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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, >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.

Background: Liver involvement in light chain amyloidosis (AL) is seen in up to 20% of patients and is typically encountered as part of multi-organ involvement. Liver involvement is associated with a poor prognosis. The goal of this study was to assess the prognostic impact of the hepatic response criteria, which were published in 2005 and were not broadly assessed for their prognostic value. Patients and methods: Ten centers across the USA and Europe participated in this study.AL amyloidosis patients who were diagnosed between 2010 and 2015, had liver involvement with serum alkaline phosphatase (AP) >1.5 upper reference limit (URL), and achieved hematologic response to therapy were included in this study. Hepatic response was assessed at 6, 12, and 24 months from therapy initiation and at best response. Based on a receiver operation characteristic analysis, a 50% reduction in AP was set as the optimal cut point for discrimination of 5-year overall survival (OS) in the 12-months response assessment landmark (area under the curve 0.67). Therefore, hepatic response was defined as a reduction in AP >50% from baseline value in addition to AP normalization, regardless of AP percentage reduction. Hepatic progression was defined as >50% increase in serum AP. OS was assessed from therapy initiation until death or last follow-up and was plotted using the Kaplan-Meier method. The log-rank test used to compare survival between groups. For fixed-time point survival analysis, patients who died before the landmark were excluded. Hepatic response at a fixed time points, when missing, was imputed based on available data from adjacent time points (imputation of hepatic response was performed in 15%, 23%, and 22% of evaluable patients at 6-, 12-, and 24-month landmarks, respectively). Multivariate Cox proportional models were set to determine independent prognostic factors for OS using variables with p-value <0.1 in a univariate analysis. P-values <0.05 were considered significant. Results: One hundred and sixteen patients (n=116) are included. The median age was 60 years, and the median serum AP was X2.6 URL. Concomitant kidney involvement was present in 63.8% of patients, while coexisting heart involvement was seen in 56% of patients. Hematologic VGPR or better was achieved in 69% of patients. AP decrease deepened with time, with a median reduction at 6-, 12-, 24-months and best response being 22%, 34%, 53%, and 56%, respectively. Overall, 65% of patients (n=75) achieved hepatic response, of whom 71 patients based on reduction in AP >50% and 4 patients for reaching AP within normal reference but not meeting >50% reduction in AP (40- 46% reduction in AP). The median time to hepatic response was 13.8 months, longer for patients undergoing autologous stem cell transplantation (ASCT) as their primary therapy compared to non-transplant therapies (24 vs 12.6 months, P=0.1). With a median follow-up of 105 months, 42 patients died (36.2% of the study cohort). The 2-, 5- and 10-year OS rates were 83%, 67%, and 61%, respectively. Achievement of hepatic response as early as 12 months and at best response was associated with a longer survival (Figure). Hepatic response was an independent prognostic factor in a multivariate analysis, after adjusting for other known prognostic factors (age, cardiac stage, hematologic response, and primary therapy). Predictors of hepatic response include higher baseline AP level, lower total bilirubin, hematologic ≥VGPR, and cardiac and renal responses, when applicable. Hepatic progression was borderline associated with inferior OS (5-year OS 47% vs 70% among non-progressors, P=0.08). Conclusions: Hepatic response and progression measured by the change in alkaline phosphatase are prognostic in AL amyloidosis. These criteria are independent of other prognostic markers, and thus may have clinical implications for patients' care.

