Citations

Background: Perinatal and early-life factors may influence non-Hodgkin lymphoma (NHL) risk, but study results have been mixed and exposure data for childhood ages are limited. Herein, we investigated associations of these exposures with risk of NHL and common subtypes. Methods: This case–control study included 2280 NHL cases and 2253 controls, enrolled from 2002 to 2014 at the Mayo Clinic Rochester. Self-reported perinatal and early-life exposures included maternal age at birth, birth order, birthweight, time breastfed, height and weight at ages 7, 12, and 18 years relative to peers, and age and weight when growth ceased. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for design variables and potential confounders. Linear trend tests were performed for ordinal variables, and heterogeneity tests were performed to evaluate whether associations varied across four NHL subtypes. Results: After multivariable adjustment, greater birth weight (OR = 1.15 for quartile 4 vs. 1; p-trend = 0.04), weight at age 7 relative to peers (compared to average, OR = 1.05 for heavy and OR = 0.87 for thin; p-trend = 0.002), and weight when growth ceased (OR = 1.30 for quartile 4 vs. 1; p-trend < 0.001) were associated with increased NHL risk. An inverse association was observed for breastfeeding duration with NHL risk (OR = 0.77 for >6 months vs. never; 95% CI 0.61–0.97). Associations did not significantly vary by major NHL subtype (p-heterogeneity > 0.05). Other perinatal and early-life exposures were not associated with NHL risk. Conclusions: Greater body weight at birth and through childhood may be associated with increased NHL risk, potentially extending the life-course perspective on adiposity and lymphomagenesis, with implications for prevention.

Abstract Background: Although some vaccines seem to be associated with a lower risk of lymphoma, their impact on outcomes is largely unknown. Methods: Data from a large prospective lymphoma cohort study were utilized to estimate associations of self-reported history of vaccination against hepatitis A, hepatitis B, influenza, and yellow fever with event-free survival (EFS) and overall survival (OS) using Cox proportional hazard models. Results: None of the vaccines were associated with EFS [hazard ratio (HR) 0.77–1] or OS (HRs 0.96–1.04). Similarly, there were no significant associations between the vaccines and outcomes for each lymphoma subtype. Conclusions: Prior vaccination against selected viruses was not associated with EFS or OS among patients with lymphoma. Impact: We did not find evidence for an impact of prior vaccination on lymphoma prognosis.

Abstract Glioblastoma (GBM), isocitrate dehydrogenase wild-type (IDHwt) and central nervous system diffuse large B-cell lymphoma (CNS-DLBCL) are aggressive brain tumors with overlapping MRI features, yet distinct treatment approaches. Noninvasive tools are needed to aid in differential diagnosis. Deep learning on T1 postcontrast and T2-weighted MRI sequences were used to differentiate GBM and CNS-DLBCL. A three-stage temporal study design was utilized. Model development was performed on 146 patients with CNS-DLBCL and 146 age-matched, sex-matched, and MRI year–matched patients with GBM diagnosed at Mayo Clinic between 1998 and 2019. Models were tested on independent temporal test cohorts. Initial testing included 240 independent GBM diagnosed at Mayo Clinic between 1998 and 2019. The prospective test cohort included 37 patients with CNS-DLBCL and 256 patients with GBM diagnosed at Mayo Clinic after January 1, 2020, and 36 patients with CNS-DLBCL diagnosed at an external institution. Of the patients diagnosed at Mayo Clinic, 47% had MRIs generated from non-Mayo institutions. Two different model approaches were compared: (i) ensemble approach using area under the receiver operating characteristic curve (AUC) and cross-validation for model selection and (ii) loss approach minimizing cross-entropy loss and cross-validation to evaluate prediction performance. The AUCs on the prospective test cohort were 0.84 [95% confidence interval (CI), 0.78–0.90] and 0.83 (95% CI, 0.77–0.88) for the ensemble and loss approaches, respectively. Stability of ensemble prediction improved with the increasing number of models. Stratified AUC analysis demonstrated consistent performance across sex and age. We utilized a robust temporal study design and applied 2 different analytic approaches to develop a classification model. The findings confirm the feasibility of using MRI-based deep learning models to differentiate GBM from CNS-DLBCL. Significance: GBM, IDHwt and CNS-DLBCL are aggressive brain tumors with overlapping MRI features, yet distinct treatment approaches. Noninvasive tools are needed to aid in differential diagnosis. We developed MRI-based deep learning models to differentiate GBM, IDHwt from CNS-DLBCL using a rigorous three-stage temporal design that included prospective validation. The model AUC on a prospective cohort was 0.84.

