Hegenbart, Ute

ABSTRACT High dose melphalan (HDM) with autologous stem cell transplant is an established treatment for systemic light chain amyloidosis, but its incremental benefit in the era of effective standard intensity therapy is unknown. We retrospectively analyzed 475 transplant‐eligible patients who completed standard intensity treatment with or without HDM within 12 months at six centers in Europe and the United States between 2010 and 2024 to evaluate outcomes by baseline risk factors, hematologic response, and receipt of HDM. Death was an equally competing risk after the 12‐month landmark chosen to address early non‐proportional hazards and to ensure completion of first‐line therapy. BMPC > 20% was associated with inferior outcomes (HR 1.7), and gain/amp 1q with shorter TTP (HR 2.15), whereas other high‐risk FISH abnormalities were not. In multivariable models, VGPR/CR after standard intensity therapy was associated with longer TTP (HR 0.49/0.29), while gain/amp 1q remained independently associated with shorter TTP (HR 2.18). Receipt of daratumumab and HDM were associated with longer TTP (HR 0.44/0.61). HDM benefited patients who had not achieved CR after standard intensity therapy (mTTP 21.0 vs. 5.7 months without HDM), whereas patients already in CR did not benefit. Higher BMPC at diagnosis was associated with earlier progression in patients not receiving HDM (HR 1.9 for 5%–20% and 4.09 for > 20%), a risk attenuated in the HDM cohort. Gain/amp 1q remained associated with shorter TTP regardless of HDM exposure. These findings support a selective role for HDM, primarily benefiting patients with residual disease after standard intensity therapy or higher BMPC burden at diagnosis.

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 Rapid and profound reduction of free light chains (FLCs) improves outcomes in AL amyloidosis; however, early FLC kinetics with daratumumab‐based frontline therapy remain undefined. We retrospectively analyzed 315 patients treated with daratumumab–bortezomib–cyclophosphamide–dexamethasone (Dara–VCd) or Dara–Vd at eight centers. Involved FLC (iFLC), the difference between iFLC and uninvolved FLC (dFLC), and hematologic response (≥very good partial response [VGPR]) were assessed at baseline and at 1, 3, and 6 months, and correlated with light chain isotype, disease burden (bone‐marrow plasma‐cell percentage [%BMPC], baseline dFLC), and cytogenetics. Hematological ≥VGPR increased from 49.8% at 1 month to 66.0% at 3 months. The kappa isotype showed slower responses, with higher iFLC/dFLC and lower ≥VGPR at each time point compared to lambda. Higher %BMPC or baseline dFLC predicted persistently elevated iFLC/dFLC and reduced ≥VGPR. The t(11;14) translocation was associated with lower baseline FLC but similar subsequent kinetics. BMPC < 10% and dFLC < 18 mg/dL independently predicted early ≥VGPR (in ≤1 month). Early ≥VGPR conferred superior hematologic event‐free survival (heme‐EFS) and overall survival (OS) versus later responders (P < 0.001). At a 3‐month landmark, achieving dFLC < 1 mg/dL further stratified prognosis, conferring longer heme‐EFS and OS (P < 0.01). Frontline Dara‐based therapy elicits rapid, deep responses in AL amyloidosis; early ≥VGPR (within 1 month) and dFLC < 1 mg/dL by 3 months predict durable EFS and OS, whereas higher baseline disease burden delays hematologic response.

ABSTRACTThe optimal conditioning schedule and CD34+ cell dose for autologous stem cell transplantation (ASCT) for AL amyloidosis is unknown. Patients (n = 1704) who underwent ASCT for AL amyloidosis between 2003 and 2020 in 9 centers were included. Data on melphalan conditioning dose, number of conditioning days, whether a rest day between conditioning and stem cell infusion was given or not, and infused CD34+ cell dose were collected. Full‐dose melphalan (≥ 180 mg/m2) was administered in 63.7% of the patients, and 80.4% had melphalan split into 2‐day conditioning. A rest day (day −1) between the conditioning regimen and stem cell infusion was provided in 52.5% of patients. The median infused CD34+ cell count was 4.7 × 106/kg. An infused CD34+ cell count ≥ 4.5 × 106/kg was associated with a shorter time to neutrophil and platelet engraftment. In a nominal regression analysis, full‐dose melphalan, 1‐day melphalan conditioning, and omitting a rest day between conditioning and stem cell infusion were independent predictors of post‐ASCT higher deep hematological response. The median follow‐up was 8.6 years, and 38% of patients died. Independent predictors of superior overall survival in multivariate Cox regression analysis included full‐dose melphalan, having no rest day, and infused CD34+ cells ≥ 4.5 × 106/kg. Independent predictors of higher day‐100 transplant‐related mortality (TRM) in nominal logistic regression analysis included poorer performance status, NT‐proBNP/BNP ≥ 1800/400 pg/mL, serum albumin < 2.5 g/dL, CD34+ cells < 4.5 × 106/kg, and not having a rest day. In conclusion, 1 day of melphalan conditioning and administration of CD34+ cells ≥ 4.5 × 106/kg are recommended for ASCT in AL amyloidosis.

