Leukemia最新文献

{"title":"Targeting ABCD1-ACOX1-MET/IGF1R axis suppresses multiple myeloma","authors":"Zhannan Han, Zhibo Yan, Zhehan Ma, Yihui Wang, Maja Beus, Junqi Lu, Loren B. Weidenhammer, Kiran Lakhani, Jingyun Lee, John D. Civils, Cristina M. Furdui, Liang Liu, Jian Wu, Yubin Kang, Erhard Bieberich, Lawrence H. Boise, Mikhail A. Nikiforov","doi":"10.1038/s41375-025-02522-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02522-9","url":null,"abstract":"<p>Multiple myeloma (MM) remains an incurable hematological malignancy that necessitates the identification of novel therapeutic strategies. Here, we report that intracellular levels of very long chain fatty acids (VLCFAs) control the cytotoxicity of MM chemotherapeutic agents. Inhibition of VLCFA biosynthesis reduced cell death in MM cells caused by the proteasome inhibitor, bortezomib. Conversely, inhibition of VLCFA degradation via suppression of peroxisomal acyl-CoA oxidase 1 (ACOX1) increased the cytotoxicity of bortezomib, its next-generation analog, carfilzomib, and the immunomodulatory agent lenalidomide. Furthermore, treatment with an orally available ACOX1 inhibitor cooperated with bortezomib in suppressing the growth of bortezomib-resistant MM xenografts in mice. Increased VLCFA levels caused by genetic or pharmacological inhibition of VLCFA degradation reduced the activity of two major kinases involved in MM pathogenesis, MET proto-oncogene (MET) and insulin-like growth factor 1 receptor (IGF1R). Mechanistically, inhibition of ACOX1 promoted the accumulation of VLCFA-containing cerebrosides, altered MET and IGF1R interaction with a cerebroside analog, and selectively inhibited the association of these kinases with the plasma membrane signaling platforms, importantly, without disrupting the platforms’ integrity. Our study revealed a specific metabolic vulnerability of MM cells and identified a targetable axis linking VLCFA metabolism to the regulation of MET and IGF1R activity.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"26 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma","authors":"Luciano J. Costa, Rahul Banerjee, Hira Mian, Katja Weisel, Susan Bal, Benjamin A. Derman, Maung M. Htut, Chandramouli Nagarajan, Cesar Rodriguez, Joshua Richter, Matthew J. Frigault, Jing C. Ye, Niels W. C. J. van de Donk, Peter M. Voorhees, Benjamin Puliafito, Nizar Bahlis, Rakesh Popat, Wee Joo Chng, P. Joy Ho, Gurbakhash Kaur, Prashant Kapoor, Juan Du, Fredrik Schjesvold, Jesus Berdeja, Hermann Einsele, Adam D. Cohen, Joseph Mikhael, Yelak Biru, S. Vincent Rajkumar, Yi Lin, Thomas G. Martin, Ajai Chari","doi":"10.1038/s41375-024-02482-6","DOIUrl":"https://doi.org/10.1038/s41375-024-02482-6","url":null,"abstract":"<p>T-cell redirecting therapy (TCRT), specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) represent a remarkable advance in the treatment of multiple myeloma (MM). There are several products available around the world and several more in development targeting primarily B-cell maturation antigen (BCMA) and G protein–coupled receptor class C group 5 member D (GRPC5D). The relatively rapid availability of multiple immunotherapies brings the necessity to understand how a certain agent may affect the safety and efficacy of a subsequent immunotherapy so MM physicians and patients can aim at optimal sequential use of these therapies. The International Myeloma Working Group conveyed panel of experts to review patient and disease-related factors affecting efficacy and safety of immunotherapy, summarize existing information on sequencing therapy and provide a series of core recommendations.