Abstract Prognostic indices such as the CLL International Prognostic Index (CLL-IPI) and the International Prognostic Score for Early-stage CLL (IPS-E) can predict time to first treatment (TTFT) in patients with early-stage CLL. Their ability to predict risk of infection - a leading contributor to morbidity and mortality in CLL - remains uncertain. The CLL-TIM is a machine-learning model developed in Europe that integrates clinical, laboratory, and infection-related data to predict TTFT or infection risk within 2-years of diagnosis, Receiver Operating Characteristic - Area Under the Curve (ROC-AUC) 0.74; Agius et al., Nat Comm 11, 363 2020. We conducted the first validation of CLL-TIM in a US cohort of newly diagnosed CLL patients and compared its performance with the CLL-IPI and IPS-E indices. Adults with newly diagnosed CLL (2000-2020) were identified through the Rochester Epidemiology Project using International Classification of Disease (ICD) codes; all diagnoses were confirmed. We replicated the variable selection from the original CLL-TIM model and applied it to our cohort. The primary endpoint was a 2-year composite of either TTFT or incident infection (defined as having blood cultures drawn). Model performance was evaluated using ROC-AUC consistent with the original CLL-TIM methods. CLL-IPI and IPS-E performance was assessed using time-dependent ROC-AUC; pairwise differences in discrimination were tested using DeLong. We identified 454 CLL patients with a median age of 72 years [range, 30-97], 166 (37%) were female, Rai Stage was 0-II in 399 (92%) patients. IGHV genes were unmutated in 130/305 (42%) patients and TP53 disruption (either del17p by FISH or TP53 mutation) was present in 24/329 (8%) patients. At 2-years, 55 (12%) patients received CLL therapy, and 56 (12%) patients had an infection. The 2-year composite endpoint was observed in 94 (21%) patients. The ROC-AUC was 0.74 (95% CI 0.68-0.80) for CLL-TIM, 0.69 for CLL-IPI (95% CI 0.63-0.75, p=0.11 compared to CLL-TIM) , and 0.68 for IPS-E (95% CI 0.62-0.74, p=0.02 compared to CLL-TIM). We also evaluated the ROC-AUC using all the prognostic models for each individual endpoints. The corresponding ROC-AUC for TTFT at 2 years were 0.79, 0.74, and 0.76 for CLL-TIM, CLL-IPI, and IPS-E, respectively; and for infection at 2 years were 0.68, 0.57, and 0.52, respectively. This is the first validation of the CLL-TIM in a US-based cohort of newly diagnosed CLL patients. Although the CLL-TIM model exceeded the minimally meaningful discrimination threshold (AUC &gt;0.7) for individual patient-level risk prediction, there was no statistical difference in AUC between CLL-TIM and CLL-IPI, suggesting either model can predict the composite endpoint at 2 years. Most of the observed discrimination was driven by prediction of TTFT rather than infection, underscoring the need to develop more infection-specific risk models for newly diagnosed CLL. Citation Format: Raphael Mwangi, Tait D. Shanafelt, Soren Basnet, Emily L. West, Owen Keegan, Timothy G. Call, Yao Yuan, Bryan Alexis Vallejo, Paul J. Hampel, Lindsey E. Roeker, Yucai Wang, Saad J. Kenderian, Sara J. Achenbach, Aaron D. Norman, Kari G. Rabe, Neil E. Kay, James R. Cerhan, Curtis A. Hanson, Susan L. Slager, Sameer A. Parikh. Validation of the CLL treatment infection model (CLL-TIM) in patients with newly diagnosed chronic lymphocytic leukemia (CLL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4228.

