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Yilin Ning,1,2 Peh Joo Ho,3,4 Nathalie C Støer,5,6 Ka Keat Lim,7,8 Hwee-Lin Wee,3,9 Mikael Hartman,1– 3,10 Marie Reilly,11 Chuen Seng Tan3 1NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore; 2Yong Loo Lin School of Medicine, Department of Surgery, National University of Singapore and National University Health System, Singapore, Singapore; 3Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore; 4Genome Institute of Singapore, Singapore, Singapore; 5Norwegian National Advisory Unit on Women’s Health, Oslo University Hospital, Oslo, Norway; 6Department of Research, Cancer Registry of Norway, Oslo, Norway; 7Department of Population Health Sciences, School of Population Health & Environmental Sciences (SPHES), Faculty of Life Sciences & Medicine, King’s College London, London, UK; 8Programme in Health Services & Systems Research, Duke-NUS Medical School, Singapore, Singapore; 9Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore; 10Department of Surgery, National University Hospital, Singapore, Singapore; 11Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SwedenCorrespondence: Chuen Seng TanSaw Swee Hock School of Public Health, National University of Singapore and National University Health System, Tahir Foundation Building, 12 Science Drive 2, #10-01, Singapore, 117549, SingaporeTel +65-66013206Email ephtcs@nus.edu.sgPurpose: Assessing the clinical importance of an exposure effect on a quality of life (QoL) score often requires quantifying the effect in terms of a difference in scores. Using the linear regression model (LRM) for this purpose assumes the ordinal score is a proxy for an underlying continuous variable, but the analysis offers no assessment for the validity of the assumption. We propose an approach that assesses the proxy assumption and estimates the exposure effect by using the cumulative link model (CLM).Patients and methods: CLM is a well-established regression model that assumes an ordinal score is an ordered category generated from applying thresholds to a latent continuous variable. Our approach assesses the proxy assumption by testing whether these thresholds are equidistant. We compared the performance of CLM and LRM using simulated ordinal data and illustrated their application to the effect of time since diagnosis on five subscales of fatigue among breast cancer survivors measured using the Multidimensional Fatigue Inventory.Results: CLM had good performance in estimating the difference in means with simulated ordinal data satisfying the proxy assumption, even when the outcome had only a few categories. When the proxy assumption was inadequate, both the CLM and LRM had biased estimates with poor coverage. The proxy assumption was appropriate for four of the five subscales in our real data application to fatigue scores, which highlighted the importance of assessing the proxy assumption to avoid reporting invalid estimates in terms of the difference in scores.Conclusion: The proxy assumption is critical to the interpretation of the exposure effect on the difference in mean QoL scores. CLM offers a valid test for the presence of an association, a method for assessing the proxy assumption, and when the assumption is adequate, an assessment for clinical significance using the difference in means.Keywords: cumulative link model, ordered probit model, ordinal outcome, ordinal regression, probit link, quality of life

Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels., Competing Interests: Declaration of interests P.A.F. conducts research funded by Amgen, Novartis, and Pfizer. He received Honoraria from Roche, Novartis, and Pfizer. A.R.M. received funds from AstraZeneca for contribution to sponsored quality assessments and variant interpretation of VUSs in BRCA1 and BRCA2. The funds were paid to the institution., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The barrier function of skin epidermis is crucial for our bodies to interface with the environment. Because epidermis continuously turns over throughout the lifetime, this barrier must be actively maintained by regeneration. Although several transcription factors have been established as essential activators in epidermal differentiation, it is unclear whether additional factors remain to be identified. In this study, we show that CASZ1, a multi zinc-finger transcription factor previously characterized in nonepithelial cell types, shows highest expression in skin epidermis. CASZ1 expression is upregulated during epidermal terminal differentiation. In addition, CASZ1 expression is impaired in several skin disorders with impaired barrier function, such as atopic dermatitis, psoriasis, and squamous cell carcinoma. Using transcriptome profiling coupled with RNA interference, we identified 674 differentially expressed genes with CASZ1 knockdown. Downregulated genes account for 91.2% of these differentially expressed genes and were enriched for barrier function. In organotypic epidermal regeneration, CASZ1 knockdown promoted proliferation and strongly impaired multiple terminal differentiation markers. Mechanistically, we found that CASZ1 upregulation in differentiation requires the action of both the master transcription factor, p63, and the histone acetyltransferase, p300. Taken together, our findings identify CASZ1 as an essential activator of epidermal differentiation, paving the way for future studies understanding of CASZ1 roles in skin disease., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Idiopathic granulomatous mastitis (IGM) is a rare condition characterised by chronic inflammation and granuloma formation in the breast. The aetiology of IGM is unclear. By focusing on the protein-coding regions of the genome, where most disease-related mutations often occur, whole-exome sequencing (WES) is a powerful approach for investigating rare and complex conditions, like IGM. We report WES results on paired blood and tissue samples from eight IGM patients. Samples were processed using standard genomic protocols. Somatic variants were called with two analytical pipelines: nf-core/sarek with Strelka2 and GATK4 with Mutect2 . Our WES study of eight patients did not find evidence supporting a clear genetic component. The discrepancies between variant calling algorithms, along with the considerable genetic heterogeneity observed amongst the eight IGM cases, indicate that common genetic drivers are not readily identifiable. With only three genes, CHIT1 , CEP170 , and CTR9 , recurrently altering in multiple cases, the genetic basis of IGM remains uncertain. The absence of validation for somatic variants by Sanger sequencing raises further questions about the role of genetic mutations in the disease. Other potential contributors to the disease should be explored.

