bims-hemali Biomed News
on Hematologic malignancies
Issue of 2025–10–05
37 papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό



  1. Rinsho Ketsueki. 2025 ;66(9): 1033-1041
      Asciminib is a first-in-class allosteric inhibitor that specifically targets the myristoyl pocket of BCR::ABL1 and has shown efficacy in patients with chronic myeloid leukemia (CML) who are resistant or intolerant to prior tyrosine kinase inhibitors (TKIs). Despite its unique mechanism of action, several resistance mechanisms to asciminib have been identified. BCR::ABL1 kinase domain mutations, including A337V, C464W, and compound mutations involving T315I, can interfere with asciminib binding or allosteric regulation. Additionally, BCR::ABL1 transcript variants lacking the SH3 domain, such as e13a3 and e14a3, exhibit primary resistance by disrupting the autoinhibited conformation required for asciminib activity. Non-BCR::ABL1 mechanisms that also contribute to resistance include overexpression of efflux transporters such as ABCG2 and P-glycoprotein, which reduce intracellular drug accumulation. Moreover, novel insertion mutations like p.I293_K294insSLLRD have been shown to impair the allosteric inhibition of ABL1. Combination therapies with ponatinib or other agents, as well as newer TKIs like olverembatinib, have demonstrated potential in overcoming resistance in preclinical and clinical models. Understanding these diverse resistance mechanisms is critical for optimizing asciminib-based treatment strategies and guiding the development of effective combination therapies for patients with resistant CML.
    Keywords:  Asciminib; BCR::ABL1 mutations; Chronic myeloid leukemia; TKI resistance
    DOI:  https://doi.org/10.11406/rinketsu.66.1033
  2. J Clin Oncol. 2025 Sep 30. JCO2500307
       PURPOSE: Older patients with ALL receiving conventional chemotherapy have poor survival due to toxic death and relapse. We hypothesized that a chemotherapy-free, targeted regimen using the anti-CD22 antibody-calicheamicin conjugate inotuzumab ozogamicin followed by the bispecific anti-CD19/CD3 T-cell engager blinatumomab would reduce toxic death and yield high rates of prolonged remission and survival.
    METHODS: Eligible patients were age 60 years and older with untreated, Philadelphia chromosome (Ph)-negative, CD22-positive, B-cell ALL. Patients received up to two cycles of inotuzumab ozogamicin followed by four or five cycles of blinatumomab with intrathecal methotrexate CNS prophylaxis. The primary end point was 1-year event-free survival (EFS).
    RESULTS: The 33 eligible patients had a median age of 71 years (range, 60-84) and a median CD22 expression of 92% (range, 21%-100%). Eight (24%) had previous chemotherapy or radiation for other cancers, six for multiple myeloma. The composite complete remission rate was 85% after two cycles of inotuzumab ozogamicin and 97% by the end of two cycles of blinatumomab. At a median follow-up of 30 months, the 1-year EFS and overall survival were 75% (95% CI, 61 to 92) and 85% (95% CI, 73 to 98), respectively. EFS was shorter with lower CD22 expression or detectable measurable residual disease at any time point.
    CONCLUSION: Inotuzumab ozogamicin then blinatumomab without maintenance chemotherapy in older patients with untreated, Ph-negative, CD22-positive, B-cell ALL yields a high remission rate and excellent EFS. Given the lack of standard, safe, and effective therapies in this population, the regimen should be considered a standard treatment option.
    DOI:  https://doi.org/10.1200/JCO-25-00307
  3. Front Pharmacol. 2025 ;16 1652373
      Chronic myeloid leukemia (CML) can be effectively treated inhibiting the disease-causing BCR::ABL1 kinase by tyrosine kinase inhibitors (TKIs). Although therapy is initially tremendously successful, resistance may occur in up to 25% of CML patients. Besides aberrations in the BCR::ABL1 kinase domain, a variety of resistance mechanisms are currently discussed, among them epigenetic reprogramming. The histone-modifying enzyme lysine methyltransferase 2D (KMT2D/MLL2) belongs to the most frequently mutated genes in cancer and is also known for its association with hereditary Kabuki syndrome. However, its role in CML is widely unknown. In the present study, we analyzed the role of the KMT2D p. (Arg191Trp) variant in imatinib-resistant CML, which was recurrently acquired in imatinib resistance in vitro. SiRNA-mediated KMT2D knockdown, but also introduction of the p. (Arg191Trp) variant into treatment-naïve K-562 cells led to impaired imatinib susceptibility visible by increased cell numbers, proliferation rates and metabolic activities under imatinib exposure (p < 0.001). The effect of KMT2D p. (Arg191Trp) could be overcome by inhibiting histone demethylation with the demethylase inhibitor LSD1. In addition, rescue of KMT2D expression in imatinib-resistant cells reinstated the response to imatinib treatment. Furthermore, gene expression analysis revealed upregulation of CCNE2 in cells harboring KMT2D p. (Arg191Trp) potentially explaining increase in cell proliferation under imatinib exposure. Overall, our findings demonstrate that the loss of the tumor suppressor KMT2D promotes TKI resistance in CML. Thus, KMT2D status could serve as an additional biomarker for TKI resistance, while restoration of its expression might be a therapeutic option to overcome this resistance.
    Keywords:  KMT2D; chronic myeloid leukemia; drug resistance; epigenetics; histone modification; imatinib
    DOI:  https://doi.org/10.3389/fphar.2025.1652373
  4. J Clin Oncol. 2025 Oct 02. 101200JCO2501957
       PURPOSE: Prognosis for patients with refractory/relapsed large B-cell lymphoma (LBCL) considered ineligible for curative-intent therapy is poor. The combination of mosunetuzumab, a T-cell-engaging bispecific antibody, and polatuzumab vedotin, an antibody-drug conjugate, (Mosun-Pola), represents a novel fixed-duration outpatient therapy.
    METHODS: In the phase 3 SUNMO trial, patients with refractory/relapsed LBCL who were ineligible for autologous stem cell transplant were randomized (2:1) to receive Mosun-Pola or rituximab, gemcitabine, and oxaliplatin (R-GemOx). Dual primary endpoints were centrally-assessed overall response rate and progression-free survival. Overall survival was a key secondary endpoint.
