Minimal residual disease (MRD) testing has underpinned the evaluation and expansion of therapeutic options for patients with multiple myeloma (MM). Imaging is essential for evaluating residual disease status, overcoming sampling errors inherent with other MRD modalities. The accuracy of whole-body MRI (WB-MRI) has led to its incorporation into MM diagnostic imaging guidelines. We report here on the prospective iTIMM trial (image-guided theranostics in MM; NCT02403102), designed to evaluate imaging residual disease using contemporary, functional WB-MRI as per MY-RADS protocol. In iTIMM, 70 MM patients planned to undergo autologous stem cell transplantation ASCT in newly diagnosed MM or at first relapse, underwent WB-MRI before start of induction and at day 100 post-ASCT. Patients with residual disease post-ASCT (RAC2 or higher) had shorter progression-free survival (median 24 months, 95% confidence interval (CI): 19-41 vs. 42 months, 95% CI: 37-not evaluable (NE), log-rank p = 0.013; hazard ratio (HR) 2.09 (95% CI: 1.15-3.78) and overall survival (median 47 months, 95% CI: 30.9-NE vs. NE (95% CI: NE-NE), p = 0.002, HR = 5.45 (95% CI: 1.67-17.87) than those without (RAC1). Imaging response also refined the prognostic association of bone marrow MRD and serological response. Our results support WB-MRI implementation for evaluation of residual disease alongside conventional laboratory-based assessments.

Introduction: Renal impairment is a recognised complication of multiple myeloma (MM). Bortezomib and dexamethasone are used as first line therapy but are associated with important side effects. Objectives: We investigated outcomes of patients with MM requiring renal replacement therapy (RRT), assessed renal and haematological responses, and compared effects of different chemotherapy regimens. Patients and Methods: Retrospective study of 67 patients with MM with associated renal impairment managed at our centre from 2007–2017. Approximately 29 patients required RRT and were included in the final analysis. Results: Bortezomib was administered to treat 65.5% patients; overall response rate was 84.2% (complete 21.1%, partial 63.1%). The remaining patients were treated with other agents; of these 50% responded to therapy, all with partial response. Bortezomib was associated with improved survival (P=0.02), however a higher proportion of patients experienced side effects (P=0.02). Of the patients who received bortezomib, 47% came off RRT, compared to 10% of patients who did not (P=0.04). Independence from RRT had the best association with survival (P=0.07). Patients who came off RRT had significant reduction in serum free light chains after two cycles of chemotherapy; those remaining dialysis-dependent showed variable changes in free light chain levels (P=0.02). Conclusion: Bortezomib treatment resulted in a significant improvement in survival, albeit with more side effects. Gaining independence from RRT was associated with better patient survival. A greater degree of reduction of free light chains corresponded to an increased likelihood of being independent of dialysis; this could be used as a marker for renal recovery and overall prognosis.

During the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and ef ficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high -risk MCL ( TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 >= 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high -risk, and 8.9% autologous transplant candidates. All patients received >= 1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade >= 3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median followup, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) ( P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression -free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio [HR], 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first -line treatment of MCL, including older and transplant -ineligible patients. PFS and OS were signi ficantly inferior in one-third of patients with high -risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.

