Recent advances in multiple myeloma (MM) therapy, including quadruplet regimens, chimeric antigen receptor T cell therapies, and bispecific antibodies, have dramatically improved outcomes, necessitating disease assessment tools that are more sensitive than the conventional serological criteria. Consequently, minimal residual disease (MRD) negativity has emerged as a robust surrogate endpoint for survival. This review summarizes the current methodologies for MRD detection, primarily next-generation sequencing (NGS) and next-generation flow (NGF), and evaluates the prognostic significance of MRD negativity across the disease spectrum. We herein discuss key data from major clinical trials in both newly diagnosed and relapsed/refractory settings, highlighting the high rates of MRD negativity achieved with novel therapeutic classes. A central focus is the evolving paradigm of MRD-adapted therapy, which utilizes dynamic MRD assessment to guide treatment decisions by allowing escalation in high-risk patients or de-escalation to reduce toxicity in deep responders. In addition, we address the optimal timing for MRD testing and the challenges of integrating these assessments into routine clinical practice. In conclusion, this review emphasizes the growing utility of MRD as not only a prognostic biomarker but also a critical tool to drive personalized treatment strategies and further enhance long-term outcomes in MM patients.

To explore the correlation between serum and glucocorticoid inducible kinase-1 (SGK1) expression levels and the multiple myeloma (MM) progression in patients after autologous stem cell transplantation (ASCT).A total of 100 MM patients who received ASCT in the Hematology Department of our hospital during January 2020 to December 2022 were selected as the research subjects. The mRNA level of SGK1 was detected by RT-PCR. Taking the median relative expression level of SGK1 mRNA (2.15) as the critical value, these subjects were divided into SGK1 high expression group (SGK1 mRNA ≥ 2.15, n = 43) and SGK1 low expression group (SGK1 mRNA < 2.15, n = 57). The expression level of SGK1 was detected by IHC. The correlation was analyzed by Spearman correlation coefficient. The survival curve drawn through Kaplan-Meier method was further verified using Log-rank test. Cox proportional hazard regression model was used for multivariate analysis to screen independent risk factors. The receiver's working characteristic (ROC) curve was drawn to evaluate the predictive value.The H-Score was significantly higher in the SGK1 high expression group (8.52 ± 2.13) than the low expression group (3.27 ± 1.68) (t = 11.240, P < 0.001). After induction therapy, SGK1 high expression group had much lower proportion of achieving complete remission (CR), and markedly higher serum levels of β2-MG and LDH than SGK1 low expression group (P < 0.05). The expression of SGK1 in patients with partial remission (PR) was significantly higher than those with CR and very good partial remission (VGPR) (P < 0.01). Median TTP, median PFS and median OS were significantly lower in SGK1 high expression group than the SGK1 low expression group (Log-rank P < 0.01). Three months after transplantation, the positive rate of Minimal residual disease (MRD) was 48.84% (21/43) in SGK1 high expression group and 22.81% (13/57) in SGK1 low expression group (P < 0.01). The expression level of SGK1 was positively correlated with serum β2-MG (r = 0.452, P < 0.01), LDH (r = 0.388, P < 0.01), the proportion of plasma cells in bone marrow (r = 0.321, P < 0.01), and pre-transplant remission status (CR = 1, VGPR = 2, PR = 3; r = 0.413, P < 0.01), but negatively correlated with PFS (r= - 0.527, P < 0.01) and OS (r= - 0.482, P < 0.01). High SGK1 expression, serum β2-MG, and positive LDH and MRD were independent risk factors (P < 0.05). The ROC curve analysis of predicting disease progression after transplantation based on the relative expression level of SGK1 mRNA showed the area under the curve (AUC) of 0.883 (95% CI: 0.785-0.934), an optimal cutoff value of 2.18, a sensitivity of 94.32%, and a specificity of 73.63%.High expression of SGK1 was an independent risk factor for disease progression after ASCT in MM patients, which was closely related to the short survival time and high MRD positive rate. The expression level of SGK1 had a certain predictive effect on the disease progression after transplantation.

Stem cells at the tumor frontier: Mechanistic insights, therapeutic challenges, and emerging horizons.

Multiple myeloma is an incurable plasma cell malignancy. Its prognosis improved with the introduction of proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, but outcomes for triple-class-exposed (TCE) myeloma remained poor. New therapeutic options including CAR-T cell therapy and bispecific antibodies have now further improved prognosis, even in TCE myeloma. While true cure remains challenging, functional cure, defined as long-term disease control through a favorable immune environment suppressing minimal residual disease (MRD), is currently considered a realistic therapeutic goal.

