PURPOSES:Current methods for detecting monoclonal (M) proteins, such as immunofixation electrophoresis (IFE), serum protein electrophoresis (SPEP) and serum free light chains (sFLC), are limited by insufficient sensitivity and suboptimal efficiency. This study evaluated the performance and supplementary value of matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) for the detection of M-protein. METHODS:The M protein in the blood samples of 137 newly diagnosed plasma cell disorder (PCD) patients were detected using MALDI-TOF-MS. Using SPEP/IFE/sFLC as the gold standard, the performance of MALDI‑TOF MS was assessed; discrepant results were confirmed by urine IFE. RESULTS:The cohort included multiple PCD subtypes, detailly, 116 multiple myeloma (MM, 84.7%), 7 amyloid light-chain (AL) amyloidosis (5.1%), 6 MM combined with AL amyloidosis (4.4%), 4 monoclonal gammopathy of undetermined significance (MGUS, 2.9%), and others. Serum-based MALDI-TOF-MS demonstrated a high detection rate for M-protein identification compared to SPEP, serum IFE, sFLC and urine IFE (98.5% vs. 75.9% vs. 86.9% vs. 71.5% vs. 76.0%). Plasma-based testing achieved a concordance rate of 89.1% (122/137). Using IFE/sFLC results as the gold standard, the sensitivity of MALDI-TOF-MS for the identification of κ and λ light chains (LC) was 75.8% and 80.0%, respectively. For IgG and IgA identification, the sensitivity of MALDI-TOF-MS was 93.5% (58/62) and 65.5% (19/29), respectively. Additionally, MALDI-TOF-MS detected LC glycosylation in 17 patients and other post-translational modifications (PTMs) in 4 patients. Notably, post-treatment monitoring revealed that two patients with eliminated glycosylation peaks achieved complete response, while one with persistent glycosylation had a very good partial response. CONCLUSIONS:MALDI-TOF-MS is a reliable tool for M-protein detection, offering high detection rate, LC glycosylation identification, and PTM analysis. Additionally, in a small cohort, we observed that changes in the abnormal peaks detected by MALDI-TOF-MS may correlate with treatment response.

Purpose: This study aimed to explore the manifestations of posttraumatic growth (PTG) and its influencing factors among ovarian cancer patients undergoing chemotherapy. Methods: A descriptive qualitative study was employed. Between May 2023 and June 2024, 12 patients undergoing chemotherapy for ovarian cancer were recruited from a tertiary hospital in Hangzhou, China. Data were collected through semi-structured interviews and analyzed using conventional content analysis. Results: Three major themes and nine subthemes emerged: (1) Manifestations of PTG, including adopting healthy lifestyles, enhancing self-management awareness, maintaining a positive psychological state, and developing harmonious interpersonal relationships; (2) Facilitators of PTG, including medical resource accessibility, family support, and an optimistic personality; (3) Barriers to PTG, including family burden and conflict, and negative illness perception. Conclusion: PTG among ovarian cancer patients undergoing chemotherapy manifests as an integrated process of behavioral, psychological, and social adaptation. Family support and illness perception may modulate the degree of PTG. Future research should adopt multi-center and longitudinal designs to validate and extend these findings.

Mitosis is tightly regulated at multiple levels to ensure chromosome stability. The transient phosphorylation of histone H3 at Threonine 3 (H3T3) during cell division is critical for proper chromosome condensation and the accurate segregation of sister chromatids. While Haspin has been identified as the kinase responsible for H3T3 phosphorylation during mitosis, the phosphatases that counteract this modification to maintain balanced phosphorylation levels remain under investigation. In this study, we systematically screened phosphatases encoded in the human genome and identified the nuclear phosphatase SCP4 as an H3T3 phosphatase. SCP4 modulates H3T3 phosphorylation levels and influences the chromosomal recruitment of chromosomal passenger complex (CPC) during mitosis. Aberrant SCP4 expression leads to defective chromosome separation during metaphase and chromosome lagging in anaphase, resulting in aneuploidy. Notably, in SCP4 knockout mice, zygotes exhibit mitotic defects during the first cleavage at the two-cell stage, highlighting SCP4's essential role in ensuring faithful cell division. In summary, we identify SCP4 as a novel phosphatase regulating H3T3 phosphorylation and chromosome dynamics during mitosis, providing new insights into mechanisms safeguarding genomic stability.

