Cook, Joselle

Introduction: Light-chain (AL) amyloidosis is caused by the secretion of immunoglobulin light chains by monoclonal plasma cells. The increase in the levels of these monoclonal proteins may proceed the development of any clinical symptoms, and their identification in the serum and urine remains an integral part of establishing a diagnosis of AL amyloidosis. This systematic review aims to evaluate the diagnostic test accuracy of serum immunofixation (SIFE), urine immunofixation (UIFE), and free light chain (FLC) ratio for the diagnosis of AL amyloidosis. Methods: As part of the ASH AL Amyloidosis Diagnostic Guideline, we performed systematic reviews for 7 prioritized PICO questions related to the screening, diagnosis and organ involvement evaluation of AL amyloidosis. Electronic searches were conducted on PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception till January 2024. Two reviewers independently and in duplicate performed title and abstract screening and full text article screening on LASER AI, with conflicts resolved by a third reviewer. Eligible studies were those that included patients who performed one of the three tests (SIFE, UIFE, and κ/λ FLC) and had their AL amyloidosis diagnosis confirmed via a biopsy. Diagnostic test accuracy measures of interest were sensitivity, specificity, positive and negative predictive value. Statistical analysis was performed on OpenMeta[Analyst]. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of evidence. Results: After deduplication, we retrieved 29,237 studies from electronic databases. 31 studies with 3973 patients reported on the use of serum immunofixation (SIFE) with a pooled sensitivity of 72.4% (95% CI 68.1%-76.4%). 27 studies with 2855 patients reported on the use of urine immunofixation UIFE for the diagnosis of AL amyloidosis with a pooled sensitivity of 78.6% (95% CI 74.6%-82%). 29 studies with 5305 patients reported on the use of κ/λ FLC ratio amyloidosis with a pooled sensitivity of 79.9% (95% CI 73.7%-84.9%). 24 studies reported on the use of both SIFE and UIFE with a sample size of 3751 patients and a pooled sensitivity of 90% (95% CI 85.3%-93.3%). 3 studies reported on the use SIFE and κ/λ FLC ratio with 321 patients and a pooled sensitivity of 97.7% (95% CI 95.6%-99.9%). Finally, we identified 10 studies that performed SIFE,UIFE, and κ/λ FLC ratio concurrently with 1926 patients and a pooled sensitivity of 99% (95% CI 97%-99.7%) of all three tests and considering a result abnormal if any of the components had a positive result. We also identified 5 studies with 957 patients reporting on the concurrent use of SIFE, UIFE, and κ/λ FLC ratio for the diagnosis AL amyloidosis and differentiation of AL from ATTR amyloidosis in a population of patients with suspected cardiac amyloid involvement, the pooled sensitivity was found to be 99%(95% CI 99%-100%) and with a pooled specificity of 77%(95% CI 75%-80%). Certainty of evidence moderate for all outcomes. Conclusion: The combined use of SIFE, UIFE, and κ/λ FLC ratio has a high sensitivity for the diagnosis of AL amyloidosis, and the tests remain a valuable initial screening of AL amyloidosis and differentiation from ATTR amyloidosis.

Introduction: In patients with systemic light-chain amyloidosis, cardiac involvement is common. Cardiac involvement (presence and severity) is the most important predictor of mortality in patients with AL amyloidosis. Endomyocardial biopsy remains the gold standard, but it is a costly and invasive test. Consequently, cardiac biomarkers are used for screening for cardiac involvement and have significant prognostic value.In this systematic review, we aim to estimate the diagnostic test accuracy (DTA) of Nt-proBNP, BNP, and high sensitivity troponin for cardiac amyloidosis. Methods: As part of the American Society of Hematology guidelines on the diagnosis of Amyloidosis, we searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception till January 2024 for relevant studies. Two reviewers independently performed title and abstract screening and full-text article screening on LASER Al and extracted relevant data using piloted Excel sheets. The panel judged whether the reference test is acceptable or not. Acceptable reference test is EMB alone or a combination of extracardiac biopsy plus cardiac imaging (CMR or echocardiography) with or without positive cardiac biomarkers (troponin or BNP or NT-proBNP). For statistical analysis, we only included studies reporting on both the sensitivity and specificity of the cardiac biomarker. We used Stata 18.0 software for meta-analysis. We evaluated risk of bias using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of the evidence. We report diagnostic test accuracy as sensitivity (95% confidence interval) and specificity (95% confidence interval). Results: After screening 29,237 studies, a total of 10 studies addressed DTA of Nt-proBNP for cardiac amyloidosis. These studies used a wide variety of cutoffs for diagnosis of cardiac involvement, ranging from 150 to 5000 ng/L and a cutoff of 332 ng/L was the most studied and reported. The pooled estimates for sensitivity and specificity of Nt-proBNP using 332 as cutoffs are 0.99 ( 0.97, 1) and 0.53 (0.3, 0.75), respectively. The pooled estimates were based on 4 studies (n=645) with moderate certainty in the evidence. For BNP, DTA was assessed in 3 studies (n= 257). Each study used a different cutoff for BNP (73, 100, and 412 ng/L). The sensitivity and specificity of BNP in each study were comparable and not significantly affected by the cutoff variation. Pooled sensitivity and specificity across studies, were 0.87 (0.80, 0.92), and 0.79 (0.71, 0.85), respectively. The certainty in evidence for the DTA of BNP was low. Eight studies reported on DTA of high sensitivity troponin, with cutoffs ranging from 14 to 86 ng/L. Meta-analysis of studies reporting on cutoff 14 ng/L yielded sensitivity of 0.94 (0.87, 0.97) and specificity of 0.11 (0.08, 0.16) with moderate certainty evidence. Increasing the cutoff to 35 ng/l led to a decrease in sensitivity to 0.82 (0.66, 0.92) and an increase in specificity to 0.86 (0.74, 0.93) with low certainty evidence. Conclusion: Cardiac biomarkers are highly sensitive, valuable initial tests for increasing suspicion of cardiac involvement in patients with AL amyloidosis. However, they lack specificity and, on their own, are insufficient for a definitive diagnosis of cardiac involvement. These biomarkers may be used in conjunction with other diagnostic tests to accurately identify and assess the extent of cardiac involvement.

