Review
Immunology
Stefan Forster, Ramin Radpour, Adrian F. Ochsenbein
Summary: Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells in the bone marrow. The interaction between myeloma cells and the tumor microenvironment (TME) plays a crucial role in MM progression. Understanding the molecular mechanisms that drive MM and therapy resistance is essential for developing successful therapies and preventing MM recurrence. This review summarizes key mechanisms and emerging therapies in MM, including autocrine signaling, interactions with TME, and drug-resistance mechanisms.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Aleksander Salomon-Perzynski, Joanna Barankiewicz, Marcin Machnicki, Irena Misiewicz-Krzeminska, Michal Pawlak, Sylwia Radomska, Agnieszka Krzywdzinska, Aleksandra Bluszcz, Piotr Stawinski, Malgorzata Rydzanicz, Natalia Jakacka, Iwona Solarska, Katarzyna Borg, Zofia Spyra-Gorny, Tomasz Szpila, Bartosz Pula, Sebastian Grosicki, Tomasz Stoklosa, Rafal Ploski, Ewa Lech-Maranda, Jana Jakubikova, Krzysztof Jamroziak
Summary: Tracking genetic changes during multiple myeloma progression reveals different patterns of mutation evolution, with mutation loss pathway associated with better treatment response. Many druggable genes are mutated, even in heavily pre-treated patients. Redefining R-ISS at relapse is clinically valuable.
Review
Medicine, General & Internal
Aleksander Salomon-Perzynski, Krzysztof Jamroziak, Eliza Glodkowska-Mrowka
Summary: Plasma cell dyscrasias are a heterogeneous group of diseases characterized by expansion of bone marrow plasma cells. Malignant transformation depends on a sequence of well-defined disease stages and requires development of multiple driver lesions, leading to genetically complex tumors that are difficult to treat. Understanding the mechanisms underlying tumor evolution and identifying mutations driving this evolution are crucial for effective treatment and disease control.
Article
Biochemistry & Molecular Biology
Yuanzheng Liang, Haiyan He, Weida Wang, Henan Wang, Shaowen Mo, Ruiying Fu, Xindi Liu, Qiong Song, Zhongjun Xia, Liang Wang
Summary: This study establishes a global cell ecological landscape of bone marrow in multiple myeloma (MM) patients using single-cell RNA sequencing and single-molecule long-read genome sequencing data. The findings reveal the interaction between malignant clonal evolution pattern and tumor microenvironment in MM.
Article
Oncology
Sarah Sandmann, Katharina Karsch, Peter Bartel, Rita Exeler, Tobias J. J. Brix, Elias K. K. Mai, Julian Varghese, Georg Lenz, Cyrus Khandanpour
Summary: In multiple myeloma, clonal evolution is associated with disease progression and treatment response.
FRONTIERS IN ONCOLOGY
(2022)
Review
Oncology
Kazuhito Suzuki, Kaichi Nishiwaki, Shingo Yano
Summary: Multiple myeloma is an incurable hematological malignancy due to acquired drug resistance. Microenvironment and clonal evolution contribute to the development of de novo and acquired drug resistance in myeloma cells. Treatment with proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and autologous stem cell transplantation has improved prognosis by enhancing the bone marrow microenvironment. Initial treatment is crucial in addressing both types of drug resistance and should include a combination of these agents. This review highlights the importance of anti-myeloma agents in targeting the microenvironment and clonal evolution to overcome drug resistance.
Article
Oncology
Akanksha Farswan, Lingaraja Jena, Gurvinder Kaur, Anubha Gupta, Ritu Gupta, Lata Rani, Atul Sharma, Lalit Kumar
Summary: The study revealed the presence of evolving clonal heterogeneity in multiple myeloma, with some patients showing branching evolution and varying numbers of clonal genotypes during progression from diagnosis.
