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Detection of light chain (LC) monoclonal gammopathies (MG) traditionally relies on serum free LC (FLC) κ, λ, and their ratio (κ/λ) reference ranges based on a mostly White population. We investigated FLC values in a racially diverse population by screening 10,035 individuals for heavy chain MG, identifying 9,028 negative cases whose FLC were measured. Participants included 4,149 from the PROMISE Study (US, n=2,383; South Africa, n=1,766) and 4,879 from the Mass General Brigham Biobank, with 44% self-identifying as Black. Using standard FLC reference ranges, 1,074 out of 10,035 individuals (10.7%) were diagnosed with LC-MGUS, with 99% being κ-restricted. In the US, 14.8% of Black and 4% of White individuals were diagnosed (p<0.01). Among US participants of African (AFR) and European (EUR) genetic ancestry, 14.4% AFR and 2.9% EUR were diagnosed (p<0.01). Among South Africans (100% Black), 27.8% were diagnosed using standard ranges. To avoid overdiagnosis, we propose a new κ/λ ratio reference range (0.686 to 2.10) for populations of African descent with normal renal function, with standard values for κ and λ being 7.97 to 77.50 mg/L and 6.20 to 49.20 mg/L, respectively. This reduces LC-MGUS overdiagnosis by 91% (10.7% vs. 0.97%). Using the new reference, LC-MGUS accounts for 8.8% of MGUS cases, with 74% being κ-restricted, consistent with LC myeloma rates. These findings highlight the importance of basing disease definitions, such as MGUS, on diverse populations. Adopting our proposed FLC reference values would reduce MGUS overdiagnosis among Black individuals, avoiding unnecessary financial, psychological, and medical consequences., (Copyright © 2024 American Society of Hematology.)

Background: Chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS) and immune effector cell-associated hematotoxicity (ICAHT), predisposing for life-threatening infections., Methods: This retrospective observational study examined a total of 129 patients with RRMM who had received idecabtagene vicleucel (ide-cel) at two major myeloma centers in Germany and one center in the USA to assess the Endothelial Activation and Stress Index (EASIX) as a risk marker for an unfavorable clinical course and outcome after CAR T-cell therapy. EASIX is calculated by lactate dehydrogenase (U/L) × creatinine (mg/dL) / platelets (10 9 cells/L) and was determined before lymphodepletion (baseline) and at the day of CAR T-cell infusion (day 0). The analysis was extended to EASIX derivatives and the CAR-HEMATOTOX score., Results: An elevated baseline EASIX (>median) was identified as a risk marker for severe late ICAHT, manifesting with an impaired hematopoietic reconstitution and pronounced cytopenias during the late post-CAR-T period. Patients with high EASIX levels (>upper quartile) were particularly at risk, as evidenced by an increased rate of an aplastic phenotype of neutrophil recovery, severe late-onset infections and ICANS. Finally, we found associations between baseline EASIX and an inferior progression-free and overall survival. Moreover, the EASIX at day 0 also demonstrated potential to serve as a risk marker for post-CAR-T complications and adverse outcomes., Conclusions: In conclusion, EASIX aids in risk stratification at clinically relevant time points prior to CAR T-cell therapy with ide-cel. Increased EASIX levels might help clinicians to identify vulnerable patients to adapt peri-CAR-T management at an early stage., Competing Interests: Competing interests: JF has received honoraria from BMS and Stemline and travel and congress participation grants from Janssen-Cilag. XZ declares advisory services for and has received travel support from SkylineDx. JK has received honoraria from AstraZeneca. EKM declares a consulting or advisory role for Amgen, BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Pfizer, Sanofi, Stemline and Takeda. He has received honoraria from Amgen, BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Pfizer, Sanofi, Stemline and Takeda, research funding from BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi and Takeda and travel support from BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi, Stemline and Takeda. MJF declares consulting activity for Pfizer and Kerna Ventures. CSM has received honoraria and travel support from Janssen-Cilag. IB has received honoraria from Oncopeptide and travel support from Janssen. ON reports receiving consulting fees from Janssen, BMS, Takeda, GPCR therapeutics, Sanofi and Pfizer. AS has received travel grants from Hexal and Jazz Pharmaceuticals and research grants from Therakos/Mallinckrodt. She is a consultant for Janssen-Cilag and BMS and co-founder of TolerogenixX Ltd. AS is part-time employee of TolerogenixX Ltd. MS declares an advisory role or expert testimony for MSD, Novartis, BMS and Pierre Fabre. He is co-founder and shareholder of TolerogenixX GmbH, Heidelberg. He has received financial support for research on biosimilars