Anish K. Simhal, Ross S. Firestone, Jung Hun Oh, Viswatej Avutu, Larry Norton, Malin Hultcrantz, Saad Z. Usmani, Kylee H. Maclachlan, Joseph O. Deasy
{"title":"High WEE1 expression is independently linked to poor survival in multiple myeloma","authors":"Anish K. Simhal, Ross S. Firestone, Jung Hun Oh, Viswatej Avutu, Larry Norton, Malin Hultcrantz, Saad Z. Usmani, Kylee H. Maclachlan, Joseph O. Deasy","doi":"10.1038/s41408-025-01230-y","DOIUrl":"https://doi.org/10.1038/s41408-025-01230-y","url":null,"abstract":"<p>Current prognostic scores in multiple myeloma (MM) currently rely on disease burden and a limited set of genomic alterations. Some studies have suggested gene expression panels may predict clinical outcomes, but none are presently utilized in clinical practice. The tyrosine kinase <i>WEE1</i> is a critical cell cycle regulator during the S-phase and G2M checkpoint. Abnormal <i>WEE1</i> expression has been implicated in multiple cancers including breast, ovarian, and gastric cancers, but its prognostic signal in MM has not been thoroughly reported. We, therefore, analyzed the MMRF CoMMpass dataset (<i>N</i> = 659) and identified a high-risk group (top tertile) and a low-risk group (bottom tertile) based on <i>WEE1</i> expression sorted in descending order. PFS was significantly different (<i>p</i> < 1e-9) between the groups, which was validated in two independent microarray gene expression profiling (GEP) datasets from the Total Therapy 2 (<i>N</i> = 341) and 3 (<i>N</i> = 214) trials. Our results show that <i>WEE1</i> expression is prognostic independent of known biomarkers, differentiates outcomes associated with known markers, is upregulated independently of its interacting neighbors, and is associated with dysregulated P53 pathways. This suggests that <i>WEE1</i> expression levels may have clinical utility in prognosticating outcomes in newly diagnosed MM and may support the application of <i>WEE1</i> inhibitors to MM preclinical models. Determining the causes of abnormal <i>WEE1</i> expression may uncover novel therapeutic pathways.</p>","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"31 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451473","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}
Adam S. Kittai, Ying Huang, Sarah Miller, John N. Allan, Seema A. Bhat, David A. Bond, Danielle M. Brander, John C. Byrd, Julio C. Chavez, Elise Chong, Matthew S. Davids, Alexey V. Danilov, Wei Ding, Mark R. Dowling, Kaitlyn Dvorak-Kornaus, Hannah Freedman, Paul J. Hampel, Carrie Ho, Steven R. Hwang, Prioty Islam, Nikita Malakhov, Matthew Matasar, Cecelia Miller, Zulfa Omer, Sameer A. Parikh, Erin Parry, Kari G. Rabe, Philipp W. Raess, Manoj Rai, Lindsey Roeker, Joanna Rhodes, Kerry A. Rogers, Aditi Saha, Jake Schade, Hamish W. Scott, Mazyar Shadman, Geoffrey Shouse, Alan Skarbnik, Stephen Spurgeon, Deborah M. Stephens, Meghan C. Thompson, Philip A. Thompson, Yucai Wang, Max Yano, Jennifer A. Woyach
{"title":"Outcomes of patients with Richter transformation who received no prior chemoimmunotherapy for their CLL","authors":"Adam S. Kittai, Ying Huang, Sarah Miller, John N. Allan, Seema A. Bhat, David A. Bond, Danielle M. Brander, John C. Byrd, Julio C. Chavez, Elise Chong, Matthew S. Davids, Alexey V. Danilov, Wei Ding, Mark R. Dowling, Kaitlyn Dvorak-Kornaus, Hannah Freedman, Paul J. Hampel, Carrie Ho, Steven R. Hwang, Prioty Islam, Nikita Malakhov, Matthew Matasar, Cecelia Miller, Zulfa Omer, Sameer A. Parikh, Erin Parry, Kari G. Rabe, Philipp W. Raess, Manoj Rai, Lindsey Roeker, Joanna Rhodes, Kerry A. Rogers, Aditi Saha, Jake Schade, Hamish W. Scott, Mazyar Shadman, Geoffrey Shouse, Alan Skarbnik, Stephen Spurgeon, Deborah M. Stephens, Meghan C. Thompson, Philip A. Thompson, Yucai Wang, Max Yano, Jennifer A. Woyach","doi":"10.1038/s41408-025-01236-6","DOIUrl":"https://doi.org/10.1038/s41408-025-01236-6","url":null,"abstract":"","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"15 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451471","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}
Rongtao Xue, Min Dai, Erlie Jiang, Xueying Ou, Fen Huang, Zhiping Fan, Na Xu, Chenhua Yan, Danian Nie, Xinquan Liang, Hong Chen, Jieyu Ye, Ling Jiang, Hui Liu, Hua Jin, Ren Lin, Yu Zhang, Jing Sun, Mingzhe Han, Qifa Liu, Yu Wang, Li Xuan