AMERICAN JOURNAL OF CANCER RESEARCH
(2021)
Article
Cell Biology
Jiadai Xu, Yue Wang, Zheng Wei, Jingli Zhuang, Jing Li, Yifeng Sun, Liang Ren, Yawen Wang, Panpan Li, Shiyang Gu, Yian Zhang, Jifeng Jiang, Chen Chen, Yu Zhang, Peng Liu
Summary: This study investigated the clonal structure evolution and potential regulatory networks in relapsed/refractory multiple myeloma (RRMM) patients undergoing multiline therapies. Through genomic sequencing, the researchers observed dynamic changes in the genome and identified factors influencing disease progression. They found that mutant-allele tumor heterogeneity and tumor mutation burden exhibited different trends during the course of the disease. Additionally, somatic single nucleotide variants that disappeared after previous treatment reappeared in later stages. Chromosomal instability and homologous recombination deficiency scores increased during disease progression. The study also deciphered the gene regulatory networks of multiple myeloma cells. Overall, the findings provide insights into the understanding of RRMM and identify a potential driver gene, RUNX3.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Hematology
Erica K. Barnell, Zachary L. Skidmore, Kenneth F. Newcomer, Monique Chavez, Katie M. Campbell, Kelsy C. Cotto, Nicholas C. Spies, Marianna B. Ruzinova, Tianjiao Wang, Brooj Abro, Friederike Kreisel, Bijal A. Parikh, Eric J. Duncavage, John L. Frater, Yi-Shan Lee, Anjum Hassan, Justin A. King, Daniel R. Kohnen, Mark A. Fiala, John S. Welch, Geoffrey L. Uy, Kiran Vij, Ravi Vij, Malachi Griffith, Obi L. Griffith, Lukas D. Wartma
Summary: In patients with multiple myeloma treated with lenalidomide, the development of B-cell acute lymphoblastic leukemia (B-ALL) is observed. However, there is no shared mutational overlap between the two malignancies, suggesting that B-ALL arises from a separate population of cells likely caused by a TP53 mutation. The presence of TP53 variants in rare cells at the initiation of lenalidomide treatment increases the risk of B-ALL development.
Article
Transplantation
Seung Min Song, Junseok Jeon, Hye Ryoun Jang, Kihyun Kim, Wooseong Huh, Yoon-Goo Kim, Jung Eun Lee
Summary: This study investigated the incidence and risk factors of acute kidney injury (AKI) and tumor lysis syndrome (TLS) in patients with multiple myeloma (MM) after bortezomib-based chemotherapy. The results showed that the incidence of AKI and TLS was 17% and 13% respectively, with some overlap between the two. Lower estimated glomerular filtration rate (eGFR), lower serum albumin level, renal amyloidosis, and use of acyclovir during bortezomib treatment were predictors of AKI. Beta-2-microglobulin level and absence of high-risk chromosome abnormalities were associated with higher risk of TLS.
NEPHROLOGY DIALYSIS TRANSPLANTATION
(2023)
Article
Hematology
Yu Jia Shen, Yuji Mishima, Jiantao Shi, Romanos Sklavenitis-Pistofidis, Robert A. Redd, Michele Moschetta, Salomon Manier, Aldo M. Roccaro, Antonio Sacco, Yu-Tzu Tai, Francois Mercier, Yawara Kawano, Nang Kham Su, Brianna Berrios, John G. Doench, David E. Root, Franziska Michor, David T. Scadden, Irene M. Ghobrial
Summary: Clonal evolution plays a key role in tumor progression, dissemination, and relapse in multiple myeloma (MM). By developing a clone-tracking system, researchers studied clonal behavior in the bone marrow microenvironment, identifying specific clones able to adapt and colonize distant sites. RNA sequencing revealed a progression signature in MM tumor cells, leading to the prediction of 28 master regulators, with HMGA1 and PA2G4 validated as key players in MM progression and dissemination, impacting cell functions like proliferation, migration, and adhesion. This study successfully replicates key characteristics of human MM disease progression and suggests potential therapeutic targets.
Article
Oncology
Oren Pasvolsky, Denai R. Milton, Mikael Rauf, Sassine Ghanem, Adeel Masood, Ali H. Mohamedi, Mark R. Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Guilin Tang, Hans C. Lee, Krina K. Patel, Partow Kebriaei, Sheeba K. Thomas, Donna M. Weber, Robert Z. Orlowski, Katy Rezvani, Richard Champlin, Elizabeth J. Shpall, Pei Lin, Muzaffar H. Qazilbash
Summary: A retrospective analysis showed that the presence and degree of clonal plasma cells (CPC) in the autograft were highly predictive of inferior progression free survival (PFS) and overall survival (OS) in multiple myeloma (MM) patients undergoing autologous hematopoietic stem cell transplantation (autoHCT).
