Citations

ABSTRACT The prognostic relevance of multiple myeloma (MM)‐defined high‐risk (HR) cytogenetic abnormalities in AL amyloidosis is incompletely defined. We retrospectively evaluated 517 newly diagnosed AL amyloidosis patients seen at Mayo Clinic between 2012 and 2021 who had baseline plasma cell FISH. HR cytogenetics were defined as t (4;14), t (14;16), t (14;20), del(17p), or 1q gain/amplification (+1q). HR abnormalities were identified in 151 patients (29%); +1q accounted for most HR cases (122/151, 81%). Compared with standard‐risk (SR), patients harboring +1q demonstrated a greater clonal disease burden, including higher dFLC and bone marrow plasma cells, greater intact immunoglobulin secretion, higher plasma cell proliferative index, and enrichment for modified SLiM‐CRAB features. Hematologic and organ response patterns of +1q patients were generally comparable to SR patients, whereas non‐1q HR patients had a higher proportion of early hematologic responses. Patients harboring +1q demonstrated significantly inferior overall survival (OS) compared with both non‐1q HR patients and SR patients (median OS 57 months vs. not reached vs. 120 months, p = 0.02). In multivariable piecewise Cox analysis, the adverse prognostic impact of +1q was most evident beyond 24 months from diagnosis (HR 2.89, 95% CI 1.64–5.09, p < 0.001), whereas non‐1q HR lesions were not independently prognostic. These findings suggest that +1q identifies a biologically distinct AL amyloidosis subset characterized by plasma cell–dominant features and inferior long‐term disease control. In contrast, other MM‐defined HR cytogenetic abnormalities appear to have limited prognostic relevance in AL amyloidosis.

Abstract Introduction Clozapine-induced constipation may occur in at least 60% of patients, with first-line options typically involving polyethylene glycol or sennosides. However, there may be adherence barriers to an over-the-counter bowel regimen due to the dosage form, lack of insurance coverage, or lack of benefit. One possible solution to address these adherence barriers may include prescribing a secretagogue laxative. However, there is limited literature supporting the use of secretagogue laxatives in clozapine-associated constipation. A case series is presented in which adherence barriers impeded the use of over-the-counter laxatives, and a secretagogue laxative was implemented to manage clozapine-induced constipation. Case Report In 4 cases, lubiprostone or linaclotide was initiated, either as monotherapy or in combination with over-the-counter laxatives. Reasons for secretagogue laxative initiation included: (1) reducing a complex over-the-counter laxative regimen, (2) a lack of insurance coverage of over-the-counter laxatives, (3) dissatisfaction with polyethylene glycol’s palatability, and (4) cognitive impairment leading to decreased adherence to polyethylene glycol. Discussion It is important that clozapine-induced constipation is managed adequately to prevent severe consequences of gastrointestinal hypomotility. In addition to timely initiation and titration of constipation pharmacotherapy, adherence should be assessed. When adherence barriers to the use of over-the-counter laxatives are present, the use of a secretagogue laxative may be an option, recognizing there is limited evidence to guide this decision. Conclusion In these cases, adherence barriers to over-the-counter laxatives were identified. A secretagogue laxative was implemented, well-tolerated, and able to be continued for the duration of follow-up.