    RESULTS: A total of 208 patients were randomized to receive Mosun-Pola (n=138) or R-GemOx (n=70). At a median follow-up of 23.2 months, the primary analysis of SUNMO demonstrated that the median progression-free survival was significantly longer with Mosun-Pola than with R-GemOx(11.5 months [95% confidence interval (CI), 5.6-18] vs 3.8 months [95% CI, 2.9-4.1]; hazard ratio for progression or death, 0.41 [95% CI, 0.3-0.6]; P<0.0001). Overall response rate was significantly greater with Mosun-Pola versus R-GemOx (70% vs 40%; P<0.0001), with a complete response rate of 51% and 24%, respectively. In the Mosun-Pola group, the rate of grade ≥2 cytokine release syndrome and usage of tocilizumab occurred in less than 5% of patients, and patient-reported outcomes were improved compared with R-GemOx.
    CONCLUSION: Mosun-Pola demonstrated superior efficacy verus R-GemOx, with significant improvements in both overall response rate and progression-free survival, and infrequent cytokine release syndrome events with a manageable safety profile.(Funded by F. Hoffmann-La Roche Ltd; ClinicalTrials.gov, NCT05171647).
    DOI:  https://doi.org/10.1200/JCO-25-01957
  5. Rinsho Ketsueki. 2025 ;66(9): 1241-1251
      Treatment strategies for chronic myeloid leukemia (CML) have changed significantly with the development of new tyrosine kinase inhibitors (TKIs). Due to its extreme rarity, pediatric CML has historically been managed based on evidence in adult patients. However, as the unique biological and clinical characteristics of pediatric CML have become increasingly apparent, the need for pediatric-specific treatment guidelines is now widely recognized. This review outlines the treatment of pediatric CML as of 2025, with a focus on clinical trial results from Japan and the latest consensus guidelines issued by the International Pediatric CML Working Group.
    Keywords:  Chronic myeloid leukemia; Pediatric CML; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.11406/rinketsu.66.1241
  6. Ann Hematol. 2025 Oct 02.
      Primary central nervous system lymphoma (PCNSL) is a rare and aggressive malignancy with limited treatment options and presents significant therapeutic challenges. Although high-dose methotrexate (HD-MTX)-based immunochemotherapy, followed by autologous stem cell transplantation (ASCT), improves outcomes in patients with PCNSL, in clinical practice, ASCT eligibility is frequently restricted by medical unsuitability, patient choice, and socioeconomic factors. In this retrospective study, we evaluated 12 newly diagnosed PCNSL patients who were treated with a combination of rituximab, HD-MTX, and lenalidomide (R2-MTX) without ASCT. With a median follow-up of 43.0 months, the R2-MTX regimen demonstrated superior clinical efficacy, achieving an overall response rate (ORR) of 91.7% (95% CI: 61.5-99.8%), with a complete response (CR) rate of 66.7% at the end of induction therapy. The median overall survival (OS) was not reached, while the median progression-free survival (PFS) was 62 months (range: 6-64 months). The estimated 2- and 5-year OS rates were 91.7% (95% CI: 76.0-100%) and 70.7% (95% CI: 52.1-99.3%), respectively, with corresponding PFS rates of 66.7% (95% CI: 50.1-93.3%) and 57.1% (95% CI: 34.5-83.7%), respectively. Treatment-related toxicities were manageable, with no grade ≥ 3 adverse events observed. The most common adverse effect was neutropenia (46.2%). Notably, patients with CARD11 mutations experienced a high rate of early relapse despite lenalidomide treatment. In conclusion, the R2-MTX regimen showed encouraging efficacy and a manageable safety profile in a small cohort of newly diagnosed PCNSL patients unsuitable for ASCT. These preliminary findings suggest that R2-MTX may be a promising therapeutic alternative, but validation in larger, prospective multicenter studies is warranted.
    Keywords:  Adverse effects; Efficacy; First-line therapy; Lenalidomide; Primary central nervous system lymphoma
    DOI:  https://doi.org/10.1007/s00277-025-06593-7
  7. Lancet Oncol. 2025 Oct;pii: S1470-2045(25)00280-3. [Epub ahead of print]26(10): 1323-1333
       BACKGROUND: Patients with frailty and newly diagnosed multiple myeloma have worse outcomes due to higher rates of adverse events (AEs) and treatment discontinuation. This study evaluated a dexamethasone-sparing regimen of daratumumab plus lenalidomide versus lenalidomide plus dexamethasone in frail patients with newly diagnosed multiple myeloma.
    METHODS: In this prospective, randomised, open-label trial, conducted at 61 active Intergroup Francophone of Myeloma centres, patients aged 65 years or older with newly diagnosed multiple myeloma and an Eastern Cooperative Oncology Group proxy frailty score of 2 or more were randomly assigned 2:1 to receive daratumumab (1800 mg subcutaneously) plus oral lenalidomide (25 mg daily for 21 days of a 28 day cycle) and dexamethasone (20mg weekly) for two cycles (dexamethasone-sparing group) or lenalidomide (25 mg daily) and oral dexamethasone (20 mg weekly; control group), with stratification by International Staging System, age, and centre. The primary endpoint was progression-free survival. Efficacy was assessed in the intention-to-treat population and safety was assessed in all patients exposed to at least one dose of randomised intervention. This trial is registered with ClinicalTrials.gov, NCT03993912, and is complete.
    FINDINGS: From Oct 18, 2019 to July 20, 2021, 335 patients were screened, of whom 295 patients were randomly assigned (200 to lenalidomide plus daratumumab, 95 to lenalidomide plus dexamethasone). The median age was 81 years (IQR 77-84), with 180 (61%) aged older than 80 years, and 151 (51%) patients were female and 144 (49%) were male. Median follow-up was 46·3 months (IQR 46·0-52·7). Median progression-free survival was 53·4 months (95% CI 35·3-not reached) in the dexamethasone-sparing group versus 22·5 months (16·5-39·0) in the control group (hazard ratio [HR] 0·51, 95% CI 0·37-0·70, p<0·0001). The most common grade 3-5 AEs were neutropenia (110 [55%] of 200 patients in the dexamethasone-sparing group vs 23 [24%] of 95 patients in the control group), and infection (38 [19%] vs 20 [21%]). Serious adverse events occurred in 126 patients (63%) in the dexamethasone-sparing group and 66 patients (69%) in the control group. AEs leading to death occurred in 23 patients (12%) in the dexamethasone-sparing group and 12 patients (13%) in the control group, with 4 (2%) and 2 (2%) grade 5 treatment-emergent adverse events, respectively.
    INTERPRETATION: In the IFM2017-03 trial, use of lenalidomide plus daratumumab, with dexamethasone limited to the first 2 treatment cycles, reduced the risk of progression or death compared with lenalidomide plus dexamethasone, with no additional safety concerns. Lenalidomide plus daratumumab could therefore be considered as a treatment option for older patients with frailty and newly diagnosed multiple myeloma.