Chimeric antigen receptor (CAR) T-cell therapy has shown promise in patients with late-line refractory multiple myeloma, with response rates ranging from 73 to 98%. To date, three products have been approved: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), which are approved by the US Food and Drug Administration, the European Medicines Agency, Health Canada (ide-cel only), and Brazil ANVISA (cilta-cel only); and equecabtagene autoleucel (eque-cel), which was approved by the Chinese National Medical Products Administration. CAR T-cell therapy is different from previous anti-myeloma therapeutics with unique toxic effects that require distinct mitigation strategies. Thus, a panel of experts from the International Myeloma Working Group was assembled to provide guidance for clinical use of CAR T-cell therapy in myeloma. This consensus opinion is from experts in the field of haematopoietic cell transplantation, cell therapy, and multiple myeloma therapeutics., Competing Interests: Declaration of interests YL received consultancy fees from Janssen, Sanofi, NexImmune, Caribou, Bristol Myers Squibb (BMS), Pfizer, Regeneron, and Genentech; research fees from Janssen and BMS; serves on advisory boards for Janssen, Sanofi, BMS, Regeneron, and Genentech; serves on scientific advisory boards for NexImmune and Caribou; and serves on the data safety monitor board for Pfizer. LQ received consultancy fees from Beigene, Xi'an, Janssen, Pfizer, Sanofi, and AstraZeneca; and is on the speaker board for Beigene, Xi'an, Janssen, Pfizer, Sanofi, AstraZeneca, and Roche. SU receives consultancy fees from AbbVie, Amgen, BMS, EdoPharma, Genentech, Gilead, GlaxoSmithKline (GSK), Janssen, Karyopharm Therapeutics, Merck, Oncopeptides, Sanofi, Seagen, Secura Bio, SkylineDx, and Takeda; and received research funding from AbbVie, Amgen, Array Biopharma, BMS, EdoPharma, Genentech, Gilead, GSK, Janssen, Merck, Moderna, Pharmacyclics, Seagen, Sanofi, SkylineDx, Takeda, and TeneoBio. CWJ received honoraria from AbbVie, Amgen, BMS, Pfizer, Sanofi, Regeneron, GSK, and Janssen; and research funding from Novartis, Janssen, and BMS Celgene. LC received research grants from Amgen, Janssen, BMS, Genentech, Caribou, and AbbVie; and honoraria from Amgen, Janssen, AbbVie, Pfizer, Sanofi, and Adaptive Biotechnologies. BD received advisory board and consulting fees from Janssen and COTA; research fees from GSK and Amgen; honoraria from the Multiple Myeloma Research Foundation and Plexus Communications; and is an independent reviewer for BMS. HE has an advisory role for and received consulting fees from BMS Celgene, Janssen, Amgen, GSK, and Sanofi; and received research funding from BMS Celgene, Janssen, Amgen, GSK, and Sanofi. CFdL received institutional grants from BMS, Janssen, and Amgen; honoraria from Amgen, Jassen, BMS, GSK, and Sanofi; support for attending meetings or travel from Janssen, BMS, GSK, and Amgen; is on data safety monitoring or advisory boards for Janssen, BMS, Amgen, Pfizer, and Sanofi; and received funding from the Spanish Institute of Health, the Asociación Española Contra el Cancer (AECC), the “La Caixa” Foundation, and AGAUR. RH received grants from Janssen, Amgen, Celgene, BMS, Novartis, and Takeda; consulting fees from Janssen, Amgen, Celgene, BMS, Novartis, Takeda, AbbVie, PharmaMar, Oncopeptides, Sanofi, and GSK; and honoraria from Janssen, Amgen, Celgene, BMS, PharmaMar, and Takeda. PJH serves on advisory boards (honoraria not accepted) for Antengene, Gilead, iTeos Therapeutics, Janssen, Novartis, and Pfizer. EK received honoraria from Janssen, Pfizer, GSK, and Prothena; and research support to the institution from GSK, Janssen, and Pfizer. JM-L received consultancy fees from Janssen, BMS, Sanofi, GSK, Novartis, Menarini, Incity, Roche, Gilead, Pfizer, and Karyopharm; and research funding from BMS, Janssen, Incity, Amgen, and Pfizer. M-VM received honoraria for serving on advisory boards and received fees for lectures from Janssen, BMS Celgene, Novartis, GSK, Sanofi, Amgen, Pfizer, AbbVie, and Regeneron. JM received consultancy fees from Amgen, BMS, Janssen, Sanofi, and Takeda; and research funding from BMS Clinical Trial. PM serves on advisory boards and received honoraria from Janssen and BMS Celgene. CN received consultancy fees from Janssen, BMS, Sanofi, GSK, Pfizer, Amgen, AstraZeneca, and DKSH; and research funding from Janssen and Amgen. AN serves on advisory boards and received honoraria from Adaptive Biotechnologies, Amgen, BMS, Cellectar Biosciences, GSK, Janssen, K36 therapeutics, ONK therapeutics, Pfizer, Sanofi, and Takeda; received research grants from Aduro Biotech, Amgen, Arch Oncology, BMS, Cellectis, Genentech, GSK, Janssen, Karyopharm, Kite Pharma, Merck, Pfizer, and Takeda; and received grants for investigator initiated studies from Amgen, GSK, Janssen, Merck, and Takeda. FS received consultancy fees from AbbVie, GSK, Celgene, Takeda, Janssen, Oncopeptides, Sanofi, and BMS; honoraria from Amgen, BMS, Takeda, AbbVie, Janssen, Novartis, SkyliteDX, Oncopeptides, Sanofi, Pfizer, Daiki-Sankyo, and GSK; and research grants from Celgene, Janssen, Oncopeptides, Sanofi, GSK, and Targovax. SS received research grants from Magenta Therapeutics, BMS, Allogene, Jansse, Novartis, AbbVie, Sanofi, Oncopeptides, Takeda, Kite, and Regeneron; and consultancy fees from Magenta Therapeutics, BMS, Janssen, AbbVie, Sanofi, Oncopeptides, Takeda, Kite, and Regeneron. NWCJvdD received research grants from Janssen, Amgen, Celgene, Novartis, Cellectis, and BMS; and serves on advisory boards for Janssen, Amgen, Celgene, BMS, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, AbbVie, and Servier (all paid to institution). KW received research grants from AbbVie, Amgen, BMS Celgene, Janssen, GSK, Sanofi, and Takeda; honoraria from AbbVie, Amgen, Adaptive Biotech, Astra Zeneca, BMS Celgene, BeiGene, Janssen, GSK, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche Pharma, Sanofi, Stemline, Takeda, and Menarini; and consulting fees from AbbVie, Amgen, Adaptive Biotech, BMS Celgene, BeiGene, Janssen, GSK, Karyopharm, Oncopeptides, Pfizer, Roche Pharma, Sanofi, Takeda, and Menarini. SZ serves on advisory boards for Janssen, BMS, Takeda, Sanofi, Oncopeptides, and Amgen (no personal fees). PRO received honoraria for consulting or advisory board from BMS Celgene, Janssen, Roche, AbbVie, Pfizer, GSK, Sanofi, H3Biomedicine; travel grants from Pfizer; serves on steering committees for BMS Celgene, Regeneron, and Janssen; and is on the speakers bureau for Janssen, BMS Celgene, GSK, Sanofi, and AbbVie. LDA received consulting fees and serves on advisory boards for Janssen, Celgene, BMS, Amgen, GSK, AbbVie, Beigene, Cellectar, Sanofi, and Prothena. SK received consultancy fees from Oncopeptides, AbbVie, Celgene, Janssen, Takeda, Adaptive, KITE, and MedImmune AstraZeneca; and research grants from AbbVie, Celgene, Janssen, Takeda, Adaptive, KITE, MedImmune AstraZeneca, Merck, Novartis, Roche, and Sanofi. TM received research funding from Sanofi. All other authors declare no competing interests. IMWG are listed in the appendix (pp 9–21)., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background and Purpose: Renal impairment (RI) confers adverse prognosis in myeloma; its reversal and avoidance of dialysis are crucial. We investigated whether serum free light chain (SFLC) measurements can predict renal outcome, to enable change in therapy to optimize prognosis and avoid dialysis., Patients and Methods: We investigated 36 myeloma patients (17 newly diagnosed [ND]; 19 relapsed refractory [RR]; with median of 5 prior lines) with eGFR 15-40 ml/min treated with carfilzomib (Cfz)-dexamethasone to determine whether SFLC kinetics can predict renal outcomes, and assess efficacy and tolerability., Results: The change in involved SFLC at Cycle 2 Day 1 was significantly correlated with renal function; for every one log 10 reduction in involved SFLC, eGFR increased by 9.0-15.0 mL/min at cycles 2-4, with SFLC reduction of 54%-78%. At a median follow-up of 30.6 months, renal outcomes were favorable-CR renal 25%, MR renal 36%. Disease responses (ND 100%, RR 75%), progression-free survival (ND 32.2 months, RR 11.1 months) and overall survival (ND not reached, RR 42.0 months) were comparable to patients without RI. There was significant toxicity, including Cfz-related cardiac impairment of 20% within a cohort with high co-morbidity, and a high incidence of infections., Conclusion: We propose that one log 10 reduction in involved SFLC at Cycle 2 Day 1 is an appropriate target for reducing the risk of dialysis in myeloma patients with RI; below this threshold patients may benefit from a change in therapy. While Cfz-dexamethasone achieved favorable renal and disease outcomes, toxicity can be significant in this vulnerable cohort., Competing Interests: Disclosure PJH: Member of advisory board (no honorarium accepted): Antengene, Gilead, iTeos therapeutics, Janssen, Pfizer; Research support: Novartis, PM: Research funding: Janssen, Pfizer; Member of advisory board (no personal funds received): Amgen BMS, Caelum, EUSA, Janssen, Pfizer, SkylineDx, Takeda, CEB: Member of advisory board: Amgen, Janssen, BMS, Takeda, Antengene and Skyline, BEB is an independent statistician who has provided statistical services to a wide range of companies, including Janssen and Pfizer, JT: research funding BMS, Roche, Cellectar, Beigene, SG: Member of advisory board: Janssen, Pfizer, BridgeBio, AS, AKE, NH and DEJ report no relevant conflicts of interests, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Belantamab mafodotin had single-agent activity in patients with relapsed or refractory multiple myeloma, a finding that supports further evaluation of the agent in combination with standard-care therapies., Methods: In this phase 3, open-label, randomized trial, we evaluated belantamab mafodotin, bortezomib, and dexamethasone (BVd), as compared with daratumumab, bortezomib, and dexamethasone (DVd), in patients who had progression of multiple myeloma after at least one line of therapy. The primary end point was progression-free survival. Key secondary end points were overall survival, response duration, and minimal residual disease (MRD)-negative status., Results: In total, 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients). At a median follow-up of 28.2 months (range, 0.1 to 40.0), median progression-free survival was 36.6 months (95% confidence interval [CI], 28.4 to not reached) in the BVd group and 13.4 months (95% CI, 11.1 to 17.5) in the DVd group (hazard ratio for disease progression or death, 0.41; 95% CI, 0.31 to 0.53; P<0.001). Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group. An analysis of the restricted mean response duration favored BVd over DVd (P<0.001). A complete response or better plus MRD-negative status occurred in 25% of the patients in the BVd group and 10% of those in the DVd group. Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group and 78% of those in the DVd group. Ocular events were more common in the BVd group than in the DVd group (79% vs. 29%); such events were managed with dose modifications, and events of worsening visual acuity mostly resolved., Conclusions: As compared with DVd therapy, BVd therapy conferred a significant benefit with respect to progression-free survival among patients who had relapsed or refractory multiple myeloma after at least one line of therapy. Most patients had grade 3 or higher adverse events. (Funded by GSK; DREAMM-7 ClinicalTrials.gov number, NCT04246047; EudraCT number, 2018-003993-29.)., (Copyright © 2024 Massachusetts Medical Society.)

