Wiedmeier-Nutor, Erin J

AbstractBackgroundThe prognosis in patients with advanced cardiac amyloidosis (CA) remains poor.ObjectivesWe sought to describe survival post heart transplantation (HT) in amyloid compared with non‐amyloid recipients, highlight waitlist times within the new allocation system across three Organ Procurement and Transplantation Network (OPTN) regions, and describe multiorgan transplantation (MOT) in hereditary amyloidosis.MethodsThis is a retrospective review of end‐stage CA patients who underwent HT at Mayo Clinic from January 2007 to December 2020. Wait time was compared in the new versus old OPTN allocation era starting December 18, 2018 by Wilcoxon rank sum test. All‐cause mortality for those with and without CA was compared using Kaplan–Meier estimates with log rank analysis, censoring December 16, 2022.ResultsFifty‐five patients with CA underwent HT between 2007 and 2020, 8 light chain amyloidosis (AL) (14.5%), 28 hereditary transthyretin (ATTRv) (50.9%), 17 wildtype transthyretin (ATTRwt) (30.9%), and 2 hereditary apolipoprotein A1 (AApoA1) amyloidosis patients (3.6%). No significant difference in overall survival post‐transplant was seen in amyloid compared with non‐amyloid (p = 0.816). Median time to HT was shorter in the new system, 45 days (IQR 24, 78) versus 174 days (IQR 76.5, 483.5), p = 0.006. There was a decline in MOT in hereditary amyloidosis over time with the concomitant rise in disease‐targeted therapies.ConclusionsHT survival in CA patients was similar to non‐amyloid patients. The new allocation system benefits this cohort with shorter wait times. There is less MOT in hereditary amyloidosis with increased utilization of disease‐targeted therapy.

Background: Light chain (AL) amyloidosis is a rare and understudied plasma cell disorder. It is caused by abnormal misfolding of monoclonal immunoglobulin light chains, leading to extracellular deposition of amyloid, ultimately resulting in organ dysfunction and death. Since AL amyloidosis is uncommon, therapies are adapted from the more common plasma cell disorders like multiple myeloma. Daratumumab, a monoclonal antibody targeting CD38, was first tested in several prospective and retrospective studies in AL patients with relapsed refractory disease. The ANDROMEDA study (Kastritis E et al, NEJM 2021) established daratumumab in combination with CyBorD (Cyclophosphamide-Bortezomib-Dexamethasone) followed by daratumumab maintenance as the new standard of care compared to CyBorD alone for newly diagnosed patients. Consequently, daratumumab maintenance has become universally offered to all newly diagnosed AL amyloidosis patients. Notably, there was no second randomization before the initiation of maintenance therapy in ANDROMEDA. Hence, a critical question that remains is whether the superior efficacy observed in the investigational arm of the ANDROMEDA trial is solely a result of the addition of daratumumab during the induction phase or if the maintenance phase contributed to the favorable outcomes in the investigational arm. We hypothesize that a shorter duration of maintenance would prove non-inferior to the standard duration of daratumumab maintenance in patients with AL amyloidosis that have responded to Daratumumab-CyBorD induction. To answer this question we are conducting a pragmatic phase 2 randomized trial assessing the optimal duration of daratumumab maintenance in patients with AL amyloidosis who have responded to Daratumumab-CyBorD induction. Study Design, Patients and Methods: We use broadened eligibility criteria consistent with pragmatic trial design. The estimated total enrollment is up to 96 patients. The main eligibility criteria are patients with biopsy-proven AL Amyloidosis who have completed 6 cycles of Dara-CyBorD-based induction treatment and achieved an adequate response to induction (defined as hematological complete response (CR), hematological very good partial response (VGPR), or hematological partial response (PR) with at least one organ response). Patients in whom bortezomib and/or cyclophosphamide were omitted from induction due to toxicity concerns or adverse effects are allowed. The major exclusion criteria are patients who were concomitantly diagnosed with multiple myeloma based on International Myeloma Working Group (IMWG) criteria. This phase II, open-label, multicenter trial (NCT05898646) randomizes patients who have attained an adequate response to 6 cycles of Dara-CyBorD-based induction in a 1:1 ratio, using a dynamic allocation procedure that balances the marginal distributions of the stratification factors (age, cardiac stage, and t(11;14) status). Randomization is to either single-agent daratumumab maintenance of 6 cycles duration (experimental arm) or 18 cycles of daratumumab maintenance (control arm) (cycle = 28 days). Treatment is allowed to be given at a local facility After completing maintenance treatment, patients will follow up every 3 months for up to 36 months from registration. The primary endpoint of the trial is to evaluate the non-inferiority of a shorter (6 cycles) daratumumab maintenance measured by event-free survival (EFS) compared to the standard maintenance of 18 cycles in newly diagnosed AL amyloidosis who receive 6 cycles of daratumumab-CyBorD based induction. EFS in this study is defined as time from registration to any of the following events: hematological progression, organ progression, subsequent anti-plasma cell therapy in the absence of hematological progression but with persistent organ dysfunction or death, whichever occurs first. Secondary endpoints are depth of hematological and organ response, bone marrow measurable residual disease negativity rate, duration of response, quality of life, and survival. By investigating whether a shorter duration of maintenance is non-inferior to the standard duration, we aim to inform clinical practice and potentially reduce the toxicities associated with prolonged maintenance therapy, including hypogammaglobulinemia, recurrent infections, the need for intravenous gammaglobulin replacement, and financial toxicity.