Patients with renal allograft failure undergoing hemodialysis may be associated with an increased risk of preeclampsia. Preeclampsia can present with systemic manifestations, including organ bleeding. In this case, a suspected placental abruption was eventually confirmed to be caused by the rupture of an ovarian Sertoli–Leydig cell tumor (SLCT). A DICER1 mutation was subsequently identified in the patient. A 30-year-old primigravid woman with a history of thyroidectomy and renal allograft failure on maintenance hemodialysis presented at 29 weeks of gestation with a blood pressure of 180/110 mmHg and sudden onset of abdominal pain. She was diagnosed with preeclampsia. Due to suspected placental abruption and acute fetal distress, an emergency cesarean section was performed, resulting in the delivery of a healthy baby girl. During the operation, approximately 600 g of intraperitoneal blood clots were found, secondary to a ruptured ovarian cyst. Histopathological examination revealed a moderately to poorly differentiated ovarian SLCT. Targeted next-generation sequencing identified a new DICER1 variant (c.3175 dup: p.Tyr1059LeufsTer32 in exon 20 of chr14:95571502) in peripheral blood samples. The frameshift variant induces a premature termination classified as likely pathogenic based on ACMG criteria. Analysis of the family pedigree reveals a clustering of earlier-onset renal disease. During the 22-month follow-up period, following the decline of adjuvant chemotherapy, the patient experienced a second unintended pregnancy that required medical termination. No evidence of SLCT recurrence was observed. This case report presents a unique pregnant patient with a history of thyroidectomy and living-renal allograft failure requiring hemodialysis, who developed preeclampsia and a ruptured ovarian SLCT. To our knowledge, this appears to be the first combination of a DICER1-mutation-associated ovarian SLCT in a pregnant patient with transplant failure. This highlights the pivotal need for systematic preconception counseling and effective contraceptive education in this population. A well-coordinated multidisciplinary team approach was imperative to secure optimal maternal and fetal outcomes.

Secondary neuroinflammation is a major driver of progressive damage after traumatic brain injury (TBI), yet pharmacological interventions are limited by poor drug accumulation in the injured brain. Here, we report tiered-targeting liposomal nanoparticles (TTL-NPs) for the precise delivery of the pyroptosis inhibitor disulfiram (DSF). Cloaked with endothelial cell membranes, TTL-NPs exploit homotypic interactions to improve BBB penetration. A hierarchically engineered peptide enables sequential delivery: nanoparticles first hitchhike neutrophils in peripheral blood via elastase binding and subsequently expose a neuronal targeting peptide (Tet1) after matrix metalloproteinase cleavage within the inflamed milieu, thereby detaching from the neutrophils and secondary targeting to neurons. In a murine TBI model, TTL-NPs enhanced DSF accumulation at the lesion sites, suppressed pyroptosis, preserved BBB integrity, alleviated neuroinflammation, and promoted cognitive recovery. This work integrates biomimetic camouflage with inflammation-responsive tiered targeting to achieve spatiotemporal control of pyroptosis inhibition, offering a promising strategy for TBI therapy and other central nervous system diseases.

Tuberous sclerosis complex-associated lymphangioleiomyomatosis (TSC-LAM) is a rare systemic disorder characterized by smooth muscle-like cell proliferation, leading to cystic lung destruction, predominantly affecting women of reproductive age. We report a female patient in her mid-30s who presented with recurrent spontaneous pneumothoraces temporally associated with menstruation, diffuse bilateral pulmonary cysts on high-resolution computed tomography, bilateral renal angiomyolipomas, and facial angiofibromas. Genetic testing confirmed TSC-LAM. The patient was initiated on sirolimus (1 mg/day) with therapeutic drug monitoring to maintain trough levels within the target range. Regular follow-up included pulmonary function tests, serial imaging, and genetic counseling with cascade screening for offspring. After treatment, the disease remained clinically stable without significant adverse effects; imaging demonstrated no progression of pulmonary cysts and a reduction in renal angiomyolipoma volume. This case underscores the importance of early recognition, individualized sirolimus dosing to balance efficacy and toxicity, and systematic family screening for early detection and prevention of disease transmission in this heritable condition.