    FUNDING: The study was funded by Johnson & Johnson.
    DOI:  https://doi.org/10.1016/S1470-2045(25)00280-3
  8. Acta Haematol. 2025 Oct 02. 1-22
       INTRODUCTION: The treatment of relapsed or refractory (R/R) Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) remains challenging after failure to several tyrosine kinase inhibitors. This study evaluated the clinical outcomes of ponatinib in a real-world cohort with R/R Ph-positive ALL, including those treated at the stage of measurable residual disease (MRD) relapse.
    METHODS: We retrospectively analyzed 79 adults with R/R Ph-positive ALL treated with ponatinib monotherapy. At the start of treatment, 55 patients (69.6%) were in hematologic relapse, while 24 (30.4%) were in MRD relapse. We evaluated CR rate, MRD response, survival outcomes, and predictors of response and survival according to various clinical and genetic parameters.
    RESULTS: CR was achieved in 48 (60.7%) patients, and 22 of 46 with MRD data (47.8%) achieved CMR. Ponatinib initiation at MRD relapse was associated with higher odds of better molecular response. In multivariate analysis, age under 60 and MRD response better than MMR were linked to improved OS. However, 2-year OS remained poor at 29.5% (95% CI: 18.9-40.9%). Allo-HCT was performed in 38 patients (48.1%), with a 2-year post-transplant OS of 29.1% (95% CI: 12.9-47.6%). Prior allo-HCT was associated with inferior OS and DFS.
    CONCLUSION: Ponatinib achieved an acceptable CR rate and MRD response in R/R Ph-positive ALL, but long-term survival remained poor despite allo-HCT. These results support earlier use of ponatinib in the salvage setting and highlight the need for combination strategies to overcome the limited durability of monotherapy in patients with R/R Ph-positive ALL.
    DOI:  https://doi.org/10.1159/000548544
  9. Clin Lymphoma Myeloma Leuk. 2025 Sep 02. pii: S2152-2650(25)02893-9. [Epub ahead of print]
       BACKGROUND: Ponatinib, a third-generation tyrosine kinase inhibitor, has demonstrated its activity against chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, real-world data, particularly in Asian populations, remain limited.
    METHODS: Patients with CML or Ph+ ALL treated with ponatinib in Taiwan between March 2013 and November 2024 were retrospectively collected. Molecular and cytogenetic data, efficacy outcomes (complete hematologic response [CHR], molecular response [MR], progression-free survival [PFS], overall survival [OS]), and adverse events were analyzed.
    RESULTS: Among 52 patients (27 CML and 25 Ph+ ALL; median follow-up: 50.7 months), 94% received ponatinib due to relapsed or refractory disease. Among patients without prior CHR, 89% reached CHR at 12 months. Among patients without prior MR, 57% had MR2.0, 53% MR3.0, and 26% MR5.0 at 12 months. MR2.0 at 6 months and MR3.0 at 12 months correlated with improved outcome in patients with CML. Additional chromosomal abnormalities (ACAs) were identified in 36% of patients and were associated with inferior survival, whereas kinase domain mutations in 78% of studied patients, including T315I (57%), did not affect the outcome. MR3.0 at any time predicted superior OS and PFS in patients with CML, and MR5.0 with superior PFS in patients with Ph+ ALL. One patient (1.9%) had an arterial occlusive event.
    CONCLUSION: Ponatinib demonstrated substantial real-world efficacy in pretreated patients with CML and Ph+ ALL, with MR3.0 in CML and MR5.0 in Ph+ ALL emerging as favorable prognostic markers. In contrast, the presence of ACAs was associated with shorter survival.
    Keywords:  Adverse events; BCR::ABL1-positive leukemia; Molecular response
    DOI:  https://doi.org/10.1016/j.clml.2025.09.003
  10. Exp Hematol Oncol. 2025 Sep 30. 14(1): 119
       BACKGROUND: Zevorcabtagene autoleucel (zevor-cel) is a fully human autologous CAR T-cell therapy targeting B-cell maturation antigen approved in China since 2024 for patients with relapsed/refractory multiple myeloma (RRMM).
    METHODS: LUMMICAR STUDY 1 is a phase 2, single-arm study conducted across 23 centers in China. RRMM patients aged ≥ 18 to ≤ 75 years with measurable disease who had received ≥ 3 prior lines of therapy, with adequate organ function and bone marrow reserve, with an Eastern Cooperative Oncology Group (ECOG) score of 0-1, were eligible. Patients previously treated with any CAR T-cell therapy, or any BCMA-directed therapy were ineligible. The primary endpoint was objective response rate (ORR) determined by an Independent Review Committee. The secondary endpoints included ORR determined by investigator, additional efficacy outcomes including complete response (CR)/ stringent complete response (sCR) rate, duration of response (DOR), minimal residual disease negativity, safety outcomes including incidence and severity of adverse events, and pharmacokinetics of zevor-cel.
    RESULTS: Overall, 125 patients underwent apheresis, 105 patients received lymphodepletion, 102 patients (median age of 59.5 [range: 38, 75] years; 53.9% male and 46.1% female) received zevor-cel. The ORR was 92.2% (95% CI 85.13-96.55) with 70 patients (68.6%) achieving sCR and 3 (2.9%) achieving CR. At a median follow-up of 20.3 (interquartile range [IQR] 12.5, 23.8) months, 45 (44.1%) progression-free survival (PFS) events and 20 (19.6%) overall survival (OS) events were observed, the DOR, PFS and OS data were not mature. Cytokine release syndrome was reported in 92 (90.2%) patients, with grade 3 or 4 events in 7 (6.9%) patients. Immune effector cell associated neurotoxicity syndrome was reported in 2 patients at grade 1; no zevor-cel-related grade ≥ 3 neurotoxicity occurred.
    CONCLUSION: Zevor-cel induces deep and durable responses in heavily pre-treated RRMM patients with a manageable safety profile.