BLOOD CANCER JOURNAL
(2023)
Article
Multidisciplinary Sciences
Agoston Gyula Szabo, Tobias Wirenfeldt Klausen, Mette Boegh Levring, Birgitte Preiss, Carsten Helleberg, Marie Fredslund Breinholt, Emil Hermansen, Lise Mette Rahbek Gjerdrum, Soren Thorgaard Bonlokke, Katrine Nielsen, Eigil Kjeldsen, Katrine Fladeland Iversen, Elena Manuela Teodorescu, Marveh Dokhi, Eva Kurt, Casper Strandholdt, Mette Klarskov Andersen, Annette Juul Vangsted
Summary: Real-world outcomes of Danish patients with multiple myeloma treated with daratumumab were worse compared to clinical trial results. Best outcomes were achieved with daratumumab in combination with IMiDs and in early lines of therapy. Patients with high-risk chromosomal abnormalities had worse outcomes, while patients with amp1q had similar outcomes to standard-risk patients.
Article
Hematology
Lauren C. Peres, Christelle M. Colin-Leitzinger, Mingxiang Teng, Julie Dutil, Raghunandan R. Alugubelli, Gabriel DeAvila, Jamie K. Teer, Dongliang Du, Qianxing Mo, Erin M. Siegel, Oliver A. Hampton, Melissa Alsina, Jason Brayer, Brandon Blue, Rachid Baz, Ariosto S. Silva, Taiga Nishihori, Kenneth H. Shain, Nancy Gillis
Summary: This study investigated the demographic, clinical, and molecular features of multiple myeloma (MM) patients of different races and ethnicities. The study found differences in age of onset, time to hematopoietic cell transplant, overall survival, tumor mutations, and tumor gene expression among the different racial and ethnic groups. These findings provide insight into the mechanisms driving clinical disparities in MM patients and highlight the importance of considering race and ethnicity in the study and treatment of MM.
Article
Oncology
J. Chen, F. Facchinetti, F. Braye, A. A. Yurchenko, L. Bigot, S. Ponce, D. Planchard, A. Gazzah, S. Nikolaev, S. Michiels, D. Vasseur, L. Lacroix, L. Tselikas, C. Nobre, K. A. Olaussen, F. Andre, J. Y. Scoazec, F. Barlesi, J. C. Soria, Y. Loriot, B. Besse, L. Friboulet
Summary: Distinct molecular driver alterations coexist with initial EGFR mutations in single cancer cells, highlighting the heterogeneity of tumors. Combining targeted treatments for these two driver alterations can achieve clinical benefit.
ANNALS OF ONCOLOGY
(2022)
Letter
Oncology
Loredana Pettine, Marta Bortolotti, Bruno Fattizzo, Matteo C. Da Via, Dario Consonni, Alessandra Pompa, Niccolo Bolli, Luca Baldini
HEMATOLOGICAL ONCOLOGY
(2023)
Article
Hematology
Nicholas Stong, Maria Ortiz-Estevez, Fadi Towfic, Mehmet Samur, Amit Agarwal, Jill Corre, Erin Flynt, Nikhil Munshi, Herve Avet-Loiseau, Anjan Thakurta
Summary: Although t(4;14) translocation is considered high risk in NDMM, only a minority of patients with t(4;14) have poor outcomes. We conducted a large-scale WGS and RNA sequencing analysis on t(4;14) and non-t(4;14) NDMM patients, and identified biomarkers associated with poor outcome, including translocation breakpoints in the NSD2 gene and expression of IgH-NSD2 fusion transcripts. The location of DNA breakpoints also significantly impacts overall survival.
Article
Oncology
Larissa Haertle, Santiago Barrio, Umair Munawar, Seungbin Han, Xiang Zhou, Michal Simicek, Cornelia Vogt, Marietta Truger, Rafael Alonso Fernandez, Maximilian Steinhardt, Julia Weingart, Renata Snaurova, Silvia Nerreter, Eva Teufel, Andoni Garitano-Trojaola, Matteo Da Via, Yanira Ruiz-Heredia, Andreas Rosenwald, Niccolo Bolli, Roman Hajek, Peter Raab, Marc S. Raab, Niels Weinhold, Claudia Haferlach, Thomas Haaf, Joaquin Martinez-Lopez, Hermann Einsele, Leo Rasche, K. Martin Kortuem
Summary: This study found that multiple myeloma cells acquire PSMD5 promoter hypermethylation under the selective pressure of proteasome inhibitor treatment, leading to the silencing of PSMD5 gene expression. This mechanism increases the cell's proteolytic capacity and contributes to proteasome inhibitor tolerance in multiple myeloma.
