Samuel M. Rubinstein

Background/Objectives: Carfilzomib (CFZ) and bortezomib (BTZ) are proteasome inhibitors used as the first-line therapy for relapsed or refractory multiple myeloma (MM) but are associated with cardiovascular adverse events (CVAEs). This study aims to identify differentially methylated positions (DMPs) and regions (DMRs), and enriched pathways associated with CVAEs related to CFZ or BTZ-based treatment. Methods: Baseline germline DNA methylation profiles from 79 MM patients (49 on CFZ and 30 on BTZ) in the Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy (PROTECT) were analyzed. Epigenome-wide analyses were performed within each group, followed by meta-analyses to identify signals common to CVAEs associated with both medicines. Results: Four DMPs were significantly associated with CFZ-CVAEs, including cg15144237 within ENSG00000224400 (p = 9.45 × 10⁻¹⁰), cg00927646 within TBX3 (p = 9.78 × 10⁻⁸), and cg10965131 within WDR86 (p = 1.00 × 10⁻⁷). One DMR was identified in the FAM166B region (p = 5.46 × 10⁻⁷). There was no evidence of any DMPs in BTZ-treated patients, however two DMPs and one DMR reached a suggestive level of significance (p < 1.00 × 10⁻⁵): cg09666417 in DNAJC18 (p = 3.41 × 10⁻⁷) and cg12987761 in USP18 (p = 5.00 × 10⁻⁷), and a DMR mapped to the WDR86/WDR86-AS1 region (p = 8.11 × 10⁻⁸). Meta-analysis did not find any significant DMPs, with the top CpG being cg17933807 in GNL2 (p = 7.38 × 10⁻⁵). Pathway enrichment analyses identified peroxisome, MAPK, Rap1, adherens junction, phospholipase D, autophagy, and aldosterone-related pathways to be implicated in CVAEs. Conclusions: Our study identified distinct DMPs, DMRs, and pathways enrichment associated with CVAE, suggesting epigenetic contributors to CVAEs and supporting the need for larger validation studies.

Carfilzomib is highly effective in the treatment of multiple myeloma, but it has been associated with cardiovascular adverse events that impact patient outcomes. Our prior global metabolomic analyses indicated an association between hydrophilic bile acids and carfilzomib‐cardiotoxicity risk, although a causal relationship remained to be determined. Here, our objective was to validate the previously identified bile acids in an independent cohort and investigate whether these hydrophilic bile acids play a causal role in carfilzomib‐cardiotoxicity using Mendelian randomization. Using targeted metabolomics, we validated the association between glycoursodeoxycholic acid and carfilzomib‐cardiotoxicity in an independent cohort ( n = 61). We then performed two‐sample Mendelian randomization analyses, using metabolome‐wide association study results to provide the genetic instruments for bile acid levels as exposure and genome‐wide association study summary statistics from the UK Biobank ( n = 484,598) as the outcome data for cardiovascular adverse events. Causal inference was assessed with the inverse‐variance weighted method, followed by multiple sensitivity analyses. Higher glycoursodeoxycholic acid concentration (odds ratio = 0.34, P = 0.032) was associated with lower cardiotoxicity risk after adjusting for hypertension and high levels of brain natriuretic peptides. Mendelian randomization analysis demonstrated a robust causal effect of glycoursodeoxycholic acid on cardiotoxicity risk (β = −0.00065, P = 6.2 × 10 ⁻⁵ ). Gene enrichment analysis indicated pathways involving potassium channel regulation and thromboxane signaling to be implicated. This integrative metabolomic and genetic investigation supports a potential protective role of glycoursodeoxycholic acid in cardiovascular vulnerability and motivates larger, carfilzomib‐specific studies to evaluate its utility for risk stratification.

