Citations

Summary Evidence for an association between insulin‐like growth factors (IGF) and multiple myeloma (MM) is inconsistent. We examined total IGF‐I concentrations and risk of MM by combining baseline serological data among UK Biobank participants ( n = 444 187; 732 incident MM) with a two‐sample Mendelian randomisation (MR) analysis using identified genetic variants associated with circulating total IGF‐I and IGF‐binding protein 3 (IGFBP‐3) in the InterLymph consortium (2434 MM and their 2567 controls). Finally, additional lymphoid neoplasm (LN) subtypes were included for comparison with the main hypothesis. Circulating IGF‐I level was positively associated with MM risk Hazard ratio‐HR‐per one standard deviation‐SD‐increase (HR 1‐SD = 1.11, 95% confidence interval [CI]: 1.01–1.22; p ‐value = 0.03), especially closer to diagnosis. Genetically inferred IGF‐I levels were associated with increased MM risk (odds ratio [OR] = 1.27, 95% CI: 1.05–1.54) but not with any other LNs. Genetically inferred IGFBP‐3 levels showed no associations with any LN evaluated. Corroborating previous findings, in a secondary analysis, IGF‐I levels were associated with the risk of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) in males with higher body mass index (HR 1‐SD in obese male = 1.36, 95% CI: 1.14–1.61). Our serological and MR analyses suggest a contributing role of IGF‐I in the susceptibility of MM; the CLL/SLL findings warrant further investigation considering sex‐specific adiposity.

Abstract Frailty predicts adverse outcomes in multiple myeloma (MM), yet an objective frailty biomarker is lacking. Circulating senescence-associated secretory phenotype (SASP) factors correlate with frailty and adverse outcomes in chronic diseases, but their relevance in MM is unclear. In this study, we investigated the relationship between 36 plasma SASP factors, frailty, and clinical outcomes in: (1) a historical cohort using stored specimens from 59 patients with newly diagnosed MM, and (2) a prospective cohort of 36 patients initiating new MM treatment. Several SASP factors were significantly associated with frailty after adjusting for age, sex, and body mass index; GDF-15, TNF-RI, IL-6, and IL-8 showed positive correlations with both cumulative-deficit based and physical frailty indices. Additionally, significant age-adjusted associations were observed between SASP factors and treatment outcomes, including overall survival (OS), high-grade toxicity, and healthcare utilization. We developed a 5-factor SASP model that demonstrated superior predictive performance for OS compared to chronological age, R-ISS stage, and clinical frailty, and TNF-RI alone (5-year OS AUC: 0.90). These findings highlight the association between senescence biomarkers and frailty and OS, and support further investigation of SASP factors as objective frailty biomarkers in MM.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is a necessary precursor condition to multiple myeloma (MM). Given the role of autophagy in modulating MM risk, we investigated whether genetic variation in autophagy‐related genes influences susceptibility to MGUS. We analyzed the association of 34,042 common autophagy‐related single nucleotide polymorphisms (SNPs) with MGUS across six independent cohorts, five from Europe and one from North America, comprising 2317 MGUS cases and 282,358 controls. We also assessed their impact on immune parameters, including absolute counts of 91 blood‐derived immune cell subsets and 103 circulating immunological proteins. Meta‐analysis revealed a genome‐wide significant association between the ULK4 rs6599175C allele and increased MGUS risk ( p = 3.35 × 10 −8 ). Carriers of this allele showed reduced counts of memory B cell subsets (IgM+CD38+CD27+ and IgD+IgM+CD27+; p = .0038 and p = .0056, respectively) and natural effector B cells (CD24+CD38+IgD+IgM+ cells; p = .0060). Although these associations were not statistically significant after multiple testing correction, they suggest a role of ULK4 in early B‐cell differentiation. Additionally, the CDKN2A rs2811710 variant showed a suggestive association with MGUS risk ( p = 2.17 × 10 −4 ), affecting transcription factor binding involved in B‐cell proliferation and differentiation, although it lacked association with immune markers. In conclusion, we confirm a genome‐wide significant association of the ULK4 locus and MGUS risk, supporting its role in early B‐cell differentiation, and identify CDKN2A as a candidate susceptibility locus warranting further investigation.

Extramedullary presentations of multiple myeloma (MM) involving the central nervous system (CNS) carry a dismal prognosis. Although historically rare, management of extramedullary disease—including CNS manifestations—has become increasingly clinically relevant as advances in systemic therapies have prolonged control of medullary disease. CNS manifestations may occur across a variety of clinical settings and at different time points throughout the disease course. Common symptoms include visual changes, headaches, loss of sensation, confusion, and seizures. MRI identifies leptomeningeal enhancement and/or parenchymal lesions in approximately 90% of cases, and lumbar puncture with cerebrospinal fluid testing for clonal plasma cell populations is confirmatory. Encouragingly, the incorporation of novel therapeutic agents has improved historically poor outcomes in CNS MM. Novel immunotherapeutic approaches using CAR T-cell therapy and bispecific T-cell–engaging antibodies have recently demonstrated significant efficacy in consolidating responses. Multimodality treatment strategies incorporating intrathecal chemotherapy, systemic novel agents, radiation therapy, and immunotherapy hold promise for achieving more durable responses in this devastating manifestation of MM.

