Citations

Genome-wide association studies (GWAS) of multiple myeloma (MM) in individuals of genetic European ancestry (EA) have identified 35 susceptibility loci. Co-heritability analyses have revealed a strong genetic correlation between MM and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous research validated the association between a polygenic risk score (PRS) based on 23 MM risk loci and the risk of MGUS. Went and colleagues recently reported 12 new MM risk loci. We constructed a MM-PRS using all 35 MM risk variants and assessed its association with MGUS. Additionally, among individuals with MGUS, we assessed associations of MM-PRS with established prognostic factors [M-protein (<0.2 g/dL; 0.2-1.5 g/dL; >1.5 g/dL); isotype (IgG, IgA, IgM); free light chain (FLC) ratio (Normal (0.26-1.65), Abnormal (<0.26 or >1.65))]. Our study population included 1,723 individuals with MGUS seen at Mayo Clinic, Rochester, MN and 14,175 controls from the Mayo Clinic Biobank who lived in the 27-county region around Rochester, MN, and screened negative for MGUS using MALDI-TOF MS. The majority of MGUS patients and controls were of EA. We used logistic or multinomial regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). All models were adjusted for age, sex, and the first three principal components. The MM-PRS was significantly associated with MGUS when assessed continuously (OR, 1.28 per standard deviation (SD); 95% CI, 1.22-1.35). When comparing to the middle quintile of the MM-PRS distribution, individuals in the highest quintile had 1.41-fold increased risk of MGUS (95% CI, 1.21-1.64), and individuals in the lowest quintile had 0.68 decreased risk of MGUS (95% CI, 0.57-0.81). Of the 35 SNPs evaluated, 27 demonstrated consistent directions of effect for risk of MGUS with published risk estimates for MM. The effect of MM-PRS differed by isotype (P = 2.2 x 105), with higher MM-PRS associated with IgA MGUS (OR, 1.40 per SD; 95% CI, 1.08-1.81) and a lower MM-PRS associated with IgM (OR, 0.66 per SD; 95% CI, 0.52-0.84) compared to IgG MGUS. The MM-PRS was higher in MGUS patients with M-protein > 1.5 g/dL compared to M-protein of size 0.2-1.5 g/dL, although not statistically significant (OR, 1.41 per SD; 95% CI, 0.95-2.08); there were no differences in the MM-PRS between MGUS patients with M-protein size <0.2 g/dL compared to 0.2-1.5 g/dL (OR, 1.01 per SD;95% CI, 0.81-1.26). There were also no differences in MM-PRS by FLC ratio, (OR, 0.95 per SD; 95% CI, 0.852-1.10 for abnormal vs. normal). Our findings of an association of the MM-PRS with risk of MGUS provides further evidence for shared heritability between MGUS and MM. Future studies are needed to examine whether the expanded MM-PRS adds to existing models for MGUS progression. Citation Format: Angelica Macauda, Alyssa Clay-Gilmour, Cristine Allmer, Danelle Moonen, Aaron D. Normann, Nicholas J. Boddicker, Joselle M. Cook, Linda Baughn, Elizabeth E. Brown, Vincent S. Rajkumar, Esteban Braggio, David L. Murray, Susan L. Slager, Shaji Kumar, Celine M. Vachon. Implications of multiple myeloma polygenic risk scores (PRS) for MGUS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2274.

PURPOSE Cytokine release syndrome (CRS) of any grade occurs in 56%-80% of bispecific antibodies (BsAbs) used in multiple myeloma (MM). Risk mitigation strategies are required to expedite escalation of care if toxicities develop. The rarity of grade 3 or 4 CRS compels protocolized outpatient management of BsAbs as outpatient practice may avoid hospital admissions and costly resource utilization without compromising safety. MATERIALS AND METHODS Patients with MM who received BsAb step-up dosing (SUD) from August 23, 2023, to March 29, 2024, were enrolled. Baseline demographics, patient outcomes, and CRS management were reviewed to assess the safety of outpatient practice. Resource utilization was also analyzed. RESULTS In this study, 34 patients received outpatient SUD of BsAbs (teclistamab n = 17, talequetamab n = 17) with 16 remaining outpatient throughout the entire SUD period. CRS occurred in seven patients who did not require hospitalization, demonstrating the safety of outpatient management of BsAb toxicity, regardless of low-grade CRS. CRS was observed in 24 patients (maximum grade 2) and immune effector cell–associated neurotoxicity syndrome in four patients (maximum grade 3). All patients with CRS received steroids, including 12 patients at home when instructed. Tocilizumab was given to 13 patients, accounting for 18 doses. If all doses of BsAbs and tocilizumab were given outpatient, the medication margin would be $115,004 in US dollars (USD). CONCLUSION An outpatient-based practice for BsAb administration demonstrated safety and cost savings. The description of our practice and results of this study provide valuable insights into the safety, feasibility, and resource stewardship of outpatient management of BsAbs. Future research should attempt to predict and stratify CRS risk to deliver a tailored supportive strategy and continued increase of outpatient management.

