Systemic amyloidosis from A (AA) to T (ATTR): a review.

Systemic amyloidosis is a rare protein misfolding and deposition disorder leading to progressive organ failure. There are over 15 types of systemic amyloidosis, each caused by a different precursor protein which promotes amyloid formation and tissue deposition. Amyloidosis can be acquired or hereditary and can affect various organs, including the heart, kidneys, liver, nerves, gastrointestinal tract, lungs, muscles, skin and soft tissues. Symptoms are usually insidious and nonspecific resulting in diagnostic delay. The field of amyloidosis has seen significant improvements over the past decade in diagnostic accuracy, prognosis prediction and management. The advent of mass spectrometry-based shotgun proteomics has revolutionized amyloid typing and has led to the discovery of new amyloid types. Accurate typing of the precursor protein is of paramount importance as the type dictates a specific management approach. In this article, we review each type of systemic amyloidosis to provide the practitioner with practical tools to improve diagnosis and management of these rare disorders.

Variable selection for monitoring sickness behavior in lactating dairy cattle with the application of control charts.

The present observational study investigated the application of multivariate cumulative sum (MCUSUM) control charts by including variables selected by principal component analysis and partial least squares (PLS) regression to identify sickness behavior in dairy cattle. Therefore, sensor information (24 variables) was collected from 480 milking cows on a German dairy farm between September 2018 and December 2019. These variables were gathered in potentially different scenarios on farm. In total, data from 749 animals were available for evaluation. Variables were chosen based on the information of 499 cows (62 healthy; 437 sick) with 93,598 observations. The available diagnoses were collected together to form 1,025 sickness events. Hence, the different numbers of selected variables were included into the MCUSUM control charts. The performance of the MCUSUM control charts was evaluated by a 10-fold cross validation; hence, 90% of the original data set (749 cows) represented the training data, and the remaining 10% was used to test the training results. On average, the 10 training data sets included 124,871 observations with 1,392 sickness events, and the 10 testing data sets included, on average, 13,704 observations with 153 sickness events. The MCUSUM generated from the variables selected by principal component analysis showed comparable results in training and testing in all scenarios; therefore, 70.0 to 97.4% of the sickness events were detected. The false-positive rates ranged from 8.5 to 29.6%, and thus they created at least 2.6 false-positive alerts per day in testing. The variables selected by the PLS regression approach showed comparable sickness detection rates (70.0-99.9%) as well as false-positive rates (8.2-62.8%) in most scenarios. The best performing scenario produced 2.5 false-positive alerts in testing. Summarizing, both approaches showed potential for practical implementation; however, the PLS variable selection approach showed fewer false positives. Therefore, the PLS regression approach could generate a more reliable sickness detection algorithm, if combined with MCUSUM control charts, and considered for practical implementation.

Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial.

BACKGROUND AND PURPOSE: Hereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO-TTR study in patients with hATTR polyneuropathy. Here, the long-term efficacy and safety of inotersen are assessed in an ongoing open-label extension (OLE) study. METHODS: Patients who completed NEURO-TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score and the Short-Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed. RESULTS: Overall, 97% (135/139) of patients who completed NEURO-TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO-TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL-DN and SF-36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure. CONCLUSION: Inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long-term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed.

Prevalence and predictors of thyroid functional abnormalities in newly diagnosed AL amyloidosis.

BACKGROUND: Data on the effect of systemic immunoglobulin light chain amyloidosis (AL amyloidosis) on thyroid function are limited. OBJECTIVE: To assess the prevalence of hypothyroidism in AL amyloidosis patients and determine its predictors. METHODS: 1142 newly diagnosed AL amyloidosis patients were grouped based on the thyroid-stimulating hormone (TSH) measurement at diagnosis: hypothyroid group (TSH above upper normal reference; >5 mIU L-1 ; n = 217, 19% of study participants) and euthyroid group (n = 925, 81%). Predictors for hypothyroidism were assessed in a binary multivariate model. Survival between groups was compared using the log-rank test and a multivariate analysis. RESULTS: Patients with hypothyroidism were older, more likely to present with renal and hepatic involvement and had a higher light chain burden compared to patients in the euthyroid group. Higher proteinuria in patients with renal involvement and lower albumin in patients with hepatic involvement were associated with hypothyroidism. In a binary logistic regression model, age ≥65 years, female sex, renal involvement, hepatic involvement, kappa light chain restriction and amiodarone use were independently associated with hypothyroidism. Ninety-three per cent of patients in the hypothyroid group with free thyroxine measurement had normal values, consistent with subclinical hypothyroidism. Patients in the hypothyroid group had a shorter survival compared to patients in the euthyroid group (4-year survival 36% vs 43%; P = 0.008), a difference that was maintained in a multivariate analysis. CONCLUSION: A significant proportion of patients with AL amyloidosis present with hypothyroidism, predominantly subclinical, which carries a survival disadvantage. Routine assessment of TSH in these patients is warranted.