ABSTRACT In recent years, daratumumab has been increasingly applied in the treatment of systemic light‐chain (AL) amyloidosis, significantly improving the prognosis of patients. Currently, the internationally recognized daratumumab treatment regimen comes from the ANDROMEDA trial. Given the low tumor burden and poor tolerance of patients with amyloidosis, in this study, we modified the ANDROMEDA‐based protocol by administering daratumumab at half the original frequency. We enrolled 48 patients with AL amyloidosis who received low‐frequency daratumumab in multiple hospitals from July 2021 to May 2024 (ChiCTR2100049253). Among these patients, 38 were newly diagnosed and 10 were relapsed and refractory patients. At 3 months, the percentage of newly diagnosed patients with hematologic response≥very good partial response (VGPR) was 75.8%, including 36.4% complete response (CR) and 39.4% VGPR, with an overall response rate (ORR) of 90.9%. The CR, VGPR and ORR rates of relapsed and refractory patients at 3 months were 40.0%, 20.0% and 90.0%, respectively. By 6 months, ≥VGPR was achieved by 86.7% of newly diagnosed patients, while CR, VGPR, and ORR in relapsed and refractory patients were 44.4%, 22.2%, and 77.8%. The 6‐month cardiac and renal response rates were 61.9% and 46.2% in newly diagnosed patients, 20.0% and 50.0% in relapsed and refractory patients, respectively. The median follow‐up time was 26.0 months. The 1‐year and 2‐year OS rates were both 89.5% for newly diagnosed patients, and 90.0% for relapsed and refractory patients. Of the 48 patients, 33 (68.8%) received maintenance therapy and 15 (31.3%) did not. The 1‐year and 2‐year OS rates were both 100.0% for patients receiving maintenance, and 66.7% for patients without maintenance. Considering the safety endpoints, 86.8% of newly diagnosed patients experienced at least one adverse event (AE). In conclusion, the low‐frequency daratumumab regimen can be considered as an effective, safe and feasible treatment strategy for AL amyloidosis.

Multiple myeloma (MM) is a hematologic malignancy driven by clonal expansion of malignant plasma cells. Despite the long-term disease control achieved with immunotherapies in some patients, treatment resistance remains a major cause of disease relapse. Accumulating evidence highlights the tumor immune microenvironment, especially macrophages, as a key contributor to immunotherapy failure in MM. Herein, we identified a subset of MM-associated macrophages with high expression of fibroblast activation protein alpha (FAPα), defined as FAPα+ macrophages. Clinical data showed that FAPα+ macrophages were enriched in the bone marrow versus peripheral blood of MM patients, and their abundance positively correlated with tumor burden. In MM mouse models, depletion of FAPα+ macrophages significantly boosted the efficacy of anti-PD-1/PD-L1 antibody therapy but not anti-CTLA-4 therapy; this combinatorial strategy also exerted enhanced anti-tumor effects in EL4 lymphoma and CT26 colorectal carcinoma models. Mechanistically, FAPα stabilized PD-L1 expression by maintaining its N-glycosylation and inhibiting proteasomal degradation, and induced PD-L1 synthesis via promoting vimentin (VIM) phosphorylation at the S72 residue. Additionally, FAPα+ macrophages accelerated T cell senescence by secreting soluble FAPα. Collectively, our findings demonstrate that FAPα+ macrophages mediate MM immune evasion via dual mechanisms, positioning them as promising therapeutic targets to potentiate anti-tumor immunotherapies.

