Nishiyama R, Hiratsuka A, Ochi T
… +11 more, Miyagi Maeshima A, Takeda W, Ito K, Aruga Y, Ikeda C, Matsui H, Iwaki N, Fukuhara S, Munakata W, Makita S, Izutsu K
Int J Hematol
· 2026 May · PMID 42118449
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Axicabtagene ciloleucel (axi-cel) has demonstrated efficacy and safety in relapsed/refractory large B cell lymphoma (r/r LBCL). However, evidence from Asian populations remains limited.This study evaluated patients with...Axicabtagene ciloleucel (axi-cel) has demonstrated efficacy and safety in relapsed/refractory large B cell lymphoma (r/r LBCL). However, evidence from Asian populations remains limited.This study evaluated patients with r/r LBCL who underwent leukapheresis for axi-cel between April 2023 and December 2025. Fifty-five patients were evaluable for safety, including 38 treated in the second-line setting (2L). CRS occurred in 53 (96%), with grade ≥ 3 in 6 (10%). ICANS occurred in 17 (31%), with grade ≥ 3 in 6 (11%). Compared with patients receiving third-line or later (3L +) treatment, 2L patients experienced higher rates of grade ≥ 3 CRS (13% vs. 6%) and any-grade ICANS (37% vs. 18%). Among the 55 patients, the overall response rate was 91%. After a median follow-up of 14.5 months, the 1.5-year PFS and OS rates were 63.1% and 83.1%, respectively. 2L showed numerically higher PFS than 3L + (1.5-year PFS: 64.9% vs. 57.0%; HR: 1.75; p = 0.248). Multivariate analysis identified three independent risk factors for PFS: low peripheral blood CD8 naive T-cell count at leukapheresis, high metabolic tumor volume, and elevated LDH level at initiation of lymphodepleting chemotherapy. Axi-cel demonstrated substantial efficacy in Japanese patients with r/r LBCL. The 2L setting was associated with higher toxicity and numerically higher PFS.
Katsuki K, Miyazaki T, Komaki M
… +16 more, Saigusa Y, Tachibana T, Sakuma T, Hasegawa K, Hirose N, Akimoto M, Izumi A, Ohashi T, Matsumura A, Suzuki T, Ishii Y, Nakajima Y, Hagihara M, Tanaka M, Fujisawa S, Nakajima H
Int J Hematol
· 2026 May · PMID 42118448
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PURPOSE: This study aimed to develop and validate a personalized prognostic model for patients with newly diagnosed with acute myeloid leukemia (AML) receiving intensive cytarabine- and anthracycline-based chemotherapy....PURPOSE: This study aimed to develop and validate a personalized prognostic model for patients with newly diagnosed with acute myeloid leukemia (AML) receiving intensive cytarabine- and anthracycline-based chemotherapy. METHODS: We retrospectively analyzed 161 patients treated at a single center and externally validated the model in 184 patients from two institutions. RESULTS: Using LASSO Cox regression, nine readily available clinical variables (age, sex, performance status, history of diabetes, respiratory disease, prior myelodysplastic syndrome or myeloproliferative neoplasm, serum albumin level, uric acid level, and adverse cytogenetic risk) were selected to construct a nomogram. The model demonstrated good discrimination of overall survival, with a concordance index of 0.721 and 0.678 in the training and validation cohorts, respectively. Calibration plots showed strong agreement between the predicted and observed outcomes. Based on the nomogram scores, the patients were stratified into three risk groups, with 3-year overall survival rates of 84.1%, 57.2%, and 11.9% in the good, intermediate, and poor-risk groups, respectively. To enhance clinical accessibility, an online tool was developed for use in real-world settings. CONCLUSION: This nomogram integrates disease- and patient-related factors and allows for individualized prognostic assessment. This may support clinical assessment through personalized risk evaluation in AML patients.