Objective: To examine the challenges faced by Asian working mothers with a focus on re-entry to the workplace. In addition, we highlight potential supports that retain women in the workforce., Design: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and registered with PROSPERO database (CRD42022341130)., Methods: Three independent reviewers were involved in the study selection to screen the search results sequentially by title, abstract, and full text using predefined inclusion and exclusion criteria. The methodological quality of each article was assessed via the Critical Appraisal Skills Programme (CASP) tool., Results: We analysed a total of 36 studies conducted across different regions: 30 from the East and 6 from Southeast Asia. Among these studies, 20 were quantitative in nature, 15 were qualitative, and one intervention. The 36 studies cover five themes: 1) policies, 2) external support sources, 3) external pressure, 4) breastfeeding and 5) health status. Within each theme the same factor can have a positive or negative impact on the mother depending on her having a pro-career or pro-family mindset. Companies can take various initiatives to support working mothers, such as providing facilities for expressing breast milk at the workplace, educating staff to promote breastfeeding and accommodate childcare needs, and extending maternity leaves. However, there is a lack of literature that directly addresses the barriers and concrete support available to working mothers in Asia, beyond the scope of breastfeeding., Conclusions: Our findings underscore several obstacles that can impede a woman's seamless return to work. Pro-family and pro-career mothers have differing needs that cannot be addressed at the same time. There is a lack of comprehensive understanding regarding effective strategies or interventions that can support a positive reintegration into the workforce., (© 2024. The Author(s).)