Background:Patients with multiple myeloma (MM) and renal impairment (RI), particularly those requiring dialysis, have historically experienced poor outcomes. Despite advancements in targeted therapies, the prognosis of dialysis-dependent MM and factors influencing dialysis independence remain unclear. Objectives:This study aimed to provide a comprehensive analysis of the clinical manifestations and treatment outcomes of dialysis-dependent MM patients in China, and to explore the factors associated with dialysis independence and long-term survival. Design:We conducted a multicenter, retrospective, real-world cohort study. Methods:This multicenter, retrospective study included 122 MM patients requiring chronic hemodialysis (⩾28 days of treatment) at 4 comprehensive hospitals in China from January 2012 to November 2023. Hemodialysis resulting from causes other than MM was excluded. Logistic regression was employed for multivariate analysis of factors associated with dialysis independence, and Kaplan-Meier survival curves and Cox proportional hazard models were utilized for survival analysis. Results:Among the 122 patients, 74 patients (60.7%) were male, with a median age of 65 (39-87) years. Of these, 71.3% (n = 87) had newly diagnosed MM (NDMM), and 28.7% (n = 35) had relapsed/refractory MM (RRMM). Dialysis independence was achieved in 27 patients (22 with NDMM and 5 with RRMM). Proteasome inhibitors were used in 80.3% of patients (n = 98), while 13.9% (n = 17) received daratumumab-based regimens. After a median follow-up of 43.7 months, the median progression-free survival (PFS) was 14.4 months (95% confidence interval (CI): 3.6-25.2), and the median overall survival (OS) was 27.4 months (95% CI: 6.9-47.9). Dialysis-independent patients had significantly longer PFS (36.7 vs 9.4 months, p = 0.006) and OS (62.6 vs 17.7 months, p < 0.001). Factors associated with dialysis independence included achieving a very good partial response (VGPR), receiving daratumumab-based regimens, reduction in serum-free light chain ⩾80% after the first chemotherapy cycle, and age <65 years. Conclusion:In the era of new drugs, dialysis-dependent MM still has a poor prognosis, although dialysis independence improves survival.

Introduction:For improving outcomes of patients in early treatment, diverse detections were developed for prognosis prediction. Multiple Myeloma (MM) patients should be observed during clinical therapy for better outcomes. Combined with next-generation sequencing (NGS), Immunoglobulin (Ig) repertoire has been used for predict patient's prognosis in malignant hematological diseases previously. However, in MM, the study of immune genes landscape was rare. For T cell receptor (TCR) diversity, which was previously proved to have the potential to indicate prognosis in MM patients' overall survival time (OS). In this study, we performed correlative genomic DNA (gDNA) sequencing studies on MM patients for the immuno-gene landscape description and the prognosis association. Additionally, we introduced TCR diversity as the biomarker for NDMM patients' classification and prognosis. Methods:Bone marrow (BM) and peripheral blood (PB) samples from patients and health donor (HD) were collected. Using CD138 beads to sort malignant plasma cells in BM, and extracting gDNA to construct libraries for NGS. The DNA samples were subjected to a two-step multiplex PCR amplification process. Firstly, we employed primers that specifically targeting complementarity-determining region (CDR3) of the Ig genes as well as same regions of TCR genes. Secondly, we incorporated a unique barcode sequence and Illumina adapter to each amplified product. Subsequently, all libraries were sequenced using an Illumina NovaSeq X Plus system. Results:Firstly, NGS of Ig repertoire was used to identify tumor clonotypes and build the Ig genes landscape, in this study, 274 dominant clonotypes were identified in 79 MM patients. Patients then were classified into CR, VGPR, and other group. It's suggested patients possessed the high proportion of IGK clones before therapy with low frequency, are more likely to have better outcomes, and vice versa. Then, we conducted analysis on patients' progression-free survival (PFS) and OS. The results showed patients would have better clinical outcomes when the number of chains of the major tumor clone is 1 or 2, compared with 3 or 4 chains of the major tumor clone. After that, we applied the TCRβ sequencing, the Shannon, HVJ, and clonality diversity were used to evaluate TCR clone. It was found that the TRB diversity in PB of MM patients differs from that of HDs. Subsequently, Shannon, HVJ, and clonality were combined into the new parameter. A multivariate regression equation was used to optimize it, resulting in the formula: diversity = 0.27clonality + 0.66HVJ - 0.31*Shannon. This parameter can effectively distinguish between MM patients and HDs, with an AUC as high as 0.988. This study preliminarily established a TCR evaluation system related to MM, scoring based on the comprehensive TCR phenotype of each sample, and then conduct correlation analysis between the scoring results of each sample and the clinical outcomes. Through the ORR evaluation and the overall OS evaluation, it was found that there was no significant difference in PFS, also no concentrated area was found in death group in OS data performance. In contrast, the overall data performance of the surviving group was below 0.35%. Therefore, we used TRB clone performance of 0.35% as the cutoff value for evaluating survival prediction. At the same time, the evaluation standard for TRB clones was proposed as: “ratio = the number of MM-related TRB sequences in the sample TRB sequence / the total number of clones in the sample”. The survival curve assessment presented that the P value of the two groups in OS was below 0.05, which indicated the risk prediction value via MM prognosis predictive algorithm of TRB established in this study. Conclusion:In this study, we firstly established the Ig and TRB profiling of plasma cells and PB in NDMM patients respectively. And then, we identified the potential prognosis function of different chains number in Ig clone. Furthermore, we uncovered the TRB diversity potency as the biomarkers for MM diagnosis and prognosis in baseline stage, provided the possibility of TCR diversity to be regarded as the non-invasive liquid biopsy. This study established the foundation of exploring the immunological distinction in MM patients.