Ida N, Okura M, Tanaka S
… +2 more, Hosono N, Yamauchi T
Int J Hematol
· 2026 May · PMID 42115534
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Inotuzumab ozogamicin (IO), an anti-CD22 antibody conjugated with calicheamicin, is highly effective against relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, acquired resistance limits the long-t...Inotuzumab ozogamicin (IO), an anti-CD22 antibody conjugated with calicheamicin, is highly effective against relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, acquired resistance limits the long-term efficacy of IO. To elucidate the underlying mechanisms of IO resistance and explore strategies to overcome it, six IO-resistant B-ALL sublines were newly established. Although CD22 expression was preserved in all resistant sublines, more than 80-fold increases in 50% inhibitory concentration (IC50) were observed, accompanied by acquired resistance to IO-induced apoptosis. Microarray analysis revealed upregulation of ABCB1, which was further confirmed by overexpression of the encoded protein, the drug efflux pump P-glycoprotein (P-gp). P-gp inhibition restored IO sensitivity by inhibiting calicheamicin efflux, a key resistance mechanism. Concurrently, poly (ADP-ribose) polymerase (PARP) inhibition of DNA damage repair enhanced IO cytotoxicity. Notably, in the triplet combination of IO with P-gp and PARP inhibitors, PARP inhibition of the repair of DNA damage caused by calicheamicin accumulation following P-gp inhibition markedly enhanced the antitumor effects of IO. This approach may offer a novel and effective therapeutic strategy for IO-resistant B-ALL.
Int J Hematol
· 2026 May · PMID 42105180
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Treosulfan (Treo), a prodrug of a bifunctional alkylating agent, has been used in conditioning regimens to reduce the risk of hepatic sinusoidal obstruction syndrome. We aimed to establish a Treo-based conditioning regim...Treosulfan (Treo), a prodrug of a bifunctional alkylating agent, has been used in conditioning regimens to reduce the risk of hepatic sinusoidal obstruction syndrome. We aimed to establish a Treo-based conditioning regimen for mucopolysaccharidosis (MPS) as a phase 1 study. The regimen included thoracoabdominal irradiation, Treo, fludarabine, and antithymocyte globulin. Antithymocyte globulin was omitted in cord blood transplantation. Five patients with MPS II, aged 8 months to 21 years, were enrolled. Stem cell sources were HLA-C-mismatched unrelated bone marrow in one patient and HLA 1 to 3 allele-mismatched cord blood in four. No patients experienced grade 4 toxicities. Absolute neutrophil count > 500/µL was achieved at a median of 16 days. A pharmacokinetic study showed that AUC was 50% higher in children than in adults. Bone marrow donor chimerism at 4 weeks post-transplant was 100% in two patients and 96.7% to 98.1% in three; at 8 weeks, it was 100% in four patients and 77.1% in one who received a reduced dose of Treo. Three patients are alive, but two died at 415 and 767 days post-transplant due to factors unrelated to the conditioning regimen. Treo remains a valuable agent for conditioning regimens in MPS.
Yanada M, Shimomura Y, Yamasaki S
… +18 more, Mizuno S, Uchida N, Doki N, Fukuda T, Tanaka M, Nishida T, Eto T, Katayama Y, Yoshihara S, Ota S, Hasegawa Y, Onizuka M, Kawakita T, Sawa M, Kawamura K, Kanda J, Atsuta Y, Konuma T
Int J Hematol
· 2026 May · PMID 42081172
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This study examined changes in practice patterns and outcomes of allogeneic hematopoietic cell transplantation (HCT) over the past 20 years. Data were analyzed from a Japanese nationwide registry of consecutive adult pat...This study examined changes in practice patterns and outcomes of allogeneic hematopoietic cell transplantation (HCT) over the past 20 years. Data were analyzed from a Japanese nationwide registry of consecutive adult patients with acute myeloid leukemia who underwent allogeneic HCT between 2001 and 2020. The study population included 17,553 patients, of whom 6653 underwent allogeneic HCT in 2001-2010 and 10,900 in 2011-2020. Patients in the later period were older, were more likely to be in first complete remission, and more frequently received umbilical cord blood transplantation. After adjusting for major covariates, the 2011-2020 cohort had lower risks of overall mortality (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.80-0.89; P < 0.001), relapse (HR, 0.88; 95% CI, 0.83-0.95; P < 0.001), and non-relapse mortality (NRM; HR, 0.88; 95% CI, 0.81-0.95; P < 0.001). Subgroup analyses revealed improvements in overall survival (OS) regardless of age and disease status. The study found significant changes in allogeneic HCT practice in Japan and showed that the dual decrease in the risks of relapse and NRM contributed to the OS improvement, highlighting the substantial progress in this field over the past two decades.
