Despite several approved therapies, multiple myeloma (MM) remains an incurable disease with high unmet medical need. "Off-the-shelf" T-cell bispecific antibodies (TCBs) targeting B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GPRC5D) have demonstrated high objective response rates in heavily pretreated patients with MM; however, primary resistance, short duration of response, and relapse driven by antigen shift frequently occur. Although GPRC5D represents the most selective target in MM, recent findings indicate antigen loss occurs more frequently than with BCMA. Thus, anti-GPRC5D immunotherapies must hit hard during a short period of time. Here, we characterize forimtamig, a novel GPRC5D-targeting TCB with 2+1 format. Bivalent binding of forimtamig to GPRC5D confers higher affinity than classical 1+1 TCB formats correlating with formation of more stable immunological synapses and higher potency in tumor cell killing and T-cell activation. Using an orthotopic mouse model of MM, forimtamig recruited T effector cells to the bone marrow and induced rapid tumor killing even after the introduction of step-up dosing to mitigate cytokine release. Combination of forimtamig with standard-of-care agents including anti-CD38 antibodies, immunomodulatory drugs, and proteasome inhibitors improved depth and duration of response. The combination of forimtamig with novel therapeutic agents including BCMA TCB and cereblon E3 ligase modulatory drugs was potent and prevented occurrence of GPRC5D -negative tumor relapse. Forimtamig is currently being evaluated in phase 1 clinical trials in patients with relapsed and refractory MM for monotherapy and in combination treatments. This trial was registered at www.ClinicalTrials.gov as #NCT04557150.

In an open prospective, multicenter study enrolling 48 selected patients with chronic immune thrombocytopenia who achieved complete response for 1 year on thrombopoietin receptor agonists, half of the patients maintained a sustained response off treatment 4 years after treatment discontinuation.

BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies that are caused by the proliferation of myeloid cells that harbor a JAK-STAT pathway activating driver mutation. MPN management recommendations are based on the evaluation of different risks to prevent disease evolution-associated events while preserving patients' quality of life. Such risks can be common across all MPNs or specific to each subtype (polycythemia vera [PV], essential thrombocythemia [ET], prefibrotic myelofibrosis [MF], and primary MF). Patients with MF harbor the worse prognosis, and hematopoietic stem cell transplantation (HSCT) is the only curative treatment at the expense of a high rate of morbidity and mortality. Therefore, accurate scoring systems to estimate overall survival are crucial for the management of patients with MF and the selection for HSCT. In PV and ET, the prediction of vascular events is prioritized given their higher incidence and related morbidity and mortality. Finally, quality of life evaluation is important for all subtypes. To predict these risks and adapt MPN therapeutic strategies, clinical risk scores have been developed over the past decades and more recently have incorporated molecular risk factors for more accurate risk stratification. The large number of scoring systems available, combined with disease heterogeneity and the necessity to predict diverse outcomes, make it difficult for clinicians to choose the most appropriate score to evaluate their patients' risk in 2024. Here, we provide an overview of MPN disease evolution-associated event incidence and conduct an exhaustive comparative review of the scoring systems currently available for each risk. Finally, we propose an algorithm for the use of these scores in clinical practice in each MPN subtype.

Sterile alpha motif domain-containing protein 9 (SAMD9) and SAMD9-like (SAMD9L) are paralogous genes encoding antiviral proteins that negatively regulate cell proliferation. Heterozygous germ line gain-of-function (GoF) SAMD9/9L variants cause multisystem syndromes with variable manifestations. The unifying features are cytopenia, immunodeficiency, infections, bone marrow failure, myelodysplasia, and monosomy 7. Nonhematopoietic presentations can affect almost every organ system. Growth impairment and adrenal insufficiency are typical in SAMD9, whereas progressive neurologic deficits characterize SAMD9L. Most patients (>90%) carry germ line missense GoF variants. A subgroup of patients presenting with SAMD9L-associated inflammatory disease carry frameshift-truncating variants that are also GoF. Somatic genetic rescue occurs in two-third of patients or more and involves monosomy 7, which may spontaneously disappear (transient monosomy 7) or progress to myelodysplastic syndrome (MDS)/leukemia, and adaptive clones with somatic SAMD9/9L compensatory mutations or uniparental disomy 7q (UPD7q), both associated with remission. This manuscript examines the clinical and genetic spectrum, therapies, and outcome based on 243 published patients compiled in our registry, with additional genetic information on 62 unpublished cases. We consolidate the diverse clinical manifestations and diagnostic challenges of SAMD9/9L syndromes to enhance recognition and improve patient care. We highlight the knowledge gaps in pathomechanisms and emphasize the importance of genetic surveillance assessing disease remission vs disease progression. Insights are provided into variant curation and the necessity of testing for somatic SAMD9/9L mutations and UPD7q. Multidisciplinary care in specialized centers is critical to manage these complex disorders. Future natural history studies, especially in patients with monosomy 7, will help formulate evidence-based surveillance protocols and optimize transplant timing and outcomes.