Introduction: SystemicAL amyloidosis is a progressive and often fatal disease caused by misfolded light chains that aggregate into amyloid fibrils and deposit in vital organs, leading to organ dysfunction. Current standard of care (SoC) therapies for AL amyloidosis target the plasma cell clone to reduce or eliminate light chain production, but do not remove soluble toxic light chain aggregates or insoluble amyloid deposits. Early mortality remains high for patients with advanced disease (e.g., Mayo 2012 Stage IV disease, median overall survival <6 months). Birtamimab - a humanized monoclonal antibody that neutralizes soluble, toxic light chain aggregates and depletes insoluble amyloid deposits by inducing phagocytosis - is under investigation for the treatment of AL amyloidosis. Here, we present a pooled safety analysis from previous Phase 1-3 clinical trials, with a focus on the 2 double-blind randomized controlled trials (RCTs): PRONTO (NCT02632786) and VITAL (NCT02312206). Methods: Patients with AL amyloidosis were treated with intravenous birtamimab up to 24 mg/kg every 28 daysin the non-placebo-controlled Phase 1/2 open-label trial (NCT01707264) with open-label extension (OLE; NCT02613182) and 2 RCTs (Phase 2 PRONTO with OLE [NCT03154047] and Phase 3 VITAL). In PRONTO, patients had received ≥1 previous systemic therapy with at least a partial hematologic response and persistent cardiac dysfunction, and received birtamimab or placebo. In VITAL, newly diagnosed treatment-naïve patients with cardiac involvement received birtamimab + SoC or placebo + SoC (where SoC was a bortezomib-containing chemotherapy regimen). The analysis included all patients who received ≥1 dose of birtamimab. Pooled median exposure times were calculated, and baseline characteristics and demographics were summarized. For VITAL and PRONTO, pooled rates and severity of treatment-emergent adverse events (TEAEs) with birtamimab were compared with rates in the placebo arms. In addition, safety data from the non-placebo-controlled studies were summarized. Results: The median (range) exposure to birtamimab among 302 patients pooled from the Phase 1-3 trials was 12.24 (0.03-57.72) months. Of the 302 patients exposed to birtamimab, 295 received at least one 24-mg/kg infusion, up to 2500 mg. Analysis of the 2 randomized, placebo-controlled trials included data from 196 patients treated with birtamimab from the PRONTO (n=66) and VITAL (n=130) trials and 193 patients who received placebo (PRONTO, n=63; VITAL, n=130). Both trials had comparable treatment durations overall. The rates of TEAEs, serious and grade ≥3 TEAEs were similar between birtamimab and placebo arms within each trial and between treatment arms in the placebo-controlled pooled analysis set (PRONTO and VITAL; Table 1). Higher rates of treatment-related, serious, and grade ≥3 TEAEs were reported in VITAL compared with PRONTO, presumably due to the treatment-naïve population and receipt of concomitant SoC therapy in VITAL. In the pooled analysis set, the most common TEAEs that occurred with greater frequency in the birtamimab vs placebo arms in either trial were, respectively, fatigue (36.2%, 34.2%), diarrhea (33.2%, 33.7%), nausea (31.6%, 30.1%), constipation (31.1%, 31.6%), and dyspnea (25.0%, 24.9%). The most commonly reported (≥5%) serious and grade ≥3 TEAEs were primarily cardiac disorders (cardiac failure, syncope, cardiac arrest), consistent with the underlying disease. Infusion-associated TEAE rates were low in the pooled birtamimab and placebo arms (5.1% vs 3.6%, respectively) and were generally mild to moderate. The safety profile observed in the non-placebo-controlled Phase 1/2 trial plus OLE and PRONTO OLE (n=106) was consistent with the safety data reported in the placebo-controlled studies. Conclusions: Birtamimab was well tolerated in patients with AL amyloidosis when administered as monotherapy and did not demonstrate additive toxicity when given with SoC chemotherapy. Rates of TEAEs in the birtamimab arm were similar to rates in the placebo arm in the PRONTO and VITAL trials. The safety and efficacy of birtamimab is being further investigated in an ongoing confirmatory Phase 3 double-blind RCT in patients with Mayo Stage IV AL amyloidosis (AFFIRM-AL; NCT04973137), which is currently enrolling.

Abstract Amyloid light-chain (AL) amyloidosis is a rare, typically fatal disease characterized by the accumulation of misfolded immunoglobulin light chains (LCs). Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic LC aggregates and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis. VITAL was a phase 3 randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of birtamimab + standard of care (SOC) in 260 newly diagnosed, treatment-naive patients with AL amyloidosis. Patients received 24 mg/kg IV birtamimab + SOC or placebo + SOC every 28 days. The primary composite end point was the time to all-cause mortality (ACM) or centrally adjudicated cardiac hospitalization ≥91 days after the first study drug infusion. The trial was terminated early after an interim futility analysis; there was no significant difference in the primary composite end point (hazard ratio [HR], 0.826; 95% confidence interval [CI], 0.574-1.189; log-rank P = .303). A post hoc analysis of patients with Mayo stage IV AL amyloidosis, those at the highest risk of early mortality, showed significant improvement in the time to ACM with birtamimab at month 9 (HR, 0.413; 95% CI, 0.191-0.895; log-rank P = .021). At month 9, 74% of patients with Mayo stage IV AL amyloidosis treated with birtamimab and 49% of those given placebo survived. Overall, the rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were generally similar between treatment arms. A confirmatory phase 3 randomized, double-blind, placebo-controlled clinical trial of birtamimab in patients with Mayo stage IV AL amyloidosis (AFFIRM-AL; NCT04973137) is currently enrolling. The VITAL trial was registered at www.clinicaltrials.gov as #NCT02312206.

PURPOSE Binary cardiac response assessment using cardiac biomarkers is prognostic in light chain amyloidosis. Previous studies suggested four-level cardiac responses using N-terminal prohormone of brain natiuretic peptide improves prognostic prediction. This study was designed to validate graded cardiac response criteria using N-terminal prohormone of brain natiuretic peptide/brain natiuretic peptide. PATIENTS AND METHODS This retrospective, multicenter study included patients with light chain amyloidosis who achieved at least a hematologic partial response (PR) and were evaluable for cardiac response. Four response criteria were tested on the basis of natriuretic peptide response depth: cardiac complete response (CarCR), cardiac very good partial response (CarVGPR), cardiac PR (CarPR), and cardiac no response (CarNR). Response was classified as best response and at fixed time points (6, 12, and 24 months from therapy initiation). The study primary outcome was overall survival. RESULTS 651 patients were included. Best CarCR, CarVGPR, CarPR, and CarNR were achieved in 16%, 26.4%, 22.9%, and 34.7% of patients, respectively. Patients in cardiac stage II were more likely to achieve CarCR than patients in cardiac stage IIIA and IIIB (22% v 13.5% v 3.2%; P < .001). A deeper cardiac response was associated with a longer survival (5-year overall survival 93%, 79%, 65%, and 33% for CarCR, CarVGPR, CarPR, and CarNR, respectively; P < .001). Fixed time-point analyses and time-varying covariates Cox regression analysis, to minimize survivorship bias, affirmed the independent survival advantage of deeper cardiac responses. Four-level response performed better than two-level response as early as 12 months from therapy initiation. CONCLUSION Graded cardiac response criteria allow better assessment of cardiac improvement compared with the traditional binary response system. The study re-emphasizes the importance of early diagnosis, which increases the likelihood of deep cardiac responses.