Frequencies and geographic distributions of genetic mutations in transthyretin- and non-transthyretin-related familial amyloidosis.

Inherited forms of amyloidosis are rare; of these, transthyretin-related (ATTR) is the most common, but non-ATTR has been described as well. We studied a large case series of ATTR and a small series of non-ATTR to better determine the mutation frequencies and geographic distributions of these inherited forms of amyloidosis in the United States. We performed a retrospective cross-sectional study of 284 ATTR and non-ATTR patients seen at Mayo Clinic in Rochester, Minnesota, from 1 January 1970 through 29 January 2013. Mutations were identified by DNA sequencing, restriction fragment length polymorphism, or mass spectroscopy. The genetic testing method was unknown for several patients, but a small proportion were identified by family history or by classical clinical presentation associated with a specific mutation. The most common ATTR mutations were Thr60Ala (24%), Val30Met (15%), Val122Ile (10%), and Ser77Tyr (5%). Non-ATTR mutations included gelsolin (n = 3), apolipoprotein A-I (n = 6), apolipoprotein A-II (n = 1), fibrinogen A-α (n = 9), and lysozyme (n = 1). Although rare, ATTR and, to a lesser extent, non-ATTR are prevalent in the United States and should be considered for patients presenting in the appropriate clinical context.

Optimizing multiple Myeloma clinical trials: research direction, addressing limitations, and strategies for improvement.

Despite significant advancements in multiple myeloma (MM) treatment, including novel therapies and combination strategies, the translation of findings from randomized controlled trials (RCTs) into real-world clinical practice has been associated with several challenges. Specifically, the principles and criterion that shape the current design of MM RCTs have left out a sizable portion of patients that would particularly benefit from trial inclusion. In addition, RCTs may use primary outcomes which only partially cover patient-relevant endpoints important for evaluating treatment efficacy and quality of life. In this review, we explore the current MM RCT landscape and suggest possible solutions to improve generalizability of trial results, mitigate logistical pitfalls, and integrate real-world evidence into trials. Together, these strategies are designed to refine MM treatment guidelines and improve outcomes for all patient populations.

Estimating risk probabilities for sickness from behavioural patterns to identify health challenges in dairy cows with multivariate cumulative sum control charts.

Dairy cattle housing is characterised by increasing herd sizes and the need for assisting technical tools to monitor the cows' health. This study investigated the combination of logistic regression models with multivariate cumulative sum (MCUSUM) control charts in healthmonitoring of dairy cattle. Sensor information of 618 cows with 791 lactations (138 438 cow days), nine behavioural variables were included as parts of the behavioural patterns: physical activity ("neck activity", "leg activity", "walking duration"), resting ("lying duration", "standing duration", "transitions from lying to standing") and feeding ("feeding duration", "rumination duration", "inactivity duration") behaviour. For each of these behavioural patterns, a logistic regression model with the health status (sick vs not sick) as a dependent variable was designed after a variable selection (herd level) based on the herd dataset with 618 cows (618 lactations; 115 547 cow days), which included the variables of each behaviour pattern and the stage of lactation nested in the number of lactations as explanatory variables. The explanatory variables were added stepwise to the model, with the final model being selected with respect to the lowest values of Akaike's and Bayes' information criteria. Each model was then applied to a dataset with 173 cows (22 891 cow days) at cow level, resulting in individual daily risk probabilities for getting sick. Thus, risk probabilities of each behavioural pattern were estimated and included in the MCUSUM control charts to identify cows at risk of disease. The performance of the MCUSUM control charts was cross-validated to identify the best fitting reference value k and the threshold value h. Alerts given within 5 days prior to diagnosis were counted as detected sicknesses. The performance resulted in a block sensitivity of 70.9-81.4%, specificity of 87.9-94.2% and a false-positive rate of 5.8-12.1%. The performance was confirmed while testing the entire algorithm resulting in a mean area under the receiver operating characteristics curve of 0.89. Calculating precision and the F1-score resulted in a precision of 49.0-60.9% (training: 48.8-63.5%) and an F1-score of 61.1-65.7% in testing (training: 61.0-67.0%). The precision-recall curve (PRC) was derived from precision and recall with an area under the PRC of 0.70 in training and testing. In summary, the present study was able to develop an algorithm showing good classification potential for the online monitoring of sickness behaviour.