Summary Iron deficiency (ID) is often overlooked in patients with haematological malignancies due to other potential aetiologies. Daratumumab, an anti‐cluster of differentiation 38 (anti‐CD38) monoclonal antibody, is commonly used for treating multiple myeloma (MM) in the upfront and relapsed/refractory settings. Although anaemia is a common haematological toxicity associated with daratumumab, the contribution of ID in MM patients has not been systematically investigated. We conducted a retrospective case–control study to evaluate the prevalence of ID in newly diagnosed MM (NDMM) patients. Cases were patients receiving daratumumab, ixazomib, lenalidomide and dexamethasone (Dara‐IRD, n = 55). We compared this group with an age‐ and sex‐matched cohort of patients with NDMM who received bortezomib, lenalidomide and dexamethasone (VRD, n = 20) as induction therapy. At 1‐year, nearly 50% of Dara‐IRD‐treated patients met the criteria for ID (ferritin <30 mcg/L) compared with none of the VRD‐treated controls. All Dara‐IRD‐treated patients had a decrease in ferritin at 1‐year from baseline compared with only 45% of VRD‐treated patients. These findings identify a marked clinical signal of ID among NDMM patients receiving daratumumab‐based treatment. Although the study design does not establish causality or exclude regimen‐related confounding, it highlights the need for increased awareness of the importance of monitoring iron status in MM patients treated with daratumumab‐containing regimens.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is commonly encountered in older individuals. MGUS, by definition, is a benign finding where an expanded population of clonal plasma and B-cells produces a monoclonal antibody that is a biologically inactive. Even in patients with overt plasma cell neoplasms such as multiple myeloma, the monoclonal antibody is often a marker of disease burden but not pathogenic except in light chain cast nephropathy. However, there is a growing recognition that, in rare cases, clonal cells and/or monoclonal gammopathy not meeting criteria for hematologic malignancy can be pathogenic drivers of disease. These MGUS syndromes have been termed monoclonal gammopathies of clinical significance (MGCS), a larger umbrella under which sits the monoclonal gammopathies of renal significance (MGRS). In this review, we focus on MGCS entities beyond standard MGRS and provide a mechanism-based classification centered on the pathogenic nature of the paraprotein rather than on clonal disease burden. We highlight MGCS entities of relevance to nephrologists, including POEMS syndrome, TEMPI syndrome, monoclonal gammopathy-associated systemic capillary leak syndrome, and hematologic autoantibody-mediated disorders. Awareness and recognition of these rare processes are ultimately essential for accurate diagnosis and patient management.

Background: Ketamine and esketamine are increasingly used for treatment-resistant depression (TRD), yet their hepatic safety profile with repeated or long-term use remains poorly characterized. Chronic recreational ketamine abuse has been linked to cholestasis and cholangiopathy, raising concern that therapeutic use may carry similar risks. No systematic data exist on liver enzyme trajectories or biliary injury at subanesthetic doses used for depression. Methods: This historical cohort study included adults with TRD receiving IV ketamine or intranasal (IN) esketamine at the Mayo Clinic Ketamine Clinic (2017 to 2024). Patients were eligible if they had at least one liver enzyme value (AST, ALT, ALP, or bilirubin) within 12 months before through 3 months after treatment. Longitudinal enzyme trajectories were modeled using generalized linear-mixed models with a Gamma distribution. Clinically significant elevation was defined as ≥2× the upper limit of normal (ULN). Wilcoxon signed-rank tests compared pretreatment and post-treatment paired values. Results: Of 104 enrolled patients, 74 had liver enzyme data available; 51 had post-initiation data. Median age was 51.5 years; 72% were female. Most (78.4%) received IV ketamine. No clinically meaningful changes in enzyme trajectories were observed. Three patients (5.9%) had elevations ≥2× ULN, all attributable to alcohol use, myalgias, or pre-existing hepatic steatosis rather than (es)ketamine. Conclusions: Subanesthetic IV ketamine (0.5 mg/kg) and FDA-approved IN esketamine doses were not associated with clinically significant liver enzyme elevations in this real-world TRD cohort. Current evidence does not support routine hepatic monitoring for asymptomatic patients, although prospective, larger-scale studies are needed to confirm these findings.