Autologous stem cell transplantation (ASCT) in AL amyloidosis effectively produces a high overall hematological response rate, complete response rate, and durable remissions. However, it is a high-dose chemotherapy-based therapy with high morbidity which can be offered only to a subset of AL amyloidosis patients who are considered fit for this therapy. Transplant-related mortality (TRM) in AL amyloidosis has decreased over the past three decades due to improvement in patient selection. New therapeutic options question the utilization of ASCT. A model to predict TRM can improve the decision-making process, patient selection and further reduce TRM. AL amyloidosis patients (n=1718) from 9 centers globally, transplanted in the years 2003-2020 were included. Pre-ASCT variables of interest were assessed for association with Day-100 all-cause mortality, including age at ASCT (≥ 60 years), sex, light chain isotype, ECOG performance status (ECOG PS; 0, 1 and 2/3), the difference between involved and uninvolved light chains (dFLC; ≥180 mg/L), N-terminal prohormone of B natriuretic peptide (NT-proBNP; ≥1800 pg/mL) or B-type natriuretic peptide (BNP; ≥400 pg/mL), left ventricle ejection fraction (LVEF, &lt;50%), interventricular septum (&gt;16 mm), corrected diffusing capacity for carbon monoxide (cDLCO; ≤65% of predicted), forced expiratory volume in one second (FEV1; ≤65% of predicted), serum albumin (&lt;2.5 g/dL), estimated glomerular filtration rate (eGFR; &lt;30 mL/min/m2), alkaline phosphatase (&gt;X2 upper limit of normal), and systolic blood pressure (&lt;100 mmHg). Troponins could not be included in our modeling given the multitude of assays used across institutions and periods that could not be reconciled. A random forest (RF) classifier with 10-fold cross-validation was used to assist in variable selection. The final model variables were selected based on statistical performance and clinical relevance. The model was fitted using logistic regression. The median age at ASCT was 58, and 40% of patients were women. The most frequently involved organs were the kidneys (69%) and the heart (52%). Mayo 2004 stages I and II were collectively present in 83% of patients. Day-100 TRM occurred in 75 patients (4.4%) with the 3 main causes being shock (n=27), cardiac arrhythmia (n=26), and organ failure (n=22). Age at ASCT, sex, and light chain isotype were not predictors of Day-100 TRM. Across the other pre-ASCT variables, adverse features were present from 6.9% (LVEF &lt;50%) to 25.8% (dFLC ≥180 mg/L) of patients. Ten factors were associated with Day-100 TRM on univariate analysis. The odds ratio of these variables ranged from 1.6 to 10.2. RF classifier using all these variables identified a model with an area under the curve (AUC) of 0.72±0.12. Using the importance hierarchy function to refine the model selection, a 4-variable model [NT-proBNP/BNP ≥1800/400 pg/mL, serum albumin &lt;2.5 g/dL, ECOG PS 1 or 2/3, and systolic blood pressure &lt;100 mmHg] was built with an AUC of 0.70±0.12. Based on logistic regression coefficients, ECOG PS 2/3 was assigned two points, while other adverse predictors were assigned 1-point each (model score range 0-5). We then applied the model scoring to our study population. Score distribution was as follows: 0 (n=431, 25.1% of patients), 1 (n=688,40.1%), 2 (n=413, 24.0%), and 3 and above (n=186, 10.8%). Day-100 TRM rates were 0.46%, 3.2%, 5.8%, and 14.5% for 0, 1, 2, and ≥3 points, respectively. The respective rates for the years 2003-2011 were 1.1%, 3.3%, 6.4%, and 19.2%, while for the years 2012-2020 0%, 3.1%, 5.2%, and 8.4%. We developed a simple clinical tool to predict the Day-100 TRM risk in AL patients undergoing ASCT. This tool will allow more informed decision making weighing the individual benefits and risks of ASCT compared to other therapies.