Int J Hematol
· 2026 Jun · PMID 42036519
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Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplantation. Recent biological insights have led to a reevaluation of GVHD. It is now recognized not merely as a donor-de...Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplantation. Recent biological insights have led to a reevaluation of GVHD. It is now recognized not merely as a donor-derived immune attack, but as a complex disease characterized by the disruption of tolerance in target tissues and abnormal immune reconstitution. Therapeutic approaches are shifting from broad, nonspecific immunosuppression toward mechanism-based targeted therapies, active management of immune reconstitution, and biomarker-based risk stratification. To optimize patient outcomes, it is essential to incorporate these evolving pathophysiological mechanisms and new therapeutic strategies into clinical practice.
A 77-year-old woman with newly diagnosed immunoglobulin (Ig)G-κ multiple myeloma presented with a massive cranial paraskeletal (PS) lesion (84 × 59 × 62 mm) compressing the occipital lobe. Fluorescence in situ hybridizat...A 77-year-old woman with newly diagnosed immunoglobulin (Ig)G-κ multiple myeloma presented with a massive cranial paraskeletal (PS) lesion (84 × 59 × 62 mm) compressing the occipital lobe. Fluorescence in situ hybridization of bone marrow aspirate revealed 1q21 gain and 17p deletion. Induction therapy with isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) was initiated to avoid emergent local intervention. The response was rapid; head computed tomography on day 28 showed an approximately 80% reduction in bidimensional measurements, with near-complete radiologic resolution by the end of the second cycle. After the third cycle, elective reconstructive cranioplasty was performed. Although a pretreatment biopsy was not feasible, the resected tissue showed no detectable plasma cells. Measurable residual disease in the bone marrow was negative (< 10) after the fourth cycle. Exploratory longitudinal flow cytometry of the peripheral blood revealed baseline expansion of CD8-positive terminally differentiated effector memory re-expressing CD45RA (TEMRA) cells and persistent TEMRA subset dominance after the fourth cycle. This case suggests that upfront anti-CD38 antibody-containing quadruplet therapy can enable deferral of urgent local intervention through rapid cytoreduction in select patients with bulky cranial PS involvement, even in older adults with high-risk cytogenetic features and compromised immune profiles.
Granulocyte-colony stimulating factor (G-CSF) is widely used to mobilize peripheral blood stem cells (PBSCs) for hematopoietic cell transplantation (HCT). G-CSF is generally well-tolerated but can cause life-threatening...Granulocyte-colony stimulating factor (G-CSF) is widely used to mobilize peripheral blood stem cells (PBSCs) for hematopoietic cell transplantation (HCT). G-CSF is generally well-tolerated but can cause life-threatening complications such as splenic rupture in rare cases. Long-acting pegfilgrastim (Peg-G) is increasingly used for PBSC mobilization, but its risk for splenic rupture is less well characterized. Here, we report a case of splenic rupture secondary to Peg-G administered for PBSC mobilization in a healthy 25-year-old male haploidentical donor. He presented with left upper quadrant abdominal pain shortly after PBSC harvest 5 days following administration of Peg-G. Computed tomography (CT) revealed splenomegaly with rupture, and small bloody peri-splenic and pelvic ascites. He was managed conservatively, but the next evening his symptoms temporarily worsened, prompting a repeat CT scan, which showed no change. Thereafter, the pain did not recur, and the patient was discharged on day 8. One month later, a follow-up CT demonstrated complete resolution. To our knowledge, this is the first case of splenic rupture secondary to Peg-G for PBSC mobilization in a healthy allogeneic donor and highlights the importance of vigilance for this rare complication when G-CSF or Peg-G is used for mobilization.