Background Clinical biomarkers are essential for optimizing CAR T-cell therapy in multiple myeloma (MM). Clinicians can anticipate patient responses by evaluating predictive biomarkers, particularly earlier during treatment, tailoring treatments to enhance efficacy and survival outcomes. Ferritin, a general inflammation marker, appears to be a promising predictor of clinical outcome in MM patients receiving therapy with CAR T-cells. Our goal was to evaluate this and other biomarkers in this patient population. Methods We retrospectively analyzed MM-patients treated with idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) at Mayo Clinic Arizona between September/2019 and November/2023. We evaluated the demographic characteristics, pre-infusion bone marrow samples, adverse events, mortality, and clinical response after CAR T-cell therapy infusion, and clinical laboratory data were interpreted using reference limits established by Mayo Clinic laboratories. Statistical calculations using parametric tests were performed, and survival curves were estimated using the Kaplan-Meier analysis and compared statistically using the log-rank test and Pearson's correlation. Results Forty patients with MM received CAR T cells, and 23 and 17 patients received cilta-cel and Ide-cel, respectively. The median age was 64 years [IQR 40-80], and 62.5% were male. All patients received inpatient CAR T-cell infusions; the median vein-to-vein was 54 days (IQR: 39-109), and the median length of hospital stay was ten days (IQR: 7-25). Cytokine release syndrome (CRS) was observed in 90% of patients (3% grade ≥3), while immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 23% of patients (3% grade ≥3). At day 90, the overall response rate (ORR) was 87.5%, with 21 patients (52.5%) having a complete response (CR), 9 (22.5%) with a very good partial response (VGPR), 5 (12.5%) had a partial response (PR), 1 (2.5%) had stable disease (SD), and 4 (10%) had progressive disease (PD). 35 patients was evaluated for minimal residual assessment (MRD) using flow cytometry cut-off 10-5. Of the total population eligible (PR, VGPR, and CR) for MRD evaluation, 97% were MRD negative. The median progression-free survival (PFS) was 13.5 months on ide-cel and has not been reached on cilta-cel. The mortality rate was 23.5% Ide-cel vs 8.6% with cilta-cel. In terms of PFS, we did not find any association with age, disease risk, number of previous lines of therapy, time from last treatment to CAR T-cell infusion, absolute lymphocyte counts at leukapheresis, % of plasma cells in bone marrow pre-infusion, vein-to-vein time, use of tocilizumab, or steroids for CRS/ICANS management. However, univariate analyses showed that a ferritin level <337 mcg/L at baseline pre-CAR T-cell infusion strongly correlated independently with improved PFS (median non-reached) compared with patients with ferritin levels >337 mcg/L that had a PFS of 13.50 months HR 0.2 (95% CI 0.07 - 0.83); p=0.0245. In addition, ferritin levels <337 mcg/L pre-infusion correlated with improved overall survival (OS) (median non-reached) compared with 22.23 months in patients with higher ferritin levels HR 0.2 (95% CI 0.02 - 0.53), p=0.0069. Conclusions In conclusion, our analysis shows that ferritin levels pre-CAR T-cell infusion are independent predictive biomarkers of PFS and OS in MM-patients regardless of the CAR T-cell product received. Our cohort of MM-patients treated with the two FDA-approved CAR T-cell products showed the expected PFS, OS, and adverse events. Moreover, our results showed no significant association between clinical response and age, risk stratification, number of previous therapy lines, or other evaluated factors with disease progression. Future prospective studies will help to validate these findings and explore the mechanisms associated with high ferritin levels and their potential implications in the heightened immune-activation state in patients that express high ferritin levels and their correlation with CAR T-cell efficacy.