Background: This study aims to describe time to treatment initiation for Black and White older adults with multiple myeloma (MM), and to test the hypothesis that Black/White disparities in treatment initiation have increased over time. Methods: Black and White older adults (65+) diagnosed with myeloma 2007–2017 were identified in the SEER‐Medicare database. Continuous Medicare Parts A/B coverage 12 months before and after diagnosis or until death, and Part D coverage for 12 months following diagnosis or until death were required for inclusion. We explored time to treatment initiation by race across three diagnosis time periods (2007–10, 2011–2014, 2015–2017) using Cox proportional hazard models. We estimated cumulative incidence of treatment initiation by race at 3, 6, and 12 months after diagnosis for all time periods. Results: White MM patients were more likely to initiate treatment than Black MM patients across time periods. Hazard ratios (HR) and 95% confidence intervals (CI) ranged from HR = 1.35 (95% CI: 1.25, 1.46) to HR = 1.36 (95% CI: 1.27, 1.44). Black/White differences in the cumulative incidence of treatment initiation at 3, 6, and 12 months were also significant and persistent across time periods, ranging from 0.09 (95% CI: 0.02, 0.15) to 0.11 (95% CI: 0.05, 0.17). Contrary to our hypothesis, Black/White disparities were not increasing over time. Conclusion: Our results suggest that Black patients initiate MM treatment later than White patients and are less likely to ever initiate treatment. Contrary to our hypothesis, Black/White disparities are not increasing over time and have remained static.

Background/Objectives: Carfilzomib (CFZ) and bortezomib (BTZ) are proteasome inhibitors used as the first-line therapy for relapsed or refractory multiple myeloma (MM) but are associated with cardiovascular adverse events (CVAEs). This study aims to identify differentially methylated positions (DMPs) and regions (DMRs), and enriched pathways in patients who developed CFZ- and BTZ- related CVAEs. Methods: Baseline germline DNA methylation profiles from 79 MM patients (49 on CFZ and 30 on BTZ) in the Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy (PROTECT) were analyzed. Epigenome-wide analyses within each group identified DMPs, DMRs, and enriched pathways associated with CVAEs compared with individuals without CVAEs. Results: Four DMPs were significantly associated with CFZ-CVAE: cg15144237 within ENSG00000224400 (p = 9.45x10⁻¹⁰), cg00927646 within TBX3 (p = 9.78x10⁻⁸), and cg10965131 within WDR86 (p = 1.00x10⁻⁷). One DMR was identified in the FAM166B region (p = 5.46x10⁻⁷). There was no evidence of any DMPs in BTZ-CVAE patients, however two DMPs and one DMR reached a suggestive level of significance (p < 1.00x10⁻⁵): cg09666417 in DNAJC18 (p = 3.41x10⁻⁷) and cg12987761 in USP18 (p = 5.00x10⁻⁷), and a DMR mapped to the WDR86/WDR86-AS1 region (p = 8.11x10⁻⁸). Meta-analysis did not find any significant DMPs, with the top CpG being cg17933807 in GNL2 (p = 7.38 x10⁻⁵). Pathway enrichment analyses identified peroxisome, MAPK, Rap1, adherens junction, phospholipase D, autophagy, and aldosterone-related pathways to be implicated in CVAEs. Conclusions: Our study identified distinct DMP, DMR, and pathway enrichment associated with CVAE, suggesting epigenetic contributors to CVAEs and supporting the need for larger validation studies.

VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an increasingly recognized disorder that occurs due to somatic mutations of a ubiquitin-activating enzyme encoded by ubiquitin-like modifier activating enzyme 1 gene, UBA1. Clinical findings associated with VEXAS syndrome include recurrent fevers, polychondritis, periorbital edema, pleural effusions, myocarditis and/or pericarditis, hepatosplenomegaly, myelodysplastic syndrome, cytopenias, inflammatory arthritis, neutrophilic dermatosis, and deep venous thrombosis. Novel renal manifestations like interstitial nephritis are infrequent, and to our knowledge, acute renal failure due to C3 glomerulonephritis (C3GN) has not yet been reported. Overwhelming systemic inflammation can result in morbid end-organ damage and death. While there is no formal guideline or established protocol for its management, treatment of VEXAS syndrome with tocilizumab, an interleukin-6 (IL-6)-directed therapy, has been described in the literature. Here, we report a case of a 71-year-old male patient presenting with C3GN as an initial manifestation of VEXAS syndrome and explore the rationale for our approach to treatment with IL-6 blockade. Our patient was initially treated with two inpatient doses of tocilizumab with successful transition to siltuximab in the outpatient setting. He continues to benefit from ongoing siltuximab treatment for more than one year to date without any safety issues or relapse of VEXAS syndrome.

