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MGP Panel is a comprehensive targeted genomics panel for molecular profiling of multiple myeloma patients

Sudha, Parvathi; Ahsan, Aarif; Ashby, Cody; Kausar, Tasneem; Khera, Akhil; Kazeroun, Mohammad; Hsu, Chih-Chao; Wang, Lin; Fitzsimons, Evelyn; Salminen, Outi; Blaney, Patrick; Czader, Magdalena; Williams, Jonathan; Abu Zaid, Mohammad I; Ansari-Pour, Naser; Yong, Kwee L; van Rhee, Frits; Pierceall, William E; Morgan, Gareth J; Flynt, Erin; Gooding, Sarah; Abonour, Rafat; Ramasamy, Karthik; Thakurta, Anjan; Walker, Brian A
PURPOSE/OBJECTIVE:We designed a comprehensive multiple myeloma (MM) targeted sequencing panel to identify common genomic abnormalities in a single assay and validated it against known standards. EXPERIMENTAL DESIGN/METHODS:The panel comprised 228 genes/exons for mutations, 6 regions for translocations, and 56 regions for copy number abnormalities (CNAs). Toward panel validation, targeted sequencing was conducted on 233 patient samples and further validated using clinical fluorescence in situ hybridization (FISH) (translocations), multiplex ligation probe analysis (MLPA) (CNAs), whole genome sequencing (WGS) (CNAs, mutations, translocations) or droplet digital PCR (ddPCR) of known standards (mutations). RESULTS:Canonical IgH translocations were detected in 43.2% of patients by sequencing, and aligned with FISH except for one patient. CNAs determined by sequencing and MLPA for 22 regions were comparable in 103 samples and concordance between platforms was R2=0.969. VAFs for 74 mutations were compared between sequencing and ddPCR with concordance of R2=0.9849. CONCLUSIONS:In summary, we have developed a targeted sequencing panel that is as robust or superior to FISH and WGS. This molecular panel is cost effective, comprehensive, clinically actionable and can be routinely deployed to assist risk stratification at diagnosis or post-treatment to guide sequencing of therapies.
PMID: 35522533
ISSN: 1557-3265
CID: 5216472

Minimal Residual Disease After Autologous Stem-Cell Transplant for Patients With Myeloma: Prognostic Significance and the Impact of Lenalidomide Maintenance and Molecular Risk

de Tute, Ruth M; Pawlyn, Charlotte; Cairns, David A; Davies, Faith E; Menzies, Tom; Rawstron, Andy; Jones, John R; Hockaday, Anna; Henderson, Rowena; Cook, Gordon; Drayson, Mark T; Jenner, Matthew W; Kaiser, Martin F; Gregory, Walter M; Morgan, Gareth J; Jackson, Graham H; Owen, Roger G
PURPOSE/OBJECTIVE:Minimal residual disease (MRD) can predict outcomes in patients with multiple myeloma, but limited data are available on the prognostic impact of MRD when assessed at serial time points in the context of maintenance therapy after autologous stem-cell transplant (ASCT) and the interaction between MRD and molecular risk. METHODS:Data from a large phase III trial (Myeloma XI) were examined to determine the relationship between MRD status, progression-free survival (PFS), and overall survival (OS) in post-ASCT patients randomly assigned to lenalidomide maintenance or no maintenance at 3 months after ASCT. MRD status was assessed by flow cytometry (median sensitivity 0.004%) before maintenance random assignment (ASCT + 3) and 6 months later (ASCT + 9). RESULTS:= .0077). The findings were very similar when restricted to patients with complete response/near complete response. Sustained MRD negativity from ASCT + 3 to ASCT + 9 or the conversion to MRD negativity by ASCT + 9 was associated with the longest PFS/OS. Patients randomly assigned to lenalidomide maintenance were more likely to convert from being MRD-positive before maintenance random assignment to MRD-negative 6 months later (lenalidomide 30%, observation 17%). High-risk molecular features had an adverse effect on PFS and OS even for those patients achieving MRD-negative status. On multivariable analysis of MRD status, maintenance therapy and molecular risk maintained prognostic impact at both ASCT + 3 and ASCT + 9. CONCLUSION/CONCLUSIONS:In patients with multiple myeloma, MRD status at both ASCT + 3 and ASCT + 9 is a powerful predictor of PFS and OS.
PMID: 35377708
ISSN: 1527-7755
CID: 5204792