Abstract Lineage switch (LS), defined as the immunophenotypic transformation of acute leukemia, has emerged as a mechanism of relapse after antigen-targeted immunotherapy, which is associated with dismal outcomes. Through an international collaborative effort, we identified cases of LS after a host of antigen-targeted therapies (eg, CD19, CD22, CD38, and CD7), described how LS was diagnosed, reviewed treatment approaches, and analyzed overall outcomes for this form of postimmunotherapy relapse. Collectively, 75 cases of LS were evaluated, including 53 (70.7%) cases of B-cell acute lymphoblastic leukemia (B-ALL) transforming to acute myeloid leukemia (AML), 17 (22.7%) cases of B-ALL transforming to mixed phenotypic acute leukemia (MPAL)/acute leukemias of ambiguous lineage (ALAL), and 5 (6.7%) cases of rare LS presentation (ie, T-cell ALL to AML). An additional 10 cases with incomplete changes in immunophenotype, referred to as “lineage drift” were also described. With a primary focus on the 70 cases of LS from B-ALL to AML or MPAL/ALAL, LS emerged at a median of 1.5 months (range, 0-36.5) after immunotherapy, with 81.4% presenting with LS within the first 6 months from the most proximal immunotherapy. Although most involved KMT2A rearrangements (n = 45, 64.3%), other rare cytogenetic and/or molecular alterations were uniquely observed. Treatment outcomes were generally poor, with remission rates of <40%. The median overall survival after LS diagnosis was 4.8 months. Outcomes were similarly poor for those with rare immunophenotypes of LS or lineage drift. This global initiative robustly categorizes lineage changes after immunotherapy and, through enhanced understanding, establishes a foundation for improving outcomes of LS.

Summary: Facial synkinesis manifests as involuntary muscle movements alongside volitional facial actions and is typically managed with a combination of neuromuscular retraining, botulinum toxin injections, and in some cases, selective neurectomy. Some patients with synkinesis describe persistent neck tightness or pain at the level of the mandibular angle and horizontally towards the midline, similar to the anatomic course of the posterior belly of digastric (PBD) and stylohyoid muscles. There are limited studies exploring the involvement of the PBD and stylohyoid muscles in facial synkinesis and the use of chemodenervation as treatment. Herein, we present 2 patients with facial synkinesis and ipsilateral neck tightness and pain who underwent novel surgical treatment in the form of the standard selective neurectomy procedure along with a myectomy of the PBD and stylohyoid muscles. Following completion of the standard steps of selective neurectomy, the PBD and stylohyoid muscles were carefully dissected and separated from the surrounding structures. Both muscles were divided using bipolar electrocautery. Both patients reported improvement of neck pain and tightness immediately after the intervention and at the 6.5-month follow-up visit. These preliminary results show promise in aiding a subset of patients with synkinesis-related neck pain and tightness.

Fungal pericarditis is a rare disease but its incidence has risen in parallel with the global increase in invasive fungal infections. This systematic review analyzes data from previously reported cases of fungal pericarditis to provide an improved understanding of the etiology, clinical presentation, management, and outcomes of this rare disease. We reviewed Medline and Scopus databases from 1 January 1990 to 29 January 2024 for case reports that documented the isolation of a fungal pathogen from pericardial fluid or tissue. Of the 2330 articles screened, 101 cases met the inclusion criteria. Patients with fungal pericarditis and the involvement of at least one other organ—usually the lungs, brain, or kidney—had worse outcomes than patients with isolated pericardial disease. Immunosuppression was reported in 50% of cases and was associated with worse outcomes in adults. Patients who presented with chest pain, received adequate empiric antifungal therapy, and underwent pericardiocentesis and pericardiectomy had improved survival. The most common isolated pathogens were Candida spp., followed by Aspergillus spp. and Mucor spp., with the latter two linked to worse outcomes. Only 35% of patients received empiric antifungal medications before the causative pathogen was identified, and mortality was associated with a delay in appropriate therapy. Immunosuppression, disseminated disease, and presence of shock/multiorgan failure were additional risk factors associated with death. Fungal pericarditis carries a mortality rate of up to 50%, with nearly half of patients being immunocompromised. Clinicians frequently do not consider fungal pericarditis in the differential diagnoses, which leads to delays in treatment and poorer outcomes. Further prospective multicenter studies are urgently needed to better understand the epidemiology, improve diagnostic testing and management, and decrease unacceptably high mortality in patients with fungal pericarditis.