Abstract: In newly diagnosed transplant-ineligible patients with myeloma, daratumumab has improved outcomes when added to the standard-of-care regimens. In a randomized trial, we tested whether similar improvements would be observed when daratumumab was added to the bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen. Transplant-ineligible patients with untreated myeloma were randomized to receive VCD or VCD plus daratumumab (VCDD). A total of 121 patients were randomized: 57 in the VCD arm and 64 in the VCDD arm. Baseline characteristics were balanced between the 2 arms. The median progression-free survival (PFS) was 16.8 months (95% confidence interval [CI], 15.3-21.7) and 25.8 months (95% CI, 19.9-33.5) in the VCD and VCDD arms, respectively (hazard ratio, 0.67; log-rank test P = .066). In a preplanned analysis, it was demonstrated that the daratumumab-containing arm showed a significant improvement in PFS from 18 months onward, based on estimates at fixed time points after randomization. The proportions of patients who were progression-free at the following time points were: 18 months, 48% vs 68% (P = .0002); 24 months, 36% vs 52% (P = .0001); and 30 months, 27% vs 41% (P < .0001) in the VCD and VCDD arms, respectively. The best overall response and very good partial response rate were significantly higher in the daratumumab arm compared with the VCD and VCDD arms, respectively (65% vs 86%, P = .007; and 28% vs 52%, P = .009). Seventy-two percent of the VCDD patients completed the 9 cycles of induction therapy with no grade 3 or 4 peripheral neuropathy adverse events. This study supports VCDD as an option for the initial treatment of transplant-ineligible patients with myeloma. This trial was registered at the Australian New Zealand Clinical Trials Registry (ACTRN12617000202369)., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

A decade after International Myeloma Working Group (IMWG) biomarkers (SLiM criteria) were introduced, this real-world study examined their impact on diagnosis, therapy and outcomes in myeloma. Using the ANZ MRDR, 3489 newly diagnosed patients from 2013 to 2023, comprising 3232 diagnosed by CRAB ('CRAB patients', including 1758 who also satisfied ≥1 SLiM criteria) and 257 by SLiM ('SLiM patients') criteria were analysed. CRAB patients had higher R-ISS and lower performance status, with no difference in cytogenetic risk. SLiM patients had improved progression-free survival (PFS, 37.5 vs. 32.2 months, hazard ratio [HR] 1.31 [1.08-1.59], p = 0.003), overall survival (80.9 vs. 73.2 months, HR 1.64 [1.26-2.13], p < 0.001) and PFS2 (54.6 vs. 40.3 months, HR 1.51 [1.22-1.86], p < 0.001) compared with CRAB patients, partially explained by earlier diagnosis, with no differential impact between the plasma cell and light-chain criteria on PFS. However, 34% of CRAB patients did not manifest SLiM characteristics, raising the possibility that SLiM features are associated with different biological behaviours contributing to a better prognosis, for example, improved PFS2 in SLiM patients suggested less disease resistance at first relapse. These data support earlier initiation of therapy by SLiM. The superior survival outcomes of SLiM versus CRAB patients highlight the importance of defining these subgroups when interpreting therapeutic outcomes at induction and first relapse., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

PCAB (prednisone, cyclophosphamide, doxorubicin, carmustine) is a single-day regimen previously used for induction and now in relapsed/refractory multiple myeloma (RRMM). We retrospectively analysed the outcomes of 85 patients from five Australian centres. These included 30 patients (35.3%) who received PCAB with one additional agent (bortezomib most frequently). Median age of the patients was 65 years (37-80), with a median of four (1-8) prior lines of therapy. ORR was 37% (CR 4.9%). Median progression free survival and overall survival were 4.4 months (95% CI 3.5-6.7) and 7.4 months (95% CI 6.4-10.2), respectively. Extramedullary disease (EMD) was associated with shorter survival. Grade 3 or 4 cytopenia and febrile neutropenia occurred in 76.2% and 39.1%, respectively, with six (7.1%) treatment-related mortalities. Median inpatient stay was 3.3 days/28-day cycle (IQR 0.6-13), and for patients who died, a median of 20.2% of days alive were spent inpatient (IQR 6.4-39.1%). Three patients were successfully bridged to CAR T-cell therapy using PCAB, despite being penta-exposed and having EMD. PCAB may be considered as a useful salvage therapy amongst other polychemotherapy regimens in late relapse. Further studies is warranted to investigate and define its role as a bridging therapy to novel therapeutics., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Serious infection is common in patients with multiple myeloma due to immune deficiency from the underlying disease and/or its treatment. Immunoglobulin replacement is one approach to reduce infection risk in these patients. However, few real-world data exist on its use in patients with myeloma. We investigated immunoglobulin use in Australia, New Zealand and Asia-Pacific using registry data and explored its association with survival outcomes. A total of 2374 patients with a median follow-up time of 29.5 months (interquartile range 13.3-54.3 months) were included in the analysis - 1673 from Australia, 313 Korea, 281 New Zealand and 107 Singapore. Overall, 7.1% of participants received immunoglobulin replacement within 24 months of diagnosis. Patients who received immunoglobulin replacement were likely to be younger, had lower baseline IgG levels (excluding paraprotein), were more likely to have baseline hypogammaglobulinaemia, baseline severe hypogammaglobulinaemia and abnormal baseline fluorescent in-situ hybridisation status, receive first-line myeloma treatment with immunomodulatory drugs or anti-CD38 therapy and undergo upfront autologous stem cell transplant. In our patient cohort, the use of immunoglobulin was not associated with overall survival benefit at the time of last follow-up (adjusted hazard ratio 0.72, 95% CI 0.46-1.14, p  = 0.16). Understanding treatment approaches in clinical practice can help support future planning and provision of immunoglobulin resources., Competing Interests: This research project did not receive any specific grant from funding agencies in the public, commercial or not‐for‐profit sectors. However, the ANZ MRDR has received funding from Abbvie, Amgen, Antengene, Bristol‐Myers Squibb, Celgene, Gilead, GSK, Janssen, Novartis, Sanofi and Takeda. The APAC MRDR has received funding from Janssen Asia‐Pacific. Monash University has received funding from CSL Behring for other projects., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: To assess the association of a polygenic risk score (PRS) for functional genetic variants with the risk of developing breast cancer., Methods: Summary data-based Mendelian randomization (SMR) and heterogeneity in dependent instruments (HEIDI) were used to identify breast cancer risk variants associated with gene expression and DNA methylation levels. A new SMR-based PRS was computed from the identified variants (functional PRS) and compared to an established 313-variant breast cancer PRS (GWAS PRS). The two scores were evaluated in 3560 breast cancer cases and 3383 non-cancer controls and also in a prospective study ( n = 10,213) comprising 418 cases., Results: We identified 149 variants showing pleiotropic association with breast cancer risk (eQTL HEIDI > 0.05 = 9, mQTL HEIDI > 0.05 = 165). The discriminatory ability of the functional PRS (AUC continuous [95% CI]: 0.540 [0.526 to 0.553]) was found to be lower than that of the GWAS PRS (AUC continuous [95% CI]: 0.609 [0.596 to 0.622]). Even when utilizing 457 distinct variants from both the functional and GWAS PRS, the combined discriminatory performance remained below that of the GWAS PRS (AUC continuous , combined [95% CI]: 0.561 [0.548 to 0.575]). A binary high/low-risk classification based on the 80th centile PRS in controls revealed a 6% increase in cases using the GWAS PRS compared to the functional PRS. The functional PRS identified an additional 12% of high-risk cases but also led to a 13% increase in high-risk classification among controls. Similar findings were observed in the SCHS prospective cohort, where the GWAS PRS outperformed the functional PRS, and the highest-performing PRS, a combined model, did not significantly improve over the GWAS PRS., Conclusions: While this study identified potentially functional variants associated with breast cancer risk, their inclusion did not substantially enhance the predictive accuracy of the GWAS PRS.

