Rajkumar, Vincent

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 < 0.05 and OR > 1.01) versus those that did not (P > 0.05 and OR < 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 <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.

Background/Objectives: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous genome-wide association studies (GWASs) have identified 35 common loci associated with MM risk and 21 associated with MGUS. The objective of this study was to identify less common and rare genetic loci predisposing to MM/MGUS through whole-exome sequencing (WES)-based linkage analysis. Methods:Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander–Green algorithm on germline WES data from 79 pedigrees with 2 or more affected relatives (120 MM, 86 MGUS, and 21 unaffected). Genome-wide linkage was evaluated using 12,946 independent single-nucleotide variants (linkage disequilibrium r2 < 0.05). Results: Significant linkage was observed at chromosome 6q22.33–q24.2 by the non-parametric model (logarithm-of-odds (LOD) = 3.3) and suggestive linkage by the dominant parametric model (heterogeneity LOD (HLOD) = 2.5). Fourteen rare variants within this region were prioritized using family-specific partial LOD scores and in silico functional prediction tools. Nine of these variants, REPS1, THEMIS, TAAR6, AHI1, VNN1, VNN3, MTFR2/FAM54A, LAMA2, and PHACTR2, overlapped immune-regulatory regions in blood cell lines and were not previously identified in GWASs. Conclusions: This study demonstrates the utility of applying a linkage analysis framework to familial WES data for identifying genomic regions and candidate genes that may contribute to MM/MGUS predisposition. These findings provide new insight into the inherited risk and etiology of familial MM and MGUS.

Abstract Background New immunoglobulin free light chain (FLC) assays are available. Despite analytical differences, it seems possible to use free light chain ratios (FLCr) generated by different assays and apply similar cut-points for the diagnosis of multiple myeloma. It is still unknown if we can use different assays for risk stratification of patients with monoclonal gammopathy of undetermined significance (MGUS). Methods Patients diagnosed with MGUS (N = 923) had FLC tested using a nephelometric FreeLite (Binding Site) assay on BNII instruments (Siemens) and a Sebia FLC assay (Sebia) on a DS2 ELISA analyzer (Dynex). Patients were followed up for progression to any plasma cell dyscrasia (PCD) for several decades. The Mayo MGUS risk stratification model for progression was assessed with both assays (M-spike &gt;1.5 g/dL; non-IgG isotype and abnormal FLCr), using package insert reference intervals (RI) and a new metric called principal component 2 (PC2). Results There were 94 events of progression to PCD in the cohort during a median of 38 years of follow-up. Freelite and Sebia FLC showed similar hazard ratios in the risk models for elevated FLCr. An alternative clinical decision point lower than the package insert RI was evaluated for the Sebia assay, which improved risk stratification for patients with a low FLCr. The PC2 metric showed similar performance to the FLCr in models, without superior benefit. Conclusions The Sebia ELISA-based FLC assay can be employed in an MGUS risk stratification model with similar performance to the original 2005 risk stratification model using the FreeLite assay.

Abstract Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

SummaryMeasurable residual disease (MRD) assessment by marrow‐based next‐generation flow cytometry (NGF) following autologous stem cell transplantation (ASCT) may lead to false‐negative results due to patchy marrow involvement and extramedullary disease in patients with multiple myeloma. We assessed the value of simultaneous MRD evaluation with NGF and serum matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (MASS‐FIX). Of all 61 complete responders who were NGF‐negative for MRD, around day‐100 post ASCT, 59% were MASS‐FIX‐positive. At median follow‐up of 26 months, 69% of MASS‐FIX(+)/NGF(−) patients were alive and progression‐free versus 96% of MASS‐FIX(‐)/NGF(−) patients, P = 0·02. MASS‐FIX, a simple peripheral blood‐based assay complements marrow‐based NGF to accurately prognosticate patients with myeloma.