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"58 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probability of remission with reinduction with 7+3 versus high-dose cytarabine: analysis of SWOG trial S1203","authors":"Megan Othus, Guillermo Garcia-Manero, Frederick R. Appelbaum, Harry P. Erba, Eliana Dietrich, Suravi Raychaudhuri, Jacob Appelbaum, Elihu Estey, Mary-Elizabeth Percival","doi":"10.1038/s41375-024-02512-3","DOIUrl":"https://doi.org/10.1038/s41375-024-02512-3","url":null,"abstract":"&lt;p&gt;In patients with acute myeloid leukemia (AML), the goal of intensive induction chemotherapy is to induce a morphologic complete remission (with or without count recovery, CR or CRi respectively), which is strongly correlated with overall survival (OS) [1, 2]. Intensive chemotherapy is defined as the standard 7+3 regimen or regimens using cytarabine at daily doses of ≥1 g/m&lt;sup&gt;2&lt;/sup&gt;, (such as FLAG-ida, CLAG-M, or high-dose cytarabine combined with idarubicin known as IA). A common clinical question is whether patients whose disease has not achieved a CR after the first course of induction should receive a second identical course or change to a different, often investigational, regimen [3]. Because results with the latter are by definition unknown, the decision must rest on the expected results with a second course of 7+3 or a high-dose cytarabine-containing regimen. Analyzing SWOG trials S8600, S9031, S9333, and S0106, conducted in the 1980s,1990s, and 2000s, we previously reported a CR rate of 44% among 242 patients given a second course of 7+3 after failure of a first, compared to a CR rate of 48% among the 987 patients who received a first course [4]. Notably, in the most recent of these studies (S0106), though CR was still achieved in a high percentage of patients, survival was considerably longer if CR was observed after the first course [5]. In contrast to the similar rate of CR after the first or second course of 7+3 in SWOG trials, a single-center analysis by Ravandi et al. noted a CR rate of 76% with an initial high-dose cytarabine-containing course, but reported a rate of 32% in 129 patients receiving a second similar course [6]. SWOG Cancer Network trial S1203 randomized patients with untreated AML who were 60 years of age or younger among 7+3, IA, and IA + vorinostat, thereby allowing a comparison of rates of CR and CRi after 1 and 2 cycles of induction therapy in a group of patients who met the same eligibility criteria and underwent randomization. This report analyzes data from patients randomized to the 7+3 and IA arms.&lt;/p&gt;&lt;p&gt;The primary outcome of S1203 has been previously reported [7]. All patients had untreated AML and were &lt;span&gt;(le)&lt;/span&gt;60 years of age. Patients randomized to 7+3 (&lt;i&gt;n&lt;/i&gt; = 261) received 100 mg/m&lt;sup&gt;2&lt;/sup&gt; cytarabine on days 1–7 by continuous infusion and 90 mg/m&lt;sup&gt;2&lt;/sup&gt; daunorubicin on days 1–3. Patients randomized to IA (&lt;i&gt;n&lt;/i&gt; = 261) received 1500 mg/m&lt;sup&gt;2&lt;/sup&gt; cytarabine on days 1–4 by continuous infusion and 12 mg/m&lt;sup&gt;2&lt;/sup&gt; Idarubicin on days 1–3. CR and CRi were defined per contemporary consensus criteria (CR: ANC &lt;span&gt;(ge)&lt;/span&gt; 1000/mcl, platelet count &lt;span&gt;(ge)&lt;/span&gt;100,000/mcl, &lt;5% bone marrow blasts; CRi same as CR but either ANC or platelet criteria not met). Patients who did not achieve morphologic CR or CRi after the first cycle of induction were eligible for a second cycle. Patients randomized to 7+3 were to have a marrow examination at approximately day 14 and if r","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"20 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effective eradication of acute myeloid leukemia stem cells with FLT3-directed antibody-drug conjugates","authors":"Marina Able, Marc-André Kasper, Binje Vick, Jonathan Schwach, Xiang Gao, Saskia Schmitt, Belay Tizazu, Amrei Fischer, Sarah Künzl, Marit Leilich, Isabelle Mai, Philipp Ochtrop, Andreas Stengl, Mark A. R. de Geus, Michael von Bergwelt-Baildon, Dominik Schumacher, Jonas Helma, Christian P. R. Hackenberger, Katharina S. Götze, Irmela Jeremias, Heinrich Leonhardt, Michaela Feuring, Karsten Spiekermann","doi":"10.1038/s41375-024-02510-5","DOIUrl":"https://doi.org/10.1038/s41375-024-02510-5","url":null,"abstract":"<p>Refractory disease and relapse are major challenges in acute myeloid leukemia (AML) therapy attributed to survival of leukemic stem cells (LSC). To target LSCs, antibody-drug conjugates (ADCs) provide an elegant solution, combining the specificity of antibodies with highly potent payloads. We aimed to investigate if FLT3-20D9h3-ADCs delivering either the DNA-alkylator duocarmycin (DUBA) or the microtubule-toxin monomethyl auristatin F (MMAF) can eradicate quiescent LSCs. We show here that DUBA more potently kills cell-cycle arrested AML cells compared to microtubule-targeting auristatins. Due to limited stability of 20D9h3-DUBA ADC in vivo, we analyzed both ADCs in advanced in vitro stem cell assays. 