Background and Significance: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor to multiple myeloma (MM), affecting approximately 3.2% of people over 50 years old. Whilst about 1% of MGUS cases progress to MM annually, most are asymptomatic and detected incidentally, leading to inconsistent management and follow-up practices. The SECURE study aims to address gaps in understanding routes to diagnosis, risk factors of MGUS progression and psychological effects of living with an MGUS diagnosis. This study will generate prospective data to fill these gaps in the literature. Study Design and Methods: SECURE is a national longitudinal observational study set to recruit 2000 MGUS patients from over 30 NHS sites across the UK. Recruitment started in September 2023 and is planned to end in December 2025, with each participant followed for 60 months. Data collection will conclude in December 2030, and final analysis will be completed by December 2031. Patients with MGUS aged 18 or older will be invited to participate and provide informed consent. Exclusion criteria include i) patients with a light chain ratio of 0.3 to 3.0 without monoclonal protein on serum electrophoresis or immunofixation, and ii) those with rapidly rising M-protein or serum free light chains (FLC) indicative of myeloma at diagnosis. Data collection involves baseline assessments, annual questionnaires, bone marrow and blood samples analysed and stored at the Botnar Research Centre, University of Oxford. Recruitment is ongoing across 21 NHS sites in England and Wales, with 254 patients enrolled as of July 2024. Early data cut of 134 risk-stratified patients show a median age of 71 years (range 35-91), of which 53% are male, and 88.8% are of White ethnicity. Risk factors for MGUS progression were noted in 34 (25%) patients with a M-protein value ≥15 g/L, 85 (63.4%) with an abnormal FLC ratio, and 49 (36.6%) patients with non-IgG type MGUS. Risk stratification shows 22 (16.4%) patients at low risk, 55 (41%) at low-intermediate risk, 44 (32.8%) at high-intermediate risk, and 3 (2.2%) at high risk of disease progression. The primary outcome is the incidence rate of MM during the follow-up period. Secondary objectives include MGUS monitoring patterns, incidence of MGCS, routes of MGUS diagnosis, family linkage, quality of life change, and psychological effects. Exploratory endpoints will include health resource utilisation and identifying biochemical and genomic predictive biomarkers for progression to MM. The study will collect clinical and laboratory parameters, including protein, genomic and immune function markers. The primary outcome will be estimated yearly until the end of the follow-up, with 95% confidence intervals. Descriptive statistics will summarise the dataset overall and stratified by myeloma status at the end of the follow-up. Continuous variables will be summarised using mean (SD) or median (IQR), and binary/categorical variables using proportions. Analyses will be exploratory, identifying hypothesis generating observations that may guide future research. Kaplan-Meier survival analysis and Cox regression will be used for time-to-event data, linear regression for continuous measures, and logistic regression for binary outcomes. Multivariable analyses may control for confounding factors. We propose to characterise circulating germline genetic variants and somatic variants to identify those associated with MGUS development and progression to MM. The study will investigate the clinical utility of a targeted sequencing panel for genomic risk stratification of MGUS. Metabolomic analysis will identify biomarkers of MGUS progression. We will also explore post-translational modifications (PTMs) of serum free light chains as potential biomarkers for MGUS progression. The results of the SECURE study will be compared to the iSTOPMM study, an ongoing screening trial in Iceland. iSTOPMM actively screens the population to identify MGUS cases, whereas SECURE recruits prior incidentally detected MGUS patients. SECURE preliminary data showed that incidental MGUS patients had 36.6% (31.2% iSTOPMM) with non-IgG MGUS, 63.4% (35.8% iSTOPMM) with abnormal FLC, and 25.4% (3.3% iSTOPMM) with M-protein ≥15 g/L. These results highlight the differences in incidental MGUS (SECURE cohort) and can provide tools for managing MGUS monitoring in clinical practice.

Multiple myeloma is a bone marrow-based plasma cell tumour that develops from asymptomatic pre-cursor conditions smouldering myeloma and monoclonal gammopathy of uncertain significance and all are characterised by the presence of a monoclonal protein in the blood. Diagnosis and distinction between these conditions is based on blood tests, the bone marrow biopsy and cross sectional imaging. There are various risk stratification models that group patients with smouldering myeloma into risk groups based on risk of progression to symptomatic disease. Management is mainly observational for patients with smouldering myeloma although clinical trials for high-risk disease may be available. Restaging is required if evidence for progression.

This Good Practice Paper provides recommendations for the use of advanced imaging for earlier diagnosis and morbidity prevention in multiple myeloma. It describes how advanced imaging contributes to optimal healthcare resource utilisation by in newly diagnosed and relapsed myeloma, and provides a perspective on future directions of myeloma imaging, including machine learning assisted reporting.

