Kastritis, Efstathios

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.

Summary: While the current approach to precursor hematologic conditions is to “watch and wait,” this may change with the development of therapies that are safe and extend survival or delay the onset of symptomatic disease. The goal of future therapies in precursor hematologic conditions is to improve survival and prevent or delay the development of symptomatic disease while maximizing safety. Clinical trial considerations in this field include identifying an appropriate at-risk population, safety assessments, dose selection, primary and secondary trial endpoints including surrogate endpoints, control arms, and quality-of-life metrics, all of which may enable more precise benefit–risk assessment.

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.

Introduction: Teclistamab (TEC) is a bispecific BCMA-CD3 directed T-cell antibody (BsAb), recently approved by EMA and FDA. Approval was based on the MajesTEC-1 study showing high overall response rates (≥PR in 63.0%) in heavily pretreated patients with relapsed multiple myeloma (RRMM). Few reports have described Real-World experience despite that TEC can induce unique side effects including cytokine release syndrome (CRS), neurotoxicity (ICANS) and a high incidence of infection (MajesTEC-1: incidence 76.4%; ≥Gr3: 44.8%). Thus, we performed a Real-World analysis of TEC therapy from 7 International Myeloma Foundation (IMF) associated MM academic centers. Methods: Patients treated with standard-of-care TEC were included. Data was collected until 7/28/2023. Results: 103 pts were included; median age 63 (range 33-91y); 15 pts. (14.5%) >75 yrs; 56.5% were male, 71.8% Caucasian, 11.6% Hispanic, and 12.6% Asian. Pts received a median of 6 PLT (range 1-16); 75% were triple-class-refractory (n=41/52 (79%), 30/85 (35%) had high-risk cytogenetics/FISH and 32/80 (40%) had 1q21 gain. At least 57/76 (75%) of pts would not have been eligible for MajesTEC-1 (mostly from prior BCMA (n=28 CAR-T, n=14 ADC; n=3 BsAb; n=5 CAR-T+ADC). 14 pts had CrCl <30ml/min with 2 on HD. Median number of hospital days was 8 (n= 72) but 31 patients were treated entirely as outpatients (Mayo clinic (MN, AZ, FL)). CRS was seen in 52 (50.4%) (all grade 1: except 6 Gr2, 1 Gr4), generally resolved within 24 hrs and was managed with tocilizumab alone (n= 27) or dex alone (n=9) or dex+toci (n=12). CRS was more common with inpatient (56.9%) vs outpatient (35.4%) TEC Rx. CrCl <30 ml, did not appear to alter the incidence or severity of CRS (50%; 1 Gr4). ICANS was infrequent (n=5; 4.85%), 1 pt with Gr 4-Sz requiring HD-steroids and TEC discontinuation). Infections were common, seen in 54 (52.4%) of patients, the majority were viral URI or CMV reactivation (n=26; 3 pts receiving CMV Rx, 1 pt with CMV organ disease). IVIG was given in 43/67 (64%) pts. The overall response rate for evaluable patients (n=82) was 63%; (sCR/CR 14; VGPR 23; PR 15; MR 2, SD 14; PD 14). In evaluable pts treated with prior BCMA (n=43), the ORR was 53% (sCR/CR 4; VGPR 14; PR 5; 1 MR; SD 10; PD 9). The most common reason for treatment discontinuation was PD (26.2%). 14 pts have died by the time of data cut-off (7/28/23), with the most common cause of death being disease progression. Conclusions: In this Real-World evaluation of TEC, a high ORR was seen, similar to the MajesTEC-1 study. Responses were rapid and are expected to deepen over time (median f/u 5m). CRS rates were similar to MajesTEC-1 and no new toxicity signal was noted. The rates of infection appear low but may be related to short follow-up. Details regarding the incidence and types of infection and the global use of IVIG will be described. With longer follow-up, additional efficacy/toxicity data will be presented.

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.