Yokoyama S, Onozawa M, Kimura H
… +24 more, Ara T, Nagai J, Yoshida S, Miyashita N, Matsukawa T, Goto H, Hirabayashi S, Kanaya M, Mori A, Hidaka D, Hashiguchi J, Wakasa K, Ibata M, Takeda Y, Miyagishima T, Yamamoto S, Fujimoto K, Suzuki T, Saga T, Sakai H, Kakinoki Y, Oyake T, Kondo T, Teshima T
Chronic myelogenous leukemia that carries the BCR::ABL1 fusion gene without cytogenetically detectable Philadelphia (Ph) chromosomes is termed masked Ph. However, the prevalence and clinical relevance of masked Ph in acu...Chronic myelogenous leukemia that carries the BCR::ABL1 fusion gene without cytogenetically detectable Philadelphia (Ph) chromosomes is termed masked Ph. However, the prevalence and clinical relevance of masked Ph in acute lymphoblastic leukemia (ALL) remain unclear. Using the Hokkaido Leukemia Net real-world multicenter cohort, we analyzed 160 B-cell ALL patients diagnosed between 2017 and 2024 with available cytogenetic and molecular data. Among 92 BCR::ABL1-positive cases, 19 (20.7%) lacked a cytogenetically visible Ph chromosome and were classified as masked-Ph ALL. Compared with Ph + ALL, masked-Ph patients were older and had lower white blood cell counts and bone marrow blast percentages at diagnosis. Most BCR::ABL1-positive patients received tyrosine kinase inhibitors (TKIs) during induction, resulting in comparable complete remission rates and similar overall survival between masked-Ph and Ph + ALL; both groups showed superior outcomes compared with BCR::ABL1-negative ALL. The number of metaphases analyzed by G-banding was significantly lower in masked-Ph ALL, suggesting underdetection by conventional cytogenetics. One case exhibited an atypical FISH pattern consistent with a cryptic microinsertion. These findings indicate that masked-Ph ALL is relatively common and may be overlooked without molecular testing, underscoring the importance of incorporating RT-PCR and FISH at diagnosis.
Tacrolimus (TAC) is a pivotal immunosuppressant used to prevent graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation (HSCT). However, because lymphocytes express P-glycoprotein (P-gp), which...Tacrolimus (TAC) is a pivotal immunosuppressant used to prevent graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation (HSCT). However, because lymphocytes express P-glycoprotein (P-gp), which actively effluxes TAC, blood TAC concentrations do not necessarily reflect intracellular drug levels. Rather, the expression and activity of P-gp are influenced by multiple factors that change dynamically after transplantation, including inflammatory cytokines and gut microbiota. This study longitudinally assessed P-gp activity in peripheral blood mononuclear cells from HSCT recipients. Serial measurements were taken between days 14 and 41 following transplantation. Although blood TAC trough concentrations remained within the therapeutic range (10-15 ng/mL) throughout this period, P-gp activity increased progressively from the early (days 14-17) to the intermediate (days 38-41) post-transplantation phases. Notably, although the TAC blood concentration did not change significantly between days 14 and 17 and GVHD onset, P-gp activity was significantly elevated at GVHD onset (p < 0.05). These findings suggest fluctuations in P-gp activity may play a role in the onset of GVHD. Early assessment of P-gp activity after HSCT may serve as a biomarker for predicting GVHD development; however, further studies are required to validate its clinical utility.
The randomized, phase 3 DREAMM-7 trial (NCT04246047) previously demonstrated the efficacy and safety of belantamab mafodotin, bortezomib, and dexamethasone (BVd) versus daratumumab, bortezomib, and dexamethasone (DVd) in...The randomized, phase 3 DREAMM-7 trial (NCT04246047) previously demonstrated the efficacy and safety of belantamab mafodotin, bortezomib, and dexamethasone (BVd) versus daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed/refractory multiple myeloma (RRMM) and ≥ 1 prior therapy. The results in the Japan expansion cohort of DREAMM-7, consisting of 24 patients randomized to receive BVd (N = 10) or DVd (N = 14), are presented here. The median follow-up was 19.4 months (range, 1.3-30.3). Median progression-free survival (PFS) was not reached (NR; 95% CI, 7.0-NR) with BVd versus 11.1 months (95% CI, 4.9-NR) with DVd (PFS hazard ratio, 0.40; 95% CI, 0.11-1.52). The overall response rate was 90.0% (95% CI, 55.5-99.7) versus 71.4% (95% CI, 41.9-91.6); median duration of response was NR (95% CI, 9.7-NR) versus 14.5 months (95% CI, 3.5-NR). Safety trends in the Japan expansion cohort were similar to those in the global cohort. Ocular adverse reactions were more common with BVd and were manageable with dose modification. No new safety signals were reported. As in the global cohort, results in the Japan expansion cohort demonstrated the safety and efficacy of BVd in patients with RRMM and ≥ 1 prior therapy.