Phage contamination poses a significant threat to industrial fermentation, leading to substantial economic losses. Virulent T-even type phages (T2/T4/T6) represent particularly concerning biological hazards in fermentation systems. This paper developed a novel CRISPR/Cas12a-based system integrated with recombinase polymerase amplification (RPA), enabling ultrasensitive identification of T-even type phages. This method targeted the TerL gene of T-even type phages as a detection marker. The optimized RPA-CRISPR assay demonstrated exceptional sensitivity with a limit of detection (LOD) reaching 1 aM for synthetic targets. Besides, this system achieved detection thresholds of 1 and 10 PFU/μL for T2 and T4 phages, respectively. Comparative validation with quantitative PCR (qPCR) confirmed the method's reliability through strong correlation in the detection for both spiked and wastewater samples. The detection platform exhibited remarkable potential for rapid, sensitive monitoring of T-even type phages contamination in fermentation processes, offering promising application prospects for quality control in biochemical industries.

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains the mainstay of treatment for adults with high-risk acute lymphoblastic leukemia (ALL). Due to the crucial role of measurable residual disease (MRD) before Allo-HSCT in predicting relapse and the promising anti-leukemia effect of blinatumomab, we documented a short-course, low-dose conditioning regimen incorporating blinatumomab for Allo-HSCT in three ALL patients with positive MRD. Following the administration of the blinatumomab-containing conditioning regimen, all patients attained complete remission (CR) with negative MRD status, and no severe adverse events were observed. After a 2-year follow-up, 2/3 of patients remained disease-free and attained long-term survival following transplantation. These cases indicated a short-term blinatumomab conditioning regimen may effectively prolong patient survival, improve prognosis, and offer a safe and cost-effective treatment for high-risk ALL patients with positive MRD. The addition of blinatumomab to the conditioning regimen of Allo-HSCT is feasible for high-risk ALL patients with positive MRD.

PURPOSE:Multiple myeloma (MM) is a terminally differentiated plasma cell hematological malignancy. The revised international staging system (RISS) is commonly used in patients with de novo MM, but it has limitations in predicting prognosis. Better biomarkers need to added to the staging system. RESULTS:This retrospective study included a total of 302 patients. Smooth curve fitting analysis showed that serum ferritin levels were associated with relapse and all-cause death. The K-M curve analysis indicated that MM patients with higher ferritin levels had shorter PFS (p < 0.0056) and OS (p = 0.0014). Multivariate Cox regression analysis also showed MM patients with high serum ferritin had poor PFS (p = 0.0012) and OS (p = 0.0258), with independent correlation. The prediction model of ROC analysis based on Cox regression validated ferritin had a predictive value for PFS and OS, and increased the predictive value of ISS and RISS for OS. CONCLUSION:We revealed that baseline serum ferritin levels were associated with prognosis in patients with MM, and patients with higher serum ferritin have poorer PFS and OS. Serum ferritin could increase the prediction value. The study provided a new evidence for searching for prognostic biomarkers in MM patients.

