detected. Surgical cardiac intervention was promptly performed and a chemotherapy regimen was started. Meantime, a kidney biopsy revealed a light-chain deposition disease. Conclusions This case highlights that multiple organ involvement in patients with MM may result from a combination of paraprotein-dependent and -independent factors. Moreover, in patients with not acute massive pulmonary embolism and intracardiac right masses, surgical pulmonary embolectomy should be promptly performed to preserve RV function and to avoid prevent pulmonary hypertension development.

The characteristics of patients with kidney light chain deposition disease concurrent with light chain amyloidosis

The type of monoclonal light chain nephropathy is thought to be largely a function of the structural and physiochemical properties of light chains; hence most affected patients have only one light chain kidney disease type. Here, we report the first series of kidney light chain deposition disease (LCDD) concomitant with light chain amyloidosis (LCDD+AL), with or without light chain cast nephropathy (LCCN). Our LCDD+AL cohort consisted of 37 patients (54% females, median age 70 years (range 40-86)). All cases showed Congo red-positive amyloid deposits staining for one light chain isotype on immunofluorescence (62% lambda), and LCDD with diffuse linear staining of glomerular and tubular basement membranes for one light chain isotype (97% same isotype as the amyloidogenic light chain) and ultrastructural non-fibrillar punctate deposits. Twelve of 37 cases (about 1/3 of patients) had concomitant LCCN of same light chain isotype. Proteomic analysis of amyloid and/or LCDD deposits in eight revealed a single light chain variable domain mutable subgroup in all cases (including three with separate microdissections of LCDD and amyloid light chain deposits). Clinical data on 21 patients showed proteinuria (100%), hematuria (75%), kidney insufficiency and nephrotic syndrome (55%). Extra-kidney involvement was present in 43% of the patients. Multiple myeloma occurred in 68% (about 2/3) of these patients; none had lymphoma. On follow up (median 16 months), 63% developed kidney failure and 56% died. The median kidney and patient survivals were 12 and 32 months, respectively. LCDD+AL mainly affected patients 60 years of age or older. Thus, LCDD+AL could be caused by two pathological light chains produced by subclones stemming from one immunoglobulin light chain lambda or kappa rearrangement, with a distinct mutated complementary determining region.

SPOT Protein/Creatinine Ratio As an Alternative for 24-Hour Urine Collection for Proteinuria in Patients with Multiple Myeloma

Background: Proteinuria is observed in >80% of patients with multiple myeloma (MM) and most often consists of free light chains (FLC) and albumin. The standard method of following patients with light-chain MM includes a 24-hour urine collection to determine the degree of monoclonal proteinuria as response criteria are in part based on this parameter. This is often cumbersome, especially in the elderly population and frequently raises concerns for accuracy. An untimed urine collection to provide a spot protein-to-creatinine (SPOT) ratio has been proposed as a reliable and quicker alternative, but its correlation with 24-hour urine protein collection in MM patients is not well established. Our group previously demonstrated a good correlation between the two methods in a small study of 15 patients. We now present the updated results with urine samples from 40 patients to evaluate the correlation between SPOT ratio and 24-hour collection in patients with MM.Methods: With the approval of the Institutional Review Boards, patients with MM were enrolled in the study after obtaining informed consent. The patients were provided with detailed instructions and supplies to collect a 24-hour urine collection and up to three additional urine samples at different time points during the day. For all the samples submitted, urine protein was measured by benzethonium chloride turbidimetry and creatinine by an IDMS-standardized enzymatic method on a Siemens ADVIA 1800 or the pyrocatechol violet method on the Ortho Vitros 5.1. A linear regression method using R version 3.2.2 was used to correlate values obtained by the two methods. A Bland-Altman plot was used to analyze the limits of agreement between the two methods of measuring proteinuria.Results: Sixty-four urine samples were obtained for SPOT ratio analysis from 40 patients between 2015-2020. Only complete 24-hour urine samples containing ≥ 0.7 g creatinine were included. The median age of participants was 68.5 [interquartile range (IQR) 59-73] years. Twenty-three (57.5%) of the patients were female. Thirteen patients had only light chain disease, while the remaining 27 patients had either IgG/IgA paired ƙ/ƛ myeloma. Thirty (75%) patients were on therapy at the time of sample collection. A linear regression model of the 24-hour urine protein versus the SPOT ratio was performed. The average 24-hour protein was 457.2 +/- 805.9 mg. The average SPOT ratio was 327.5 +/- 724.0 mg prot/gram Cr. The linear regression line was y = -7.1 + 0.7x where y is the 24-hour urine protein & x is the spot ratio value. The coefficient of the linear regression model was significant (p<0.001). The adjusted R2 value was 0.63 for the model.Conclusion: In patients with MM, there is a strong correlation between 24-hour urine protein & SPOT ratio, particularly for proteinuria under 1,000 mg. Given its accuracy and lack of inconvenience for the patients, SPOT ratio may be a suitable alternative to 24-hour urine protein collection. In patients with a high SPOT ratio, a 24-hour urine testing should be performed to confirm the results. Before 24-hour urine collection in myeloma can be completely abandoned, studies in larger patient cohorts are needed to differentiate between the monoclonal protein component and other proteins in urine. [Display omitted] DisclosuresJamshed: Takeda: Honoraria. Hillengass: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Beijing Medical Award Foundation: Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Axxess Network: 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; Beijing Life Oasis Public Service Center: Speakers Bureau; Curio Science: Speakers Bureau; Adaptive: Membership on an entity's Board of Directors or advisory committees; Skyline: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees.