Treatment with the anti-CD38 therapeutic monoclonal antibodies (mAbs) daratumumab (DARA) and isatuximab (ISA) achieves deep responses in patients with multiple myeloma (MM), often resulting in measurable residual disease...Treatment with the anti-CD38 therapeutic monoclonal antibodies (mAbs) daratumumab (DARA) and isatuximab (ISA) achieves deep responses in patients with multiple myeloma (MM), often resulting in measurable residual disease (MRD) negativity. CD38 is one of the key surface markers used for flow cytometric MRD assessment in MM; however, DARA is known to interfere with CD38 detection by conventional anti-CD38 mAbs. The impact of ISA on CD38 detection remains unclear. This study aimed to develop optimized methods for accurate detection of CD38 on MM cells by flow cytometry. The anti-CD38-variable heavy chain of heavy chain (VHH) Ab from the JK36 clone enabled clearer detection of surface CD38 on DARA-treated MM cells compared with the anti-CD38 multi-epitope (ME) Abs and anti-CD38 mAbs (T16 and HB7 clones). In contrast, in ISA-treated MM cells, the anti-CD38 mAbs demonstrated superior CD38 detection compared with the anti-CD38 ME Ab and anti-CD38 VHH Ab. These trends were confirmed in primary bone marrow samples from MM patients treated with anti-CD38 therapeutic mAbs. These findings underscore the importance of selecting appropriate anti-CD38 Abs based on treatment history to ensure accurate flow cytometric evaluation of MM cells in patients treated with DARA or ISA.
Shimizu Y, Takagi S, Higuchi M
… +14 more, Kuno M, Watanabe O, Yamaguchi K, Kageyama K, Taya Y, Kaji D, Nishida A, Yamamoto H, Araoka H, Asano-Mori Y, Yamamoto G, Wake A, Taniguchi S, Uchida N
Int J Hematol
· 2026 May · PMID 41973298
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Late-onset sinusoidal obstruction syndrome (SOS) after allogeneic hematopoietic cell transplantation remains difficult to diagnose and treat. We retrospectively analyzed 14 umbilical cord blood transplant recipients who...Late-onset sinusoidal obstruction syndrome (SOS) after allogeneic hematopoietic cell transplantation remains difficult to diagnose and treat. We retrospectively analyzed 14 umbilical cord blood transplant recipients who developed late-onset SOS and received defibrotide at Toranomon Hospital between 2019 and 2021. All patients presented with very severe SOS accompanied by multiorgan failure. The cumulative incidence of complete remission was 35.7% at one year after initiation of defibrotide therapy. Overall survival was 57.1% at day 100 and 35.7% at two years after SOS diagnosis. Patients with anicteric SOS tended to have better survival than those with icteric disease. Defibrotide was generally well tolerated, with only two grade ≥ 3 bleeding events. Despite the small sample size and retrospective design, these findings suggest that Defibrotide may provide clinical benefit in patients with late-onset SOS following umbilical cord blood transplantation.
The adoption of posttransplant cyclophosphamide (PTCy) as graft-versus-host disease prophylaxis has reduced non-relapse mortality in allogeneic hematopoietic cell transplantation (allo-HCT) by overcoming the barrier of H...The adoption of posttransplant cyclophosphamide (PTCy) as graft-versus-host disease prophylaxis has reduced non-relapse mortality in allogeneic hematopoietic cell transplantation (allo-HCT) by overcoming the barrier of HLA disparity. Allo-HCT from an HLA-haploidentical-related donor with PTCy (PTCy-haplo) has become a feasible allo-HCT platform. Even in the PTCy era, allo-HCT from an HLA-matched related donor (MRD) has achieved the highest overall survival. However, the optimal donor choice when an MRD is unavailable remains a subject of debate. We discuss outcomes of PTCy-haplo compared with alternative donor sources, such as HLA-matched unrelated donors, HLA-mismatched unrelated donors, and cord blood, and propose a provisional donor selection matrix that combines HLA matching with clinical urgency. In clinical practice, even when multiple donor candidates are available, it is rare to find one with all favorable prognostic factors, including donor age, CD34 cell dose, HLA-related factors, anti-HLA antibodies, donor sex, cytomegalovirus serostatus, and donor coordination period. Therefore, it is crucial to select the most suitable donor for each case rather than aiming for a perfect match. Further efforts should focus not only on identifying new prognostic factors but also on developing improved donor selection algorithms that account for the hierarchy among factors and integrate them effectively.