{"title":"Effect of pre-transplant cytoreductive therapy on the outcomes of patients with MDS or secondary AML evolving from MDS undergoing allo-HSCT: a secondary analysis of an RCT","authors":"Rongtao Xue, Min Dai, Erlie Jiang, Xueying Ou, Fen Huang, Zhiping Fan, Na Xu, Chenhua Yan, Danian Nie, Xinquan Liang, Hong Chen, Jieyu Ye, Ling Jiang, Hui Liu, Hua Jin, Ren Lin, Yu Zhang, Jing Sun, Mingzhe Han, Qifa Liu, Yu Wang, Li Xuan","doi":"10.1038/s41408-025-01233-9","DOIUrl":"https://doi.org/10.1038/s41408-025-01233-9","url":null,"abstract":"","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"51 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451474","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}
Saurabh Zanwar, Dragan Jevremovic, Prashant Kapoor, Horatiu Olteanu, Francis Buadi, Pedro Horna, Wilson Gonsalves, Gregory Otteson, Abiola Bukunmi Bolarinwa, Suzanne Hayman, Nadine Abdallah, Moritz Binder, Joselle Cook, Angela Dispenzieri, David Dingli, Morie A. Gertz, Taxiarchis Kourelis, Nelson Leung, Yi Lin, Eli Muchtar, Rahma Warsame, Amie Fonder, Miriam Hobbs, Yi Lisa Hwa, Michelle Rogers, Robert A. Kyle, S. Vincent Rajkumar, Shaji Kumar
{"title":"Clonal plasma cell proportion in the synthetic phase identifies a unique high-risk cohort in multiple myeloma","authors":"Saurabh Zanwar, Dragan Jevremovic, Prashant Kapoor, Horatiu Olteanu, Francis Buadi, Pedro Horna, Wilson Gonsalves, Gregory Otteson, Abiola Bukunmi Bolarinwa, Suzanne Hayman, Nadine Abdallah, Moritz Binder, Joselle Cook, Angela Dispenzieri, David Dingli, Morie A. Gertz, Taxiarchis Kourelis, Nelson Leung, Yi Lin, Eli Muchtar, Rahma Warsame, Amie Fonder, Miriam Hobbs, Yi Lisa Hwa, Michelle Rogers, Robert A. Kyle, S. Vincent Rajkumar, Shaji Kumar","doi":"10.1038/s41408-025-01232-w","DOIUrl":"https://doi.org/10.1038/s41408-025-01232-w","url":null,"abstract":"<p>Risk stratification models based on cytogenetics and disease burden help identify high-risk patients with newly diagnosed multiple myeloma (NDMM). However, some high-risk patients remain undetected. This study evaluated the prognostic utility of the proportion of clonal plasma cells in the S-phase of the cell cycle for NDMM. Patients with active multiple myeloma diagnosed between 01/01/2013 and 01/31/2023 who underwent S-phase assessment were included. The S-phase proportion was calculated by analyzing DNA content between G0/G1 and G2/M peaks. Among 823 patients, 16% (135) had S-phase ≥2% at diagnosis. Patients with S-phase ≥2% exhibited significantly worse median progression-free survival (PFS) of 1.4 years (95% CI: 1.2–1.9) compared to 2.9 years (95% CI: 2.6–3.3) for those with S-phase <2% (HR 1.6, <i>p</i> < 0.0001). Median overall survival (OS) was also significantly lower at 3.9 years (95% CI: 2.9–5.7) versus 9.2 years (95% CI: 7.9–not reached; HR 2.2, <i>p</i> < 0.0001). Multivariate analysis confirmed S-phase ≥2% as an independent predictor of inferior PFS (HR 1.56, <i>p</i> = 0.001) and OS (HR 2, <i>p</i> < 0.0001) after adjusting for R2-ISS risk, age, renal function, and treatment strategies. Among patients with S-phase ≥2%, 53% (68/129) experienced progression-free survival (PFS) under 18 months with upfront therapy. Elevated S-phase was associated with a 2.5-fold higher risk of progression within 18 months [OR 2.55 (95% CI: 1.7–3.7), <i>p</i> < 0.001]. Patients with elevated S-phase but no IMS-high risk had a median OS of 5.7 years (95% CI: 4.7–9.2), similar to the IMS-high risk cohort without elevated S-phase (5.4 years, 95% CI: 4–NR). Those with both elevated S-phase and IMS-high risk had significantly worse OS (3.1 years, 95% CI: 1.6–NR, <i>p</i> = 0.043). These findings suggest that S-phase ≥2% is a powerful, independent prognostic marker for NDMM.</p>","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"10 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143434915","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}
Pralay Mukhopadhyay, Hesham A. Abdullah, Joanna B. Opalinska, Prani Paka, Eric Richards, Katja Weisel, Suzanne Trudel, Maria-Victoria Mateos, Meletios Athanasios Dimopoulos, Sagar Lonial