ABSTRACT Systemic AL amyloidosis is a clonal plasma cell dyscrasia, where toxic free light chains (FLCs) lead to vital organ damage, with risk of early mortality despite effective therapies. Notably, there is a paucity of data on the incidence and predictors of early mortality in the daratumumab (Dara) era. We conducted a multi‐center retrospective cohort study to develop and validate a risk‐prediction model for early mortality (all‐cause death within 6 months) in patients treated with Dara‐based frontline regimens. We used univariate analysis to identify covariates for a logistic regression model predictive of 6‐month mortality and generated a clinical risk score. Among 339 patients across eight centers, 36 (10.6%) experienced early mortality. Multivariate analysis identified four independent predictors: NT‐proBN P > 5300 pg/mL (odds ratio [OR] 3.83, p = 0.006), A ge > 75 years (OR 2.96, p = 0.073), absence of t(11;14) on C ytogenetics (OR 3.0, p = 0.022), and E COG performance status (OR 1.72 per unit increase, p = 0.044). The resulting PACE score stratified patients into three risk groups with a 6‐month mortality of 1.2% (low‐risk), 11.7% (intermediate‐risk), and 50.0% (high‐risk). The PACE score demonstrated superior discrimination (C‐index 0.78) for early mortality compared to Mayo 2004 (0.69) and Mayo 2012 (0.55) staging systems. External validation confirmed robust discrimination (C‐index 0.73) with corresponding 6‐month mortality rates of 4.2%, 15.25%, and 37.04% across respective risk groups. The PACE score provides a clinically applicable tool for early mortality risk stratification in AL amyloidosis patients receiving Dara‐based therapy, and will enable improved patient counseling, clinical trial design, and identification of ultra‐high‐risk patients requiring intensive monitoring and novel therapies.

Abstract Patients with multiple myeloma have an elevated risk of severe complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) infection. To demonstrate proof of concept for a pandemic preparedness and response network, the American Society of Hematology Research Collaborative Multiple Myeloma Program developed a prospective, decentralized study within a site-based provider network. In the COVID-19 outcomes in myeloma and the impact of vaccines (COSMIC) study, patients provided consent, permitted electronic health record data collection, completed patient-reported outcomes at baseline, day 30, and day 180 through an electronic study portal, and were compensated for participation. Clinicians at participating sites facilitated study recruitment and shared best practices monthly to accelerate study execution. The COSMIC study rapidly consented 201 patients from 8 participating sites over 4 months (22 January 2024 through 17 May 2024). Consented participants were 30 to 93 years old, with a median age of 67; 46% were female, 69% were non-Hispanic White, 17% were non-Hispanic Black, and 8% were Hispanic/Latino. Patient-reported data completion was 97% at baseline, 81% at 1 month, and 79% at 6 months. At baseline, 55% of patients reported a history of COVID-19 infection and had received a median of 4 SARS-CoV-2 vaccines. For all patients, there were an additional 18 COVID-19 infections and 57 vaccines received during the 6-month observation period. There were no significant differences in health-related quality of life over time or by history of COVID-19 infection. COSMIC demonstrates the feasibility of an innovative evidence generation strategy to drive rapid accrual of patients to address an evolving area of need. This trial was registered at www.clinicaltrials.gov as #NCT05831787.

Abstract Progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is driven by coordinated metabolic reprogramming within clonal plasma cells and the bone marrow microenvironment. We applied high-resolution MALDI–FT-ICR mass spectrometry imaging (MSI) to archived FFPE bone-marrow biopsies, integrated with matched bone marrow plasma metabolomics, to map spatial and systemic metabolic alterations. Spatial clustering delineated plasma-cell–rich niches, while Hill-based diversity and β-diversity metrics quantified intra- and inter-compartment heterogeneity. MM niches exhibited elevated 3-hydroxykynurenine, rewired tryptophan–kynurenine flux, and increased nucleotide and bioactive lipid metabolism associated with proliferation. Notably, some MGUS-like samples displayed MM-like metabolic niches undetectable in bone marrow plasma alone, underscoring spatial heterogeneity. Cross-compartment integration revealed conserved metabolic signatures and systemic redistribution of key metabolites, consistent with ecological reorganization and niche divergence during progression. These findings establish spatial metabolomics of biopsies as a framework to dissect intramedullary metabolic heterogeneity and enable metabolite-based risk stratification in plasma-cell disorders.