This Good Practice Paper provides recommendations for the diagnosis and initial management of transplant-eligible high-risk myeloma patients. It describes recent updates to the genetic diagnostics of high-risk myeloma and provides recommendations for treatment on the basis of recent prospective clinical trial evidence.

Objectives: Patients with myeloma often face significant diagnostic delay, with up to one-third of UK patients diagnosed after an emergency presentation (EP). Compared with other routes, patients presenting as an emergency have more advanced disease, increased complications, and poorer prognosis.Methods: An economic model was developed using a decision-tree framework and lifetime time horizon to estimate costs related to different presentation routes (EP, general practitioner [GP] 2-week wait, GP urgent, GP routine, and consultant to consultant) for UK patients diagnosed as having myeloma. After diagnosis, patients received one of 3 first-line management options (observation, active treatment, or end-of-life care). Inputs were derived from UK health technology assessments and targeted literature reviews, or based on authors' clinical experience where data were unavailable. Active treatment, complication, and end-of-life care costs were included.Results: The average per-patient cost of treating myeloma (across all routes) was estimated at 146 pound 261. The average per -patient cost associated with EP (152 pound 677) was the highest; differences were minimal compared with GP 2-week wait (149631) pound and consultant to consultant (147 pound 237). GP urgent (140025) pound and GP routine (130212) pound were associated with marginally lower costs. Complication (42252) pound and end-of-life care (11273) pound costs were numerically higher for EP than other routes (25 pound 021-38 pound 170 and 9772- pound 10 pound 458, respectively).Conclusions: An economic benefit may be associated with earlier diagnosis, gained via reduced complication and end-of-life care costs. Strategies to expedite myeloma diagnosis and minimize EPs have the potential to improve patient outcomes and may result in long-term savings that could offset any upfront costs associated with their implementation.

British Journal of HaematologyEarly View ERRATUMFree Access Correction to “Recommendations for laboratory testing of UK patients with acute myeloid leukaemia” This article corrects the following: Recommendations for laboratory testing of UK patients with acute myeloid leukaemia Priyanka Mehta, Nick Telford, Chris Wragg, Richard Dillon, Sylvie Freeman, Damian Finnegan, Angela Hamblin, Mhairi Copland, Steve Knapper, Volume 200Issue 2British Journal of Haematology pages: 150-159 First Published online: October 24, 2022 First published: 14 March 2023 https://doi.org/10.1111/bjh.18713 Correspondence Priyanka Mehta, Haematology, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK. Email: [email protected] AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat In the Acknowledgements section of the published article,1 Professor Barbara Bain was incorrectly mentioned as a Dame. The first sentence should read as follows: The BSH Haematology Oncology task force members at the time of writing this good practice paper were Professor Barbara Bain, Dr Robert Sellers, Dr Gail Jones, Dr David Bloxham, Dr Mamta Garg, Dr Simon Stern, Dr Nilima Parry-Jones, Dr Guy Pratt, Dr Tracey Chan. We apologise for this error. REFERENCE 1Mehta P, Telford N, Wragg C, Dillon R, Freeman S, Finnegan D, et al. Recommendations for laboratory testing of UK patients with acute myeloid leukaemia. Br J Haematol. 2023; 200(2): 150– 9. https://doi.org/10.1111/bjh.18516 Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

This Good Practice Paper provides recommendations for the diagnosis, risk stratification and management of the monoclonal gammopathy of undetermined significance (MGUS). It describes the recently recognised entity of the monoclonal gammopathy of clinical significance (MGCS), and recommends how it should be managed. The potential for targeted population screening for MGUS is also discussed.