Venetoclax, a first-in-class BH3 mimetic drug that targets B-cell lymphoma-2 (BCL-2), has improved the outcomes of patients with chronic lymphocytic leukemia (CLL). Early measurements of the depth of the venetoclax treatment response, assessed by minimal residual disease, are strong predictors of long-term clinical outcomes. However, there are limited data on the early changes induced by venetoclax treatment that might inform strategies to improve responses. To address this gap, we conducted longitudinal mass cytometric profiling of blood cells from patients with CLL during the first 5 weeks of venetoclax monotherapy. At baseline, we resolved CLL heterogeneity at the single-cell level to define multiple subpopulations in all patients based on proliferative, metabolic, and cell survival proteins. Venetoclax induced a significant reduction in all CLL subpopulations and caused rapid upregulation of the prosurvival BCL-2, BCL-extra large, and mantle cell lymphoma-1 proteins in surviving cells, which had reduced sensitivity to the drug. In mouse models, the venetoclax-induced elevation of survival proteins in B cells and CLL-like cells that persisted was recapitulated, and genetic models demonstrated that extensive apoptosis and access to the B-cell cytokine, B-cell activating factor (BAFF), were essential. Accordingly, in patients with CLL who were treated with venetoclax or the anti-CD20 antibody obinutuzumab there was marked elevation in BAFF and an increase in prosurvival proteins in leukemic cells that persisted. Overall, these data highlight the rapid adaptation of CLL cells to targeted therapies through homeostatic factors and support cotargeting of cytokine signals to achieve deeper and more durable long-term responses.

Mosunetuzumab, a CD20×CD3 T-cell engaging bispecific antibody, redirects T cells to eliminate malignant B cells. We present updated efficacy and safety data of a pivotal phase 1/2 study after a median follow-up of 37.4 months in 90 patients with relapsed/refractory (R/R) follicular lymphoma (FL) and ≥2 prior lines of therapy treated with fixed-duration mosunetuzumab. Investigator-assessed complete response (CR) rate and objective response rate were 60.0% (95% confidence interval [CI], 49.1-70.2) and 77.8% (95% CI, 67.8-85.9), respectively. Among 70 responders, median duration of response was 35.9 months (95% CI, 20.7 to not estimable [NE]). Among 54 patients who achieved CR, 49 remained in CR at the end of treatment; median duration of CR was not reached (NR; 95% CI, 33.0 to NE); Kaplan-Meier-estimated 30-month remission rate was 72.4% (95% CI, 59.2-85.6). Estimated 36-month overall survival (OS) rate was 82.4% (95% CI, 73.8-91.0); median OS was NR (95% CI, NE to NE). Median progression-free survival was 24.0 months (95% CI, 12.0 to NE). Median time to CD19+ B-cell recovery was 18.4 months (95% CI, 12.8-25.0) after 8 cycles of mosunetuzumab treatment. No new cytokine release syndrome events or fatal, serious, or grade ≥3 adverse events were reported. With extended follow-up, mosunetuzumab demonstrated high response rates, durable remissions, and manageable safety with no long-term concerns. This supports outpatient mosunetuzumab administration as an off-the-shelf, fixed-duration, safe, and effective treatment for patients with R/R FL, including those with high-risk disease. This trial was registered at www.clinicaltrials.gov as #NCT02500407.

The structure of human coagulation factor XIII (FXIII), a heterotetrameric plasma protransglutaminase that covalently cross-links preformed fibrin polymers, remains elusive until today. The heterotetrameric complex is composed of 2 catalytic FXIII-A and 2 protective FXIII-B subunits. Structural etiology underlying FXIII deficiency has so far been derived from crystallographic structures, all of which are currently available for the FXIII-A2 homodimer only. Here, we present the cryogenic electron microscopy (cryo-EM) structure of a native, human plasma-derived FXIII-A2B2 complex at 2.4 Å resolution. The structure provides detailed information on FXIII subunit interacting interfaces as the 2 subunits interact strongly in plasma. The native FXIII-A2B2 complex reveals a pseudosymmetric heterotetramer of 2 FXIII-B monomers intercalating with a symmetric FXIII-A2 dimer forming a "crown"-like assembly. The symmetry axes of the A2 and B2 homodimers are twisted relative to each other such that Sushi domain 1 interacts with the catalytic core of the A subunit, and Sushi domain 2 with the symmetry related A' subunit, and vice versa. We also report 4 novel mutations in the F13A1 gene encoding the FXIII-A subunit from a cohort of patients with severe FXIII deficiency. Our structure reveals the etiological basis of homozygous and heterozygous pathogenic mutations and explains the conditional dominant negative effects of heterozygous mutations. This atomistic description of complex interfaces is consistent with previous biochemical data and shows a congruence between the structural biochemistry of the FXIII complex and the clinical features of FXIII deficiency.