Background: Despite substantial improvements in early mortality (EM) for patients with systemic light chain amyloidosis (AL), rates remained high in the bortezomib-era, at approximately 25% (Muchtar et al. Blood. 2017). However, the therapeutic landscape in AL amyloidosis has changed with the ANDROMEDA trial, which led to the approval of daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone (Dara-VCd) in the frontline setting. The incidence and predictors of EM in the context of daratumumab-based frontline therapy have not been studied. Methods: We performed an international multicenter retrospective cohort study of all consecutive patients with newly diagnosed AL treated with frontline Dara-VCd or Dara-Vd, and followed until 12/31/2023. EM was defined as death from any cause within 6 months of treatment initiation. Our primary objective was to identify the rate and significant predictors of EM. Univariate logistic regression was used to identify significant predictors of EM, which were then included in a multivariate logistic regression model. The receiver operator characteristic (ROC) analysis was used to determine the best threshold values that discriminated EM rates for the following continuous variables: age, dFLC (involved-uninvolved), eGFR, NT-proBNP, albumin, and high-sensitivity Troponin-T (hs-TnT). Other variables tested in univariate analysis were the following: ECOG performance status, NYHA functional class, sex, race, light chain isotype, percent bone marrow plasma cells, status of the following cytogenetic abnormalities-t(11;14), +1q, hyperdiploidy, del(13q), high-risk translocations, and del(17p), and the number of organs involved (2 vs 1). To build the clinical prediction score, each variable was weighted according to the β coefficient (natural logarithm of odds ratio) obtained from the multivariable regression. The β coefficients were rounded to the nearest 0.5 and multiplied by 2 to obtain an even number. Results The study cohort included 335 AL patients treated with daratumumab-based frontline therapy (92.2% Dara-VCd, 7.8% Dara-Vd), with all surviving patients having at least 6 months of follow-up. The median age at diagnosis was 66.5 years (range, 59.4 - 71.3), and 6.7% (n = 22) were Non-Hispanic blacks. Median dFLC at diagnosis was 22.91 mg/dL (range, 0.2-1093.4), and median NT-proBNP was 2415 pg/mL (range, 13-70,000). Mayo 2004 stages IIIA/IIIB represented 44% of the total cohort, with 17% having ECOG ≥ 2 and 25.4% having NYHA Class III/IV symptoms. The cumulative incidence of EM was 10.7%, with the incidence in patients with Mayo 2004 stage I, II, IIIA, and IIIB being 0%, 8%, 12.5%, and 25% respectively. On univariate analysis with unadjusted odds ratio (OR), the following variables significantly predicted EM: Age ≥ 75 (OR=2.8, p=0.013) ECOG ≥ 2, (OR 4.9, p&lt;0.001), NYHA Class ≥ III (OR=4.95, p&lt;0.001), dFLC ≥9 mg/dL (OR, 10.18, p=0.023), eGFR &lt;33 mL/min/1.73 m2 (OR=2.7, p=0.026), NT-proBNP &gt;5276 pg/mL (OR=7.69, p &lt;0.001), hs-TnT &gt;70 ng/L (OR=5.88, p&lt;0.001), and absence of t(11; 14) (OR=2.33, p=0.041). These variables were entered into multivariate regression, except for ECOG and NYHA, which were combined to create a single variable (values ranging from 0-8), and hs-TnT was dropped due to substantial missing data as centers used different troponin assays. NT-proBNP was rounded to 5300 pg/ml for ease of clinical application. Based on the multivariate analysis, the following scores were assigned to each variable: Age ≥75 (2.0), ECOG+NYHA (1.0 x combined score), NT-proBNP &gt;5,300 pg/ml (2.0), and absence of t(11;14) (3.0). This led to a score ranging from 1-15, and two risk-groups: low-risk (score &lt;9; 87.5%) and high-risk (score ≥9; 12.5%). The respective cumulative incidence of EM was 6.1% versus 50% (p&lt;0.001). The c-index of the model was 0.725 (95% CI, 0.676-0.774). Conclusion: Using variables that are readily available in the clinic, we have developed a two-tiered risk-prediction model for EM in AL amyloidosis in the context of daratumumab-based frontline therapy. The model needs to be externally validated in an independent dataset.