    Keywords:  BCMA; CAR T cells; CT053; Chimeric antigen receptor T cell; Relapsed/refractory multiple myeloma; Targeted immunotherapy; Zevor-cel; Zevorcabtagene autoleucel
    DOI:  https://doi.org/10.1186/s40164-025-00710-y
  11. Haematologica. 2025 Oct 02.
      Patient-guided dose reduction, as explored in the RODEO study, offers a promising approach to alleviate the burden of tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML). Supported by shared decision-making (SDM) and a patient decision aid, this strategy aims to reduce TKI toxicity while maintaining effectiveness. This interim analysis evaluates its effectiveness at six months, focusing on intervention failure, i.e., TKI dose re-escalation due to loss of major molecular remission (MMR) of BCR::ABL1 (>0.1%IS) or expected loss of MMR, and patient-reported healthrelated quality of life (HRQoL) and symptom burden. The SDM-process and decisional conflict are also evaluated. This is a prospective, single-arm, multicenter trial including 148 patients with chronicphase CML in at least MMR. Patients and their treating hematologists were engaged in an SDMprocess and selected a reduced TKI dose. BCR::ABL1 monitoring was conducted regularly; HRQoL and symptom burden was assessed using EORTC QLQ-C30, QLQ-CML24, and IL156. SDM and decisional conflict were evaluated via SDM-Q-9, SDM-Q-Doc, and the Decisional Conflict Scale. Of 146 patients analyzed, 2.8% experienced intervention failure at six months. Modest statistically significant improvements were seen in multiple symptom scales. SDM was well-evaluated, with low decisional conflict by patients. Patient-guided dose reduction appears safe and beneficial at six months followup.
    DOI:  https://doi.org/10.3324/haematol.2025.288516
  12. Front Oncol. 2025 ;15 1577908
      The use of the BCL2 inhibitor venetoclax in combination with hypomethylating agents (HMA) is a revolution for the treatment of frail and elderly acute myeloid leukemia (AML) patients. This effective treatment strategy is increasingly more and more applicable for other subsets of AML patients and is currently being tested in numerous clinical trials in combination with other drugs in all treatment lines. In particular, venetoclax combinations can also serve as a definitive therapy or as an effective bridge to allogeneic hematopoietic stem cell transplantation (HSCT). However, the factors affecting response to venetoclax in the abovementioned AML patients are not completely clear and understood until today. The aim of this review is to describe the molecular and clinical patterns of response and durable remission of venetoclax-based combinations in AML patients. Hence, mutations in IDH1, IDH2, ASXL1, NPM1, DDX41, chromatin-cohesin complex and splicing-factor genes predict superior response to venetoclax, while inferior response to the drug has been observed for FLT3-ITD, KRAS, NRAS and TP53 gene mutations. Intriguingly, the achievement of measurable residual disease (MRD) negativity in the first four cycles of venetoclax administration characterizes a subgroup of NPM1-mutated AML patients with a more favorable outcome. Even though focus will be given on factors influencing response to the drug in this review, the main mechanisms of resistance to venetoclax in AML patients will also be discussed.
    Keywords:  BCL2 (B-cell lymphoma 2) inhibition; MCL1 (myeloid cell leukemia sequence 1) overexpression; acute myeloid leukemia (AML); azacitidine (AZA); hypomethylating agents (HMAs); resistance; response; venetoclax (VEN)
    DOI:  https://doi.org/10.3389/fonc.2025.1577908
  13. Am J Hematol. 2025 Oct 01.
      
    Keywords:  IgM MGUS; Waldenström macroglobulinemia; immunoglobulin heavy chain translocation; multiple myeloma
    DOI:  https://doi.org/10.1002/ajh.70097
  14. Am J Hematol. 2025 Oct 04.
      Light chain multiple myeloma (LCMM) is a subtype of multiple myeloma (MM) characterized by the exclusive production of immunoglobulin light chains and accounts for 15%-20% of newly diagnosed MM. A comprehensive comparison of LCMM with MM producing intact immunoglobulin (non-LCMM) remains limited. In this retrospective study, we described distinct clinical and cytogenetic features and assessed long-term outcomes in 852 LCMM patients diagnosed between 01/01/2004 and 12/31/2022, compared with non-LCMM controls matched for age, sex, and year of diagnosis. On univariable analysis, LCMM patients were more likely to present with elevated creatinine (> 2 mg/dL), beta-2-microglobulin ≥ 5.5 mg/L, elevated LDH, hypercalcemia, t(11;14), del(13q), and t(6;14). Conversely, IMS-IMWG high-risk disease, hyperdiploidy, t(4;14), and serum albumin < 3.5 g/dL were less common. On multivariable analysis, elevated creatinine (OR: 5.1, 95% CI: 1.2-27, p = 0.04), t(11;14) (OR: 2.6, 95% CI: 1.3-5.2, p = 0.006), and del(13q) (OR: 4.1, 95% CI: 2.1-8.2, p < 0.001) were independently associated with LCMM, while IMS-IMWG high-risk disease (OR: 0.3, 95% CI: 0.1-0.8, p = 0.02) and hyperdiploidy (OR: 0.3, 95% CI: 0.1-0.7, p = 0.002) were less frequent. Despite these differences, progression-free survival with frontline treatment (HR: 0.97, 95% CI: 0.84-1.11, p = 0.63) and overall survival (HR: 0.99, 95% CI: 0.87-1.13, p = 0.94) were similar between LCMM and non-LCMM patients. This study highlights the distinct clinical and cytogenetic features of LCMM, marked by higher rates of renal failure, t(11;14), and del(13q), lower prevalence of IMS-IMWG high-risk disease, and comparable survival outcomes.
    Keywords:  IMS/IMWG high risk; cast nephropathy; light chain multiple myeloma; overall survival; progression free survival; t(11;14)
    DOI:  https://doi.org/10.1002/ajh.70099
  15. Rinsho Ketsueki. 2025 ;66(9): 959-964
      Acute lymphoblastic leukemia (ALL) is a hematologic neoplastic disease characterized by monoclonal proliferation of lymphoid progenitor cells that have ceased to differentiate, primarily in the bone marrow. Although outcomes of adult ALL remain poorer than those of pediatric ALL, they have dramatically improved in the past decade with better understanding of prognostic factors and the advent of novel therapies. In particular, BCR-ABL1 tyrosine kinase inhibitors and targeted agents against cell surface antigens (CD19, CD20, and CD22) have revolutionized the treatment of ALL. Clinical adoption of genomic screening and sensitive MRD assays should also inform appropriate treatment selection based on recurrence risk. This article outlines the current classification approach for ALL stratification and discusses future prospects for ALL treatment strategies.