Abstract Measurable residual disease (MRD) is a powerful prognostic tool in multiple myeloma, but predictors of achieving MRD negativity after autologous stem cell transplantation (ASCT) are not well defined. We studied 814 patients who achieved at least a very good partial response after ASCT between January 2016 and January 2023 and underwent MRD assessment by next-generation flow cytometry. Overall, 387 (48%) achieved MRD negativity after ASCT. The presence of t(11;14) (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.4–3.2; P&lt; .01) and pretransplant response less than complete remission (OR, 2.1; 95% CI, 1.2-3.7; P&lt; .01) independently predicted MRD positivity. Patients who were MRD positive had inferior progression-free survival (PFS; hazard ratio [HR], 1.99; 95% CI, 1.53-2.58; P&lt; .001) and overall survival (HR, 1.62; 95% CI, 1.10-2.28; P = .009). Despite lower MRD-negative rate, 5-year PFS was similar among t(11;14) MRD positive (58%) and patients who were MRD negative (63%; P = .12). In patients who were MRD negative, the 5-year PFS was 73% in those without ≥2 HRCA compared with 55% in those with ≥2 HRCA (HR 1.9, 95% CI 1.2–3.3; P = .01). In the MRD-positive cohort, 5-year PFS was 53% in patients without ≥2 HRCA vs 17% in those with ≥2 HRCA (HR, 2.4; 95% CI, 1.6-3.6; P&lt; .01). In addition, higher residual clonal plasma cell burden within MRD-positive disease was associated with inferior PFS (HR, 2.4; 95% CI, 1.2-6.9; P = .002). This study highlights that the presence of t(11;14) independently predicts MRD positivity after ASCT, although it does not significantly affect prognosis in this subgroup.

The Pulmonary Embolism Reporting and Data System (PE-RADS) provides a standardized framework for reporting acute pulmonary embolism at CT and MR angiography to guide treatment considerations based on clot location and right heart imaging features.

ABSTRACT Pulmonary hypertension (PH) comprises a heterogeneous group of disorders characterized by elevated pressure in the pulmonary arteries. Despite advances in awareness, utilization of non‐invasive screening with echocardiography, increasing number of targeted therapies, and evolving clinical guidelines emphasizing referral to PH specialty centers, barriers to timely diagnosis and treatment persist. Key challenges span patient‐related and system‐level domains that hinder the effective diagnosis, management, and treatment of PH, particularly pulmonary arterial hypertension (PAH). In this article, the obstacles to PH care are examined and actionable recommendations are proposed. By integrating patient‐related and system‐level perspectives, this review provides a framework to bridge persistent gaps in PH care delivery in the United States.

Abstract Extramedullary disease (EMD) is increasingly recognized in relapsed/refractory multiple myeloma (MM), with central nervous system involvement (CNS-MM) representing a rare but highly aggressive manifestation associated with dismal outcomes. Data on its incidence and optimal management, particularly in the era of cellular and bispecific therapies, remain limited. We conducted a retrospective analysis of patients with MM with pathology-confirmed EMD treated at our institution between January 2000 and December 2023. CNS-MM was defined by parenchymal or leptomeningeal involvement. Clinical features, cytogenetics, treatments, and outcomes were analyzed, with predictors of CNS involvement evaluated among patients with EMD. Among 304 patients with EMD, 20 (6.5%) had CNS-MM. CNS involvement occurred a median of 19.2 months after MM diagnosis, though 15% presented at diagnosis. CNS-MM was strongly associated with high-risk cytogenetics (odds ratio [OR], 3.7) and additional visceral EMD (OR, 4.6). Median overall survival (OS) from CNS-MM diagnosis was 4.2 months. Outcomes were significantly improved in patients receiving chimeric antigen receptor T-cell therapy or bispecific antibodies, with a median OS of 19.2 months vs 1.2 months in those who did not receive immune effector therapies. Intrathecal (IT) chemotherapy demonstrated limited and transient benefit. In conclusion, CNS-MM is an aggressive complication enriched in high-risk, multifocal EMD with extremely poor prognosis. Cellular and bispecific therapies show promising activity and may meaningfully improve survival, whereas IT therapy appears to have limited efficacy. Prospective studies are needed to define optimal treatment strategies for CNS-MM.