Abstract We performed an international retrospective study on 283 patients with light chain (AL) amyloidosis to investigate the prognostic impact of cytogenetic abnormalities by fluorescence in situ hybridization, when treated with frontline daratumumab–based therapy. The cytogenetic subgroups of interest were t(11;14), gain/amp(1q) (hereafter, +1q), hyperdiploidy, deletion(13q), del(17p), and myeloma high-risk (HR) translocations (t[4;14], t[14;16], or t[14;20]). The end points of interest were rate of hematologic complete response (heme-CR), very good partial response (VGPR) or better, and hematologic event-free survival (heme-EFS). The incidence of abnormalities was as follows: t(11;14), 53.4%; deletion (13q), 28.9%; +1q, 22.3%; hyperdiploidy, 19.4%; HR translocations, 6.6%; and deletion(17p), 4.5%. The heme-CR rate by cytogenetic subgroups were as follows: t(11;14) vs no t(11;14), 45.2% vs 41.8% (P=0.597); del(13q) vs no del(13q), 46.8% vs 42.8% (P=0.594); +1q vs no +1q, 30.2% vs 47.9% (P=0.022); hyperdiploidy vs no hyperdiploidy, 39.5% vs 44.9% (P=0.541); HR translocations vs none, 45.5% vs 43.1% (P=0.877); and del(17p) vs no del(17p), 50.0% vs 42.9% (P=0.658), respectively. Similarly, +1q was the only subgroup with a significantly lower VGPR or better rate (64.2% vs 79.0%; P=0.033). At a median follow-up of 19.8 months, the median heme-EFS was 49.6 months (95% CI, 24.7-not reached [NR]), and the 2-year overall survival (OS) was 80.98% (95% CI, 75.6-85.4). The presence of +1q was significantly associated with worse heme-EFS on multivariate analysis (HR 2.06, 95% CI, 1.14-3.71; P=0.017). Notably, there was no adverse prognostic impact of t(11;14) on heme-EFS or OS. In conclusion, +1q is associated with worse outcome in the daratumumab-era. Clinical trials testing novel frontline immunotherapies should be enriched in +1q to further improve outcomes in this subgroup.

ImportanceKidney light chain (AL) amyloidosis is associated with a risk of progression to kidney replacement therapy (KRT) and death. Several studies have shown that a greater reduction in proteinuria following successful anticlonal therapy is associated with improved outcomes.ObjectiveTo validate graded kidney response criteria and their association with kidney and overall survival (OS).Design, Setting, and ParticipantsThis retrospective, multicenter cohort was conducted at 10 referral centers for amyloidosis from 2010 to 2015 and included patients with kidney AL amyloidosis that was evaluable for kidney response and who achieved at least hematologic partial response within 12 months of diagnosis. The median follow-up was 69 (54-88) months. Data analysis was conducted in 2023.ExposureFour kidney response categories based on the reduction in pretreatment 24-hour urine protein (24-hour UP) levels: complete response (kidCR, 24-hour UP ≤200 mg), very good partial response (kidVGPR, &amp;gt;60% reduction in 24-hour UP), partial response (kidPR, 31%-60% reduction), and no response (kidNR, ≤30% reduction). Kidney response was assessed at landmark points (6, 12, and 24 months) and best kidney response.Main Outcomes and MeasuresCumulative incidence of progression to KRT and OS.ResultsSeven-hundred and thirty-two patients (335 women [45.8%]) were included, with a median (IQR) age of 63 (55-69) years. The median (IQR) baseline 24-hour proteinuria and estimated glomerular filtration rate was 5.3 (2.8-8.5) g per 24 hours and 72 (48-92) mL/min/1.73m2, respectively. In a competing-risk analysis, the 5-year cumulative incidence rates of progression to KRT decreased with deeper kidney responses as early as 6 months from therapy initiation (11%, 12%, 2.1%, and 0% for kidNR, kidPR, kidVGPR, and kidCR, respectively; P = .002) and were maintained at 12 months and 24 months and best kidney response. Patients able to achieve kidCR/kidVGPR by 24 months and at best response had significantly better OS compared with kidPR/kidNR. Kidney progression, defined as a 25% or greater decrease in estimated glomerular filtration rate, was associated with cumulative incidence of progression to KRT and OS.Conclusions and RelevanceThe results of this cohort study suggest that graded kidney response criteria offers clinically and prognostically meaningful information for treating patients with kidney AL amyloidosis. The response criteria potentially inform kidney survival based on the depth of reduction in 24-hour proteinuria levels and demonstrate an OS advantage for those able to achieve kidCR/kidVGPR compared with kidPR/kidNR. Taken together, achievement of at least kidVGPR by 12 months is needed to ultimately improve kidney and patient survival.