Ixazomib with cyclophosphamide and dexamethasone in relapsed or refractory myeloma: MUKeight phase II randomised controlled trial results

Auner, Holger W; Brown, Sarah R; Walker, Katrina; Kendall, Jessica; Dawkins, Bryony; Meads, David; Morgan, Gareth J; Kaiser, Martin F; Cook, Mark; Roberts, Sadie; Parrish, Christopher; Cook, Gordon
The all-oral combination of ixazomib, cyclophosphamide, and dexamethasone (ICD) is well tolerated and effective in newly diagnosed and relapsed multiple myeloma (MM). We carried out MUKeight, a randomised, controlled, open, parallel group, multi-centre phase II trial in patients with relapsed MM after prior treatment with thalidomide, lenalidomide, and a proteasome inhibitor (ISRCTN58227268), with the primary objective to test whether ICD has improved clinical activity compared to cyclophosphamide and dexamethasone (CD) in terms of progression-free survival (PFS). Between January 2016 and December 2018, 112 participants were randomised between ICD (n = 58) and CD (n = 54) in 33 UK centres. Patients had a median age of 70 years and had received a median of four prior lines of therapy. 74% were classed as frail. Median PFS in the ICD arm was 5.6 months, compared to 6.7 months with CD (hazard ratio (HR) = 1.21, 80% CI 0.9-1.6, p = 0.3634). Response rates and overall survival were not significantly different between ICD and CD. Dose modifications or omissions, and serious adverse events (SAEs), occurred more often in the ICD arm. In summary, the addition of ixazomib to cyclophosphamide and dexamethasone did not improve outcomes in the comparatively frail patients enroled in the MUKeight trial.
PMID: 35365598
ISSN: 2044-5385
CID: 5201462

Impact of Etiological Cytogenetic Abnormalities on the Depth of Immunoparesis and Survival in Newly Diagnosed Multiple Myeloma

Caro, Jessica; Cairns, David; Menzies, Tom; Boyle, Eileen; Pawlyn, Charlotte; Cook, Gordon; Kaiser, Martin; Walker, Brian A; Owen, Roger; Jackson, Graham H; Morgan, Gareth J; Heaney, Jennifer; Drayson, Mark T; Davies, Faith E
INTRODUCTION/BACKGROUND/BACKGROUND:Immunoparesis, or low polyclonal immunoglobulin levels, is commonly seen in multiple myeloma (MM), and is associated with poor clinical outcomes. MM can be divided into subgroups with distinct biology and outcomes based on etiologic cytogenetic abnormalities. These include hyperdiploidy and translocations of t(11;14), t(4;14), t(14;16), and t(14;20), with the latter 3 associated with high-risk disease. We hypothesized that the different etiologic cytogenetic abnormalities drive bone marrow microenvironmental changes, resulting in different degrees of immunoparesis, and subgroup-dependent effects on clinical outcomes. MATERIALS AND METHODS/METHODS:We performed a retrospective review of 985 newly diagnosed patients enrolled in the Myeloma IX and XI trials. Immunoglobulin levels, survival outcomes, and infection rates were evaluated for each cytogenetic subgroup. RESULTS:A significant proportion of patients with high-risk t(4;14), t(14;16), or t(14;20) had suppressed polyclonal immunoglobulins compared to standard-risk patients with hyperdiploidy or t(11;14). The clinical impact of immunoparesis depended on the cytogenetic subgroup, with the degree of IgM suppression effecting progression-free and overall survival only in the hyperdiploid subgroup. There was no significant difference in infection rates amongst the etiologic subgroups. CONCLUSION/CONCLUSIONS:These findings demonstrate that the etiologic cytogenetic subgroup influences the degree and clinical impact of immunoparesis. This suggests that the underlying cytogenetic abnormality affects remodeling of the bone marrow plasma cell niche, resulting in suppressed normal plasma cell function, and low immunoglobulin levels.
PMID: 34876373
ISSN: 2152-2669
CID: 5110212