Antibiotic (ABX)-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapies. In this study, we observed that prior exposure to broad-spectrum ABXs with extended anaerobic coverage such as piperacillin-tazobactam and meropenem was associated with worse anti-CD19 CAR-T therapy survival outcomes in patients with large B-cell lymphoma (N = 422) than other ABX classes. In a discovery subset of these patients (n = 67), we found that the use of these ABXs was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n = 58). Broader evaluation of circulating microbial metabolites revealed reductions in indole and cresol derivatives, as well as trimethylamine N-oxide, in patients who received ABX treatment (discovery, n = 40; validation, n = 28). These findings were recapitulated in an immune-competent CAR-T mouse model, in which meropenem-induced dysbiosis led to a systemic dysmetabolome and decreased murine anti-CD19 CAR-T efficacy. Furthermore, we demonstrate that SCFAs can enhance the metabolic fitness of CAR-Ts, leading to improved tumor killing capacity. Together, these results suggest that broad-spectrum ABX deplete metabolically active commensals whose metabolites are essential for enhancing CAR-T efficacy, shedding light on the intricate relationship between ABX exposure, microbiome function and their impact on CAR-T efficacy. This highlights the potential for modulating the microbiome to augment CAR-T immunotherapy. This trial was registered at www.clinicaltrials.gov as #NCT06218602.

High-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2), or "double-hit lymphoma," has been associated with a high risk of central nervous system (CNS) relapse. However, historic estimates are impacted by selection bias. We report CNS relapse rates associated with HGBCL-DH-BCL2 from a population-based cohort with complete fluorescence in situ hybridization testing, as well as diffuse large B-cell lymphoma morphology (DLBCL) tumors expressing the dark-zone gene expression signature (DZsig), which was originally derived from HGBCL-DH-BCL2. The 2-year CNS relapse risk in HGBCL-DH-BCL2 was 6.8%. CNS relapses were early, predominantly leptomeningeal (73%), and co-occurred with systemic relapse (64%). High-risk CNS International Prognostic Index (CNS-IPI) and concordant bone marrow involvement were associated with an elevated CNS relapse risk in HGBCL-DH-BCL2. The "refined cell-of-origin" classification assigned 20% of DLBCL morphology tumors with germinal center B-cell-like phenotype (GCB-DLBCL) into a distinct subgroup based on DZsig expression (DZsig+). CNS relapse risk in DZsig+ (2 year: 6.4%) was independent of HGBCL-DH-BCL2 status and was further stratified by the CNS-IPI. CNS relapse in DZsig-negative GCB-DLBCL was rare (2-year risk, 1.4%; P = .04 vs DZsig+) and exclusively parenchymal. Altogether, the CNS relapse risk in HGBCL-DH-BCL2 is lower than previously reported, and DZsig refines risk stratification in GCB-DLBCL.

Soluble B-cell maturation antigen (sBCMA) is elevated on multiple myeloma (MM) cells. We investigated whether sBCMA levels correlated with other myeloma tumor volume indicators and its utility in monitoring oligosecretory/nonsecretory (O-S/Non-S) MM. In 115 patients with newly diagnosed MM, sBCMA was compared with M-protein levels, bone marrow plasma cells (BMPCs), circulating tumor cells (CTCs), and total diffusion volume (tDV; estimated by whole-body diffusion-weighted magnetic resonance imaging) at diagnosis. sBCMA levels increased significantly with International Staging System stage, chromosome 1q21 gain/amplification, and CTC levels. sBCMA also correlated strongly with %BMPC (r = 0.65) and moderately with tDV (r = 0.55) and paraprotein levels (involved immunoglobulin in IgG and IgA subtypes, r = 0.44 and 0.4; involved free light-chain levels in light-chain-only MM, r = 0.61, all P < .05). Longitudinal changes in sBCMA were consistent with disease status in both 17 O-S/Non-S and other secretory MM cases. Furthermore, sBCMA levels increased as early as 6 months prerelapse in almost all O-S/Non-S relapsed patients. Thus, sBCMA correlates strongly with total tumor volume in MM, as assessed using different modalities. We suggest that sBCMA is useful, not only for monitoring responses in patients with O-S/Non-S MM but also for early relapse detection and prediction.