Multiple myeloma (MM) patients risk diagnostic delays and irreversible organ damage. In those with newly diagnosed myeloma, we explored the presenting symptoms to identify early signals of MM and their relationships to organ damage. The symptoms were recorded in patients’ own words at diagnosis and included diagnostic time intervals. Those seen by a haematologist >6 months prior to MM diagnosis were classified as precursor disease (PD). Most (962/977) patients provided data. Back pain (38%), other pain (31%) and systemic symptoms (28%) predominated. Patients rarely complain of ‘bone pain’, simply ‘pain’. Vertebral fractures are under-recognised as pathological and are the predominant irreversible organ damage (27% of patients), impacting the performance status (PS) and associated with back pain (odds ratio (OR) 6.14 [CI 4.47–8.44]), bone disease (OR 3.71 [CI 1.88–7.32]) and age >65 years (OR 1.58 [CI 1.15–2.17]). Renal failure is less frequent and associated with gastrointestinal symptoms (OR 2.23 [CI1.28–3.91]), age >65 years (OR 2.14 [CI1.28–3.91]) and absence of back pain (OR 0.44 [CI 0.29–0.67]). Patients with known PD (n = 149) had fewer vertebral fractures (p = 0.001), fewer adverse features (p = 0.001), less decline in PS (p = 0.001) and a lower stage (p = 0.04) than 813 with de novo MM. Our data suggest subgroups suitable for trials of ‘symptom-directed’ screening: those with back pain, unexplained pain, a general decline in health or low-impact vertebral compression fractures.

8012 Background: Early and sensitive detection of bone marrow disease and stratified patient management according to clinical risk can confer survival advantages in multiple myeloma (MM). Whole body MRI (WB MRI) and Fluorodeoxyglucose (FDG) PET/CT are included in international guidelines for imaging in patients with a suspected diagnosis of MM. However prospective studies comparing detection of MM by contemporary WB MRI as per recent MY-RADS consensus against FDG PET/CT are lacking. We report here protocol-defined endpoints from the prospective iTIMM (NCT02403102) study, comparing WB MRI and PET/CT, their relationship with serum and bone marrow estimates of disease burden, as well as molecular tumor characteristics. Methods: Patients with newly diagnosed MM or at first relapse planned to receive chemotherapy and autologous stem cell transplantation were enrolled in iTIMM. Matched baseline WB MRI and FDG PET/CT were performed and baseline clinical data including tumor genetics collected. Scans were double reported for presence of focal and diffuse disease by expert MRI and PET/CT radiologists, blinded to each other’s assessment. Paired methods were used to compare burden and patterns of disease on WB MRI compared to FDG PET/CT at baseline. Primary and secondary trial endpoints include relationship between post-treatment WB MRI response and progression-free survival, for which follow-up is ongoing. Exploratory endpoints include comparison of baseline WB MRI and PET/CT and their correlation with laboratory parameters, for which data is complete and reported here. Results: From May 2015 to March 2018, sixty patients (35 male; mean age 60 years) underwent baseline WB MRI as per MY-RADS consensus and FDG PET/CT. At least one focal lesion was detected in 50/60 patients (83.3%) by WB MRI and in 36/60 patients (60%) by PET/CT. WB MRI was more sensitive ( P< 0.05) across anatomical regions except for ribs and cervical spine. Four patients in our study showed two or more focal lesions ≥5 mm only on WB MRI but not PET/CT. All lesions detected by WB MRI but not PET/CT resolved in follow-up scans after treatment, excluding false positives. In 49/60 (81.7%) patients, diffuse disease was detected by WB MRI, compared to 10/60 (16.7%) by PET-CT; WB MRI was more sensitive across all anatomical areas ( P< 0.05). Plasma cell infiltration and paraprotein levels were significantly higher for patients with diffuse disease on WB MRI, but not on PET/CT. All genetically high-risk tumours, defined by t(4;14), t(14;16), del(1p), gain(1q) or del(17p), showed diffuse infiltration on WB MRI. Conclusions: WB MRI increases detection of focal and diffuse disease compared with FDG PET/CT, including improved detection of focal lesions meeting criteria for active disease as per International Myeloma Working Group diagnostic criteria, proposing it as a gold standard for tumor imaging in MM. Clinical trial information: NCT02403102.