    Keywords:  Acute lymphoblastic leukemia; Allogeneic hematopoietic stem cell transplantation; Immunotherapy; Molecular targeted therapy
    DOI:  https://doi.org/10.11406/rinketsu.66.959
  16. Haematologica. 2025 Oct 02.
      Triplet regimens with a hypomethylating agent, venetoclax and a FLT3 inhibitor yield high rates of response in newly diagnosed FLT3-mutated AML. However, the long-term outcomes and patterns of relapse with these triplet regimens are not well-established. In this retrospective analysis, 73 patients with newly diagnosed FLT3-mutated AML received a frontline FLT3 inhibitor-containing triplet regimen. The composite complete remission (CR) and CR with incomplete hematologic recovery (CRi) rate was 93%. Next-generation sequencing FLT3-ITD MRD negativity (sensitivity: 0.005%) was achieved in 60% of patients after cycle 2 and 90% after cycle 4. The estimated 3-year relapse-free survival (RFS) for FLT3-ITD-mutated and FLT3 TKD-mutated AML was 38% and 76%, respectively, and the 3-year overall survival (OS) was 45% and 76%, respectively. Neither age, NPM1 co-mutation, ELN 2022 risk, nor allogeneic stem cell transplantation in first remission significantly impacted OS. Baseline RAS pathway mutations were associated with poor long-term survival (3-year OS 22% versus 63% without RAS pathway mutation). FLT3 wild type relapses accounted for 65% of relapses, and new RAS pathway mutations were observed in 24% of relapses. Outcomes were poor after relapse (median OS of 6.1 months), particularly for those with persistently detectable FLT3 mutations. Triplet combinations of an HMA, venetoclax and a FLT3 inhibitor result in durable remission and encouraging long-term OS in older adults with newly diagnosed FLT3-mutated AML. However, better strategies to prevent FLT3 wild type relapses and to overcome RAS pathway-mediated resistance are still needed.
    DOI:  https://doi.org/10.3324/haematol.2025.288553
  17. Cancer Med. 2025 Oct;14(19): e71276
       INTRODUCTION: Cytokine release syndrome (CRS) is a common adverse event associated with T-cell redirection therapies (TCRT), including talquetamab, the first GPRC5D × CD3 bispecific antibody approved for relapsed/refractory multiple myeloma (RRMM). We describe CRS with talquetamab and implications for clinical practice.
    METHODS: Patients without prior TCRT received talquetamab 0.4 mg/kg weekly (QW) and 0.8 mg/kg every other week (Q2W), with two or three step-up doses, respectively, plus pretreatment with a glucocorticoid, antihistamine, and antipyretic. A separate cohort of patients with prior TCRT received talquetamab at either the QW or Q2W schedule. CRS was graded per American Society for Transplantation and Cellular Therapy criteria and managed per study protocol.
    RESULTS: Across talquetamab QW (n = 143), Q2W (n = 145), and prior TCRT (n = 51) cohorts, most CRS events occurred during step-up doses and were grade 1 or 2; grade 3 CRS events were rare. Approximately one-third of patients experienced more than one CRS event. Fewer patients experienced subsequent CRS events if tocilizumab was used versus not used to treat their first CRS event. Overall response rates with talquetamab were similar among patients with and without tocilizumab to manage CRS. Baseline characteristics were not associated with CRS incidence, recurrence, duration, or severity, whereas immune biomarkers showed some trends in association with CRS parameters.
    CONCLUSION: CRS outcomes with talquetamab were consistent with those seen with other TCRT in RRMM, including teclistamab (BCMA×CD3 bispecific antibody), indicating a similar clinical approach, including early vigilance and prompt treatment of CRS.
    TRIAL REGISTRATION: NCT03399799/NCT04634552.
    Keywords:  GPRC5D; clinical management; cytokine release syndrome; interleukin‐6; talquetamab; tocilizumab
    DOI:  https://doi.org/10.1002/cam4.71276
  18. Blood Adv. 2025 Sep 30. pii: bloodadvances.2025017244. [Epub ahead of print]
      Despite the use of FLT3 inhibitors, outcomes for patients with FLT3 mutated (FLT3mut) AML remain suboptimal because of high rates of relapse. We evaluated the safety and efficacy of the combination of daunorubicin, cytarabine (DA), gemtuzumab ozogamicin (GO) and midostaurin (DAGO+m) for younger patients with newly diagnosed FLT3mut AML in the UK NCRI AML19 trial. 195 patients were randomised to receive DA with either one or two doses of GO (DAGO1 and DAGO2). 77 had a FLT3 mutation (60 had FLT3-ITD) and received midostaurin for two weeks after each chemotherapy course and then as maintainance for one year unless transplanted. 39 patients received midostaurin with DAGO1 (DAGO1+m) and 38 with DAGO2 (DAGO2+m). Their median age was 51y (range 20-74) and 16 (20%) were aged >60y. The overall response rate (CR + CRi) was 91%. Day 30 and day 60 mortality was 0% with no increase in toxicity compared to patients treated contemporaneously with DAGO1 and DAGO2 without midostaurin. 2y overall survival was 77%. 2y event-free survival and cumulative incidence of relapse were 62% and 31% respectively. MRD clearance was enhanced compared to patients with FLT3-mutated AML treated with DAGO1 and DAGO2 without midostaurin. 81% of evaluable patients were NPM1 MRD negative by RT-qPCR in the peripheral blood after course 2 (76% with DAGO1+m and 86% with DAGO2+m), 79% were MRD negative in the bone marrow by FLT3-ITD NGS, and all patients had FLT3-MRD levels below 0.01%. DAGO+m appears safe and effective . DAGO2+m will now be evaluated in a randomised study (OPTIMISE-FLT3, ISRCTN 34016918). Trial: ISRCTN78449203.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017244
  19. Front Med (Lausanne). 2025 ;12 1638176
       Introduction: Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk myeloid malignancies remains a major therapeutic challenge, with conventional chemotherapy offering limited survival benefits. BCL-2 inhibition combined with hypomethylating agents (HMAs) has emerged as a potential therapeutic option, but comparative data in this setting are scarce.
    Methods: We conducted a single-center retrospective study of 106 consecutive patients with post-transplant acute myeloid leukemia (AML) recurrence treated between 2020 and 2024. Patients received either venetoclax plus HMAs (n = 53) or intensive chemotherapy (n = 53). Outcomes assessed included complete remission (CR) rate, overall survival (OS), measurable residual disease (MRD) clearance, and treatment-related toxicities. Multivariable Cox regression analysis was performed to evaluate survival predictors.
