Citations

Abstract This retrospective analysis examined 15 years of autologous stem cell transplantation (ASCT) for light chain (AL) amyloidosis at the Mayo Clinic (2010-2024). We aimed to assess ASCT utilization trends, factors influencing practice changes, and current indications amid newer therapies. Four hundred and forty-one ASCTs were divided into cohort 1 (2010-2019) and cohort 2 (2020-2024), revealing a significant ASCT reduction in cohort 2 (385 vs 56, average 71% annual decrease). Cohort 2 patients were older, more likely to have relapsed/refractory disease, and had higher baseline bone marrow plasma cell burden compared to cohort 1. Pre-ASCT induction was more frequent in cohort 2 (89.3% vs 56.4%), with daratumumab (Dara)–cyclophosphamide-bortezomib-dexamethasone (CyBorD) replacing CyBorD as the predominant induction regimen. Lymphoma-based regimens were also more common in cohort 2 (15.1% vs 5.3%, P = .02). Day-100 satisfactory hematological response improved in cohort 2 (91.1% vs 72.7%, P = .001), although hematological complete response rates did not significantly differ (50.9% vs 38.8%, P = .09). In summary, there is a decrease in the utilization of ASCT in AL amyloidosis. This procedure is primarily reserved for patients with suboptimal responses, relapsed/refractory disease, lymphoplasmacytic clones (predominantly immunoglobulin M amyloidosis), or high bone marrow plasma cell burden (myeloma phenotype). This study underscores a significant shift in ASCT practice, driven by novel therapies, emphasizing more personalized management in AL amyloidosis.

Importance Monoclonal gammopathy of undetermined significance (MGUS) is associated with an increased risk of cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have demonstrated cardiorenal benefits in patients with type 2 diabetes, but their effectiveness in patients with MGUS remains unexplored. Objective To assess the effectiveness of GLP-1 RAs for primary prevention of major adverse cardiovascular and cerebrovascular events (MACCE) in patients with MGUS and diabetes. Design, Setting, and Participants This retrospective cohort study used a propensity score–matched analysis of data from the TriNetX Global Database, encompassing patients diagnosed with diabetes and MGUS between January 1, 2018, and January 13, 2023. Patients with prior heart failure (HF), ischemic heart disease, coronary revascularization, or stroke or transient ischemic attack before MGUS diagnosis were excluded. The cohort was divided into 2 groups: GLP-1 RA users and nonusers at baseline. After 1:1 propensity score matching, GLP-1 RA users and nonusers were compared up to 5 years from the MGUS diagnosis date. Data analyses were completed January 19, 2025. Exposure GLP-1 RA use within 1 year before MGUS diagnosis. Main Outcomes and Measures The primary end point was MACCE, defined as a composite of all-cause mortality, new-onset HF, acute coronary syndrome, and stroke or transient ischemic attack. Secondary end points included individual MACCE components, decompensated HF, and acute kidney injury or end-stage kidney disease. Results A total of 4871 patients with MGUS (mean [SD] age, 68.9 [10.1] years; 2366 [48.5%] male) were included (473 GLP-1 RA users and 4398 non-users). A total of 460 users were matched to 460 nonusers, with balanced characteristics (mean [SD] age, 65.0 [10.6] vs 65.1 [11.0] years; 229 [49.7%] male vs 234 [50.8%] male), including 14 patients (3.0%) vs 13 patients (2.8%) identifying as Asian, 8 (21.3%) vs 92 (20.0%) as Black or African American, 25 patients (5.4%) vs 20 patients (4.3%) as Hispanic or Latino, and 243 patients (52.8%) vs 250 patients (54.3%) as White. GLP-1 RA use was associated with a significantly lower risk of MACCE (hazard ratio [HR], 0.75; 95% CI, 0.60-0.93). Significant reductions were also observed in all-cause mortality (HR, 0.57; 95% CI, 0.37-0.87), new-onset HF (HR, 0.69; 95% CI, 0.54-0.90), decompensated HF (HR, 0.60; 95% CI, 0.43-0.84), and acute kidney injury or end-stage kidney disease (HR, 0.73; 95% CI, 0.57-0.92). Conclusions and Relevance The findings of this cohort study of GLP-1 RA use vs no use in patients with MGUS and diabetes suggest the potential of GLP-1 RA for primary prevention of MACCE. These findings warrant further investigation in prospective randomized trials.