Purpose: The major aim of our meta-analysis was to review the effectiveness of various treatment modalities for achieving successful remission and preventing recurrence for women with idiopathic granulomatous mastitis (IGM). This knowledge is instrumental in developing evidence-based guidelines for clinicians to improve management strategies and outcomes for patients with IGM., Methods: A systematic literature search was performed on MEDLINE (Ovid), Embase (Elsevier), PubMed, Cochrane Library, Web of Science, and Google Scholar; studies published to 19 January 2022 were included. A meta-analysis of 57 observational studies was performed. The results of two randomized controlled trials were also examined., Results: There were 3,035 IGM patients across the observational and randomised studies. Overall recurrence and remission rates across all treatment strategies in 59 studies are 87.9% (2,667/3035) and 13.5% (359/2667), respectively. The studies reported 19 different treatment strategies, comprising observation, medical monotherapies, surgery, and combinations involving medical therapies, with and without surgery. Among monotherapy treatment, surgical management had the highest pooled remission rate (0.99 [95% confidence interval (CI) = 0.97-1.00]); among combination therapy, this was steroids and surgery (0.99 [0.94-1.00]). Antibiotic monotherapy had the lowest remission rate (0.72 [0.37-0.96]). The highest recurrence rates belonged to treatments that combined antibiotics and surgery (0.54 [0.02-1.00]), and antibiotics, steroids, and surgery (0.57 [0.00-1.00]). Most successful for preventing recurrence were observation (0.03 [0.00-0.10]), methotrexate (0.08 [0.00-0.24]), and steroids and surgery (0.05 [0.01-0.12]). There is a significant association between longer follow-up duration and recurrence rate reported, p  = 0.002., Conclusion: Combination therapies, especially those incorporating antibiotics, steroids, and surgery, have demonstrated higher remission rates, challenging the use of antibiotic monotherapy. There is an increased emphasis on the need for personalised, multi-pronged approach for preventing IGM recurrence, with longer follow-up care. More prospective future work in IGM research, with standardised diagnostic criteria, treatment protocols, and reporting guidelines will be important for developing treatment protocols and guidelines clinicians can adhere to in the clinical management of IGM patients. Systematic review registration : PROSPERO (CRD42022301386)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ong, Ho, Liow, Tan, Goh, Li and Hartman.)

