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Anthropometric traits and risk of multiple myeloma: differences by race, sex and diagnostic clinical features

Arnold, Kevin D; Ong, Krystle L; Ravi, Gayathri; Cutshall, Hannah; Purnell, Kalyn; Wessel, Meredith C; Godby, Kelly N; Bal, Susan; Giri, Smith; Rogers, Laura Q; Demark-Wahnefried, Wendy; Davies, Faith E; Costa, Luciano J; Morgan, Gareth J; Birmann, Brenda M; Brown, Elizabeth E
BACKGROUND:Obesity is an established modifiable risk factor for multiple myeloma (MM). However, associations of obesity and MM risk in Black populations, for whom obesity and MM are more common, is less clear. METHODS:Using participants enrolled in the Integrative Molecular And Genetic Epidemiology study, we evaluated the association of anthropometric traits with MM risk overall, stratified by race and sex. Among cases, we assessed the association of BMI with the presence of myeloma-defining events. RESULTS:) were more likely to present at diagnosis with low renal function (OR = 1.62, 95% CI 1.09-2.40), deletion 13q (OR = 1.73, 95% CI 1.08-2.76) and lytic lesions or compression fractures (OR = 2.39, 95% CI 0.82-7.01) and less likely to present with severe diffuse osteopenia (OR = 0.51, 95% CI 0.31-0.81). CONCLUSIONS:Findings underscore the importance of obesity as a modifiable risk factor for MM, particularly in high-risk populations, and for the clinical presentation of disease.
PMID: 38849476
ISSN: 1532-1827
CID: 5665902

1q amplification and PHF19 expressing high-risk cells are associated with relapsed/refractory multiple myeloma

Johnson, Travis S; Sudha, Parvathi; Liu, Enze; Becker, Nathan; Robertson, Sylvia; Blaney, Patrick; Morgan, Gareth; Chopra, Vivek S; Dos Santos, Cedric; Nixon, Michael; Huang, Kun; Suvannasankha, Attaya; Zaid, Mohammad Abu; Abonour, Rafat; Walker, Brian A
Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers can be identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and is already studied using RNA-seq. In this study, we generate a large (325,025 cells and 49 patients) single cell multi-omic dataset and jointly quantify ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identify an association between one plasma cell subtype with myeloma progression that we call relapsed/refractory plasma cells (RRPCs). These cells are associated with chromosome 1q alterations, TP53 mutations, and higher expression of PHF19. We also identify downstream regulation of cell cycle inhibitors in these cells, possible regulation by the transcription factor (TF) PBX1 on chromosome 1q, and determine that PHF19 may be acting primarily through this subset of cells.
PMID: 38755140
ISSN: 2041-1723
CID: 5656262

The genomic landscape of Vk*MYC myeloma highlights shared pathways of transformation between mice and humans

Maura, Francesco; Coffey, David G; Stein, Caleb K; Braggio, Esteban; Ziccheddu, Bachisio; Sharik, Meaghen E; Du, Megan T; Tafoya Alvarado, Yuliza; Shi, Chang-Xin; Zhu, Yuan Xiao; Meermeier, Erin W; Morgan, Gareth J; Landgren, Ola; Bergsagel, P Leif; Chesi, Marta
Multiple myeloma (MM) is a heterogeneous disease characterized by frequent MYC translocations. Sporadic MYC activation in the germinal center of genetically engineered Vk*MYC mice is sufficient to induce plasma cell tumors in which a variety of secondary mutations are spontaneously acquired and selected over time. Analysis of 119 Vk*MYC myeloma reveals recurrent copy number alterations, structural variations, chromothripsis, driver mutations, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) mutational activity, and a progressive decrease in immunoglobulin transcription that inversely correlates with proliferation. Moreover, we identify frequent insertional mutagenesis by endogenous retro-elements as a murine specific mechanism to activate NF-kB and IL6 signaling pathways shared with human MM. Despite the increased genomic complexity associated with progression, advanced tumors remain dependent on MYC. In summary, here we credential the Vk*MYC mouse as a unique resource to explore MM genomic evolution and describe a fully annotated collection of diverse and immortalized murine MM tumors.
PMCID:11076575
PMID: 38714690
ISSN: 2041-1723
CID: 5658362

Round Table Discussion on Optimal Clinical Trial Design in Precursor Multiple Myeloma

Ghobrial, Irene M; Gormley, Nicole; Kumar, Shaji K; Mateos, Maria-Victoria; Bergsagel, P Leif; Chesi, Marta; Dhodapkar, Madhav V; Dispenzieri, Angela; Fonseca, Rafael; Getz, Gad; Kastritis, Efstathios; Kristinsson, Sigurdur Y; Martinez-Climent, Jose Angel; Manier, Salomon; Marinac, Catherine R; Maura, Francesco; Morgan, Gareth J; Davies, Faith E; Nadeem, Omar; Nuvolone, Mario; Paiva, Bruno; O'Donnell, Elizabeth; Prosper, Felipe; Shah, Urvi A; Sklavenitis-Pistofidis, Romanos; Sperling, Adam S; Vassiliou, George S; Munshi, Nikhil C; Castle, Philip E; Anderson, Kenneth C; San Miguel, Jesus F
While the current approach to precursor hematologic conditions is to "watch and wait," this may change with the development of therapies that are safe and extend survival or delay the onset of symptomatic disease. The goal of future therapies in precursor hematologic conditions is to improve survival and prevent or delay the development of symptomatic disease while maximizing safety. Clinical trial considerations in this field include identifying an appropriate at-risk population, safety assessments, dose selection, primary and secondary trial endpoints including surrogate endpoints, control arms, and quality-of-life metrics, all of which may enable more precise benefit-risk assessment.
PMCID:11061588
PMID: 38441243
ISSN: 2643-3249
CID: 5657122