Summary: Monoclonal Immunoglobulin deposition disease (MIDD) is characterised by deposits of intact monoclonal light chains in the kidney leading to renal dysfunction. In this study, we retrospectively investigated the underlying plasma cell cytogenetic abnormalities in MIDD. CyclinD1 (11;14) translocation was identified in 12/27 (45%) patients. Among the patients without translocation, del13q and hyperdiploidy were the most common abnormalities. Patients in the non‐t (11;14) group had a higher baseline light‐chain ratio, higher proteinuria and lower eGFR as compared to patients with t (11;14). Haematological VGPR or higher was seen in 58% of t (11;14), and 30% without t (11;14), possibly related to higher use of Daratumumab‐based therapy in the t (11;14) group. With a median follow‐up of 750 days, 30% (8/24) progressed to end stage renal disease (ESRD). eGFR 3 g/24 h (HR 9, 95% CI 1.27–63.90, p = 0.02) at diagnosis were significantly associated with progression to ESRD. Renal survival was better in t (11;14) as compared to the non‐t (11;14) group (HR 0.11, p = 0.06). Translocation (11;14) is a common abnormality in MIDD and affects the presentation and outcomes. Identification of this abnormality should lead to exploration of BCL2 inhibitors in this disease.

This study investigates the association between circulating microRNA (miRNA) expression and cardiovascular adverse events (CVAE) in multiple myeloma (MM) patients treated with a carfilzomib (CFZ)-based regimen. A cohort of 60 MM patients from the Prospective Observation of Cardiac Safety with Proteasome Inhibitor (PROTECT) study was analyzed. Among these, 31 patients (51.6%) developed CVAE post-CFZ treatment. The Taqman OpenArray Human microRNA panels were used for miRNA profiling. We identified 13 differentially expressed miRNAs at baseline, with higher expressions of miR-125a-5p, miR-15a-5p, miR-18a-3p, and miR-152-3p and lower expression of miR-140-3p in patients who later developed CVAE compared to those free of CVAE, adjusting for age, gender, race, and higher B-type natriuretic peptide levels. We also identified three miRNAs, including miR-150-5p, that were differentially expressed in patients with and without CVAE post-treatment. Additionally, five miRNAs responded differently to CFZ treatment in CVAE vs. non-CVAE patients, including significantly elevated post-treatment expression of miR-140-3p and lower expressions of miR-598, miR-152, miR-21, and miR-323a in CVAE patients. Pathway enrichment analysis highlighted the involvement of these miRNAs in cardiovascular diseases and vascular processes. These findings suggest that specific miRNAs could serve as predictive biomarkers for CVAE and provide insights into the underlying mechanisms of CFZ-CVAE. Further investigation is warranted before these findings can be applied in clinical settings.

As a treatment for relapsed or refractory multiple myeloma (MM), carfilzomib has been associated with a significant risk of cardiovascular adverse events (CVAE). The goals of our study were to evaluate the metabolomic profile of MM patients to identify those at high risk prior to carfilzomib treatment and to explore the mechanisms of carfilzomib‐CVAE to inform potential strategies to protect patients from this cardiotoxicity. Global metabolomic profiling was performed on the baseline and post‐baseline plasma samples of 60 MM patients treated with carfilzomib‐based therapy, including 31 who experienced CVAE, in a prospective cohort study. Baseline metabolites and post‐baseline/baseline metabolite ratios that differ between the CVAE and no‐CVAE patients were identified using unadjusted and adjusted methods. A baseline metabolomic risk score was created to stratify patients. We observed a lower abundance of tauroursodeoxycholic acid (T‐UDCA) in CVAE patients at baseline (odds ratio [OR] = 0.47, 95% confidence interval [CI] = 0.21–0.94, p = 0.044) compared with the no‐CVAE patients. A metabolite risk score was able to stratify patients into three risk groups. The area under the receiver‐operating curve of the model with clinical predictors and metabolite risk score was 0.93. Glycochenodeoxycholic acid (OR = 0.56, 95% CI = 0.31–0.87, p = 0.023) was significantly lower in post‐baseline/baseline ratios of CVAE patients compared with no‐CVAE patients. Following metabolomic analysis, we created a baseline metabolite risk score that can stratify MM patients into different risk groups. The result also provided intriguing clues about the mechanism of carfilzomib‐CVAE and potential cardioprotective strategies.