Background: Sickle cell disease (SCD) is the most common monogenic disorder worldwide. In deoxygenated conditions, the altered beta chain (haemoglobin S [HbS]) polymerises and distorts the erythrocyte, resulting in pain crises, vasculopathy and end-organ damage. Clinical complications of SCD cause substantial morbidity, and therapy demands expertise and resources. Optimising care for patients and planning resource allocation for the future requires an understanding of the disease in the Australian population. The Australian Haemoglobinopathy Registry (HbR) is a collaborative initiative of specialist centres collating and analysing data on patients with haemoglobin disorders., Aims: To provide a snapshot of SCD in Australia over a 12-month period based on data from the HbR., Methods: Patients with a clinically significant sickling disorder across 12 clinical sites were included for analysis. Data include demographic and diagnostic details, as well as details of the clinical management of the condition over a 12-month period., Results: Data on 359 SCD patients demonstrate a shift in the demographic of patients in Australia, with a growing proportion of sub-Saharan African ethnicities associated with the HbSS genotype. Acute and chronic complications are common, and patients require significant outpatient and inpatient support. Prevalence of disease complications and therapeutic trends are in keeping with other high-income countries., Conclusions: This study provides the first national picture of SCD in Australia, describing the characteristics and needs of SCD patients, elucidating demand for current and novel therapy and facilitating the planning of services for this vulnerable population., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Multiple myeloma remains an incurable disease, despite the development of numerous drug classes and combinations that have contributed to improved overall survival. Immunotherapies directed against cancer cell-surface antigens, such as chimeric antigen receptor (CAR) T-cell therapy and T-cell-redirecting bispecific antibodies, have recently received regulatory approvals and shown unprecedented efficacy. However, these immunotherapies have unique mechanisms of action and toxicities that are different to previous treatments for myeloma, so experiences from clinical trials and early access programmes are essential for providing specific recommendations for management of patients, especially as these agents become available across many parts of the world. Here, we provide expert consensus clinical practice guidelines for the use of bispecific antibodies for the treatment of myeloma. The International Myeloma Working Group is also involved in the collection of prospective real-time data of patients treated with such immunotherapies, with the aim of learning continuously and adapting clinical practices to optimise the management of patients receiving immunotherapies., Competing Interests: Declaration of interests PR-O reports personal fees derived from consulting or advisory board roles from Celgene-BMS, Janssen, Roche, AbbVie, Pfizer, GSK, Sanofi, and H3Biomedicine; steering committee membership from Celgene-BMS, Regeneron, and Janssen; speaker's bureau fess from Janssen, Celgene-BMS, GSK, Sanofi, and AbbVie; and a travel grant from Pfizer. SU reports grants and personal fees from AbbVie, Amgen, BMS, EdoPharma, Genentech, Gilead, GSK, Merck, Sanofi, and Seagen; speakers’ bureau fees, consulting and advisory board participation, and steering committee membership from Janssen; participation on advisory boards from Karyopharm Therapeutics, Oncopeptides, Secura Bio, SkylineDx, and Takeda; and grants from Moderna, TeneoBio, and Pharmacyclics, outside the submitted work. ADC reports personal fees and participation on advisory boards from GSK; personal fees from Bristol Myers Squibb, Janssen, AbbVie, Pfizer, iTeos, Ichnos, Arcellx, and Legend; personal fees and participation on advisory boards from Genentech/Roche; participation on advisory boards from Novartis, outside the submitted work; and has a patent licensed for Novartis. NWCJvdD reports personal fees from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, Cellectis, Bristol Myers Squibb/Celgene, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, AbbVie, and Servier, outside the submitted work. JGP-L reports personal fees from Janssen and GSK, outside the submitted work. MVM reports personal fees from Janssen, Celgene/Bristol Myers Squibb, Novartis, GSK, Sanofi, Amgen, Pfizer, AbbVie, and Regeneron, outside the submitted work. HE reports personal fees and research support from Bristol Myers Squibb/Celgene, Janssen, Sanofi, and GSK; and personal fees from Amgen, Takeda, and Novartis; outside the submitted work. MM reports personal fees from Janssen, Bristol Myers Squibb, WebMD global, GSK, and CDR-Life; and research funding from Siemens and BeiGene; outside the submitted work. BAD reports advisory board participation and consulting fees from COTA and Janssen; personal fees from Multiple Myeloma Research Foundation; honoraria for CME-related activities from Plexus Communications; research funding from Amgen and GSK; and involvement as an independent reviewer of a clinical trial for BMS; outside the submitted work. NP reports research funding and accomodation expenses from Amgen, Bristol Myers Squibb, Janssen, Takeda, and The Binding Site; research funding from Sanofi, and personal fees from Pfizer, outside the submitted work. PJH reports personal fees from Antengene, Gilead, iTeos Therapeutics, Janssen, Novartis, and Pfizer, outside the submitted work. W-JC reports personal fees from AbbVie, Amgen, Pfizer, Sanofi, Regeneron, GSK, and Novartis; and grants and personal fees from Bristol Myers Squibb, Janssen, and Novartis, outside the submitted work. GG reports personal fees from and is a shareholder of XNK Therapeutics Sweden, and personal fees from Fujimoto Pharmaceutical corporation, outside the submitted work. FS reports personal fees from AbbVie, GSK, Celgene, Takeda, Janssen, Oncopeptides, Sanofi, BMS, Novartis, SkyliteDX, Pfizer, and Daiki-Sankyo, outside the submitted work. JCY reports personal fees from Janssen, Sanofi, BMS, Regeneron, GSK, Pfizer, Menarini, outside the submitted work. EZ reports personal fees from Janssen, Bristol Myers Squibb, Amgen, and Takeda, outside the submitted work. RP reports personal fees and travel support from GSK and Janssen; and personal fees from Pfizer, AbbVie, Bristol Myers Squibb, and Sanofi, outside the submitted work. CN reports personal fees and participation on advisory boards from Janssen; personal fees from Bristol Myers Squibb, Sanofi, GSK, Pfizer, AstraZeneca, and DKSH; and personal fees and participation on advisory boards from Amgen, outside the submitted work. YL reports grants and personal fees from Janssen; personal fees from Sanofi, NexImmune, Caribou, Bristol Myers Squibb, Regeneron, and Genentech; and personal fees and participation on data safety monitoring boards from Pfizer, outside the submitted work. AC reports personal fees from AbbVie, Adaptive, Amgen, Antengene, Bristol Myers Squibb, Forus, Genetech/Roche, GSK, Janssen, Karyopharm, Millenium/Takeda, and Sanofi/Genzyme, outside the submitted work. JM reports personal fees from Amgen, Sanofi, Bristol Myers Squibb, Janssen, and Takeda, outside the submitted work. MC reports personal fees from Janssen, Celgene/Bristol Myers Squibb, GSK, Sanofi, Amgen, Menarini-Stemline, AbbVie, and Pfizer, outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Abstract: Tisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the third- or later-line setting. The primary analysis (median follow-up, 17 months) of the phase 2 ELARA trial reported high response rates and excellent safety profile in patients with extensively pretreated r/r FL. Here, we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after median follow-up of 29 months (interquartile range, 22.2-37.7). As of 29 March 2022, 97 patients with r/r FL (grades 1-3A) received tisagenlecleucel infusion (0.6 × 108-6 × 108 chimeric antigen receptor-positive viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment, blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached. Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% confidence interval [CI], 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T cells and higher baseline levels of naïve CD8+ T cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA. This trial was registered at www.clinicaltrials.gov as #NCT03568461., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Two-dimensional spectral mapping is used to visualize how resonant Auger-Meitner spectra are influenced by the site of the initial core-electron excitation and the symmetry of the core-excited state in the trifluoroethyl acetate molecule (ESCA). We observe a significant enhancement of electron yield for excitation of the COO 1s → π* and CF 3 1s → σ* resonances unlike excitation at resonances involving the CH 3 and CH 2 sites. The CF 3 1s → π* and CF 3 1s → σ* resonance spectra are very different from each other, with the latter populating most valence states equally. Two complementary electronic structure calculations for the photoelectron cross section and Auger-Meitner intensity are shown to effectively reproduce the site- and state-selective nature of the resonant enhancement features. The site of the core-electron excitation and the respective final state hole locality increase the sensistivity of the photoelectron signal at specific functional group sites. This showcases resonant Auger-Meitner decay as a potentially powerful tool for selectively probing structural changes at specific functional group sites of polyatomic molecules.

Multiple myeloma (MM) is an incurable disease of the bone marrow (BM) characterized by the uncontrolled proliferation of neoplastic plasma cells. While CD8+ T cells have an established role in disease control, few studies have focused on these cells within the MM tumor microenvironment (TME). We analyzed CD8+ T cells in the BM and peripheral blood (PB) of untreated patients with MM and non-myeloma controls using flow cytometry, mass cytometry and single-cell RNA sequencing, using several novel bioinformatics workflows. Inter-tissue differences were most evident in the differential expression of Granzymes B and K, which were strongly associated with two distinct subsets of CD8+ T cells delineated by the expression of CD69, accounting for roughly 50% of BM-CD8+ T cells of all assessed cohorts. While few differences were observable between health and disease in the BM-restricted CD8CD69+ T-cell subset, the CD8+CD69- T-cell subset in the BM of untreated MM patients demonstrated increased representation of highly differentiated effector cells and evident compositional parallels between the PB, absent in age-matched controls, where a marked reduction of effector cells was observed. We demonstrate the transcriptional signature of BM-CD8+ T cells from patients with MM more closely resembles TCR-activated CD8+ T cells from age-matched controls than their resting counterparts.