Molecular pathological tumor diagnostics are becoming increasingly important in the context of personalized medicine. Modern high-throughput methods now enable routine molecular tumor profiling to identify genetic aberrations. Tissue biopsies are firmly established in routine clinical practice and remain the gold standard for initial diagnosis and are generally aprerequisite for tumor resection. They provide essential histological and immunohistochemical information; however, obtaining them can sometimes be difficult or involve risks and is often limited by the availability of tumor material. Furthermore, due to intratumoral heterogeneity, the entire spectrum of mutations is not always captured, which can influence the selection of targeted therapies. Against this backdrop, liquid biopsy is gaining importance as aminimally invasive, complementary approach. It enables the analysis of tumor-associated genetic alterations in circulating tumor DNA (ctDNA) and allows for repeated and systemic detection of molecular changes. For selected clinical questions, ctDNA analysis is already established in routine clinical practice, particularly for the identification of predictive markers and the detection of therapy-associated resistance mechanisms, for example in non-small cell lung cancer (NSCLC) or breast cancer. However, its widespread application is limited by methodological challenges, primarily due to the low amount of ctDNA and the resulting high demands on sensitivity and specificity. This is particularly true for early detection, which remains the subject of intensive research and controversial discussions. ctDNA-based therapy monitoring and the detection of minimal residual disease (MRD) represent promising approaches but require further prospective studies for standardization and integration into clinical guidelines. This review summarizes the possibilities, limitations, and available methods as well as current and potential applications of liquid biopsy in molecular diagnostics.

Early venetoclax dose escalation at minimal residual disease progression may benefit selected acute myeloid leukaemia patients.

Smoldering multiple myeloma (SMM) represents a heterogeneous precursor stage between monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma (MM). Advances in diagnostic criteria, particularly the adoption of the SLiM-CRAB framework, have improved the distinction between SMM and MM and reduced the risk of misclassification. Contemporary risk stratification models, such as the Mayo 20/2/20 criteria and International Myeloma Working Group refinements, integrate both static and dynamic biomarkers to provide more accurate predictions of progression. Genomic and immunological studies have further revealed key drivers of disease evolution, patterns of clonal evolution, and immune dysregulation, which may guide therapeutic decisions. Clinical trials have demonstrated that early intervention with lenalidomide or daratumumab can delay progression. In contrast, intensive multi-agent regimens, such as those used in the GEM-CESAR and ASCENT trials, have achieved high rates of minimal residual disease negativity and suggest curative potential. Nevertheless, the long-term survival benefits of these strategies remain uncertain, and the risks of toxicity in asymptomatic patients require careful consideration. Ongoing studies, including CAR-PRISM and ImmunoPRISM, are evaluating cellular and antibody-based therapies for high-risk SMM. Collectively, these advances highlight the need for refined, individualized approaches that balance the benefits and risks in the management of SMM.

Clonotypic B cells have been proposed as a potential disease reservoir in multiple myeloma and light-chain amyloidosis, but Gonzalez and colleagues demonstrate that they do not necessarily share the malignant potential of disease clones. Their study shows that the key genetic hallmarks of disease are largely restricted to the plasma-cell compartment and raises caution that assays detecting minimal residual disease may yield false-positive results by detecting rare clonotypic B cells. See related article by Gonzalez et al., p. 558.

New therapies are improving outcomes even in advanced stages of multiple myeloma. To describe the experience of bispecific antibodies (BsAbs) in Mexico. The study included 41 patients with triple-class refractory (88%) and penta-drug refractory (61%) myeloma. The median number of prior treatment lines was 3, and the median time to response was 2 months. Step-up dosages were administered on an outpatient basis in 34 patients (83%). BsAbs were administered every 2 weeks to 19 patients (46%) and monthly to 17 patients (41.5%). Thirteen of these (31.5%) switched to monthly doses early in treatment and maintained their response. Twenty-five of 38 evaluated patients (66%) achieved a complete response or better, and 84% were negative for minimal residual disease. The median response duration was 10 months, while median progression-free survival and overall survival were 12 and 13 months, respectively. Extramedullary disease, no complete response, positivity for minimal residual disease, and penta-refractoriness were associated with poor outcomes. The adverse events were lower than those reported in clinical trials. In conclusion, using outpatient step-up dosing followed by planned de-escalation to monthly doses of BsAbs in responding patients with MM is feasible, safe, and effective, and may improve access to this novel therapy.