Abstract Background: CLL incidence differs by ancestry, with higher rates in individuals of European ancestry (EA) than African ancestry (AA). The contribution of epigenetic variation to these disparities remains unclear. We investigated chromatin accessibility, histone modifications, and gene expression in CLL patients of EA and AA to identify ancestry-associated epigenetic signatures. Methods: ATAC-seq was performed on blood clonal B cells from 15 AA and 51 EA patients; CUT&Tag profiling of six histone marks (H3K4me1, H3K4me3, H3K27ac, H3K9me3, H3K27me3, H3K36me3) was done in 8 AA and 12 EA cases; RNA-seq was generated for all samples. Ancestry was genetically confirmed. Differential regions were linked to genes using ENCODE and Hi-C datasets. Results: ATAC-seq revealed 4,955 regions with increased and 3,000 with decreased accessibility in AA vs EA (fold change &gt;2, FDR ≤0.05). Regions with increased accessibility mapped to 2,313 genes; 599 were upregulated and enriched in TNF-α/NF-κB (p=1.40E-53) and apoptosis pathways (p=6.90E-11). Regions with decreased accessibility linked to 1,953 genes; 317 were downregulated, enriched in interferon-γ response (p=1.04E-03) and IL-6/JAK/STAT3 signaling (p=6.41E-03). Histone profiling showed ancestry-specific changes across all marks. For H3K27ac (active enhancer), 68 genes with a decreased signal in AA were downregulated and enriched in interferon-γ (p=1.55E-06) and IL-6/JAK/STAT3 (p=9.62E-05) pathways. Increased H3K27me3 (repressive histone modification) in AA affected 399 genes enriched in IL-6/JAK/STAT3 (p=8.13E-09) and interferon-γ (p=2.48E-05) pathways. These findings suggest coordinated regulation by active and repressive chromatin states. Conclusions: Despite limited sample size, this study suggests differences between AA and EA ancestries may exist in epigenetic signatures in CLL, implicating chromatin accessibility and histone modifications in pathways relevant to tumor biology. These signatures may also contribute to the differences in CLL incidence by ancestry. Future studies with more patients and functional validation experiments are needed to clarify the role of these epigenetic differences in CLL pathogenesis. Citation Format: Zhiquan Wang, Huihuang Yan, Mingma Sherpa, Daniel Bihnam, Cristine Allmer, Chantal McCabe, Daniel O’Brien, Dennis P. Robinson, James R. Cerhan, Neil E. Kay, Sameer A. Parikh, Esteban Braggio, Susan Slager. Ancestry-associated epigenetic differences in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5064.