Background: Clinical management of Asian BRCA1 and BRCA2 pathogenic variants (PV) carriers remains challenging due to imprecise age-specific breast (BC) and ovarian cancer (OC) risks estimates. We aimed to refine these estimates using six multi-ethnic studies in Asia., Methods: Data were collected on 271 BRCA1 and 301 BRCA2 families from Malaysia and Singapore, ascertained through population/hospital-based case-series (88%) and genetic clinics (12%). Age-specific cancer risks were estimated using a modified segregation analysis method, adjusted for ascertainment., Findings: BC and OC relative risks (RRs) varied across age groups for both BRCA1 and BRCA 2. The age-specific RR estimates were similar across ethnicities and country of residence. For BRCA1 carriers of Malay, Indian and Chinese ancestry born between 1950 and 1959 in Malaysia, the cumulative risk (95% CI) of BC by age 80 was 40% (36%-44%), 49% (44%-53%) and 55% (51%-60%), respectively. The corresponding estimates for BRCA2 were 29% (26-32%), 36% (33%-40%) and 42% (38%-45%). The corresponding cumulative BC risks for Singapore residents from the same birth cohort, where the underlying population cancer incidences are higher compared to Malaysia, were higher, varying by ancestry group between 57 and 61% for BRCA1, and between 43 and 47% for BRCA2 carriers. The cumulative risk of OC by age 80 was 31% (27-36%) for BRCA1 and 12% (10%-15%) for BRCA2 carriers in Malaysia born between 1950 and 1959; and 42% (34-50%) for BRCA1 and 20% (14-27%) for BRCA2 carriers of the same birth cohort in Singapore. There was evidence of increased BC and OC risks for women from >1960 birth cohorts (p-value = 3.6 × 10 -5 for BRCA1 and 0.018 for BRCA 2)., Interpretation: The absolute age-specific cancer risks of Asian carriers vary depending on the underlying population-specific cancer incidences, and hence should be customised to allow for more accurate cancer risk management., Funding: Wellcome Trust [grant no: v203477/Z/16/Z]; CRUK (PPRPGM-Nov20∖100002)., Competing Interests: Z.Z received honorarium from AstraZeneca. J.N received research funding from AstraZeneca and MiRXES. A.C.A is listed as creator of the BOADICEA model which has been licensed by Cambridge Enterprise, from which University of Cambridge may receive royalties. N.A.M.T received honoraria for lectures from Zuellig Pharma Sdn Bhd and Astra Zeneca, received support for attending meetings and/or travel from MSD and Astra Zeneca. S.Y.Y received speaker's honoraria from Astra Zeneca, she is the president of Genetic Counselling Society Malaysia., (© 2024 The Author(s).)

Despite widespread vaccination rates, we are living with high transmission rates of SARS-CoV-2. Although overall hospitalisation rates are falling, the risk of serious infection remains high for patients who are immunocompromised because of haematological malignancies. In light of the ongoing pandemic and the development of multiple agents for treatment, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 management in patients with haematological disorders. It is our recommendation that both patients with haematological malignancies and treating specialists be educated regarding the preventive and treatment options available and that patients continue to receive adequate vaccinations, keeping in mind the suboptimal vaccine responses that occur in haematology patients, in particular, those with B-cell malignancies and on B-cell-targeting or depleting therapy. Patients with haematological malignancies should receive treatment for COVID-19 in accordance with the severity of their symptoms, but even mild infections should prompt early treatment with antiviral agents. The issue of de-isolation following COVID-19 infection and optimal time to treatment for haematological malignancies is discussed but remains an area with evolving data. This position statement is to be used in conjunction with advice from infectious disease, respiratory and intensive care specialists, and current guidelines from the National COVID-19 Clinical Evidence Taskforce and the New Zealand Ministry of Health and Cancer Agency Te Aho o Te Kahu COVID-19 Guidelines., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Background: In the last few decades, the life expectancy of patients with transfusion-dependent thalassaemia (TDT) and sickle cell disease (SCD) has improved significantly, in part because of improved iron chelation. Fertility challenges and pregnancy complications have historically limited reproductive options in this group; however, improved multi-disciplinary care has made infertility a chronic disease complication requiring attention. Despite this, there are very few reports and no Australian data describing fertility and pregnancy outcomes in this population., Aims: To identify the rate of assisted reproductive technologies (ART) utilisation in our female transfusion-dependent haemoglobinopathy patients and to establish the nature of maternal and neonatal complications in this cohort., Methods: A 20-year retrospective analysis (1997-2017) at an Australian centre captured data on conception rates, use of assisted reproductive techniques (ART), and pregnancy and neonatal outcomes in female transfusion-dependent haemoglobinopathy patients., Results: Conception was attempted in 14 women (11 TDT and three SCD) during the study period. A total of 28 pregnancies resulting in 25 live births were recorded. ART supported 13 conceptions. A positive association was not identified between elevated mean serum ferritin and ART use; however, all patients with an established diagnosis of hypogonadotropic hypogonadism (HH) required ART. Maternal complications included gestational diabetes mellitus and post-partum haemorrhage. There were no cardiac complications. Two-thirds of women underwent lower segment caesarean section, with prematurity complicating 20% of births. There were no neonatal or maternal deaths., Conclusion: Pregnancy is an achievable goal for women with transfusion-dependent haemoglobinopathies, although the support of ART may be required in a subset of patients., (© 2023 Royal Australasian College of Physicians.)

Background: Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed., Methods: In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status., Results: At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group., Conclusions: The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.)., (Copyright © 2023 Massachusetts Medical Society.)