Serological Response to the BNT162b2 mRNA or Chadox-Ncov-19 COVID-19 Vaccine after First and Second Doses in Plasma Cell Disorder Patients: Influence of Host and Disease Factors

BackgroundPlasma cell disorders (PCD) are at risk of inadequate immune responses to COVID-19 vaccines due to recognised humoral and cellular immune dysfunction which is multi-factorial and related to host and disease factors. With an estimated risk of 33% mortality from contracting COVID-19 in this population, protection with an anti-SARS-CoV-2 vaccination is critical. Initial extension to vaccination intervals in the United Kingdom to 12 weeks in December 2020 led to concerns that PCD patients would be left vulnerable for an extended period.MethodsA clinical audit was performed on measured serological responses in PCD patients after first and second doses of the BNT162b2 and ChAdOx-1 nCoV-19 vaccines. Antibody levels were measured using Elecsys Anti-SARS-CoV-2S assay (Roche) for quantitative detection of IgG Abs, specific for the SARS-CoV-2 spike-protein. Positive cut-off of 0.80 U/mL defined serological response. Testing was performed at (or closest to) 4 and 8-weeks post-dose. Baseline nucleocapsid Ab results were available from previous screening in a subset of patients. All patients on CIT underwent 4-weekly swabs. Clinical information was retrieved from medical records.Results188 PCD patients (155 multiple myeloma, 18 amyloid, 10 SMM/MGUS, other 5 PCD), median age 64 (range 32-84), had serological assessment after both vaccine doses. Fourteen with previous COVID-19 infection were excluded. Of 174 patients, 112 were tested after first dose. 88% (153) were on chemo-immunotherapy treatment (CIT). Seropositive rate after first dose was 63% (71/112); of those with available negative baseline antibody test, 62% (31/50) seroconverted. After second dose, 89% (154/174) were seropositive; of those with negative baseline antibody, 90% (61/68) seroconverted. Expectedly, paired median titres after second dose were significantly higher than post first dose (n=112, 3.245 U/mL (IQR 0.4-25.55) vs 518 U/mL (IQR 29.40-2187) p<0.0001) (Figure 1A). Of 41 patients seronegative after first dose, 25 (61%) seroconverted after second, though with lower titres than those only requiring one dose (Figure 1B). Active CIT, disease response less than PR, >=4 lines therapy, light-chain disease, male gender and not responding to first dose were significant factors for not responding to two vaccine doses. We explored <400 U/mL as sub-optimal response (in keeping with upcoming booster study eligibility, OCTAVE-DUO(1), also encompassing the lower quartile of reported healthy controls(2)), which included 43% (75/174) patients. Age 70 years, male gender, >=4 lines of treatment were independent predictors of less-than-optimal response (anti-CD38 CIT of borderline significance). Importantly, vaccine dosing intervals classified as =<42 vs >42 days (Figure 1C) or 28 +/- 14 days vs 84 +/- 14 days (excluding n=66 in neither) (Figure 1D) did not show difference in both definitions of response, neither did vaccine type. Fourteen with previous COVID-19 infection responded to one vaccine dose, median titres 2121 U/mL (IQR 23.48-2500)) rising to median 2500 U/mL (IQR 2500-2500) after second dose (Figure 1E), significantly higher than those without previous infection.ConclusionSerological response to COVID-19 vaccine is lower in PCD patients than reported healthy controls at 63% after first dose, rising to 89% after second dose, despite extended dosing intervals. PCD patients should be prioritised for shorter intervals, as we show that patients seronegative after first dose, respond after second dose. Further work in PCD is needed to understand how Ab levels correlate to neutralisation capability, cellular responses, protection from infection and how long seroconversion lasts to better define correlates of protection. A booster vaccination or prophylactic passive antibody strategy may be required for those identified at risk, shown not to have responded to two vaccine doses or to have less-than-optimal response. Results from these trials will be eagerly awaited.

Epidemiology and clinical manifestations of cardiac amyloidosis.

Cardiac amyloidosis, once considered a rare disease, has garnered significant attention over thelast few years due to three key reasons: first, increased recognition of this disease in conjunction with various common cardiac conditions such as heart failure with preserved ejection fraction and aortic stenosis; second, due to the advent of promising new therapies for light chain disease (AL), transthyretin (ATTR) cardiomyopathy, and amyloid neuropathy; finally, the advancements in cardiac imaging including echocardiography, magnetic resonance imaging, and nuclear cardiac scintigraphy aid in non-biopsy diagnosis of ATTR cardiac amyloidosis. The hereditary forms of ATTR have further come into importance with the availability of genetic testing and increased prevalence of certain mutations in African Americans. Recognition of non-cardiac clues to this disease has gained importance and reiterates that high clinical suspicion, detailed patient history, and examination with appropriate use of imaging are vital to confirm the diagnosis.

Multimodality imaging approach to cardiac amyloidosis: part 2.

With recent advances in cardiac imaging, genetics, and treatment options, cardiac amyloidosis (CA) is now recognized as an important and under diagnosed condition contributing to cardiovascular morbidity and mortality. Although still considered a rare disease, CA is now recognized as an important contributorto heart failure with preserved ejection fraction (HFPEF) andlow gradient aortic stenosis, twoimportant conditions commonly faced in clinicalpractice. This review uses clinicalscenarios to highlight the complementary role of traditionalimaging tools such as electrocardiogram (ECG) and echocardiography (echo) in conjunction withadvanced cardiac imaging with cardiac magnetic resonance (CMR) and nuclear cardiac scintigraphy using bone avid tracers in the comprehensive workup of CA. We also highlight the importance of workup of light chain disease as part of integration of imaging findings anddiscussthe key aspects of various imaging modalities. Finally, an algorithm integrating clinical suspicion, laboratory testing, and imagingin the workup of CA is presented.

Light chain deposition disease in kidney transplantation: a case report

Light chain deposition disease in kidney transplantation: a case report