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive and rare B-cell non-Hodgkin lymphoma with poor prognosis, even with treatment. Despite its clinical importance, the etiology of MCL remains largely unknown. Some studies have reported a positive association with family history, suggesting that genetic factors could contribute to risk. Methods: To identify germline genetic variants associated with risk, we conducted the first genome-wide association studies (GWAS) and GWAS meta-analysis for MCL, comprising 1,163 cases and 61,271 controls. The most significant loci were taken forward for replication in three independent studies, including 576 cases and 771,773 controls. To identify potential target genes and pathways of discovered loci, we conducted F-MAGMA, colocalization, and transcriptome-wide association study (TWAS) analyses. To gain insight into underlying regulatory mechanisms, we performed integrative epigenomic analyses using DNase I hotspots and histone mark ChIP-seq data across diverse cell types applying the FORGE2 framework. Results: In the joint analyses, we identified eight genome-wide significant loci (P&lt;5x10-8) associated with MCL risk, several of which were located near genes with known DNA repair (ATM), telomere (TERT), or RNA-binding functions (RBM20). Further analyses using F-MAGMA, which uses DNase-seq data to prioritize genes from GWAS, identified genes that were significantly associated with risk, including SP140, a chromatin reader and immune regulator of pathogen response. This gene also displayed strong colocalization with our lead variant in whole blood (COLOC posterior probability PP4=0.97). TWAS demonstrated significant associations with SP140 and ACTA2, which has been linked to cell proliferation (P&lt;3x10-6). Enrichment for DNase I hotspots was observed in B and T lymphocytes (q-value&lt;0.05), providing evidence for a role in immune cell-specific regulatory regions. Enrichment for enhancer-associated histone mark H3K4me1 was observed in B cells (q-value&lt;0.01), highlighting a role for immune cell-specific enhancers. Transcription factor (TF) motif enrichment analysis pointed to TFs critical for B-cell development and differentiation, notably TCF3 and EP300 (q&lt;0.01 for both), suggesting an association between B-cell lineage regulation and MCL risk. Finally, genome-wide SNP-based heritability was estimated to be 17%, underscoring the importance of common variants in MCL risk. Conclusion: Our study provides novel insight into the inherited susceptibility of MCL by identifying eight significant loci and estimating substantial common variant heritability. These findings highlight a role for several distinct biological pathways -specifically DNA repair, telomerase function, and B-cell differentiation- in the etiology of MCL, offering new targets for mechanistic investigation. Citation Format: Charles E. Breeze, Alyssa Clay-Gilmour, Hanla A. Park, Ólafur B. Davíðsson, Angelica Macauda, Brenda M. Birmann, Elizabeth E. Brown, Murat Güler, Michelle A. T. Hildebrandt, Alexandra Nieters, Krystle Ong, Jojo Biel-Nielsen Dietz, Karin E. Smedby, Karl Smith-Byrne, Rosalie Griffin, Sophia S. Wang, Susan Slager, James R. Cerhan, Jonathan N. Hofmann, Qing Lan, Nathaniel Rothman, Ingrid Glimelius, Henrik Hjalgrim, James Mckay, Sonja I. Berndt. Genome-wide association study of mantle cell lymphoma identifies novel loci suggesting a critical role for B-cell chromatin readers and DNA repair mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3602.