PBRM1 is frequently mutated in cancers of epithelial origin. How PBRM1 regulates normal epithelial homeostasis, prior to cancer initiation, remains unclear. Here, we show that PBRM1's gene regulatory roles differ drastically between cell states, leveraging human skin epithelium (epidermis) as a research platform. In progenitors, PBRM1 predominantly functions to repress terminal differentiation to sustain progenitors' regenerative potential; in the differentiation state, however, PBRM1 switches toward an activator. Between these two cell states, PBRM1 retains its genomic binding but associates with differential interacting proteins. Our targeted screen identified the E3 SUMO ligase PIAS1 as a key interactor. PIAS1 co-localizes with PBRM1 on chromatin to directly repress differentiation genes in progenitors, and PIAS1's chromatin binding drastically diminishes in differentiation. Furthermore, SUMOylation contributes to PBRM1's repressive function in progenitor maintenance. Thus, our findings highlight PBRM1's cell-state-specific regulatory roles influenced by its protein interactome despite its stable chromatin binding., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The Global Breast Cancer Initiative (GBCI) Framework, launched by the World Health Organisation (WHO) in 2023, emphasises assessing, strengthening, and scaling up services for the early detection and management of breast cancer. This study aims to determine the feasibility of monitoring the status of breast cancer control in the 21 Asian National Cancer Centers Alliance (ANCCA) countries based on the three GBCI Framework key performance indicators (KPIs): stage at diagnosis, time to diagnosis, and treatment completion., Methods: We reviewed published literature on breast cancer control among 21 ANCCA countries from May to July 2023 to establish data availability and compiled the latest descriptive statistics and sources of the indicators using a standardised data collection form. We performed bivariate Pearson's correlation analysis to measure the strength of correlation between stage at diagnosis, mortality and survival rates, and universal health coverage., Findings: Only 12 (57%) ANCCA member countries published national cancer registry reports on breast cancer age-standardised incidence rate (ASIR) and age-standardised mortality rate (ASMR). Indonesia, Myanmar, and Nepal had provincial data and others relied on WHO's Global Cancer Observatory (GLOBOCAN) estimates. GLOBOCAN data differed from the reported national statistics by 5-10% in Bhutan, Indonesia, Iran, the Republic of Korea, Singapore, and Thailand and >10% in China, India, Malaysia, Mongolia, and Sri Lanka. The proportion of patients diagnosed in stages I and II strongly correlated with the five-year survival rate and with the universal health coverage (UHC) index. Three countries (14%) reported national data with >60% of invasive breast cancer patients diagnosed at stages I and II, and a five-year survival rate of >80%. Over 60% of the ANCCA countries had no published national data on breast cancer staging, the time interval from presentation to diagnosis, and diagnosis to treatment. Five (24%) countries reported data on treatment completion. The definition of delayed diagnosis and treatment completion varied across countries., Interpretation: GBCI's Pillar 1 KPI correlates strongly with five-year survival rate and with the UHC index. Most ANCCA countries lacked national data on cancer staging, timely diagnosis, and treatment completion KPIs. While institutional-level data were available in some countries, they may not represent the nationwide status. Strengthening cancer surveillance is crucial for effective breast cancer control. The GBCI Framework indicators warrant more detailed definitions for standardised data collection. Surrogate indicators which are measurable and manageable in country-specific settings, could be considered for monitoring GBCI indicators. Ensuring UHC and addressing health inequalities are essential to early diagnosis and treatment of breast cancer., Funding: Funding for this research article's processing fee (APC) will be provided by the affiliated institution to support the open-access publication of this work. The funding body is not involved in the study design; collection, management, analysis and interpretation of data; or the decision to submit for publication. The funding body will be informed of any planned publications, and documentation provided., Competing Interests: The authors have no conflicts of interest to declare. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions or policies of their affiliated institutions. Where authors are identified as personnel of the World Health Organisation (WHO), the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the WHO. Where maps are concerned, all rights are reserved by the WHO. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate borderlines for which there may not yet be full agreement., (© 2023 Published by Elsevier Ltd.)

Background: Exposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in breast cancer patients., Methods: We performed DNAm analysis in 125 breast cancer patients with blood drawn before and after chemotherapy, using the Illumina MethylationEPIC array. DNAm changes of 588,798 individual CpGs (including 41,207 promoter regions) were evaluated using linear regression models adjusted for monocyte proportion. Gene set enrichment analyses (GSEA) were conducted to identify key Gene Ontology (GO) biological processes or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with chemotherapy. Results were validated in a separate cohort of breast cancer patients who were treated (n = 1273) and not treated (n = 872) by chemotherapy (1808 blood, 337 saliva)., Results: A total of 141 differentially methylated CpGs and 11 promoters were significantly associated with chemotherapy after multiple testing corrections in both the paired sample and single time point analyses. GSEA of promoter regions (pre-ranked by test statistics) identified six suppressed biological processes (p < 4.67e-8) related to sensory perception and detection of chemical stimuli, including smell perception (GO:0007606, GO:0007608, GO:0009593, GO:0050906, GO:0050907, and GO:0050911). The same six biological processes were significantly suppressed in the validation dataset (p < 9.02e-14). The KEGG pathway olfactory transduction (hsa04740) was also found to be significantly suppressed (p paired-samples  = 1.72e-9, p single-timepoint-blood  = 2.03e-15 and p single-timepoint-saliva  = 7.52e-56)., Conclusion: The enrichment of imprinted genes within biological processes and pathways suggests a biological mechanism by which chemotherapy could affect the perception of smell., (© 2023. The Author(s).)

Purpose: The benefit of using individual risk prediction tools to identify high-risk individuals for breast cancer (BC) screening is uncertain, despite the personalized approach of risk-based screening., Methods: We studied the overlap of predicted high-risk individuals among 246,142 women enrolled in the UK Biobank. Risk predictors assessed include the Gail model (Gail), BC family history (FH, binary), BC polygenic risk score (PRS), and presence of loss-of-function (LoF) variants in BC predisposition genes. Youden J-index was used to select optimal thresholds for defining high-risk., Results: In total, 147,399 were considered at high risk for developing BC within the next 2 years by at least 1 of the 4 risk prediction tools examined (Gail 2-year > 0.5%: 47%, PRS 2-yea r > 0.7%: 30%, FH: 6%, and LoF: 1%); 92,851 (38%) were flagged by only 1 risk predictor. The overlap between individuals flagged as high-risk because of genetic (PRS) and Gail model risk factors was 30%. The best-performing combinatorial model comprises a union of high-risk women identified by PRS, FH, and, LoF (AUC 2-year [95% CI]: 62.2 [60.8 to 63.6]). Assigning individual weights to each risk prediction tool increased discriminatory ability., Conclusion: Risk-based BC screening may require a multipronged approach that includes PRS, predisposition genes, FH, and other recognized risk factors., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor T-cell therapies are promising new options for patients with relapsed or refractory diffuse large B-cell lymphoma or acute lymphoblastic leukaemia. They increase complete response rates and the chances of achieving prolonged remission. Chimeric antigen receptor T cells are specially modified lymphocytes designed to stimulate the body's own immune system to target malignant cells. The process involves an initial harvest of the patient's own T cells, genetic modification, T-cell expansion and then reinfusion. Cytokine release syndrome is a major short-term complication of chimeric antigen receptor T-cell therapy. The presentation typically resembles septic shock and can be fatal. Immune effector cell-associated neurotoxicity syndrome is another major short-term complication. It presents with a spectrum of neurological deficits ranging from headache, delirium and anxiety to seizures and coma. There are early promising results with chimeric antigen receptor T-cell therapies in other cancers. These include mantle cell lymphoma, multiple myeloma and some solid organ tumours such as glioblastoma multiforme., Competing Interests: Conflicts of interest: Vinay Vanguru participates in advisory boards and educational talks for Novartis, Gilead and Janssen. Phoebe Ho participates in an advisory board, with no honorarium, for Gilead., ((c) Therapeutic Guidelines.)

Background: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease., Methods: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival., Results: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%)., Conclusions: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.)., (Copyright © 2023 Massachusetts Medical Society.)