Genomic Classification and Individualized Prognosis in Multiple Myeloma

Maura, Francesco; Rajanna, Arjun Raj; Ziccheddu, Bachisio; Poos, Alexandra M; Derkach, Andriy; Maclachlan, Kylee; Durante, Michael; Diamond, Benjamin; Papadimitriou, Marios; Davies, Faith; Boyle, Eileen M; Walker, Brian; Hultcrantz, Malin; Silva, Ariosto; Hampton, Oliver; Teer, Jamie K; Siegel, Erin M; Bolli, Niccolò; Jackson, Graham H; Kaiser, Martin; Pawlyn, Charlotte; Cook, Gordon; Kazandjian, Dickran; Stein, Caleb; Chesi, Marta; Bergsagel, Leif; Mai, Elias K; Goldschmidt, Hartmut; Weisel, Katja C; Fenk, Roland; Raab, Marc S; Van Rhee, Fritz; Usmani, Saad; Shain, Kenneth H; Weinhold, Niels; Morgan, Gareth; Landgren, Ola
PURPOSE/OBJECTIVE:Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years. METHODS:To decipher and predict the molecular and clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available clinical, genomic, and therapeutic data. RESULTS:translocations, APOBEC mutational signatures, and copy-number signatures (reflecting the complex structural variant chromothripsis). IRMMa accuracy and superiority compared with other prognostic models were validated on 256 patients enrolled in the GMMG-HD6 (ClinicalTrials.gov identifier: NCT02495922) clinical trial. Individualized patient risks were significantly affected across the 12 genomic groups by different treatment strategies (ie, treatment variance), which was used to identify patients for whom HDM-ASCT is particularly effective versus patients for whom the impact is limited. CONCLUSION/CONCLUSIONS:Integrating clinical, demographic, genomic, and therapeutic data, to our knowledge, we have developed the first individualized risk-prediction model enabling personally tailored therapeutic decisions for patients with NDMM.
PMID: 38194610
ISSN: 1527-7755
CID: 5655472

Approach to High-Risk Multiple Myeloma

Chen, Xiaoyi; Varma, Gaurav; Davies, Faith; Morgan, Gareth
Improving the outcome of high-risk myeloma (HRMM) is a key therapeutic aim for the next decade. To achieve this aim, it is necessary to understand in detail the genetic drivers underlying this clinical behavior and to target its biology therapeutically. Advances have already been made, with a focus on consensus guidance and the application of novel immunotherapeutic approaches. Cases of HRMM are likely to have impaired prognosis even with novel strategies. However, if disease eradication and minimal disease states are achieved, then cure may be possible.
PMID: 38195306
ISSN: 1558-1977
CID: 5628622

Progression free survival of myeloma patients who become IFE-negative correlates with the detection of residual monoclonal free light chain (FLC) by mass spectrometry

Giles, H V; Drayson, M T; Kishore, B; Pawlyn, C; Kaiser, M; Cook, G; de Tute, R; Owen, R G; Cairns, D; Menzies, T; Davies, F E; Morgan, G J; Pratt, G; Jackson, G H
Deeper responses are associated with improved survival in patients being treated for myeloma. However, the sensitivity of the current blood-based assays is limited. Historical studies suggested that normalisation of the serum free light chain (FLC) ratio in patients who were negative by immunofixation electrophoresis (IFE) was associated with improved outcomes. However, recently this has been called into question. Mass spectrometry (MS)-based FLC assessments may offer a superior methodology for the detection of monoclonal FLC due to greater sensitivity. To test this hypothesis, all available samples from patients who were IFE negative after treatment with carfilzomib and lenalidomide-based induction and autologous stem cell transplantation (ASCT) in the Myeloma XI trial underwent FLC-MS testing. FLC-MS response assessments from post-induction, day+100 post-ASCT and six months post-maintenance randomisation were compared to serum FLC assay results. Almost 40% of patients had discordant results and 28.7% of patients with a normal FLC ratio had residual monoclonal FLC detectable by FLC-MS. FLC-MS positivity was associated with reduced progression-free survival (PFS) but an abnormal FLC ratio was not. This study demonstrates that FLC-MS provides a superior methodology for the detection of residual monoclonal FLC with FLC-MS positivity identifying IFE-negative patients who are at higher risk of early progression.
PMCID:10948753
PMID: 38499538
ISSN: 2044-5385
CID: 5640222