Abstract Background. Genome-wide association studies (GWAS) have identified 35 genetic susceptibility single-nucleotide polymorphisms (SNPs) for multiple myeloma (MM) in individuals of European ancestry (EA) and shown strong genetic correlation between MM and its precursor, monoclonal gammopathy of undetermined significance (MGUS). We evaluate the contribution of the 35 MM variants to MGUS susceptibility overall and by prognostic subgroups. Methods. The study included 20,756 participants (14,486 controls, 1,883 with MGUS, and 2,163 with MM) from the Mayo Clinic. Logistic regression assuming an additive model estimated odds ratios (ORs) and 95% confidence intervals (CIs) for individual SNPs and for the MM-PRS, adjusted for age, sex, study, and principal components. The PRS was a weighted sum of 35 SNPs with effect estimates from the largest MM GWAS and was modeled continuously (per SD) and by quintiles (Q1-Q5). SNPnexus annotated variants that replicated in MGUS (P &lt; 0.05 and OR &gt; 1.01) versus those that did not (P &gt; 0.05 and OR &lt; 1.01). Results. The 35-SNP MM-PRS was strongly associated with MM risk and modestly with MGUS. Compared with the middle quintile (Q3), MM odds rose from OR=0.55 (CI=0.46-0.65, P=2.2e-11) in Q1 to OR = 1.82 (CI=1.59-2.09, P=6.2e-18) in Q5. MGUS showed a similar, attenuated pattern (Q1 OR = 0.74, CI=0.64-0.84, P=6.4e-6 / Q5 OR=1.36, CI=1.21-1.53, P=3.4e-7). Each SD increase in PRS corresponded to OR=1.52 (CI=1.45-1.59, P=1.3e-66) for MM and OR = 1.22 (CI=1.18-1.27, P=1.0e-23) for MGUS. Higher PRS values were linked to larger M-protein ((0.1-1.5 g/dL: OR=1.40, CI=1.18-1.65, P=5.8e-12) vs &lt;0.1 g/dL: OR = 1.19, CI=1.13-1.24, P=5.8e-12)) and abnormal free light chain (FLC) ratio ((OR = 1.33, CI=1.21-1.46, P=1.0e-9) vs normal ratio (OR=1.19, CI=1.14-1.25, P=1.4e-13)). Ten risk loci replicated in MGUS, mapping to genes involved in plasma-cell function, immune regulation, and DNA repair and enriched for Rho GTPase signaling, NF-κB-mediated apoptosis, and RNA polymerase II transcription, implicating early plasma-cell activation and transcriptional control. The 12 non-replicating loci, including PHC3, ATG5, and NFIC, mapped to genes involved in chromatin remodeling, autophagy, and SUMOylation, suggesting roles in stress response and genomic maintenance. Conclusions. The MM-PRS captures shared heritability between MM and MGUS and correlates with MGUS subtype and severity. Replicating variants highlight immune and cell-cycle pathways relevant to MGUS onset, whereas non-replicating loci cluster in DNA-repair and stress-response processes, underscoring their potential role in progression. Citation Format: Alyssa Ione Clay-Gilmour, Angelica Macauda, Cristine Allmer, Danelle Moonen, Aaron D. Norman, Nicholas Boddicker, Janet E. Olson, Elizabeth E. Brown, Vincent S. Rajkumar, Esteban Braggio, David Murray, Susan Slager, Shaji Kunnathu Kumar, Celine Vachon. Implications of multiple myeloma polygenic risk scores (PRS) for MGUS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3603.

Abstract Background: Hypogammaglobulinemia at the time of CLL diagnosis predicts shorter time to first therapy (TTFT). However, the depth of immunoparesis and its impact on TTFT in newly diagnosed MBL/CLL remains unexplored. Methods: We identified previously untreated MBL/CLL patients from Mayo Clinic CLL Database (2000-2024) who had serum immunoglobulin (Ig; IgG, IgM and IgA) and monoclonal protein assessed within 1 year of diagnosis. Immunoparesis was evaluated: a) qualitatively by classifying patients into preserved, partial and full Ig suppression, based on the number of suppressed Igs; and b) quantitatively by calculating the average relative difference (ARD), defined as the mean percentage below normal for all Igs. For both methods, only uninvolved Igs were considered for those with monoclonal protein. TTFT was estimated by Kaplan-Meier with competing risk of death. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI). Results: Among 1420 patients, median age at diagnosis was 65 (range 28-96); 954 (67%) were male; 493 (44.8%) had unmutated IGHV, and 86 (6.8%) had TP53 disruption. The median [range, mg/dL] serum IgG, IgA, and IgM were 889 [111-5290], 132 [1-4880], and 49 [4-9480]. Low IgG was present in 472 (33.2%), low IgA in 223 (16.4%), and low IgM in 530 (37.3%) patients. An M-spike was detected in 122 (8.6%) patients; distribution was: IgG (73), IgM (30), IgA (6), or multiple (13). By qualitative assessment, preserved Ig were seen in 664 (46.8%), partial Ig suppression in 604 (42.5%), and full suppression in 152 (10.7%) patients. By quantitative assessment, median ARD was 0.6 (-0.8 to 11.3); 280 (19.7%) patients had negative ARD, and 1140 (80.3%) had positive ARD. In those with negative ARD, 128 (9%) had partial Ig suppression and 152 (10.7%) had full Ig suppression; in those with positive ARD, 664 (46.8%) had preserved Ig and 476 (33.5%) had partial Ig suppression. Median follow-up was 14.7 years; 510 patients progressed requiring therapy. Median TTFT was 9.6 years. Median TTFT for patients with preserved Ig was 12.6 years, 8.0 years for partial Ig suppression (HR 1.4, 95%CI 1.1-1.7), and 1.8 years for full Ig suppression (HR 3.1, 95%CI 2.4-4.0). The median TTFT was 2.3 and 12.1 years for patients with negative vs positive ARD; negative ARD was associated with shorter TTFT (HR 2.4, 95%CI 2.0-2.9). After adjusting for sex and CLL-International Prognostic Index (CLL-IPI) score, full Ig suppression (HR 2.9, 95%CI 2.2-3.9) and partial Ig suppression (HR 1.6, 95% CI 1.3-2.0) were associated with shorter TTFT (model 1, c-stat 0.77); and negative ARD (HR 2.4, 95%CI 2.0-2.9) was associated with shorter TTFT (model 2, c-stat 0.76). Negative ARD identified an additional 9% of patients at higher risk for shorter TTFT beyond full Ig suppression. Conclusions: The depth of immunoparesis at diagnosis predicts TTFT and enhances risk stratification in newly diagnosed MBL/CLL. Citation Format: Yuan Yao, Kari G. Rabe, Eli Muchtar, Paul Hampel, Yucai Wang, Lindsey Roeker, Saad Kenderian, Amber Koehler, Catherine Wagner, Amy Behnken, Jose F. Leis, Mazie Tsang, Talal Hilal, Ricardo Daniel Parrondo, Susan M. Schwager, Min Shi, Curtis A. Hanson, Celine M. Vachon, Shaji Kunnathu Kumar, Esteban Braggio, Neil E. Kay, Susan Slager, Sameer A. Parikh. Depth of immunoparesis predicts time to first therapy in newly diagnosed monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1191.

ABSTRACT Soluble tumor necrosis factor receptor 2 (sTNFR2) is a member of the TNF superfamily whose normal bodily distribution is largely limited to low level expression on lymphoid cells. It has emerged as an important inducible receptor that activates a signaling pathway for cancer growth. We evaluated sTNFR2 as a prognostic biomarker for overall survival (OS) in newly diagnosed lymphoma using a prospective cohort study with banked pretreatment serum samples. sTNFR2 was higher in 1513 lymphoma patients compared to 499 age and sex matched controls ( p < 0.0001). Using Kaplan–Meier curves and Cox proportional hazards models to estimate hazard ratios [HR] (high vs. low tertile), higher levels of sTNFR2 at diagnosis were associated with inferior OS across all seven major lymphoma subtypes: Hodgkin lymphoma ( p < 0.0001; HR = 12.6), diffuse large B‐cell lymphoma ( p < 0.0001; HR = 2.6), follicular lymphoma ( p = 0.00017; HR = 2.5), mantle cell lymphoma ( p < 0.0001; HR = 4.2), small lymphocytic lymphoma ( p = 0.012; HR = 2.4), marginal zone lymphoma ( p = 0.0012; HR = 3.1), and T‐cell lymphoma ( p < 0.0001; HR = 3.1). Using CITE‐seq profiling of tumor microenvironment tissue, we sought to identify cellular source(s) of circulating sTNFR2. In tumor tissue from follicular lymphoma, high TNFR2‐expressing cells were found to be T‐regulatory (Treg) cells, suggestive of a Treg‐driven cancer. In tissue from a case of marginal zone lymphoma, high TNFR2 expression was found on CD4+ and CD8+ T cells, B cells, and monocytes but also directly on tumor cells. We conclude sTNRF2 is a strong prognostic biomarker of OS across major lymphoma subtypes and may be useful to guide therapeutic choices, including targeted therapies against immunosuppressive TNFR2‐expressing Tregs.

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.