{"title":"The clinical journey of belantamab mafodotin in relapsed or refractory multiple myeloma: lessons in drug development","authors":"Pralay Mukhopadhyay, Hesham A. Abdullah, Joanna B. Opalinska, Prani Paka, Eric Richards, Katja Weisel, Suzanne Trudel, Maria-Victoria Mateos, Meletios Athanasios Dimopoulos, Sagar Lonial","doi":"10.1038/s41408-025-01212-0","DOIUrl":"https://doi.org/10.1038/s41408-025-01212-0","url":null,"abstract":"<p>Patients with relapsed/refractory multiple myeloma (RRMM) have a poor prognosis and a need remains for novel effective therapies. Belantamab mafodotin, an anti–B-cell maturation antigen antibody-drug conjugate, was granted accelerated/conditional approval for patients with RRMM who have received at least 4 prior lines of therapy, based on response rates observed in DREAMM-1/DREAMM-2. Despite the 41% response rate and durable responses observed with belantamab mafodotin in the Phase III confirmatory DREAMM-3 trial, the marketing license for belantamab mafodotin was later withdrawn from US and European markets when the trial did not meet its primary endpoint of superiority for progression-free survival compared with pomalidomide and dexamethasone. This review reflects on key lessons arising from the clinical journey of belantamab mafodotin in RRMM. It considers how incorporating longer follow-up in DREAMM-3 may have better captured the clinical benefits of belantamab mafodotin, particularly given its multimodal, immune-related mechanism of action with responses deepening over time. A non-inferiority hypothesis may have been more appropriate rather than superiority in the context of a monotherapy versus an active doublet therapy. Further, anticipation of, and planning for, non-proportional hazards arising from response heterogeneity may have mitigated loss of statistical power. With the aim of improving the efficacy of belantamab mafodotin, other Phase III trials in the RRMM development program (DREAMM-7 and DREAMM-8) proceeded to evaluate the synergistic potential of combination regimens in earlier lines of treatment. The aim was to increase the proportion of patients responding to belantamab mafodotin (and thus the likelihood of seeing a clear separation of the progression-free survival curve versus comparator regimens). Protocol amendments reflecting DREAMM-3 learnings could also be implemented prospectively on the combinations trials to optimize the follow-up duration and mitigate risk. The wider implications of the lessons learned for clinical research in RRMM and in earlier treatment settings are discussed.</p>","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"32 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258585","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}
Cecilia Bonolo de Campos, Chantal E. McCabe, Laura A. Bruins, Daniel R. O’Brien, Sochilt Brown, Renee C. Tschumper, Cristine Allmer, Yuan Xiao Zhu, Kari G. Rabe, Sameer A. Parikh, Neil E. Kay, Huihuang Yan, James R. Cerhan, John N. Allan, Richard R. Furman, J. Brice Weinberg, Danielle M. Brander, Diane F. Jelinek, Marta Chesi, Susan L. Slager, Esteban Braggio
{"title":"Genomic characterization of chronic lymphocytic leukemia in patients of African ancestry","authors":"Cecilia Bonolo de Campos, Chantal E. McCabe, Laura A. Bruins, Daniel R. O’Brien, Sochilt Brown, Renee C. Tschumper, Cristine Allmer, Yuan Xiao Zhu, Kari G. Rabe, Sameer A. Parikh, Neil E. Kay, Huihuang Yan, James R. Cerhan, John N. Allan, Richard R. Furman, J. Brice Weinberg, Danielle M. Brander, Diane F. Jelinek, Marta Chesi, Susan L. Slager, Esteban Braggio","doi":"10.1038/s41408-024-01207-3","DOIUrl":"https://doi.org/10.1038/s41408-024-01207-3","url":null,"abstract":"<p>Despite the considerable effort to characterize the genomic landscape of chronic lymphocytic leukemia (CLL), published data have been almost exclusively derived from patients of European Ancestry (EA), with significant underrepresentation of minorities, including patients of African Ancestry (AA). To begin to address this gap, we evaluated whether differences exist in the genetic and transcriptomic features of 157 AA and 440 EA individuals diagnosed with CLL. We sequenced 59 putative driver genes and found an increased frequency of high-impact mutations in AA CLL, including genes of the DNA damage repair (DDR) pathway. Telomere erosion was also increased in AA CLL, amplifying the notion of increased genomic instability in AA CLL. Furthermore, we found transcription enrichment of the Tumor Necrosis Factor-alpha (TNFα) Signaling via NF-κB pathway in AA CLL compared to EA CLL, suggesting that tumor promoting inflammation plays an important role in AA CLL. In summary, these results suggest that genomic instability and NF-kB activation is more prevalent in AA CLL than EA CLL.</p>","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"61 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192022","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}
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