Mitophagy, the selective degradation of mitochondria by autophagy, plays a crucial role in cancer progression and therapy response. This study aims to elucidate the role of mitophagy-related genes (MRGs) in cutaneous melanoma (CM) through single-cell RNA sequencing (scRNA-seq) and machine learning approaches, ultimately developing a predictive model for patient prognosis. The scRNA-seq data, bulk transcriptomic data, and clinical data of CM were obtained from publicly available databases. The single-sample gene set enrichment analysis (ssGSEA) and weighted gene co-expression network analysis (WGCNA) were used to identify gene modules associated with mitophagy phenotypes. A machine learning framework employing ten different algorithms was used to develop the prognostic model. Based on scRNA-seq data, we identified 16 distinct cell subpopulations in melanoma, and melanoma cells exhibited significantly higher mitophagy scores. The turquoise module identified via WGCNA showed the strongest correlation with mitophagy scores. A prognostic model incorporating seven genes was developed through machine learning algorithms, achieving an average C-index of 0.754 across training and validation cohorts. Functionally, low-risk patients were enriched in interferon-gamma response and inflammatory processes, whereas high-risk patients showed enrichment in glycolysis regulation and signaling pathways such as KRAS and Wnt/β-catenin. Notably, low-risk patients demonstrated enhanced immune infiltration and greater sensitivity to immunotherapy. RT-qPCR validated the expression level of 7 model genes in human melanoma cell lines and normal melanocyte cell lines. Our study provides a comprehensive understanding of MRGs in melanoma and presents a novel prognostic model. These findings enhance our understanding of the tumor microenvironment and may guide personalized treatment strategies for CM patients.

To address the heterogeneity and intractability of colorectal cancer (CRC), this study proposes a hypothesis that the development of an innovative organoid-on-a-chip platform, which combines the biochemical properties of the decellularized intestinal matrix (dECM)-hydrogel composite material with the dynamic regulation capability of microfluidic control, can achieve dual functions: drug toxicity analysis for CRC and evaluation of the killing effect of NK cell-derived exosomes. Experiments showed that the pore structure (50-150 μm) and mechanical properties of the 5 % GelMA-dECM scaffolds accurately matched the physiological conditions and supported the long-term culture of colorectal tumor-like organs. The killing effect of NK cell-derived exosomes in the 3D environment, compared to the 2D environment, revealed their targeting of hypoxic regions. This platform is closer to the dynamic microenvironment of colorectal tumor foci than the traditional 2D model, which can reduce the reliance on animal experiments and provide optimized conditions for personalized precision medicine. Finally, this hypothesis suggests the potential for simulating the immunomicroenvironmental, with implications for clinical applications.