Effect of sample size and length of observation period on the reliability of apparent pig organ lesion prevalence.

Comprehensive identification of on-farm animal-health issues still requires extensive efforts so that in practice such monitoring is applied only sparsely. An appealing approach to improve on-farm animal health and welfare monitoring is the application of organ lesion scoring data from the abattoir as such is instantly available for every commercial farm in Europe. Unfortunately, it is also well-known that organ lesion scoring is often unreliable because results are altered by several non-health-related factors, diluting the validity of lesion scoring prevalence as a proxy for on-farm animal health. However, it is theoretically possible to improve prevalence reliability a-posteriori by application of time-series smoothing. The aim of this paper was therefore to analyse whether it is practically possible to increase apparent prevalence estimation reliability retrospectively using a running average, and, if so, which window length and smallest sample size should be preferred in such an approach. Because no gold standard for direct evaluation of lesion reliability is available for field-data, apparent prevalence reliability had to be approximated using prevalence agreement over time. Results indicate that by raising the number of lesion scores per prevalence estimate, apparent prevalence agreement over time can in general be considerably increased. Based on findings presented, a reasonable threshold for prevalence estimation is given by at least n = 50 lesions per farm/abattoir/time-series segment. Results further suggest that it is necessary to consider differences in prevalence sample size for future monitoring purposes, because prevalences that are estimated on a continuum of different sample sizes put together in one evaluation may induce substantial error in prevalence estimates.

"Real-life" data of the efficacy and safety of belantamab mafodotin in relapsed multiple myeloma-the Mayo Clinic experience.

Belantamab mafodotin is a highly selective targeted therapy for multiple myeloma. It targets the B cell maturation antigen (BCMA) on plasma cells and showed promising results in several randomized clinical trials. We report the outcomes of 36 patients treated at Mayo Clinic. Our cohort received a median of eight prior lines of therapy. Six patients received belantamab in combination with other medications (pomalidomide, cyclophosphamide, thalidomide), 13 patients (36%) were 70 years or older, two patients had a creatinine of >2.5 mg/dL, and one patient was on dialysis. All three patients with renal failure received full dose belantamab. Chimeric antigen receptor (CAR-T) therapy was used prior to belantamab in seven patients and none of them responded to belantamab therapy. The overall response rate (ORR) was 33% (CR 6%, VGPR 8%, PR 19%), like the ORR reported in the DREAMM-2 trial. Keratopathy developed in 16 patients (43%), grade 1 in six patients, grade 2 in seven patients, and grade 3 in three patients. Eight percent discontinued therapy due to keratopathy. The median PFS and OS was 2 months and 6.5 months, respectively.

Alterations in sick dairy cows' daily behavioural patterns.

The recent development of dairy production is characterised by increasing herd sizes and therefore increasingly complicated visual observation of cow behaviour, which is traditionally the basis for diagnoses of production diseases. The limitation of the direct visual behavioural observation due to the increasing number of individual cows implies a growing need for an automated detection of changes within behavioural patterns to identify cows that show sickness behaviour. Sensor systems can be used to measure behavioural patterns such as activity, resting, feeding and rumination. Behavioural patterns change with the occurrence of sickness but also interact with external factors. Changes such as prolonged lying duration or shortened feeding duration caused by metabolic disorders or infections, respectively, then serve as a detection tool for sick individuals. The aim of the present review is to outline the impact of production diseases on the daily behavioural patterns of dairy cows by referring to sickness behaviour.

Correction: Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond.

Following the publication of this article the authors noted that the MRD data under the Table 1 column "Remark" of Aspire should go to that of Pollux. The authors wish to apologize for any inconvenience caused. The corrected table is attached to this correction.

Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.

Cast nephropathy is the most common cause of renal disease in multiple myeloma, however, treatment with plasma exchange remains controversial even after 3 randomized controlled studies. We sought to determine the importance of diagnostic confirmation and goal directed therapy in the treatment of cast nephropathy in forty patients with confirmed multiple myeloma and renal failure who underwent plasma exchange. A positive renal response was defined as a decrease by half in the presenting serum creatinine and dialysis independence. No baseline differences were noted between eventual renal responders and non-responders. Three quarters of the patients with biopsy proven cast nephropathy resolved their renal disease when the free light chains present in the serum were reduced by half or more but there was no significant response when the reduction was less. The median time to a response was about 2 months. In patients without cast nephropathy, renal recovery occurred despite reductions in free light chain levels of the serum. No association was found between free light chains in the serum, urinary monoclonal proteins, overall proteinuria and cast nephropathy. We found that the relationship between renal recovery and free light chain reduction was present only in patients with biopsy proven cast nephropathy showing the importance of extracorporeal light chain removal in this disease.