OBJECTIVE: Measurable residual disease (MRD) is a key prognostic factor for outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia. To enhance predictive...OBJECTIVE: Measurable residual disease (MRD) is a key prognostic factor for outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia. To enhance predictive performance, we developed a combined MRD assessment method that integrates the proportion of residual leukemic cells of ten-color multicolor flow cytometry (MFC) with peripheral blood WT1 mRNA expression. METHODS: Forty-six patients with acute myeloid leukemia who underwent allo-HSCT at our institution between October 2013 and December 2019 were enrolled. We prospectively analyzed the prognostic impact of ten-color MFC, peripheral blood WT1 mRNA, and combined MRD assessment before transplantation. RESULTS: Both ten-color MFC-based MRD and peripheral blood WT1 mRNA levels above predefined thresholds were significantly associated with an increased risk of relapse after allo-HSCT. However, the results of the multivariate and ROC analyses suggest that ten-color MFC may be a stronger predictor than WT1 mRNA. Moreover, adding peripheral blood WT1 mRNA to ten-color MFC-based MRD reduced the predictive accuracy compared with MFC alone.
CAR T cell therapy has demonstrated remarkable efficacy in treating haematological malignancies, including B-cell lymphomas, B-cell leukaemias, and multiple myeloma. CAR T cell therapy for acute myeloid leukaemia (AML) i...CAR T cell therapy has demonstrated remarkable efficacy in treating haematological malignancies, including B-cell lymphomas, B-cell leukaemias, and multiple myeloma. CAR T cell therapy for acute myeloid leukaemia (AML) is also urgently needed. One of the major challenges is identifying AML-specific antigens, since many potential candidates (e.g. CD33, CD123, CLL-1, CD70, TIM-3 and FLT3) are also expressed on normal haematopoietic progenitors. This can lead to 'on-target/off-tumour' toxicity and bone marrow aplasia. CAR NK cell therapy for AML shows promise as a lower-toxicity, off-the-shelf alternative. NK cells have a lower inherent risk of GVHD and may cause milder CRS/ICANS. In this review, we will describe the current status of CAR T/NK cell development for AML. We will also introduce a new CAR T-cell or NK-cell therapy that targets mismatched HLA-DRB1 in patients with AML who have relapsed following an allogeneic haematopoietic stem cell transplant.
Int J Hematol
· 2026 Jun · PMID 41928036
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OBJECTIVE: This systematic review and meta-analysis compared the efficacy and safety of anti-CD38-containing quadruplet and triplet regimens in transplant-ineligible patients with newly diagnosed multiple myeloma (TIE-ND...OBJECTIVE: This systematic review and meta-analysis compared the efficacy and safety of anti-CD38-containing quadruplet and triplet regimens in transplant-ineligible patients with newly diagnosed multiple myeloma (TIE-NDMM). METHODS: A comprehensive literature search was conducted across PubMed, Embase, and Cochrane databases up to April 30, 2025. Randomized controlled trials (RCTs) comparing anti-CD38-based quadruplet and triplet regimens were analysed for outcomes including efficacy and toxicity. RESULTS: Six RCTs with 2089 patients were included. Quadruplet regimens yielded significantly greater PFS (HR 0.49, 95% CI: 0.39-0.61; P < 0.00001, I = 56%) and OS (HR 0.64, 95% CI: 0.44-0.93; P = 0.02, I = 70%) than triplet regimens. The addition of anti-CD38 increased the rates of MRD negativity (RR 1.95, 95% CI: 1.32-2.89, P = 0.0008, I = 89%) and sustained MRD negativity at ≥ 12 months (RR 2.70, 95% CI: 1.54-4/75, P = 0.0005, I = 80%), despite a slight increase in severe adverse events (RR 1.16, 95% CI: 1.05-1.30, P = 0.006, I = 17%) and grade 3/4 infections (RR 1.36, 95% CI: 1.14-1.6, P = 0.0004, I = 0%). CONCLUSION: Anti-CD38-based quadruplet regimens are superior to triplet regimens for non-frail TIE-NDMM patients, improving key efficacy outcomes with manageable safety concerns.