    Results: The venetoclax-based regimen achieved significantly higher CR rates (56.6% vs. 26.4%, p = 0.002) compared with intensive chemotherapy. Median OS was markedly improved with venetoclax plus HMAs (12.6 vs. 5.8 months; HR 0.42, p < 0.001). MRD clearance was more frequent in the venetoclax group (70.0% vs. 35.7%, p = 0.021). Safety analysis demonstrated lower incidences of severe cytopenias (36.8% vs. 64.2%, p = 0.002) and infectious complications (11.3% vs. 32.1%, p = 0.008). Multivariable modeling confirmed venetoclax-based therapy as an independent predictor of improved survival (adjusted HR 0.42, 95% CI 0.31-0.58).
    Discussion: Venetoclax in combination with HMAs provided superior clinical benefits over intensive chemotherapy in post-allo-HSCT AML relapse, achieving higher remission rates, improved survival, enhanced MRD clearance, and a favorable safety profile. These findings highlight venetoclax-based regimens as a promising therapeutic approach for this high-risk population.
    Keywords:  cytotoxic regimens; disease recurrence; myeloid neoplasia; therapeutic resistance; venetoclax
    DOI:  https://doi.org/10.3389/fmed.2025.1638176
  20. Blood Neoplasia. 2025 Nov;2(4): 100152
      Approximately 10% of patients with newly diagnosed acute myeloid leukemia (ND-AML) harbor the isocitrate dehydrogenase 1 gene mutation (mIDH1). In this real-world study evaluating ivosidenib (IVO) + hypomethylating agents (HMAs; n = 181) vs venetoclax (VEN) + HMAs (n = 99) in patients with mIDH1 ND-AML, those treated with IVO+HMA had higher rates of complete remission (CR; 42.5% vs 26.3%; P = .007), higher rates of composite CR + CR with incomplete platelet count recovery (63.0% vs 48.5%; P = .019), shorter median time to best response (3.3 vs 4.1 months; P = .006), and improved 6-month event-free survival (55.8% vs 38.4%; P = .006). Most patients treated with VEN received well under 28 days of VEN per cycle, likely due to anticipation of toxicity; outcomes with this short-schedule VEN were proportionately worse with fewer days of exposure per cycle. The between-group rate of grade ≥3 adverse events was similar within 30 days of treatment initiation, except for higher rates of febrile neutropenia for VEN+HMA vs IVO+HMA (8.1% vs 1.7%; P = .008). These findings support results from the phase 3 AGILE trial demonstrating IVO+HMA's efficacy and favorable toxicity profile in patients with mIDH1 ND-AML. IVO + azacitidine should be considered as the preferred standard of care treatment regimen in this patient subgroup.
    DOI:  https://doi.org/10.1016/j.bneo.2025.100152
  21. Rinsho Ketsueki. 2025 ;66(9): 1117-1124
      Multiple myeloma (MM) is characterized by several cytogenetic abnormalities that occur at various time points during the disease course. Cytogenetic abnormalities in MM cells are critical intrinsic factors that determine tumor characteristics, and reflect sensitivity to key drugs including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. Venetoclax, a first-in-class BCL-2 inhibitor, is currently under investigation for the treatment of t (11;14) MM. Some cytogenetic abnormalities may also be associated with poor response to BCMA-targeting bispecific antibodies and CAR-T therapy. The biological and clonal heterogeneity of MM complicates treatment stratification according to biology and risk. Consequently, cytogenetic abnormalities play an important role in treatment stratification for this heterogenous disease, and precision medicine based on cytogenetic abnormalities can be expected eventually.
    Keywords:  1q gain; Cytogenetic abnormalities; Multiple myeloma; t(11;14)
    DOI:  https://doi.org/10.11406/rinketsu.66.1117
  22. Leukemia. 2025 Sep 28.
      Positron Emission Tomography (PET)-based assessments are an integral part of response assessment in patients with multiple myeloma (MM) with extramedullary disease (EMD), yet their utility in EMD remains to be systematically studied. We retrospectively evaluated 95 patients with EMD undergoing FDG PET/CT imaging for metabolic response assessment using visual Deauville Scores (DS) and total lesion glycolysis (TLG). TLG responses were categorized as complete metabolic response (CMR; 100% reduction), major metabolic response (MMR; <100% to ≥50% reduction), and non-significant metabolic response (NMR; <50% reduction). The median progression-free survival (PFS) differed significantly by DS (22.4 vs. 4.3 vs. 2.8 months for DS ≤ 3, =4, and =5, respectively; p < 0.0001) and by TLG response (36.5 vs. 5.4 vs. 2.2 months for CMR, MMR, NMR; p < 0.0001). TLG offered better discrimination than DS, with approximately one-third of patients in each DS stratum being reclassified by the TLG stratification. In a multivariable analysis, TLG response [HR 2.6 (95% CI: 1.8-3.8), p < 0.0001] remained independently prognostic after adjusting for cytogenetics, triple-class refractoriness, and de novo EMD status. The 18-month OS rates were 89%, 42% and 19% for the TLG CMR, MMR, and NMR cohorts (p < 0.001). These findings support the integration of TLG into response criteria for EMD.
    DOI:  https://doi.org/10.1038/s41375-025-02776-3
  23. Cureus. 2025 Sep;17(9): e91401
      IgE multiple myeloma is an exceptionally unique subtype of plasma cell dyscrasia, accounting for only a marginal percentage of all multiple myeloma cases. Combined with its lack of generalized accepted treatment approaches, its rarity makes diagnosis and clinical management extremely difficult. Here, we report the case of a 50-year-old woman with no prior medical history who presented with progressive bone pain over a one-year period. She underwent an exhaustive diagnostic workup, which included imaging, laboratory workup, histopathology, and cytogenetic analysis. The integrated diagnosis was IgE multiple myeloma associated with t(11;14) translocation. The patient had primary refractoriness to two lines of therapy incorporating immunomodulatory imide drugs and proteasome inhibitors (VRD and CTD regimens). After that, she was started on the DKD protocol consisting of daratumumab (Darzalex) and carfilzomib, with which she experienced a positive clinical and hematologic response. She is now in active surveillance and continues to respond well. Research on IgE multiple myeloma is sparse due to its rarity, but so is research around prognosis, ideal treatment options, and response to newer agents. There is little data because the literature is often based on case reports.