Impact of Rare Structural Variant Events in Newly Diagnosed Multiple Myeloma

Chojnacka, Monika; Diamond, Benjamin; Ziccheddu, Bachisio; Rustad, Even; Maclachlan, Kylee; Papadimitriou, Marios; Boyle, Eileen M; Blaney, Patrick; Usmani, Saad; Morgan, Gareth; Landgren, Ola; Maura, Francesco
PURPOSE/UNASSIGNED:Whole-genome sequencing (WGS) of patients with newly diagnosed multiple myeloma (NDMM) has shown recurrent structural variant (SV) involvement in distinct regions of the genome (i.e., hotspots) and causing recurrent copy-number alterations. Together with canonical immunoglobulin translocations, these SVs are recognized as "recurrent SVs." More than half of SVs were not involved in recurrent events. The significance of these "rare SVs" has not been previously examined. EXPERIMENTAL DESIGN/UNASSIGNED:In this study, we utilize 752 WGS and 591 RNA sequencing data from patients with NDMM to determine the role of rare SVs in myeloma pathogenesis. RESULTS/UNASSIGNED:Ninety-four percent of patients harbored at least one rare SV event. Rare SVs showed an SV class-specific enrichment within genes and superenhancers associated with outlier gene expression. Furthermore, known myeloma driver genes recurrently impacted by point mutations were dysregulated by rare SVs. CONCLUSIONS/UNASSIGNED:Overall, we demonstrate the association of rare SVs with aberrant gene expression supporting a potential driver role in myeloma pathogenesis.
PMID: 37939148
ISSN: 1557-3265
CID: 5627902

Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens

Maura, Francesco; Boyle, Eileen M; Coffey, David; Maclachlan, Kylee; Gagler, Dylan; Diamond, Benjamin; Ghamlouch, Hussein; Blaney, Patrick; Ziccheddu, Bachisio; Cirrincione, Anthony; Chojnacka, Monika; Wang, Yubao; Siegel, Ariel; Hoffman, James E; Kazandjian, Dickran; Hassoun, Hani; Guzman, Emily; Mailankody, Sham; Shah, Urvi A; Tan, Carlyn; Hultcrantz, Malin; Scordo, Michael; Shah, Gunjan L; Landau, Heather; Chung, David J; Giralt, Sergio; Zhang, Yanming; Arbini, Arnaldo; Gao, Qi; Roshal, Mikhail; Dogan, Ahmet; Lesokhin, Alexander M; Davies, Faith E; Usmani, Saad Z; Korde, Neha; Morgan, Gareth J; Landgren, Ola
Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab ( NCT03290950 ), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.
PMID: 37945755
ISSN: 2662-1347
CID: 5612852

Multiomic mapping of acquired chromosome 1 copy number and structural variants to identify therapeutic vulnerabilities in multiple myeloma

Boyle, Eileen M; Blaney, Patrick; Stoeckle, James H; Wang, Yubao; Ghamlouch, Hussein; Gagler, Dylan; Braunstein, Marc; Williams, Louis; Tenenbaum, Avital; Siegel, Ariel; Chen, Xiaoyi; Varma, Gaurav; Avigan, Jason; Li, Alexander; Jinsi, Monica; Kaminetzky, David; Arbini, Arnaldo; Montes, Lydia; Corre, Jill; Rustad, Even H; Landgren, Ola; Maura, Francesco; Walker, Brian A; Bauer, Michael; Bruno, Benedetto; Tsirigos, Aristotelis; Davies, Faith E; Morgan, Gareth J
PURPOSE/OBJECTIVE:Chromosome 1 (chr1) copy number abnormalities (CNAs) and structural variants (SV) are frequent in newly diagnosed multiple myeloma (NDMM) and associate with a heterogeneous impact on outcome the drivers of which are largely unknown. EXPERIMENTAL DESIGN/METHODS:A multiomic approach comprising CRISPR, gene mapping of CNA and SV, methylation, expression, and mutational analysis was used to document the extent of chr1 molecular variants and their impact on pathway utilisation. RESULTS:We identified two distinct groups of gain(1q): focal gains associated with limited gene expression changes and a neutral prognosis, and whole-arm gains, which associate with substantial gene expression changes, complex genetics and an adverse prognosis. CRISPR identified a number of dependencies on chr1 but only limited variants associated with acquired CNAs. We identified seven regions of deletion, nine of gain, three of chromothripsis (CT) and two of templated-insertion (TI), which contain a number of potential drivers. An additional mechanism involving hypomethylation of genes at 1q may contribute to the aberrant gene expression of a number of genes. Expression changes associated with whole-arm gains were substantial and gene set enrichment analysis identified metabolic processes, apoptotic resistance, signaling via the MAPK pathway, and upregulation of transcription factors as being key drivers of the adverse prognosis associated with these variants. CONCLUSIONS:Multiple layers of genetic complexity impact the phenotype associated with CNAs on chr1 to generate its associated clinical phenotype. Whole-arm gains of 1q are the critically important prognostic group that deregulate multiple pathways, which may offer therapeutic vulnerabilities.
PMID: 37449980
ISSN: 1557-3265
CID: 5537862