Post-treatment circulating tumor DNA clinical features, prognosis in HPV-positive oropharynx cancer.

Breast cancer treatment is rapidly evolving toward precision-based de-escalation strategies for oncological safety and minimizing treatment-related morbidity. In early stage disease, minimally invasive approaches, such as non-surgical ablation techniques, including cryoablation and radiofrequency ablation, potentially constitute alternatives to conventional surgery for carefully selected low-risk tumors. Active surveillance trials challenge the necessity of immediate surgery for low-risk ductal carcinoma in situ, reflecting a paradigm shift toward risk-adapted management. In the neoadjuvant setting, achieving radiologic and pathologic complete responses, particularly in HER2-positive and triple-negative subtypes, is being investigated to determine the feasibility of omitting breast surgery under strict imaging and biopsy-guided protocols. Circulating tumor DNA-based minimal residual disease assays offer a promising tool for refining risk stratification and potentially guiding the extent of surgery and adjuvant therapy. These strategies represent a transformative movement toward biologically tailored, response-adapted, less invasive treatments for early breast cancer to optimize quality of life without compromising long-term outcomes.

CRISPR-Cas12a-based liquid biopsy technology: challenges in large-scale clinical application.

Curative-intent resection of colorectal cancer (CRC) liver metastasis (CRLM), combined with perioperative chemotherapy, is the standard of treatment for selected patients. However, accurately predicting which patients will benefit from this strategy remains challenging. Circulating tumour DNA (ctDNA) has emerged as a promising non-invasive biomarker for detecting minimal residual disease and predicting prognosis. This study aims to evaluate the prognostic value of ctDNA in patients with CRC undergoing surgery for CRLM. CRC patients undergoing LIver curative-intent MEtastasis Surgery is a prospective multicentre, observational cohort study designed to enrol 232 patients with upfront or potentially resectable CRLM. All patients will receive standard-of-care treatment. Serial blood samples will be collected at multiple time points: before chemotherapy (baseline, if applicable), before surgery, after surgery and during follow-up. The primary objective is to assess the association between preoperative ctDNA status and disease-free survival. Secondary objectives include evaluating ctDNA dynamics over time, exploring associations with clinical and pathological features and identifying prognostic factors for recurrence and survival. ctDNA will be analysed using targeted next-generation sequencing and digital droplet PCR. Outcomes will be assessed using Kaplan-Meier survival analysis, Cox proportional hazards models and multivariable regression modelling. This protocol was approved by the Comités de Protection des Personnes Ouest-I Ethics Committee (N°2022-A02593-40) on 31 January 2023. Study findings will be disseminated through peer-reviewed publications and relevant national and international conference presentations. This study was registered in ClinicalTrials.gov (NCT05627681).

Microsatellite-stable (MSS) colorectal cancer (CRC), which accounts for approximately 85% of cases annually, has demonstrated limited responsiveness to immune checkpoint blockade in the metastatic setting. Circulating tumor DNA (ctDNA) enables sensitive detection of minimal residual disease (MRD) following curative-intent therapy and identifies patients at high risk of recurrence who may benefit from additional treatment. The EMPIRE (NSABP FC-13) study is a multicenter, open-label, randomized phase II platform trial evaluating cemiplimab-based immunotherapy in patients with MSS CRC and ctDNA-defined MRD after definitive surgery and chemotherapy. Eligible patients have postoperative ctDNA positivity in the absence of radiographic recurrence and are allocated to one of three treatment arms: cemiplimab monotherapy; cemiplimab plus fianlimab (a lymphocyte activation gene-3 inhibitor); or cemiplimab plus REGN7075 (an EGFR×CD28 costimulatory bispecific antibody). The primary endpoint is ctDNA clearance at 12 weeks assessed by tumor-informed assay, with secondary endpoints including recurrence-free survival, safety and tolerability, longitudinal ctDNA kinetics, and patterns of recurrence. Arms 2 and 3 use single-stage phase II designs, whereas Arm 1 follows a Simon two-stage design with early futility stopping. The study integrates comprehensive correlative analyses to characterize mechanisms of response and resistance.Clinical trial registration: The http://www.clinicaltrials.gov identifier is NCT07058012.