    Keywords:  ige multiple myeloma; immunoglobulin e; multiple myeloma; plasma cell dyscrasia; rare; t(11.14)
    DOI:  https://doi.org/10.7759/cureus.91401
  24. Blood. 2025 Sep 30. pii: blood.2025029121. [Epub ahead of print]
      The mechanisms that lead to extramedullary tropism of acute myeloid leukemia (eAML) remain obscure and no specific therapeutic approaches for this entity exist. As the long-term survival of eAML is poor, a deeper understanding of the immune microenvironment and leukemia phenotypes underlying this entity is warranted. Here, we performed bulk and single-cell transcriptome profiling of 23 eAML biopsies from 10 patients with isolated extramedullary disease in skin and subcutaneous tissue. Unlike normal healthy skin, we found leukemia cutis to be heavily immune-infiltrated; in cases of extramedullary relapse following allogeneic stem cell transplantation, >90% of T/NK cells were donor-derived. eAML-associated T cells expressed a clear signature of T cell exhaustion, dissimilar to leukemia-associated immune populations in bone marrow relapse (n=7), but related to acute and chronic skin inflammation. Further, HLA class II was down-regulated in 4 of 7 leukemia cutis specimens, consistent with an immune escape phenotype in cases of eAML. Extramedullary and bone marrow-resident leukemia cells differed with regard to the expression of 8 homing receptor molecules (ICAM1 (encoding CD54), PECAM1 (CD31), ITGA4, ITGA6, ITGAL, ITGB4, ITGA5, and ITGAV). Serial samples obtained from one leukemia cutis case throughout consecutive immune checkpoint blockade with ipilimumab followed by nivolumab showed a consistently high degree of overlap between local and circulating T cell receptor (TCR) sequences, suggesting that only a minority of eAML-associated T cells are leukemia-specific. Our analysis reveals eAML to associate with complex changes in leukemia and T cell gene expression profiles that suggest multiple potential avenues for therapeutic targeting.
    DOI:  https://doi.org/10.1182/blood.2025029121
  25. Future Oncol. 2025 Oct 03. 1-11
       BACKGROUND: Approvals of Bruton's tyrosine kinase inhibitors (BTKis) and other novel agents have changed the Mantle Cell Lymphoma (MCL) treatment paradigm, necessitating assessment of contemporaneous, real-world (rw) treatment and outcomes by line of therapy (LOT).
    METHODS: Patients diagnosed with MCL on or after 1 January 2012 who initiated first-line (1 L) treatment in the COTA database were eligible, excluding those with concurrent primaries, history of hematologic malignancies, clinical trial participation, or missing/imprecise key dates. Rw time to next treatment (rwTTNT) and overall survival (rwOS) were evaluated using the Kaplan-Meier method from LOT start (index).
    RESULTS: Of 499 patients, most were ≥ 50 years (94.8%), male (71.5%), treated in the community (58.7%), and diagnosed with stage III/IV disease (91.2%). The most common 1 L regimen was bendamustine+rituximab (BR)±R maintenance (12.6%/23.0%, respectively). Fifty (10.0%) patients received 1 L autologous stem cell transplant. One hundred and seventy-three patients (34.7%) received 2 L, of which 72 (41.6% of 2 L) received 3 L, of which 29 (40.3% of 3 L) received 4 L +. BTKi monotherapy was the most frequently administered therapy in 2 L (26.0%).Median rwTTNT and rwOS from 1 L to 4 L were 36.8-3.2 and 86.2-8.7 months, respectively.
    CONCLUSIONS: Outcomes of patients who received 2 L+ for MCL remain poor, highlighting unmet need in the contemporary treatment paradigm.
    Keywords:  Hematologic/lymphoma; chemotherapy; novel therapy; outcomes research; real-world evidence
    DOI:  https://doi.org/10.1080/14796694.2025.2565829
  26. Blood Adv. 2025 Sep 30. pii: bloodadvances.2025017234. [Epub ahead of print]
      Brexucabtagene autoleucel (brexu-cel) is the anti-CD19 CAR-T therapy approved for the treatment of relapse/refractory (RR) mantle cell lymphoma (MCL). Our study, conducted in the scope of the french DESCAR-T registry, aimed to analyze outcomes of MCL post-brexu-cel failure. In the DESCAR-T registry, 178 RR MCL received brexu-cel. After a median follow-up (FU) of 14.5 months, 61 experienced failures. This study analyzes post CAR-T failure progression-free (PFS2) and overall survival (OS2), according to clinical characteristics and salvage treatments. At infusion, 36% of the 61 patients had a high MIPI score, 76.2% a Ki-67 index ≥ 30%, 30.2% a TP53 mutation, and 31.6% a blastoid variant. After a median FU of 15 months post-failure, median OS2 and PFS2 were 5.8 and 1.8 months, respectively. Patients experiencing early failure (<3 months) had a median OS2 of 1.8 months, compared to 6.7 and 9 months for those relapsing within 3-6 and after 6 months. Forty-nine patients received salvage therapy: 16 lenalidomide ± rituximab (Len/R2), 13 immunochemotherapy (ICT), 8 Bruton tyrosine kinase inhibitor ± venetoclax (BTKi/Ven), 7 a bispecific T-cell engager (TCE), 3 another targeted therapy, and 2 radiations. Overall, post-salvage response rate was 20% (9 CR, 1 PR). 1-year OS2 was 36% for patients treated with Len/R2 and ICT, 57% for TCE and 0% for others type of salvage. Notably, none of the TCE responders have relapsed to date (DOR of 100%). Our series highlights the poor outcomes of MCL patients following CAR-T failure and suggest a potential benefit of bispecific antibodies in this population.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017234
  27. Curr Opin Oncol. 2025 Sep 25.
       PURPOSE OF REVIEW: Measurable residual disease (MRD) is a reliable biomarker measuring the quality of morphological complete remission in acute myeloid leukemia (AML). This review will illustrate the settings where, along with drug development, MRD monitoring is by itself an actionable therapeutic target and represents not only a prognostic marker but a predictive marker of response, prompting a further relevant progress toward personalized medicine.
    RECENT FINDINGS: The double nature of certain biomarkers (e.g. PML/RARA, bcr/abl, FLT3, IDH1/2, NPM1), useful for MRD monitoring and key actors in AML development, has emerged. The use of targeted drugs (e.g. FLT3 inhibitors, IDH1/2 inhibitors) or drug combination that are particularly active in specific AML subsets (e.g. Azacytidine/Venetoclax in NPM1 mutated AML), has paved the way to clinical trial experimenting maintenance or preemptive treatment driven by MRD persistence or reappearance.
    SUMMARY: Accurate and specific MRD monitoring, coupled with the increasing development of targeted drugs, will give to clinicians an extraordinary opportunity to anticipate the treatment of AML relapse in the early phases eventually increasing drug efficacy and long-term outcome of the patients (visual abstract).