Introduction: High dose chemotherapy and autologous stem cell transplantation (ASCT) is one of the most effective therapies in light chain (AL) amyloidosis. It is associated with a high hematologic response rate and leads to durable remissions. High dose melphalan is the most frequently used conditioning chemotherapy, as has been used in multiple myeloma (MM). Melphalan dose is based on renal function, age, degree of cardiac involvement and patients' frailty and is predictive of outcomes. While studies that assessed the conditioning schedule have been conducted in MM, with variable results, no such studies were done in AL amyloidosis. Methods: In this retrospective study, we explored the impact of the conditioning schedule on post-transplant outcomes in a large multicenter study. Patients with AL amyloidosis who underwent ASCT for the primary diagnosis of AL amyloidosis between January 1, 2003, and December 31, 2020, were included in this study. Results: One thousand seven hundred and eighteen (n=1718) patients from 9 centers are included. The median age was 58 years, and 61% were male. Most patients had one (43%) or two (33%) involved organs, with the most involved organs were the kidneys (69%) followed by the heart (52%). Induction therapy was given to 52% of patients. The conditioning regimen was almost exclusively melphalan (99.2%), with 65% receiving full dose melphalan (≥170 mg/m 2). Melphalan was given over two days in most patients (80%). A rest day between conditioning and stem cell infusion was provided in 53% of patients, mostly in those who received melphalan on a single day rather than over 2 days (87% vs 44%, P&lt;0.001). Post-transplant hematologic response was available for 1569 patients (91% of patients) and were assessed from baseline. Complete response (CR) and very good partial responses (VGPR) were achieved post-ASCT in 33.7% of patients each. Low dFLC-partial response (PR) was achieved in 2.7% and PR in 18% of patients. Altogether, satisfactory post-ASCT response (CR, VGPR, or low-dFLC PR combined) was achieved in 70% of patients. Compared to no induction, less than a PR to induction was associated with a lower probability of achieving satisfactory post-ASCT response, while PR or better to induction had higher chances of satisfactory post-ASCT response (65% vs 46% vs 84%, P&lt;0.001). A single day of melphalan conditioning was associated with a higher probability of satisfactory post-ASCT response compared to two days of conditioning (82% vs 67%, P&lt;0.001). Omitting a day of rest between conditioning and stem cell infusion was also associated with higher satisfactory post-ASCT response compared to having a rest day (76% vs 65%, P&lt;0.001). The Table lists other predictors for a post-ASCT satisfactory hematologic response. In a nominal multivariate logistic regression analysis, independent predictors for higher post-ASCT satisfactory hematological response rate included: PR or better to induction therapy, female gender, kappa light chain isotype, lower dFLC at baseline, and kidney and liver involvement. In addition, full dose melphalan, conditioning given over a single day and having no rest day between conditioning and stem cell infusion were also associated with a higher likelihood of satisfactory post-ASCT response. Post-ASCT hematologic CR rate was higher in those receiving full dose conditioning (36% vs 28%, P&lt;0.001), in those having no rest day (40% vs 28%, P&lt;0.001) but not in those who received one day of conditioning versus two days (35% vs 33%, P=0.5). The rate of ICU admission was higher in those receiving no day rest (17.7% vs 12.6%), P=0.003) and among those who received reduced dose melphalan (18.1% vs 13.3%, P=0.008) but not based on number of conditioning days (P=0.56). Day 100 mortality was significantly higher in the no rest day group (5.6% vs 3.2%, P=0.01) and among those receiving reduced dose melphalan (6.8% vs 3.1%, P=0.004) compared to their counterparts, but not based on the number of days of conditioning (P=0.89). The median follow-up in the entire cohort was 104 months (95% CI 98-110). In a multivariate analysis for overall survival (OS), the conditioning dose but not the conditioning schedule was independently associated with OS. Conclusions: This study is the first to demonstrate the effect of melphalan conditioning schedule on post-transplant response. This study supports a single day melphalan conditioning in AL amyloidosis to improve post-ASCT response.