e19503 Background: The uptake of BCMA directed ADCs in MM has been hindered by ocular toxicity. Belantamab mafodotin (BM) and MEDI2228 (MEDI) are BCMA directed monoclonal antibodies conjugated to the microtubule inhibitor, monomethyl auristatin F and the alkylator, pyrrolobenzodiazepine, respectively. Differences in the ADCs payload, antibody specificity and linker stability influence ocular toxicity. We investigated the patterns of ocular toxicity and tolerability of BCMA directed ADC therapy. Methods: Retrospective study of MM patients who commenced treatment with a commercial or investigational BCMA directed ADC at the Mayo Clinic between 2019-22. Results: 111 patients were included, the median age was 69 and median follow up 40 months. The median number of prior treatments was 6, 87% of patients were triple class refractory, 50% penta class refractory, 14% had prior BCMA directed therapy and 24% had extraosseous disease. Treatments included BM (n=56, 50%), BM in combination with other MM therapy (n=12, 11%) and MEDI (n=43, 39%). The overall response rate was 30% for BM and 44% for MEDI. The median OS and PFS for BM was 8 and 2 months, the median OS and PFS for MEDI was 11 and 5 months. The median number of ADC cycles was 2.5. Ocular toxicity is summarized in the table 1. Keratopathy was more common with BM (p=0.004). Only 4 MEDI patients developed keratopathy, all grade 1 and associated with dry eyes and/or photophobia. In contrast, 60% of BM patients developed keratopathy (13% grade 3-4 keratopathy). The median time to keratopathy onset was 1 month with BM, and 2.8 with MEDI. The median time until keratopathy was 4.6 months for BM. Loss of best-corrected visual acuity (VA) was significantly more common with BM (p<0.001). The median time to any decline in VA was 1.5 months for BM and 2.3 for MEDI. The median time until VA returned to baseline was 2.4 months for BM and 2.3 for MEDI. The frequency of dose delays for ocular toxicity was comparable between ADCs, as was the number of dose reductions (16% BM vs. 12% MEDI, p=0.5). The most common reasons for treatment discontinuation were progression or death (BM=69%, MEDI=44%) and ocular toxicity (BM=18%, MEDI=30%). Conclusions: Treatment interruptions, dose reductions and drug discontinuation are common with BCMA directed ADC therapy. Further research to optimize the administration schedule of these agents is warranted. BM and MEDI produce distinct patterns of ocular side effects, namely keratopathy and reduced VA with the former, and photophobia and dry eyes with the latter. BM N = 68 MEDI N = 43 p-value 2 Prophylactic steroid eye drops 4 (6%) 28 (68%) <0.001 Prophylactic lubricant eye drops 42 (63%) 33 (80%) 0.051 Max grade keratopathy 0.004 1-2 29 (47%) 4 (19%) 3-4 8 (13%) 0 (0%) VA equal or worse than 20/40 26 (68%) 6 (20%) <0.001 Days of ADC treatment 59 (33, 167) 68 (41, 105) 0.9 Dose delay for ocular toxicity 19 (28%) 8 (19%) 0.2 n (%); Median (IQR); 2 Chisq test; Wilcoxon rank sum.

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.

Summary Amyloid light‐chain (AL) amyloidosis is a systemic clonal plasma cell disorder characterized by the production and deposition of misfolded immunoglobulin light chains (LCs), resulting in multiorgan dysfunction. Due to its intricate molecular mechanisms and diverse organ involvement, the disease poses significant diagnostic and therapeutic challenges. This review explores the molecular landscape of AL amyloidosis, emphasizing genetic, transcriptomic and proteomic alterations. Key findings include chromosomal abnormalities, somatic mutations, aberrant gene expression, disrupted protein folding pathways and the role of cytokine and chemokine secretion. These factors collectively drive the overproduction and destabilization of amyloidogenic LCs, leading to organ‐specific amyloid deposition, clinical heterogeneity and variable patient outcomes. Despite therapeutic advancements, the disease's complexity challenges the development of effective biological models. Progressing towards personalized therapies requires the development of preclinical models and the identification of biomarkers and molecular data to design targeted interventions. This review highlights the importance of integrating DNA, RNA and protein‐level analyses to deepen the understanding of AL amyloidosis pathogenesis. Such insights are pivotal for improving diagnostics, prognostics and therapeutic strategies, ultimately advancing precision medicine for this challenging disease.

Purpose Venetoclax-based treatment for chronic lymphocytic leukemia (CLL) can be a logistically burdensome regimen due to extensive required monitoring of tumor lysis syndrome (TLS). The purpose of this study was to evaluate the feasibility and safety of pharmacist and registered nurse (RN) driven management of venetoclax ramp-up in CLL. Methods This was a prospective, pilot program for patients receiving venetoclax-based therapy for CLL. Patients had nine weekly visits during the first three cycles of therapy, of which five visits were independently performed by a pharmacist or RN. Laboratory tests to evaluate TLS were ordered and monitored independently by the RN in collaboration with clinicians (physician, nurse practitioner, physician assistant). Results Thirty CLL patients, median age 67 years, 73% treated in the frontline setting, started venetoclax between May 2022 and January 2023. After the initial three weeks of obinutuzumab treatment, TLS risk prior to venetoclax initiation had improved to low (93%), medium (3%), and high (3%). There was zero incidence of laboratory or clinical TLS by Howard criteria during the venetoclax ramp-up for all patients. Pharmacist and RNs performed 139 independent visits and monitored 197 sets of TLS labs. Conclusion Use of independent pharmacist and RN visits for toxicity checks and TLS monitoring during weekly venetoclax dose ramp-up did not lead to increased incidence of TLS in patients with CLL. These visits increased both access and efficiency within the CLL clinic. This concept has the potential to be applied in other cancer care settings with a variety of treatment regimens.