Blood Cancer Discovery最新文献

First-line multiple myeloma treatment has evolved from melphalan-prednisone to quadruplet regimens incorporating proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, and autologous stem cell transplantation, yielding significantly improved survival. This review summarizes current approaches to risk stratification and therapy for newly diagnosed multiple myeloma and highlights the emerging role of measurable residual disease-adaptive strategies. We also discuss recent efforts to integrate chimeric antigen receptor T cells and bispecific antibodies into up-front treatment. As biology-driven strategies advance, select patients may achieve durable treatment-free remissions. Ongoing studies will clarify how to best tailor therapy while balancing efficacy, toxicity, and survivorship toward functional cures.

Significance: Despite unprecedented advances, multiple myeloma therapy remains largely uniform and emphasizes indefinite treatment. Herein, although summarizing current standard-of-care therapy, we advocate for individualized approaches informed by disease biology, treatment response, and emerging biomarkers. Novel strategies incorporating immunotherapies are paving the way toward treatment-free remissions and functional cures in select patients.

Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a complication seen in patients receiving chimeric antigen receptor (CAR) T cells, more frequently in those with CD22- or BCMA-targeted constructs compared with CD19. While associated with higher CAR T-cell expansion and a unique cytokine profile, the constellation of three cytokines (IFNγ, IL10, and IL1RA) correlated most strongly with IEC-HS severity and may help guide preemptive interventions. See related article by Srinagesh et al., p. XX .

The standard of care for multiple myeloma has rapidly evolved to include immune-based therapies. However, achieving durable immune control and long-term survival, particularly in high-risk patients, remains difficult. In this article, we review the immune effects of existing and emerging therapies, dissect key drivers of resistance, highlight rational combinations and treatment-sequencing strategies, and summarize ongoing clinical trials that aim to optimize durable immune control. We discuss how the application of these biological and clinical insights may help us rethink multiple myeloma treatment to fully eradicate residual disease and elicit sustained natural and/or synthetic tumor-specific immunity.

Significance: Preclinical and clinical insights are reshaping how immune-based therapies are used in multiple myeloma. This review explores how optimizing the integration of natural and synthetic immunity can support a shift from disease control to deep, durable immune eradication, paving the way for personalized immune strategies tailored to individual immune profiles.

Cancer cells display extensive heterogeneity that influences therapy response and clinical outcome, yet the underlying mechanisms remain incompletely understood. Recent studies reveal that the developmental state and molecular plasticity of target cells, together with genetic lesions, drive cellular transformation, disease heterogeneity, and treatment response in hematologic malignancies. See related article by Hartmann et al., p. XX . See related article by Wang et al., p. XX .

Chimeric antigen receptor (CAR) T cell therapy has reshaped the therapeutic landscape for multiple myeloma (MM), yet most patients treated with BCMA-targeted CAR T cells experience disease relapse. Consequently, we sought to determine if inhibition of CD28 survival signaling could increase MM sensitivity to CAR T cell therapy. Contrary to expectations, blockade of CD28 interaction with CD80/86 accelerated tumor regrowth in preclinical MM and lymphoma CAR T therapy models. Knockout studies revealed that endogenous CD28 on 4-1BB co-stimulated CAR T cells prolonged in vivo activity, reprogrammed mitochondrial metabolism to maintain redox balance, and stimulated proliferation and release of tumor-model specific inflammatory cytokines in the tumor microenvironment. Intriguingly, transient CD28 blockade decreased levels of certain TME cytokines without significantly affecting survival of CAR T cell treated mice. Collectively, these data provide direct evidence that endogenous CD28 signaling modulates CAR T cell responses in multiple myeloma and lymphoma models.

In this commentary, we open the debate on what can be expected from artificial intelligence (AI) in the diagnosis of hematologic cancers. We discuss the key factors that make AI solutions robust, trustworthy, and, above all, generalizable, with particular emphasis on the importance of dataset quality in shaping the performance and effectiveness of AI models.