Abstract Gastrointestinal complications of multiple myeloma (MM) treatment are common and include nausea, constipation, and diarrhea. However, acute gastrointestinal events like perforations are rare. We aimed to describe the characteristics and outcomes of patients with MM that had colonic perforations during their treatment. This is a retrospective study that included patients from all three Mayo Clinic sites who had MM and developed a colonic perforation. All patients were diagnosed with colonic perforations based on CT scans and were surgically treated. Patients diagnosed with AL amyloidosis, a perforated colon complicating neutropenic colitis during ASCT and those with perforation due to colonic cancer were excluded. A high dose of dexamethasone was defined as ≥40 mg dexamethasone once a week. Thirty patients met inclusion criteria. All patients received steroids at doses ≥10 mg once weekly prior to the perforation, while four (11%) were on high‐dose dexamethasone without chemotherapy. Fourteen patients were given high doses of dexamethasone. Twenty‐five patients required ostomies with all surviving surgery. Twenty‐four perforations (80%) were associated with diverticulitis. Treatment with steroids was resumed in 23 patients with no further gastrointestinal complications. The median OS was 20 months following perforation (IQR 8–59). Within the same timeframe 5854 patients were treated at Mayo Clinic for MM, making the risk of bowel perforation 0.5%. Intestinal perforations in MM are rare and, in our series, always occurred with dexamethasone ≥10 mg per week. Urgent surgery is lifesaving and resumption of anti‐myeloma treatment appears to be safe.

AbstractObjectivesHealth‐related quality of life (HRQoL) is particularly important during maintenance therapy (MT) in newly diagnosed multiple myeloma post‐transplant, when disease symptoms are limited.MethodsWe assessed HRQoL in patients randomised to 26 cycles of MT (ixazomib vs placebo) in TOURMALINE‐MM3 (NCT02181413).ResultsThe characteristics at study entry were well‐balanced between ixazomib (n = 386) and placebo (n = 251) arms. At study entry, EORTC QLQ‐C30 and MY20 scores were high for functional scales and low for symptom scales and were comparable with those of the general population. Changes in subscale scores across intervals, analysed over 30 four‐week intervals using a linear mixed‐effects model, were generally small and similar between arms for the EORTC QLQ‐C30 Global Health Status/QoL, Physical Functioning, and Pain subscales and EORTC QLQ‐MY20 Disease Symptoms subscale and Peripheral Neuropathy item. EORTC QLQ‐C30 Nausea/Vomiting and Diarrhoea subscales were consistently worse for ixazomib than for placebo, in line with the ixazomib toxicity profile. Even when least‐squares mean differences between arms were statistically significant, none reached the established minimal important clinical difference of 10 in multiple myeloma.ConclusionsIn addition to improvement in progression‐free survival with ixazomib, HRQoL was maintained in both arms. Active treatment with ixazomib did not have an adverse impact on HRQoL.

SummaryIbrutinib‐related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment‐naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off‐study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major‐response rate (MRR) was 78%. The median time to first response and best response was 2·9 [95% confidence interval (CI): 2–4] and 5·7 (95% CI: 4–12) months, respectively. The median follow‐up was 19 (95% CI: 14–21) months; 18‐month progression‐free survival (PFS) was 82%. The median time on therapy was 12·5 (95% CI: 9·3–16·7) months, and the median duration‐of‐response was 32 (range: 23–32) months. Twenty‐five patients (31%) had discontinued therapy at last follow‐up (68% due to treatment‐related toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial‐fibrillation (11%) were common non‐haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression.

Recent reports suggest that deep hematologic responses to chemotherapy are associated with improved renal outcomes in monoclonal immunoglobulin deposition disease (MIDD). Here we describe the long term outcomes and identify prognostic factors after first line treatment of the largest reported series of patients with MIDD. Between March 1992 and December 2014, 88 patients with MIDD were seen at Mayo Clinic, MN. Renal responses were defined using criteria used for light chain amyloidosis (AL) or those used by the IMWG. Sixty‐one (69%) patients had a GFR < 30 mL/min/1.73 m2 and 16 (18%) were on renal replacement therapy at diagnosis. The interval between albuminuria or elevation in creatinine and MIDD diagnosis was 12 months suggesting a delay in diagnosis. Thirty‐seven patients (42%) had at least a hematologic CR/VGPR. Fifty‐three (60%) received an autologous stem cell transplant (ASCT) or proteasome inhibitor (PI)‐based treatments. Patients receiving ASCT or PI‐based therapies were more likely to achieve at least a hematologic CR/VGPR compared to those receiving other therapies: 66% vs 2%, p < 0.0001. Patients that achieved a hematologic CR were more likely to achieve a renal response (53% vs 24%, p = 0.001). Five year overall and renal survival for the entire cohort was 67% and 57%, respectively. In multivariate analyses, a baseline GFR < 20 mL/min/1.73 m2 and a renal response (using AL or IMWG criteria) were independently predictive of progression to dialysis. This study confirms that deep hematologic responses, best achieved with ASCT or PI‐based therapies, are a prerequisite to achieving renal responses. Am. J. Hematol. 91:1123–1128, 2016. © 2016 Wiley Periodicals, Inc.