Harnessing minimal residual disease for precision medicine in locally advanced gastric cancer

Biliary tract cancer (BTC) represents a formidable clinical challenge characterized by extensive genomic heterogeneity and a poor prognosis, primarily due to advanced stage diagnosis. Although systemic therapies, including chemotherapy, targeted therapies, and immune checkpoint inhibitors, have become the standard of care, their efficacy remains modest, and subsequent treatment options are limited. BTC management is further complicated by the inherent difficulty of obtaining high-quality tissue biopsies, impeding timely genomic profiling and subsequent therapeutic decision-making. Liquid biopsy has emerged as a minimally invasive alternative, facilitating comprehensive tumor characterization through circulating tumor cells, cell-free DNA, RNA, and proteins. These approaches hold promise for early detection, assessment of minimal residual disease, identification of actionable targets, and real-time monitoring of treatment response and resistance, thereby supporting precision oncology. Despite technical challenges such as limited sensitivity for structural variations, variability across platforms, and the need for standardized validation, liquid biopsy offers transformative potential in BTC. This review discusses current strategies, clinical applications, and future directions for integrating liquid biopsy into routine practice to improve survival and quality of life in patients with BTC.

ctDNA based MRD detection in stage III NSCLC treated with chemoradiotherapy and durvalumab.

Evolving Treatment Strategies in Anal Squamous Cell Carcinoma: Integrating Chemoradiotherapy, Immunotherapy, and Emerging Biomarkers.

This national, multicenter, retrospective study analyzed 1070 patients with newly diagnosed systemic light-chain (AL) amyloidosis in China (2008-2025). Findings reveal increasing annual diagnoses and a marked shift in first-line therapy from proteasome inhibitor (PI)-based regimens to predominantly daratumumab-based regimens since 2024. Monthly kinetic assessments demonstrated that daratumumab-based induction produced deeper and faster hematologic responses than PI-based therapy [≥ very good hematologic partial response (HemVGPR): 80.3% vs. 70.8%, p = 0.012; median time to ≥ HemVGPR: 1.2 vs. 1.8 months, p = 0.001], with significantly superior cardiac overall response (63.1% vs. 53.3%, p = 0.030). Early mortality rates at 1, 3, and 6 months were 5.5%, 13.2%, and 16.2%, respectively, with daratumumab-based therapy identified as an independent protective factor for 6-month mortality. Median event-free survival (EFS) was 44.4 months, while median overall survival (OS) was not reached. Achievement of hematologic complete response (HemCR) conferred superior EFS and OS over HemVGPR (both p < 0.001), with minimal residual disease negativity further improving EFS in HemCR patients (p = 0.043). Concurrent hepatic and cardiac involvement defined a high-risk subgroup with poor outcomes (median EFS 12.8 months, OS 51.0 months). Multivariable analysis confirmed Eastern Cooperative Oncology Group (ECOG) performance status (PS) > 2, liver involvement, and gain1q as adverse prognostic factors for EFS, whereas ≥ HemVGPR was protective. For OS, liver involvement, concomitant multiple myeloma, and ECOG PS > 2 were independent risk factors, while ≥ HemVGPR and cardiac response predicted improved survival. This study establishes a contemporary benchmark for AL amyloidosis management in China, confirming the superior real-world efficacy of daratumumab-based frontline therapy.

Tumour cell dormancy is a reversible, non-proliferative state in which cancer cells arrest in the G0 phase of the cell cycle. Increasingly recognized as a critical survival strategy, dormancy enables cancer cells to withstand therapeutic insult, escape immune surveillance, and endure hostile microenvironments. Clinically, dormant cells underlie extended asymptomatic intervals following primary treatment and are notably implicated in estrogen receptor-positive (ER+) breast cancer, prostate cancer, and clear cell renal cell carcinoma. In this review, we synthesize recent insights into hypoxia-mediated dormancy and, using breast cancer bone metastasis as an archetypal model, delineate how spatiotemporally heterogeneous hypoxia shapes the metastatic cascade. Specifically, we show that graded hypoxia in the primary tumour initiates dormancy traits, while persistent hypoxia within metastatic niches - such as the bone marrow - reinforces and deepens quiescence. These transitions are orchestrated by stage-specific activation of hypoxia-inducible factor 1α (HIF-1α) and its dynamic transcriptional outputs. We further argue that a mechanistic understanding of dormancy requires integrative frameworks that bridge single-cell level regulatory programs - including cell-cycle arrest, translational inhibition, and metabolic reprogramming - with systems-level networks capturing the dynamic, multistage nature of metastasis. Such integration may uncover actionable vulnerabilities within dormant cell populations and guide the development of precision therapies targeting minimal residual disease.