Introduction Despite therapeutic advances in multiple myeloma (MM) treatment, managing heavily pretreated relapsed/refractory MM (RRMM) remains clinically challenging. Aponermin (Apo), a recombinant circularly permuted human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), is the first-in-class death receptor 4/5 agonist recently approved for RRMM. The combination of Apo with the standard carfilzomib-pomalidomide-dexamethasone (KPd) regimen was based on preclinical evidence demonstrating that proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) can enhance TRAIL-induced apoptosis. This prospective, open-label, multicenter study evaluated the efficacy and safety of Apo-KPd in this difficult-to-treat population. Methods Eligible patients were 18-75 years of age, met the diagnostic criteria for RRMM defined by International Myeloma Working Group (IMWG). Patients had previously received at least 3 different prior lines of therapy or were triple-class exposed to a PI, an IMiD and an anti-CD38 antibody. Measurable disease and adequate organ function were required. Patients received 28-day cycles of intravenous Apo (10mg/kg on days 1-5), carfilzomib (20mg/m² on days 1-2 of cycle 1, then 27mg/m² on days 1-2, 8-9, and 15-16), oral pomalidomide (4mg daily on days 1-21), and dexamethasone (20mg on days 1-2, 8-9, and 15-16) until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate (ORR) assessed by IMWG criteria. Results As of July 2025, 21 patients with RRMM were enrolled. Median age was 57 years (range 46-67) and 12 (57.1%) patients were male. The median time from diagnosis was 3.3 years (range 0.3-8.4). The patients treated in the trial received a median of 4 (range 1-7) prior lines of therapy. Patients in Durie-Salmon stage I/II/III/NA were 9.5%, 4.8%, 76.2% and 9.5%, respectively. High-risk cytogenetic abnormalities were present in 66.7% (14/21) of patients, while 76.2% (16/21) had extramedullary plasmacytoma (EMP) at screening. Most patients (85.7%, 18/21) were triple-class exposed and 61.9% (13/21) had previously received carfilzomib or pomalidomide. Seven (33.3%) patients had undergone autologous stem cell transplantation (ASCT). Seven (33.3%) patients were refractory to prior CAR-T therapy, with 5 patients having at least 2 CAR-T treatments including BCMA-CAR-T and GPRC5D-CAR-T. After a median of 2 treatment cycles, the ORR was 66.7% (14/21; 95% CI 43.0%-85.4%), with 28.6% (6/21) achieving a very good partial response (VGPR) or better. Subgroup analysis demonstrated consistent efficacy across poor-prognostic subgroups, with comparable outcomes observed between patients with >3 versus ≤ 3 prior lines of therapy (ORR 72.7% vs. 60.0%), those with versus without prior exposure to carfilzomib/pomalidomide (ORR 61.5% vs. 75.0%), those with versus without prior ASCT (ORR 71.4% vs. 64.3%), and patients with versus without EMP (ORR 68.8% vs. 60.0%). High-risk cytogenetic patients exhibited a moderately lower, though still clinically meaningful response rate compared to standard-risk patients (ORR 57.1% vs. 80.0%). Notably, among the 7 CAR-T-pretreated patients (all with EMP and heavily pretreated [median 5 prior lines]), an encouraging ORR of 57.1% was achieved (1 PR and 3 VGPR), which was comparable to that achieved in CAR-T-naïve patients (71.4%). All treatment-emergent adverse events (TEAEs) were manageable, most commonly abnormal liver function (23.8%), increased lactate dehydrogenase (23.8%), respiratory infection (19.0%), and tumor lysis syndrome (14.3%). Grade 3-4 AEs occurred in 23.8% (5/21) of patients, including tumor lysis syndrome (14.3%), neutropenia (4.8%), thrombocytopenia (4.8%) and pneumonia (4.8%). Conclusion The Apo-KPd regimen demonstrated favorable activity in heavily pretreated RRMM, including patients with poor prognostic and high-risk features. Notably, even in CAR-T-pretreated patients, who had exhausted multiple prior lines of therapy and were refractory to most available anti-myeloma agents, encouraging responses were observed. These findings highlight the potential benefits of Apo's novel mechanism of action and its synergistic effects when combined with KPd. The combination showed a manageable safety profile consistent with the known toxicities of the individual agents. These promising results warrant further investigation of this novel combination regimen in larger clinical trials.

Background: Multiple myeloma (MM) is a plasma cell malignant tumor known for its high incidence rate. Bortezomib was the first proteasome inhibitor approved for MM. Many factors can result in bortezomib’s adverse events, influencing its continuous treatment. It remains a controversial topic requiring more evidence to support its appropriate use.Methods: The P-values of single-factor analysis between basic clinical characters and bortezomib’s adverse events were used to make a heat map, and the variables with high correlation were selected as the objects of the study. Peripheral neuropathy (PN), infection, dyspepsia and constipation were considered which were common adverse events of bortezomib.Results: The multivariate-adjusted linear regression and smooth curve fitting results showed that compared with 85 patients in intravenous (IV) arm, 70 patients in the subcutaneous (SC) arm had less adverse reaction, with no significant influence on therapy efficacy. The dosage of bortezomib in 69 MM patients was 1.0 , and 1.3 mg/m2 in 86 MM patients. As to DS stage, we found that patients with DS stage III had more severe peripheral neuropathy than patients with DS stage I. As per our findings, MM patients in the reduced dose group had higher infection rate, but the efficacy was not significantly different between the two groups.Conclusions: This observational study shows that bortezomib applied via SC injection had a lower incidence of peripheral neuropathy, infection, and dyspepsia when compared to IV injection. Patients with DS stage III had higher peripheral neuropathy adverse reactions than patients with stage I. The patients with reduced dose of bortezomib were associated with increased infection in MM patients.