CLINICAL CANCER RESEARCH
(2023)
Article
Hematology
Elisa Taiana, Cecilia Bandini, Vanessa Katia Favasuli, Domenica Ronchetti, Ilaria Silvestris, Noemi Puccio, Katia Todoerti, Silvia Erratico, Domenica Giannandrea, Niccolo Bolli, Nicola Amodio, Alessia Ciarrocchi, Raffaella Chiaramonte, Yvan Torrente, Roberto Piva, Antonino Neri
Summary: Long non-coding RNA NEAT1 is deregulated in multiple myeloma patients and its silencing negatively affects MM cell proliferation and viability, indicating a role in DNA damage repair. NEAT1 overexpression provides oncogenic and prosurvival advantages, especially in stressful conditions like nutrient starvation or hypoxia. NEAT1 is involved in various DNA damage repair processes through the regulation of essential PS proteins and the molecular axis of ATM and DNA-PK kinase proteins.
Article
Hematology
Benjamin Diamond, Bachisio Ziccheddu, Kylee Maclachlan, Justin Taylor, Eileen Boyle, Juan Arango Ossa, Jacob Jahn, Maurizio Affer, Tulasigeri M. Totiger, David Coffey, Namrata Chandhok, Justin Watts, Luisa Cimmino, Sydney X. Lu, Niccolo Bolli, Kelly Bolton, Heather Landau, Jae H. Park, Karuna Ganesh, Andrew McPherson, Mikkael A. Sekeres, Alexander Lesokhin, David J. Chung, Yanming Zhang, Caleb Ho, Mikhail Roshal, Jeffrey Tyner, Stephen Nimer, Elli Papaemmanuil, Saad Usmani, Gareth Morgan, Ola Landgren, Francesco Maura
Summary: Through genomic sequencing of 39 therapy-related myeloid malignancies, it was discovered that chemotherapy can accelerate the evolution of cancer cells by inducing mutations and DNA damage. Preleukemic clones (clonal hematopoiesis, CH) that exist before chemotherapy can acquire complex events and genomic drivers after chemotherapy, leading to the development of therapy-related myeloid neoplasms.
Article
Biochemistry & Molecular Biology
Antonio Matera, Alessio Marella, Akihiro Maeda, Matteo C. Da Via, Francesca Lazzaroni, Sonia Fabris, Stefania Pioggia, Laura Porretti, Federico Colombo, Federica Torricelli, Antonino Neri, Elisa Taiana, Giuseppina Fabbiano, Valentina Traini, Elisa Genuardi, Daniela Drandi, Niccolo Bolli, Marta Lionetti
Summary: Multiple myeloma (MM) has a heterogeneous genetic background, making it difficult to track. However, each MM patient's malignant plasma cells share unique V(D)J rearranged sequences, which can serve as ideal disease biomarkers. By using single-cell RNA sequencing, the dominant clonotype in each sample can be easily identified, and clonal productive rearrangements can be accurately detected. This method may be used to track rare clonal cells and lay the foundation for functional single-cell analysis of minimal residual disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Hematology
Daniele Cattaneo, Cristina Bucelli, Alfredo Marchetti, Marta Lionetti, Elisa Fermo, Valentina Bellani, Claudio De Magistris, Akihiro Maeda, Alessio Marella, Massimo Primignani, Dario Consonni, Umberto Gianelli, Antonino Neri, Luca Baldini, Niccolo Bolli, Alessandra Iurlo
Summary: In this study, we analyzed clinical and molecular data of 58 MPN-SVT patients using NGS. Different subtypes of MPN were identified, with PV and ET being the most common. JAK2V617F was the predominant mutation, while additional mutations in genes such as TET2 and DNMT3A were also observed. Leukemic evolution was associated with a higher number of co-mutations, including high-risk lesions. However, the presence of additional somatic mutations did not affect fibrotic progression, SVT recurrence, thrombo-hemorrhagic complications, or death. The findings highlight the importance of NGS analysis in MPN-related SVT management, aiding in diagnosis and potentially impacting prognosis and treatment strategies.