Impact of pretransplant therapy in patients with newly diagnosed myeloma undergoing autologous SCT.

Autologous SCT (ASCT) remains an effective therapy for eligible patients with myeloma. Previous studies have suggested a lack of impact of the initial therapy on the outcome after ASCT. It is not clear if incorporation of new agents in the initial treatment regimens will have any impact on the outcome after ASCT. We studied 472 patients undergoing ASCT within 12 months of diagnosis to assess the effect of initial therapy on the outcome after ASCT. Patients received initial therapy with vincristine, adriamycin and dexamethasone (VAD), dexamethasone, thalidomide and dexamethasone or lenalidomide and dexamethasone. While patients treated with dexamethasone alone had higher disease burden at ASCT, no differences were observed in the response rates to ASCT, post transplant complications or treatment-related mortality among the groups. The median time to progression after ASCT was 27.1, 24.7, 21.1 months and did not reach the VAD, Dex, Thal-Dex and Len-Dex group, respectively, P=0.11. The median overall survival from ASCT was 62 months for VAD, 69.6 months for Dex and were not reached for Thal-Dex and Len-Dex groups, P=0.2. For patients undergoing early ASCT for myeloma, the nature of initial treatment utilized has no long-term impact on the outcome of ASCT.

Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma.

While initial therapies have become highly effective with introduction of lenalidomide and bortezomib and patients may opt for delayed stem cell transplantation, it is important to collect stem cells for future transplant. Given its increasing use as initial therapy, we examined if lenalidomide had any impact on the ability to collect peripheral blood stem cells (PBSC). We studied the entire cohort of patients with myeloma undergoing PBSC mobilization at our institution during a 5-year period, comparing the results between patients receiving different initial therapies. Among those mobilized with granulocyte-colony stimulating factor (G-CSF) alone, there was a significant decrease in total CD34(+) cells collected (P<0.001), average daily collection (P<0.001), day 1 collection (P<0.001) and increased number of aphereses (P=0.004) in patients treated with lenalidomide compared to those receiving dexamethasone, thalidomide-dexamethasone or VAD. A similar trend was seen in those mobilized with chemotherapy and G-CSF. A trend was seen towards decreased PBSC yield with increasing duration of lenalidomide therapy as well as increasing age (P=0.002). There was no effect on quality of PBSC collected based on similar engraftment across all groups. We recommend collection of PBSC within 6 months of initiation of therapy with lenalidomide containing regimens to minimize the risk of mobilization failures.

A practical guide to defining high-risk myeloma for clinical trials, patient counseling and choice of therapy.

Clinical outcomes for multiple myeloma (MM) are highly heterogeneous and it is now clear that pivotal genetic events are the primary harbingers of such variation. These findings have broad implications for counseling, choice of therapy and the design and interpretation of clinical investigation. Indeed, as in acute leukemias and non-hodgkins lymphoma, we believe it is no longer acceptable to consider MM a single disease entity. As such, the accurate diagnosis of MM subtypes and the adoption of common criteria for the identification and stratification of MM patients has become critical. Herein, we provide a consensus high-risk definition and offer practical guidelines for the adoption of routine diagnostic testing. Although acknowledging that more refined classifications will continue to be developed, we propose that the definition of high-risk disease (any of the t(4;14), t(14;16), t(14;20), deletion 17q13, aneuploidy or deletion chromosome 13 by metaphase cytogenetics, or plasma cell labeling index >3.0) be adopted. This classification will identify most of the 25% of MM patients for whom current therapies are inadequate and for whom investigational regimens should be vigorously pursued. Conversely, the 75% of patients remaining have more favorable outcomes using existing - albeit non-curative - therapeutic options.

Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond.