Background: A deeper understanding of the cytogenetic features has enabled robust risk stratification for patients with newly diagnosed multiple myeloma (NDMM). However, heterogeneity persists in the currently available prognostic tools and there is further room for personalization. We assess the utility of PC-PRO, a test to measure the proportion of monotypic plasma cells in the synthetic phase (S-phase) of cell cycle, as a prognostic marker for NDMM. Methods: Patients with active MM diagnosed between January 2013 and January 2023 with a flow cytometry-based S-phase assessment at diagnosis were included. Flow cytometric immunophenotyping was performed using the following antibodies: CD19, CD38, CD45, CD138, cytoplasmic kappa and lambda immunoglobulin, and DAPI (4',6-diamidino-2-phenylindole). The percentage of plasma cells in S-phase was determined by measuring the proportion of cells with DNA content of the monotypic plasma cells between the G0/G1 and G2/M peaks. Plasma cell clonality was detected through demonstrating CD38 and CD138 positivity along with immunoglobulin light chain restriction, abnormality of CD19/ CD45 expression and/or ploidy difference by DAPI staining. High-risk cytogenetic abnormalities (HRCA) by FISH were defined as follows: presence of deletion 17p (del17p), t(4;14), t(14;16), t(14;20), 1q gain/amplification, 1p deletion (when available). Additionally, the second iteration of the revised ISS (R2-ISS), incorporating both laboratory and cytogenetic features as well an adaptation of the recently proposed International Myeloma Working Group (IMWG) Classification for high-risk disease, was utilized for risk stratification. All time-to-event analyses were performed using the Kaplan Meier method and compared using the log-rank test. Univariable and multivariable Cox proportional hazards analyses were performed to assess the independent prognostic impact of S-phase. Results: A total of 823 patients were included in the study. The median follow-up was 6 years [95% Confidence interval (CI): 5.5-6.3 years] and estimated median overall survival (OS) was 8.3 years. The median S-phase value for the cohort was 0.8 % (interquartile range: 0.5-1.4%), with 135 (16%) patients harboring an S-phase of ≥2% at diagnosis. Applying the R2-ISS prognostic model to our cohort, 11% (79/706) patients were stratified to the R2-ISS high-risk cohort; 93 patients (out of 788, 12%) had 2 or more HRCA at diagnosis. Patients with a S-phase ≥2% at diagnosis had a median OS of 3.9 years (95% CI: 2.9-5.7) vs. 9.2 years [95% CI: 7.9-not reached (NR)] for patients with a S-phase <2% [Hazard ratio (HR): 2.2 (95% CI: 1.7-2.8), p<0.0001]. The median OS was inferior for cohorts with an increasing S-phase value: S-phase of 0.1-1%: HR: 1 (standard), S-phase 1.1-3%: HR 1.7 (95% CI: 1.3-2.1), S-phase >3%: HR 3.0 (95% CI: 2.2-4.1)]. On a multivariable analysis including S-phase ≥2%, age at diagnosis of MM (>65 years) and R2-ISS high-risk status, S-phase ≥2% was an independent predictor of inferior OS [hazard ratio (HR) 1.9 (95% CI: 1.4-2.6), p<0.0001]. Age >65 years [HR 1.9 (95% CI: 1.5-2.5), p<0.0001] and R2-ISS high-risk status [HR 1.8 (1.3-2.6), p=0.001] were also independent predictors of OS. Within the sub cohort of patients with 2 or more of the listed high-risk cytogenetic features (n=93, 12%), a S-phase ≥2% (n=24) was associated with a worse median OS of 1.6 years (95% CI: 0.7-NR) vs. 6.2 years (95 % CI:3.3-NR) for S-phase <2% (p=0.002). Conclusion: Flow cytometry-based determination of the proportion of monotypic plasma cells in S-phase is an easy-to-study and powerful prognostic tool for NDMM. A S-phase of ≥2% at diagnosis is a predictor of OS independent of age and R2-ISS high-risk stage. An S-phase of ≥2% was able to identify a distinct group with markedly inferior outcomes even within the sub cohort of patients with 2 or more high-risk cytogenetic features.