ANNALS OF HEMATOLOGY
(2023)
Article
Oncology
Elisabetta Sauta, Marie Robin, Matteo Bersanelli, Erica Travaglino, Manja Meggendorfer, Lin-Pierre Zhao, Juan Carlos Caballero Berrocal, Claudia Sala, Giulia Maggioni, Massimo Bernardi, Carmen Di Grazia, Luca Vago, Giulia Rivoli, Lorenza Borin, Saverio D'Amico, Cristina Astrid Tentori, Marta Ubezio, Alessia Campagna, Antonio Russo, Daniele Mannina, Luca Lanino, Patrizia Chiusolo, Luisa Giaccone, Maria Teresa Voso, Marta Riva, Esther Natalie Oliva, Matteo Zampini, Elena Riva, Olivier Nibourel, Marilena Bicchieri, Niccolo' Bolli, Alessandro Rambaldi, Francesco Passamonti, Victor Savevski, Armando Santoro, Ulrich Germing, Shahram Kordasti, Valeria Santini, Maria Diez-Campelo, Guillermo Sanz, Francesc Sole, Wolfgang Kern, Uwe Platzbecker, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Gastone Castellani, Matteo Giovanni Della Porta
Summary: The study validates the effectiveness of the Molecular International Prognostic Scoring System (IPSS-M) in predicting clinical outcomes of patients with myelodysplastic syndromes (MDS). IPSS-M improves the prognostic discrimination of the Revised International Prognostic Scoring System (IPSS-R) and enhances the accuracy of selecting candidates for hematopoietic stem cell transplantation (HSCT).
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Oncology
Maria Moscvin, Christine Ivy Liacos, Tianzeng Chen, Foteini Theodorakakou, Despina Fotiou, Shahrier Hossain, Sean Rowell, Houry Leblebjian, Eileen Regan, Peter Czarnecki, Filippo Bagnoli, Niccolo' Bolli, Paul Richardson, Helmut G. Rennke, Meletios A. Dimopoulos, Efstathios Kastritis, Giada Bianchi
Summary: This study found that germline mutations in the complement alternative pathway may predispose multiple myeloma patients receiving carfilzomib treatment to thrombotic microangiopathy (TMA). The presence of deletions in complement Factor H genes was found at a higher frequency in MM patients with carfilzomib-associated TMA compared to the general population and matched controls. Screening for complement mutations may be indicated to properly counsel patients about TMA risk with carfilzomib use.
BLOOD CANCER JOURNAL
(2023)
Letter
Oncology
Somayya Noori, Charissa Wijnands, Pieter Langerhorst, Vincent Bonifay, Christoph Stingl, Cyrille Touzeau, Jill Corre, Aurore Perrot, Philippe Moreau, Helene Caillon, Theo M. Luider, Thomas Dejoie, Joannes F. M. Jacobs, Martijn M. van Duijn
BLOOD CANCER JOURNAL
(2023)
Article
Hematology
Mohamad Mohty, Herve Avet-Loiseau, Florent Malard, Jean-Luc Harousseau
Summary: Multiple myeloma is an incurable disease with high relapse rates. Deeper and more sustainable responses have been shown to improve outcomes and potentially lead to a cure. Current definitions of disease response are suboptimal, and the aim should be to measure measurable residual disease negativity. Advanced techniques have allowed the detection of a single myeloma cell among a million healthy cells.
Letter
Hematology
Mehmet Kemal Samur, Anil Aktas Samur, Jill Corre, Romain Lannes, Parth Shah, Kenneth Anderson, Herve Avet-Loiseau, Nikhil Munshi
Article
Biochemistry & Molecular Biology
Natalia Platonova, Elisa Lazzari, Michela Colombo, Monica Falleni, Delfina Tosi, Domenica Giannandrea, Valentina Citro, Lavinia Casati, Domenica Ronchetti, Niccolo Bolli, Antonino Neri, Federica Torricelli, Leslie A. Crews, Catriona H. M. Jamieson, Raffaella Chiaramonte
Summary: The NOTCH ligands JAG1 and JAG2 have been linked to multiple myeloma (MM) cell proliferation, drug resistance, self-renewal, and communication with the tumor microenvironment. Targeting JAG1/2 shows potential as a therapeutic approach for MM. Silencing JAG1 and JAG2 leads to reduced tumor burden in a MM xenograft model, and their protein expression is correlated with the presence of MM cells in patients' bone marrow. Furthermore, JAG2 gene expression level serves as a predictive biomarker for overall survival and progression-free survival in MM patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)