Despite enormous advances, management of multiple myeloma (MM) remains challenging. Multiple factors impact the decision to treat or which regimen to use at MM relapse/progression. Recent major randomized controlled trials (RCTs) showed widely varying progression-free survivals (PFS), ranging from a median of 4 months (MM-003) to 23.6 months (ASPIRE). Based on these RCTs, next-generation proteasome inhibitors (carfilzomib and ixazomib), next-generation immunomodulatory agent (pomalidomide), and monoclonal antibodies (elotuzumab and daratumumab) were approved for relapsed and refractory MM. Daratumumab, targeting CD38, has multiple mechanisms of action including modulation of the immunosuppressive bone marrow micro-environment. In addition to the remarkable single agent activity in refractory MM, daratumumab produced deep responses and superior PFS in MM when combined with lenalidomide/dexamethasone, or bortezomib/dexamethasone. Other anti-CD38 antibodies, such as isatuximab and MOR202, are undergoing assessment. Elotuzumab, targeting SLAMF7, yielded superior response rates and PFS when combined with lenalidomide/dexamethasone. New combinations of these next generation novel agents and/or antibodies are undergoing clinical trials. Venetoclax, an oral BH3 mimetic inhibiting BCL2, showed single agent activity in MM with t(11;14), and is being studied in combination with bortezomib/dexamethasone. Selinexor, an Exportin-1 inhibitor, yielded promising results in quad- or penta-refractory MM including patients resistant to daratumumab. Pembrolizumab, an anti-PD1 check-point inhibitor, is being tested in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone. Chimeric antigen receptor-T cells targeting B-cell maturation antigen have yielded deep responses in RRMM. Finally, salvage autologous stem cell transplantation (ASCT) remains an important treatment in MM relapsing/progressing after a first ASCT. Herein, the clinical trial data of these agents are summarized, cautious interpretation of RCTs highlighted, and algorithm for salvage treatment of relapse/refractory MM proposed.

Elevated pre-transplant C-reactive protein identifies a high-risk subgroup in multiple myeloma patients undergoing delayed autologous stem cell transplantation.

The significance of elevated C-reactive protein (CRP) prior to autologous stem cell transplantation (ASCT) in multiple myeloma (MM) has not been studied. We analyzed 1111 MM patients who underwent ASCT at Mayo Clinic from 2007 to 2015. A total of 840 patients (76%) received early ASCT (⩽12 months from diagnosis) and 271 patients (24%) received delayed ASCT (>12 months from diagnosis). Elevated CRP (> upper normal limit (8 mg/L)) was seen in 14% and 22% of patients undergoing early and delayed ASCT, respectively (P=0.003). There was no correlation of CRP with pre-transplant response, bone marrow plasma cell percentage or labeling index. Patients with an elevated CRP had a higher likelihood of having circulating plasma cells prior to ASCT (33 vs 19%; P<0.001). In the early ASCT cohort, the median overall survival (OS) in patients with normal and elevated CRP was not reached and 91 months respectively (P=0.011). In the delayed ASCT cohort, the median OS in respective groups were 73 and 30 months respectively (P<0.001), with elevated CRP being an independent prognostic marker on multivariate analysis (hazard ratio 2.0; 95% confidence interval, 1.0-3.8; P=0.045). Elevated pre-transplant CRP identifies a high-risk population especially in patients undergoing delayed ASCT and should be incorporated in the pre-transplant evaluation.

Outcomes of maintenance therapy with lenalidomide or bortezomib in multiple myeloma in the setting of early autologous stem cell transplantation.

Post-transplant maintenance is widely used in multiple myeloma (MM); however, there is a lack of data on real-world outcomes. We have analyzed 577 patients with newly diagnosed MM undergoing early auto-transplantation between 2010 and 2015. A total of 341, 132 and 104 patients received no, lenalidomide (Len) or bortezomib (Bort) maintenance, respectively. Patients receiving Len or Bort maintenance had a higher incidence of high-risk cytogenetics by fluorescence in situ hybridization (31% (Len) vs 58% (Bort) vs 8% (No); P<0.001). Len maintenance led to a superior progression-free survival (PFS) compared with no maintenance (median, 37 vs 28 months, respectively; P=0.002; adjusted hazard ratio 0.48 (95% CI, 0.35-0.66)), including in subgroups with ISS stage III disease (median, 40 vs 24 months; P=0.008) and high-risk cytogenetics (median, 27 vs 16 months; P=0.032). Bort maintenance did not confer PFS benefit for the entire cohort, but improved PFS in the high-risk cytogenetic subgroup (median, 28 vs 16 months; P=0.035). Discontinuation due to toxicity was seen in 17 and 7% of patients receiving Len or Bort maintenance, respectively. Our results indicate that post-transplant maintenance with Len or Bort is well tolerated in clinical practice and improves PFS in high-risk subgroups of MM patients.