and travel grants from Hexal, financial support of educational activities and conference participation and travels grants from Kite and BMS, collaborative research grants from Novartis and funding for collaborative research from Apogenix. MT has received research funding from Kite, Regeneron and Roche. He is an advisory board member for AstraZeneca, BMS, Incyte, Janssen and Novartis. HE declares a consulting or advisory role for BMS/Celgene, Janssen, Amgen, Takeda, Sanofi, GSK, Novartis and Roche. He has received research funding from BMS/Celgene, Janssen, Amgen, GSK, Sanofi and Novartis, honoraria from BMS/Celgene, Janssen, Amgen, Takeda, Sanofi, GSK, Novartis and travel support from BMS/Celgene, Janssen and Amgen. PD reports consultancy for AbbVie, AstraZeneca, Beigene, BMS, Gilead, Miltenyi, Novartis and Riemser. He is member of the speakers’ bureau for AbbVie, AstraZeneca, BeiGene, BMS, Gilead, Novartis, Riemser and Roche and has received research support from Riemser (all to institution). NCM reports receiving personal fees from BMS, Janssen, Amgen, Takeda, OncoPep, AbbVie, Karyopharm, Novartis, Legend, Raqia, Adaptive Biotechnology, and Pfizer outside the submitted work. He has intellectual property licensed to OncoPep and held stocks in C4 Therapeutics. ASp reports receiving consulting fees from Novartis and Roche. LR consulted for Janssen, Amgen, GSK, Pfizer, BMS, Sanofi, and received honoraria from Janssen, GSK, Pfizer, BMS, Sanofi and received research funding from Skyline Dx and BMS. SS has received travel grants or honoraria for presentations from Celgene, BMS, Janssen, Takeda and Amgen. MSR declares a consulting or advisory role for BMS, Amgen, GSK, Janssen, Sanofi, Pfizer, AbbVie and Takeda. He has received research funding from BMS, Janssen, Sanofi and Heidelberg Pharma, travel support from BMS, Amgen and Janssen and honoraria from BMS, Janssen, AbbVie and Sanofi., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Myeloid neoplasms arise from preexisting clonal hematopoiesis (CH); however, the role of CH in the pathogenesis of acute lymphoblastic leukemia (ALL) is unknown. We found that 18% of adult ALL cases harbored TP53, and 16% had myeloid CH-associated gene mutations. ALL with myeloid mutations (MyM) had distinct genetic and clinical characteristics, associated with inferior survival. By using single-cell proteogenomic analysis, we demonstrated that myeloid mutations were present years before the diagnosis of ALL, and a subset of these clones expanded over time to manifest as dominant clones in ALL. Single-cell RNA sequencing revealed upregulation of genes associated with cell survival and resistance to apoptosis in B-ALL with MyM, which responds better to newer immunotherapeutic approaches. These findings define ALL with MyM as a high-risk disease that can arise from antecedent CH and offer new mechanistic insights to develop better therapeutic and preventative strategies., Significance: CH is a precursor lesion for lymphoblastic leukemogenesis. ALL with MyM has distinct genetic and clinical characteristics, associated with adverse survival outcomes after chemotherapy. CH can precede ALL years before diagnosis, and ALL with MyM is enriched with activated T cells that respond to immunotherapies such as blinatumomab. See related commentary by Iacobucci, p. 142., (©2023 The Authors; Published by the American Association for Cancer Research.)

DIS3 gene mutations occur in approximately 10% of patients with multiple myeloma (MM); furthermore, DIS3 expression can be affected by monosomy 13 and del(13q), found in roughly 40% of MM cases. Despite the high incidence of DIS3 mutations and deletions, the biological significance of DIS3 and its contribution to MM pathogenesis remain poorly understood. In this study we investigated the functional role of DIS3 in MM, by exploiting a loss-of-function approach in human MM cell lines. We found that DIS3 knockdown inhibits proliferation in MM cell lines and largely affects cell cycle progression of MM plasma cells, ultimately inducing a significant increase in the percentage of cells in the G0/G1 phase and a decrease in the S and G2/M phases. DIS3 plays an important role not only in the control of the MM plasma cell cycle, but also in the centrosome duplication cycle, which are strictly co-regulated in physiological conditions in the G1 phase. Indeed, DIS3 silencing leads to the formation of supernumerary centrosomes accompanied by the assembly of multipolar spindles during mitosis. In MM, centrosome amplification is present in about a third of patients and may represent a mechanism leading to genomic instability. These findings strongly prompt further studies investigating the relevance of DIS3 in the centrosome duplication process. Indeed, a combination of DIS3 defects and deficient spindle-assembly checkpoint can allow cells to progress through the cell cycle without proper chromosome segregation, generating aneuploid cells which ultimately lead to the development of MM.