Dispenzieri, Angela

Abstract Frailty predicts adverse outcomes in multiple myeloma (MM), yet an objective frailty biomarker is lacking. Circulating senescence-associated secretory phenotype (SASP) factors correlate with frailty and adverse outcomes in chronic diseases, but their relevance in MM is unclear. In this study, we investigated the relationship between 36 plasma SASP factors, frailty, and clinical outcomes in: (1) a historical cohort using stored specimens from 59 patients with newly diagnosed MM, and (2) a prospective cohort of 36 patients initiating new MM treatment. Several SASP factors were significantly associated with frailty after adjusting for age, sex, and body mass index; GDF-15, TNF-RI, IL-6, and IL-8 showed positive correlations with both cumulative-deficit based and physical frailty indices. Additionally, significant age-adjusted associations were observed between SASP factors and treatment outcomes, including overall survival (OS), high-grade toxicity, and healthcare utilization. We developed a 5-factor SASP model that demonstrated superior predictive performance for OS compared to chronological age, R-ISS stage, and clinical frailty, and TNF-RI alone (5-year OS AUC: 0.90). These findings highlight the association between senescence biomarkers and frailty and OS, and support further investigation of SASP factors as objective frailty biomarkers in MM.

ABSTRACT Systemic AL amyloidosis is a clonal plasma cell dyscrasia, where toxic free light chains (FLCs) lead to vital organ damage, with risk of early mortality despite effective therapies. Notably, there is a paucity of data on the incidence and predictors of early mortality in the daratumumab (Dara) era. We conducted a multi‐center retrospective cohort study to develop and validate a risk‐prediction model for early mortality (all‐cause death within 6 months) in patients treated with Dara‐based frontline regimens. We used univariate analysis to identify covariates for a logistic regression model predictive of 6‐month mortality and generated a clinical risk score. Among 339 patients across eight centers, 36 (10.6%) experienced early mortality. Multivariate analysis identified four independent predictors: NT‐proBN P > 5300 pg/mL (odds ratio [OR] 3.83, p = 0.006), A ge > 75 years (OR 2.96, p = 0.073), absence of t(11;14) on C ytogenetics (OR 3.0, p = 0.022), and E COG performance status (OR 1.72 per unit increase, p = 0.044). The resulting PACE score stratified patients into three risk groups with a 6‐month mortality of 1.2% (low‐risk), 11.7% (intermediate‐risk), and 50.0% (high‐risk). The PACE score demonstrated superior discrimination (C‐index 0.78) for early mortality compared to Mayo 2004 (0.69) and Mayo 2012 (0.55) staging systems. External validation confirmed robust discrimination (C‐index 0.73) with corresponding 6‐month mortality rates of 4.2%, 15.25%, and 37.04% across respective risk groups. The PACE score provides a clinically applicable tool for early mortality risk stratification in AL amyloidosis patients receiving Dara‐based therapy, and will enable improved patient counseling, clinical trial design, and identification of ultra‐high‐risk patients requiring intensive monitoring and novel therapies.