20D9h3-DUBA successfully eliminated leukemic progenitors in vitro in colony-forming unit and long-term culture initiating cell assays, both in patient cells and in patient-derived xenograft (PDX) cells. Further, it completely prevented engraftment of AML PDX leukemia-initiating cells in NSG mice. 20D9h3-MMAF had a similar effect in engraftment assays, but a less prominent effect in colony assays. Both ADCs did not affect healthy stem and progenitor cells at comparable doses providing the rationale for FLT3 as therapeutic LSC target. Collectively, we show that FLT3-directed ADCs with DUBA or MMAF have potent activity against AML LSCs and represent promising candidates for further clinical development.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"15 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal weight during pregnancy and risk of childhood acute lymphoblastic leukemia in offspring","authors":"Jiaye Liu, Elham Kharazmi, Qunfeng Liang, Yafei Chen, Jan Sundquist, Kristina Sundquist, Mahdi Fallah","doi":"10.1038/s41375-025-02517-6","DOIUrl":"https://doi.org/10.1038/s41375-025-02517-6","url":null,"abstract":"<p>In addition to biological factors, maternal exposures during pregnancy can contribute to leukemogenesis in offspring. We conducted a population-based cohort study in Sweden to investigate the association between risk of acute lymphoblastic leukemia (ALL) in offspring and maternal anthropometrics during pregnancy. A total of 2,961,435 live-born singletons during 1983–2018 were followed from birth to ALL diagnosis, end of age 18, or end of 2018. 1388 children were diagnosed with ALL (55.6% boys). We observed an increased risk of ALL among daughters of overweight/obese mothers in early pregnancy [Body mass index (BMI) ≥ 25 kg/m²; Standardized incidence ratio (SIR) = 1.4, 95% CI: 1.2–1.6] compared with the risk in daughters of mothers with normal BMI. This association was not found in their sons (SIR = 1.0, 95% CI: 0.9–1.1). Similar results were found for the association between ALL and maternal BMI before delivery. We did not find an association between low or high gestational weight gain (GWG) and risk of ALL (both SIRs = 1.0) in male/female offspring. These suggest that maternal overweight/obesity are important risk factors for childhood ALL in daughters, whereas GWG is not associated with risk of ALL. Further research on this mother-daughter association may shed light on a possible sex hormone/chromosome-related etiology of ALL.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"19 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase Ib study of PRT543, an oral protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced splicing factor-mutant myeloid malignancies","authors":"Jan Philipp Bewersdorf, Xiaoli Mi, Bin Lu, Andrew Kuykendall, David Sallman, Manish Patel, Don Stevens, Alexander Philipovskiy, Grerk Sutamtewagul, Lucia Masarova, Gina Keiffer, Amit Verma, Neha Bhagwat, Min Wang, Andrew Moore, Joseph Rager, Diane Heiser, Sunhee Ro, Wan-Jen Hong, Omar Abdel-Wahab, Eytan M. Stein","doi":"10.1038/s41375-025-02515-8","DOIUrl":"https://doi.org/10.1038/s41375-025-02515-8","url":null,"abstract":"<figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"49 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting LMO2-induced autocrine FLT3 signaling to overcome chemoresistance in early T-cell precursor acute lymphoblastic leukemia","authors":"Cedric S. Tremblay, Jesslyn Saw, Feng Yan, Jacqueline A. Boyle, Ovini Amarasinghe, Shokoufeh Abdollahi, Anh N. Q. Vo, Benjamin J. Shields, Chelsea Mayoh, Hannah McCalmont, Kathryn Evans, Anna Steiner, Kevin Parsons, Matthew P. McCormack, David R. Powell, Nicholas C. Wong, Stephen M. Jane, Richard B. Lock, David