Background: Despite effective front-line therapies, DLBCL & MM have high relapse rates. Novel therapies like CAR-T & bispecific antibodies (BsAb) offer deep & durable remission compared to salvage therapies, but have a unique toxicity profile (TP) that requires monitoring. With no head-to-head trials, the rationale for therapy selection may vary. This study explores provider choices, sequencing preferences, & access barriers. Methods: Two anonymous surveys (MM and DLBCL) of US-based Hematologists were conducted from 2/2024 to 6/2024, on practice settings, CAR-T & BsAb availability, treatment preferences & barriers. Responses were analyzed to assess preferences across clinical scenarios. Results: Surveys were completed by 37 MM & 45 DLBCL providers. Most were at centers offering both CAR-T & BsAb. Most gave CAR-T inpatient, & BsAb outpatient. CAR-T was given by 73% MM providers & 66% DLBCL (92% used Cilta-cel, 96% used Ide-cel; 100% used Axi-cel, 90% used Liso-cel & 73% Tisa-cel). In MM, 78% used Teclistamab, 60% Talquetamab & 24% Elranatamab. In DLBCL, 62% used Epcoritamab & 40% Glofitamab. Providers preferred CAR-T over BsAb in MM after 4+ prior lines of therapy (LOT) (89%), & in DLBCL after 2+ prior LOT (93%). CAR-T was favored more among academic providers & those at CAR-T centers. Practice volume did not impact selection. Among providers at centers with BsAb-only, CAR-T was preferred by 60% (MM) and 50% (DLBCL). Providers at centers without both favored CAR-T (MM: 75%, DLBCL: 86%). CAR-T was chosen for better outcomes, short treatment, center choice, & prior experience. Other factors that influenced decisions were lower incidence of cytopenia/infection & “BsAb effective post-CAR-T, less so vice versa” (MM), & “curative potential of CAR-T” (DLBCL). Logistical barriers & institutional constraints influenced BsAb selection: CAR-T unavailability, access to specialized centers, referral complexity, insurance delay, manufacturing delay & hospitalization needs. In MM, 78% providers preferred Cilta-cel over Ide-cel, especially academic providers & those with CAR-T experience. CAR-T volume did not impact selection. Cilta-cel was preferred due to perceived better response rate (RR), more experience, “progression-free survival (PFS) benefit”, center choice, & logistical issues with Ide-cel. Ide-cel was selected due to center choice, favorable TP & insurance preference. Teclistamab was preferred by 78% due to more experience, better RR, TP & center choice, Elranatamab by 11% (better TP, RR, & “PFS”), & Talquetamab by 11% due to having a non-BCMA target. Academic providers preferred Teclistamab (89% vs 50%), & nonacademic providers preferred Talquetamab (38% vs 4%) and Elranatamab (13% vs 8%). In DLBCL after 2+ LOT, 69% favored Axi-cel due to prior experience, RR, center choice, & logistical issues with other products. Liso-cel & Tisa-cel were chosen by 27% & 2%, respectively, due to favorable TP. Axi-cel was also preferred 2nd line by 73% for similar reasons, while 24% favored Liso-cel for its favorable TP. Epcoritamab was preferred by 56% (subcutaneous injection, more experience & center choice) & Glofitamab by 42% (shorter treatment duration, easy administration, more experience, & center choice). Practice setting & volume did not impact selection between products in DLBCL. InBCMA-naïve MM pts, majority (97%) chose an anti-BCMA agent over GPRC5D due to better RR, TP, prior experience, & center choice. InBCMA-exposed pts, most (92%) favored an anti-GPRC5D agent. In contrast in DLBCL, 80% chose CD19 CAR-T after prior CD19-directed therapy, & 18% chose CD20 BsAb. Therefore, antigen escape was less of a concern in DLBCL vs MM. For relapse after 2nd line CAR-T in DLBCL, 78% preferred BsAb over other salvage options due to better RR, TP, & more experience. Providers prioritized RR, survival, & TP in decision making. Treatment logistics, duration, frequency, & cost were less crucial. MM providers also prioritized quality of life, which was less so in DLBCL. There were no differences in priority based on practice setting & experience with CAR-T. Conclusion: The study highlights factors influencing therapy choices in MM & DLBCL. Despite CAR-T's potential for better outcomes, significant access barriers exist. Efforts to streamline referral pathways, logistics, & expanding availability are crucial to improve outcomes. Understanding these preferences & barriers can guide future management strategies.