Abstract Background Tafamidis (meglumine 80 mg/free acid 61 mg) is approved to treat transthyretin amyloid cardiomyopathy (ATTR-CM). In the pivotal phase 3 study ATTR-ACT, tafamidis significantly reduced all-cause mortality (ACM) and cardiovascular-related hospitalisations in patients with ATTR-CM (1). Real-world data further extend and support the benefit of long-term tafamidis for improving survival in contemporary patients with ATTR-CM (2). Purpose To further compare survival in a contemporary, real-world, pooled, matched cohort of patients with ATTR-CM treated vs not treated with tafamidis, adjusted for potential prognosticators of treatment effect. Methods Data were pooled from 2 studies. One study included a contemporary cohort of patients with ATTR-CM who received early access to tafamidis in the ATTR-ACT long-term extension (LTE) study but did not participate in the parent study. The other study included a contemporary cohort of patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS; NCT00628745) with predominantly cardiac or mixed phenotype ATTR-CM enrolled between 2019–2023 who received tafamidis throughout the study or never received tafamidis. THAOS was a longitudinal, observational, phase 4 study of patients with transthyretin amyloidosis and asymptomatic gene carriers. Treated patients were pooled from the 2 studies; all received the approved dose of tafamidis. Untreated patients were from THAOS. A propensity score matching procedure was used to match treated and not treated patients 1:1 on 3 significant variables identified from a multivariate logistic regression analysis: baseline age, New York Heart Association (NYHA) class and phenotype (cardiac, mixed); other variables considered were sex, estimated glomerular filtration rate (eGFR), follow-up time and modified body mass index (mBMI). Results In all, 566 patients (283 treated, 283 not treated) were included; 85 treated patients were from the LTE study and 198 were from THAOS. In treated and not treated patients, respectively, median age at enrolment was 78.0 and 78.7 years, and 89.0% and 83.4% were male (Table). The estimated adjusted survival probabilities for ACM for treated vs not treated patients were 78.0% vs 67.9% at 30 months and 70.2% vs 57.9% at 42 months (Figure). The hazard ratio (HR) for time to event for ACM was 0.62 (95% CI 0.41–0.92), favouring tafamidis. Conclusions This matched-cohort analysis showed better survival in a contemporary, real-world cohort of patients with ATTR-CM receiving the approved dose of tafamidis vs those not treated. These findings further extend results of ATTR-ACT to contemporary populations of patients with ATTR-CM treated clinically with tafamidis. These data show greater effectiveness of tafamidis for ATTR-CM in clinical practice than observed in earlier clinical trials, which may reflect earlier diagnosis and treatment in contemporary patients.

Abstract Background 99mTc-labelled cardiac scintigraphy enables noninvasive diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). Guidelines recommend using planar semiquantitative (heart to contralateral ratio, H/CL) and single photon emission computed tomography (SPECT) qualitative visual grading for diagnostic interpretation. However, planar imaging has inherent limitations, and visual grading is prone to interobserver variability, underscoring the need for standardized quantitative assessment. We developed a 3D volumetric quantitative score (3D Score) and assessed its diagnostic performance compared to myocardial tissue, the gold standard for ATTR-CM diagnosis. Methods At a single, tertiary referral center, we retrospectively identified consecutive patients from 06/2017 to 06/2024 who underwent 3-hour 99mTc-pyrophosphate or 99mTc-hydroxymethylene diphosphonate planar and SPECT/CT for suspected ATTR-CM and had archived myocardial tissue (biopsy or myectomy). On planar imaging, H/CL was calculated. On SPECT/CT, volumes of interest were drawn around the entire left ventricle (LV), avoiding calcifications, and within the right atrium (RA) blood pool. Mean uptake values were used to calculate the 3D Score (LVmean:RAmean), Fig 1A. Myocardial tissue was stained via sulfated Alcian blue and/or Congo red histochemistry. Once histologically confirmed, amyloid deposits were subtyped by liquid chromatography tandem mass spectrometry. The diagnostic performance of H/CL and 3D Score was assessed using receiver operating characteristic (ROC) curve analysis and predictive characteristics were defined. ROC areas under the curve (AUC) were compared using Delong test. Optimal cutoffs were determined using Youden’s J statistic. Baseline characteristics (demographics, echocardiogram, biomarkers) and H/CL were compared between patients above and below 3D Score cutoff. Results 239 patients were identified (median age 72 [65-78], 78% male, 46% ATTR positive). Median time between cardiac scintigraphy and myocardial tissue collection was 22 (6-65) days. Distribution of the 3D Score stratified by ATTR-CM status is illustrated in Fig 1B-C. The discriminative ability of the 3D Score was excellent (AUC 0.92) and superior to H/CL (0.87, p =0.006, Fig 1D-E). The optimal 3D Score cutoff for identifying ATTR-CM was ≥1.0 with sensitivity of 86%, specificity of 92%, positive predictive value (PPV) 90%, and negative predictive value (NPV) 89%. The optimal H/CL ratio cutoff for identifying ATTR-CM was ≥1.4 with sensitivity of 72%, specificity of 86%, PPV 81%, NPV 78%. Baseline characteristics of the overall cohort stratified by 3D Score are displayed in Table 1. Conclusions The 3D Score demonstrated excellent diagnostic performance for detecting ATTR-CM and was superior to current quantitative metrics. Future studies are needed to externally validate its performance across diverse patient cohorts and imaging centers and to investigate correlation with myocardial amyloid burden. Figure 1