J. Curtis","doi":"10.1038/s41375-024-02491-5","DOIUrl":"https://doi.org/10.1038/s41375-024-02491-5","url":null,"abstract":"<p>Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) is an immature subtype of T-cell acute lymphoblastic leukemia (T-ALL) commonly show deregulation of the LMO2-LYL1 stem cell transcription factors, activating mutations of cytokine receptor signaling, and poor early response to intensive chemotherapy. Previously, studies of the <i>Lmo2</i> transgenic mouse model of ETP-ALL identified a population of stem-like T-cell progenitors with long-term self-renewal capacity and intrinsic chemotherapy resistance linked to cellular quiescence. Here, analyses of <i>Lmo2</i> transgenic mice, patient-derived xenografts, and single-cell RNA-sequencing data from primary ETP-ALL identified a rare subpopulation of leukemic stem cells expressing high levels of the cytokine receptor FLT3. Despite a highly proliferative state, these FLT3-overexpressing cells had long-term self-renewal capacity and almost complete resistance to chemotherapy. Chromatin immunoprecipitation and assay for transposase-accessible chromatin sequencing demonstrated FLT3 and its ligand may be direct targets of the LMO2 stem-cell complex. Media conditioned by <i>Lmo2</i> transgenic thymocytes revealed an autocrine FLT3-dependent signaling loop that could be targeted by the FLT3 inhibitor gilteritinib. Consequently, gilteritinib impaired in vivo growth of ETP-ALL and improved the sensitivity to chemotherapy. Furthermore, gilteritinib enhanced response to the BCL2 inhibitor venetoclax, which may enable “chemo-free” treatment of ETP-ALL. Together, these data provide a cellular and molecular explanation for enhanced cytokine signaling in <i>LMO2</i>-driven ETP-ALL beyond activating mutations and a rationale for clinical trials of FLT3 inhibitors in ETP-ALL.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"84 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TLE4 is a repressor of the oncogenic activity of TLX3 in T-cell acute lymphoblastic leukemia","authors":"Lukas Lauwereins, Quentin Van Thillo, Sofie Demeyer, Nicole Mentens, Sarah Provost, Kris Jacobs, Olga Gielen, Lien Boogaerts, Charles E. de Bock, Guillaume Andrieu, Vahid Asnafi, Jan Cools, Alexandra Veloso","doi":"10.1038/s41375-025-02513-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02513-w","url":null,"abstract":"<p>T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disease originating from the malignant transformation of T-cell progenitors, caused by the accumulation of genetic aberrations. One-fifth of T-ALL patients are characterized by ectopic expression of the homeobox transcription factor TLX3. However, the role of TLX3 in T-ALL remains elusive, partly due to the lack of suitable study models. Strikingly, this TLX3-positive subgroup has a high frequency of FLT3 mutations, predominantly FLT3-ITD, in pediatric cases. To investigate this, we generated ex vivo cultured pro-T cells driven by the co-expression of TLX3 and FLT3-ITD, which conferred IL7 independent growth. This model allowed us to confirm that TLX3 expression and FLT3 signaling cooperate to transform T-cells and induce an oncogenic context. Data from this cell model, combined with gene expression data from TLX3 positive T-ALL cases, revealed a strong downregulation of the transcriptional repressor TLE4. Furthermore, TLE4 showed to have a repressive effect on ex vivo TLX3 T-ALL cell growth, likely caused by a partial reversal of the TLX3 transcriptional profile. In conclusion, we developed a TLX3+FLT3-ITD pro-T cell model and used it to illustrate that TLX3 directly represses TLE4 expression, which is beneficial for the oncogenic function of TLX3.