    Keywords:  actionable biomarker; measurable residual disease; personalized medicine acute myeloid leukemia
    DOI:  https://doi.org/10.1097/CCO.0000000000001197
  28. Immun Ageing. 2025 Sep 30. 22(1): 35
      Known as immunosenescence, the major dysregulation of the immune system with age is associated with poor vaccination efficacy, and increased susceptibility to infections, age-related pathologies, and neoplasms, with incidences exacerbated with age. Cellular senescence is a crucial process that puts cells in an irreversible cell-cycle arrest which prevents damaged or stressed cells from uncontrolled propagation and eventually potential malignancy. Paradoxically, senescence also contributes to the occurrence of cancer and increases the risk of metastasis through different secretory mediators. Altogether, the recent use of senotherapy to eliminate senescent cells has been shown to delay tumorigenesis, attenuate age-related deterioration of organs, and promote healthy aging. Interestingly, immune cells have been shown to specifically interact with, and kill senescent cells, thus opening new opportunities for the development of specific therapeutic strategies similar to immunotherapy in cancer. Through its detrimental impact on the immune system, immunosenescence is also leading to the accumulation of senescent cells with age thus further contributing to the occurrence and worsening of multiple age-related pathologies such as cancer. Understanding the molecular and cellular events occurring during the aging process, and triggering immunosenescence as well as the mechanisms by which senescent cells escape immune surveillance would help to improve immune responses to senescent cells and their clearance. In this review, we highlight how senescent cells interact with immune cells, and how immunosenescence-associated phenotypical and functional deregulation hinder the ability of immune cells to clear senescent cells. We further characterize strategies aimed at promoting the clearance of senescent cells by the immune system.
    Keywords:  Aging; Cancer; Cellular senescence; Immunosenescence
    DOI:  https://doi.org/10.1186/s12979-025-00518-8
  29. Front Immunol. 2025 ;16 1650568
       Background: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy has demonstrated potent short-term efficacy in patients with relapsed/refractory multiple myeloma (R/R MM); however, long-term clinical data remain limited. Here, we report extended follow-up outcomes from our single-center experience.
    Methods: Between August 20, 2018, and December 31, 2021, 11 patients with R/R MM received BCMA-targeted CAR-T-cell therapy at our center. Preconditioning consisted of cyclophosphamide and fludarabine chemotherapy, followed by infusion of 1-5×106 CAR+ T cells/kg. We evaluated overall response rate (ORR), long-term efficacy, safety profiles, and their correlations with clinical/disease characteristics.
    Results: The ORR was 72.7% (8/11), including 6 complete remissions (54.5%) and 2 partial/very good partial remissions. With a median follow-up of 23 months (range: 2-63 months), 75% (6/8) of the responders remained relapse-free, and 4 patients (50%) were alive at the time of data cutoff. The median progression-free survival (PFS) and overall survival (OS) of responders both reached 35 months. In terms of safety, most patients experienced moderate cytokine release syndrome (CRS), with 2 cases of grade 3-4 CRS.
    Conclusion: BCMA CAR-T-cell therapy exhibits favorable safety and efficacy in advanced R/R MM. Long-term follow-up confirmed durable responses in 50% of the advanced R/R MM patients who responded to the treatment (4/8).
    Keywords:  BCMA CAR-T; CAR-T-cell therapy; cellular immunotherapy; long-term follow- up; multiple myeloma
    DOI:  https://doi.org/10.3389/fimmu.2025.1650568
  30. Blood Adv. 2025 Sep 30. pii: bloodadvances.2025017118. [Epub ahead of print]
      The primary clinical approach for diffuse large B-cell lymphoma (DLBCL) in recent decades has predominantly relied on chemotherapy with R-CHOP as the cornerstone. However, given the highly heterogeneous nature of DLBCL, more than 30% of patients are prone to relapse and may even exhibit resistance to treatment. Antibody-drug conjugate (ADC) therapies have demonstrated significant advancements in clinical trials targeting DLBCL, thereby indicating a promising direction for its management. By leveraging the inherent modifiability of DNA nanostructures and the affinity of doxorubicin for DNA, we employed a combination of rituximab-based R-CHOP scheme and DNA tetrahedra to fabricate antibody-DNA nanostructure conjugate (ADNC). The RTD (Rituximab-Tetrahedron-Doxorubicin conjugate) studied in our research has been validated through in vitro cellular experiments and subcutaneous tumor models. The RTD demonstrated a robust anti-tumor effect in vitro, significantly exceeding the combined effects of rituximab and doxorubicin by more than fifty-fold. Furthermore, confirmation from a subcutaneous tumor model substantiated the potent anti-tumor efficacy of RTD while successfully mitigating cardiotoxicity and hematotoxicity associated with doxorubicin. Antibody-DNA nanostructure conjugate effectively facilitates the binding of rituximab and doxorubicin in the R-CHOP regimen, offering novel prospects for the development of next-generation ADC drugs.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017118
  31. Blood Rev. 2025 Sep 27. pii: S0268-960X(25)00084-0. [Epub ahead of print] 101339
      Multiple myeloma (MM), a clonal plasma cell malignancy, presents a therapeutic challenge, especially in selecting therapy for patients with relapsed/refractory MM (RRMM). Up to 1-3 prior lines of therapy in this population are considered early relapse. This review provides clinicians with a guide for personalized, evidence-based strategies for treatment of early RRMM. Factors influencing treatment selection, including patient-related factors (e.g., frailty and comorbidities), disease characteristics (e.g., high-risk cytogenetics), prior therapy response, and toxicity profiles, are highlighted. We outline current and emerging transformative novel therapeutics, including anti-CD38 and anti-SLAMF7 monoclonal antibodies, BCMA-directed immunotherapies, such as CAR T-cells, and bispecific antibodies. The review highlights key clinical trials on efficacy (response rates, progression-free survival, overall survival) and safety profiles (e.g., cytokine release syndrome, neurotoxicity, and infections). Crucially, it provides a practical framework for clinical decision-making, including guidance on selecting between different combination regimens, immunotherapy platforms, and considering meaningful therapeutic endpoints and survival. Relapse management following BCMA-directed therapy and potential salvage strategies are outlined. Future directions include next-generation cellular therapies, novel antibody constructs, CELMoDs, and strategies to enhance immunotherapy outcomes.
    Keywords:  Clinical evidence; Efficacy; Multiple myeloma; Personalized treatment; Relapsed refractory multiple myeloma (RRMM); Toxicity
    DOI:  https://doi.org/10.1016/j.blre.2025.101339