Recent updates to monocyte count thresholds recognize oligomonocytic chronic myelomonocytic leukemia (OM-CMML) as an early form of CMML. However, the clinical validity of these changes remains uncertain without incorporating biological and genomic factors. In this study, we analyzed a cohort of 911 patients (249 with OM-CMML, 359 with overt CMML, and 303 with myelodysplastic syndromes) using unsupervised clustering to evaluate the role of genomic determinants in refining CMML diagnosis. Our findings show that CMML molecular signatures (biallelic TET2 mutations or SRSF2-TET2 co-mutations) are linked to a distinct transcriptome, monocytic bias, classical monocytosis, and higher risk of progression to overt CMML in OM-CMML cases. We developed a weighted genomic model and diagnostic workflow showing that combining genomic signatures with bone marrow monocyte frequencies in OM-CMML more accurately predicts progression to overt CMML. These findings support integrating genomic determinants, and our clinic-ready diagnostic workflow, into the CMML diagnostic framework to improve accuracy.

Chimeric antigen receptor (CAR) T cells produce durable remissions in some patients with large B-cell lymphoma, but outcomes are poor in patients with large tumor burdens or limited CAR T-cell expansion. To understand these relationships and explore potential interventions, we applied established population pharmacokinetic/pharmacodynamic principles to model kinetics of axicabtagene ciloleucel (axi-cel) concentrations and tumor responses to axi-cel, and validated model outputs using independent cohorts. This mechanistic model reproduces and explains poor outcomes associated with high tumor burden and low CAR T-cell expansion, finding that proliferation of large lymphoma populations can outpace the cytotoxic effect of CAR T cells. A high ratio of lymphoma cells to CAR T cells is effectively a mechanism of CAR T-cell resistance, which could be modified by tumor debulking before infusion. This model predicts that reducing tumor burden before CAR T-cell infusion may improve durable remission rate. Future clinical studies optimizing bridging therapy may therefore enhance the success of CAR T-cell therapies.

Significance: A population pharmacokinetic/pharmacodynamic model of axi-cel in large B-cell lymphoma explains the observation that high tumor burden and low CAR T-cell expansion predict poor outcomes. This model suggests tumor debulking before CAR T infusion or deploying CAR T therapy in measurable residual disease-positive patients after first-line treatment could improve CAR T success rates. See related commentary by Altrock, p. 11.

Transcription factors and their cofactors are major and selective nononcogene dependencies in multiple myeloma cells. By performing a gain-of-function perturbation screen in human multiple myeloma cell lines, we identified the inhibitor of DNA binding (ID) genes as putative suppressors of multiple myeloma cell fitness. Among them, ID2 was found to be downregulated in multiple myeloma patient cells and acted as a tumor suppressor by directly binding and repressing the basic helix-loop-helix factor TCF3, also known as E2A. Lower ID2 expression in multiple myeloma cells conferred a proliferative advantage by increasing TCF3 activity, leading to a dependency on this transcription factor. In contrast, ID2 overexpression reduced TCF3 binding to DNA, which resulted in cell-cycle arrest and a halt in multiple myeloma cell proliferation. The myeloma bone marrow milieu supported this process by further decreasing the expression of ID2 and enhancing TCF3 activity, partly via IL6, revealing a mechanism by which the tumor microenvironment affects multiple myeloma cell behavior.

Significance: Multiple myeloma cells exploit the oncogenic and proliferative potential of TCF3 by downregulating the transcriptional regulator ID2, a process facilitated by the bone marrow microenvironment.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous disease with limited treatment options and a poor prognosis, especially for patients refractory to standard therapies. We report the discovery of golcadomide (CC-99282), an oral cereblon-modulating CELMoD agent designed using target-specific knowledge and optimized pharmacologic properties for the treatment of DLBCL. Golcadomide exhibited rapid, deep, and sustained degradation of transcription factors IKZF1 and IKZF3, surpassing the antitumor activity of the IMiD agent lenalidomide in preclinical models. In human lymphoma cell lines, golcadomide downregulated MYC, activated IFN-stimulated genes, and promoted antiproliferation, apoptosis, and immunogenic cell death. In mouse xenografts, golcadomide preferentially distributed to tissues known to be affected by lymphoma, resulting in enhanced tumor regression and tumor-free outcomes. Pharmacologic and CRISPR screening further revealed genes and pathways underlying golcadomide's antitumor efficacy. These findings supported golcadomide as a promising drug candidate for DLBCL, providing a strong rationale for future golcadomide-based regimens.

Significance: Golcadomide is an oral cereblon-modulating agent for the treatment of DLBCL. It exhibited rapid, deep, and sustained degradation of IKZF1 and IKZF3, preferentially accumulated in lymphoma residence tissues, and delivered robust antitumor activity. These results provide a strong rationale for continued clinical investigation of golcadomide for patients with DLBCL.