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"28 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic impact of expression of CD2, CD25, and/or CD30 in/on mast cells in systemic mastocytosis: a registry study of the European Competence Network on Mastocytosis","authors":"Axel Rüfer, Henning Nilius, Olivier Hermine, Marek Niedoszytko, Joanne N. G. Oude Elberink, Patrizia Bonadonna, Khalid Shoumariyeh, Theo Gulen, Karin Hartmann, Vito Sabato, Irena Angelova-Fischer, Daniel Baffoe, Deborah Christen, Anna Belloni Fortina, Christine Breynaert, Knut Brockow, Nikolas von Bubnoff, Horia Bumbea, Paul van Daele, Michael Doubek, Ingunn Dybedal, Chiara Elena, Christos Fokoloros, Aleksandra Górska, Marc Heizmann, Madlen Jentzsch, Saskia Klein, Johannes Lübke, Mattias Mattsson, André Mulder, Jens Panse, Tanja Daniela Schug, Mariarita Sciumè, Alex Stefan, Marlena Sztormowska, Judit Várkonyi, Friederike Wortmann, Akif Selim Yavuz, Martina Sperr, Jason Gotlib, Andreas Reiter, Massimo Triggiani, Wolfgang R. Sperr, Peter Valent","doi":"10.1038/s41375-024-02504-3","DOIUrl":"https://doi.org/10.1038/s41375-024-02504-3","url":null,"abstract":"<p>Expression of CD2, CD25 and/or CD30 in extracutaneous mast cells (MC) is a minor diagnostic criterion for systemic mastocytosis (SM) in the classification of the World Health Organization and International Consensus Classification. So far, it remains unknown whether expression of these antigens on MC is of prognostic significance in SM. We performed a retrospective multi-center study of patients with SM using the data set of the registry of the European Competence Network on Mastocytosis, including 5034 patients with various MC disorders. The percentage of CD2^-, CD25⁺ and/or CD30⁺ MC was considerably lower in patients with indolent SM compared to patients with advanced SM, including aggressive SM and MC leukemia. Whereas CD25 and CD30 expression in MC could not be associated with prognosis, we found that lack of CD2 expression in MC is associated with a significantly reduced overall survival (OS) in patients with SM (<i>p</i> &lt; 0.0001). Lack of CD2 was also associated with the presence of extramedullary involvement affecting the spleen, liver, and/or lymph nodes (odds ratio 2.63 compared to SM with CD2⁺ MC). Together, lack of CD2 expression in MC is a prognostic marker and indicator of reduced OS and extramedullary disease expansion in patients with SM.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"42 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Daratumumab plus lenalidomide/dexamethasone in untreated multiple myeloma: analysis of key subgroups of the MAIA study","authors":"Philippe Moreau, Thierry Facon, Saad Z. Usmani, Nizar Bahlis, Noopur Raje, Torben Plesner, Robert Z. Orlowski, Supratik Basu, Hareth Nahi, Cyrille Hulin, Hang Quach, Hartmut Goldschmidt, Michael O’Dwyer, Aurore Perrot, Christopher P. Venner, Katja Weisel, Mourad Tiab, Margaret Macro, Laurent Frenzel, Xavier Leleu, George Wang, Huiling Pei, Maria Krevvata, Robin Carson, Fredrik Borgsten, Shaji K. Kumar","doi":"10.1038/s41375-024-02506-1","DOIUrl":"https://doi.org/10.1038/s41375-024-02506-1","url":null,"abstract":"<p>In the MAIA study (median follow-up, 56.2 months), daratumumab plus lenalidomide and dexamethasone (D-Rd) significantly improved progression-free survival (PFS) and overall survival versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). In this post hoc analysis of clinically important subgroups in MAIA (median follow-up, 64.5 months), transplant-ineligible patients with NDMM were randomized 1:1 to D-Rd or Rd. The primary endpoint was PFS; secondary endpoints included overall response rate (ORR) and measurable residual disease (MRD)–negativity rate (10^–5). PFS favored D-Rd versus Rd in most subgroups, including patients aged ≥75 years (HR, 0.59; 95% CI, 0.44–0.79), frail patients (HR, 0.64; 95% CI, 0.48–0.85), patients with high-risk cytogenetics (HR, 0.59; 95% CI, 0.44–0.80), and patients with isolated gain(1q21) (HR, 0.36; 95% CI, 0.19–0.67). ORRs, MRD-negativity rates, and sustained (≥12 months) MRD-negativity rates were higher with D-Rd versus Rd across subgroups. In patients aged ≥75 years, rates of grade 3/4 and serious treatment-emergent adverse events (TEAEs) were similar for D-Rd and Rd, but discontinuation due to TEAEs was lower for D-Rd. Results support use of D-Rd for high-risk patients, supporting D-Rd as a standard of care for transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as NCT02252172.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"75 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}