Background Light chain (AL) amyloidosis is a rare disease caused by the misfolding of immunoglobulin light chains produced by a plasma cell dyscrasia. Patients can present with involvement of many organs, including the heart, kidneys, liver, nerves, and other sites, resulting in a high symptom burden. Timely and accurate diagnosis is important to prevent organ failure and improve patient survival. Objective These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients and clinicians in the timely and effective diagnosis of AL amyloidosis. Methods ASH formed a multidisciplinary guideline panel that included 22 individuals representing various medical specialties (academic and community hematology, nephrology, neurology, cardiology, internal medicine, and pathology) as well as 1 patient representative. The group was balanced to minimize potential bias from conflicts of interest. The University of Kansas Medical Center supported the guideline development process, including updating or performing systematic evidence reviews (up to 6 March 2023). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results The panel agreed on 12 recommendations. Conclusions The use of serum immunofixation, urine immunofixation, and serum free light chains enhances the clinical suspicion of AL amyloidosis. The diagnosis of AL amyloidosis can be made effectively through surrogate biopsies, which require both a bone marrow biopsy and fat-pad sampling; however, target organ biopsies may be favored in certain clinical situations.

Abstract Measurable residual disease (MRD) assessment has become central to risk-adapted treatment strategies in multiple myeloma, yet the prognostic value of MRD negativity following autologous stem cell transplantation (ASCT) across individual high-risk cytogenetic abnormalities (HRCAs) remains unclear. We analyzed 351 newly diagnosed patients who achieved MRD negativity (sensitivity 2.4×10 − 6 ) at Day 100 following ASCT and had baseline cytogenetic data available. Median follow-up was 50.4 months. Standard-risk cytogenetics were present in 46% (n = 162), while 34% (n = 118) had one HRCA and 20% (n = 71) had ≥ 2 HRCAs. Despite uniform MRD negativity, several HRCAs continued to confer inferior progression-free survival (PFS). Compared with the standard-risk group (4-year PFS 84%), patients with del(17p), 1q21+, t(4;14), or MAF translocations [t(14;16)/t(14;20)] had significantly lower 4-year PFS rates: 56% (HR 2.89; p = 0.0001), 60% (HR 2.46; p = 0.0001), 43% (HR 3.50; p = 0.0001), and 58% (HR 2.51; p = 0.01), respectively. Isolated del(17p) and 1q21 + also conferred inferior PFS. The 4-year PFS was 65% for patients with one HRCA (HR 2.31; p = 0.0004) and 55% for those with ≥ 2 HRCAs (HR 2.75; p = 0.0001). In this large MRD-negative post-ASCT cohort, several HRCAs, including isolated HRCAs, remained clinically meaningful drivers of inferior PFS, highlighting that early MRD negativity does not uniformly mitigate the impact of high-risk biology.

Abstract Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 and CXCR4 mutations, whose prognostic value in patients treated with chemoimmunotherapy remains unclear. Moreover, the typically prolonged progression-free survival (PFS) correlates inconsistently with overall survival (OS), underscoring the importance of examining other surrogates. Progression of disease within 24 months (POD24), an established early end point, delineates functionally high-risk patients in other indolent lymphomas. This international study evaluated 253 patients receiving frontline fixed-duration bendamustine-rituximab (BR), a common chemoimmunotherapy for WM. At a median follow-up of 5.9 years, 5-year PFS and OS were 65% and 87%, respectively; 5-year PFS was similar between MYD88L265P (90%) and MYD88wild-type (WT) subcohorts (64% each; P = .4). Among 89 patients with known CXCR4 status, the subcohort with CXCR4mutation (28%) had shorter PFS (median 3.3 vs 8.8 years; hazard ratio [HR], 2.8; P = .0036) and OS (HR, 2.6; P = .036) compared with CXCR4WT. POD24 occurred in 11.5% of patients who demonstrated inferior subsequent OS (5-year OS, 71% vs 86%; HR, 3.1; P = .005) and higher mortality (standardized mortality ratio [SMR], 3.7), unlike the non-POD24 group, whose mortality was comparable to the matched general population (SMR, 1.1). In conclusion, BR is effective irrespective of the MYD88 status, but CXCR4 mutations and POD24 portend worse outcomes. Patients without POD24 represent a cohort with distinctly favorable outcome.