Chromothripsis as a pathogenic driver of multiple myeloma

Maura, Francesco; Boyle, Eileen M; Rustad, Even H; Ashby, Cody; Kaminetzky, David; Bruno, Benedetto; Braunstein, Marc; Bauer, Michael; Blaney, Patrick; Wang, Yubao; Ghamlouch, Hussein; Williams, Louis; Stoeckle, James; Davies, Faith E; Walker, Brian A; Maclachlan, Kylee; Diamond, Ben; Landgren, Ola; Morgan, Gareth J
Analysis of the genetic basis for multiple myeloma (MM) has informed many of our current concepts of the biology that underlies disease initiation and progression. Studying these events in further detail is predicted to deliver important insights into its pathogenesis, prognosis and treatment. Information from whole genome sequencing of structural variation is revealing the role of these events as drivers of MM. In particular, we discuss how the insights we have gained from studying chromothripsis suggest that it can be used to provide information on disease initiation and that, as a consequence, it can be used for the clinical classification of myeloma precursor diseases allowing for early intervention and prognostic determination. For newly diagnosed MM, the integration of information on the presence of chromothripsis has the potential to significantly enhance current risk prediction strategies and to better characterize patients with high-risk disease biology. In this article we summarize the genetic basis for MM and the role played by chromothripsis as a critical pathogenic factor active at early disease phases.
PMID: 33958284
ISSN: 1096-3634
CID: 4866742

Inflammation and infection in plasma cell disorders: how pathogens shape the fate of patients

Caro, Jessica; Braunstein, Marc; Williams, Louis; Bruno, Benedetto; Kaminetzky, David; Siegel, Ariel; Razzo, Beatrice; Alfandari, Serge; Morgan, Gareth J; Davies, Faith E; Boyle, Eileen M
The role of infection and chronic inflammation in plasma cell disorders (PCD) has been well-described. Despite not being a diagnostic criterion, infection is a common complication of most PCD and represents a significant cause of morbidity and mortality in this population. As immune-based therapeutic agents are being increasingly used in multiple myeloma, it is important to recognize their impact on the epidemiology of infections and to identify preventive measures to improve outcomes. This review outlines the multiple factors attributed to the high infectious risk in PCD (e.g. the underlying disease status, patient age and comorbidities, and myeloma-directed treatment), with the aim of highlighting future prophylactic and preventive strategies that could be implemented in the clinic. Beyond this, infection and pathogens as an entity are believed to also influence disease biology from initiation to response to treatment and progression through a complex interplay involving pathogen exposure, chronic inflammation, and immune response. This review will outline both the direct and indirect role played by oncogenic pathogens in PCD, highlight the requirement for large-scale studies to decipher the precise implication of the microbiome and direct pathogens in the natural history of myeloma and its precursor disease states, and understand how, in turn, pathogens shape plasma cell biology.
PMID: 35110727
ISSN: 1476-5551
CID: 5153682

Redefining Non-measurable Multiple Myeloma Using Mass Spectrometry

Giles, Hannah Victoria; Cook, Mark A; Drayson, Mark Trehane; Cook, Gordon; Wright, Nicola Jane; North, Simon John; Harding, Stephen; Cairns, David A; Hockaday, Anna; Kaiser, Martin F; Moss, Paul; Davies, Faith E; Morgan, Gareth J; Jackson, Graham; Pratt, Guy
PMID: 34871382
ISSN: 1528-0020
CID: 5110122

Plasma cells expression from smouldering myeloma to myeloma reveals the importance of the PRC2 complex, cell cycle progression, and the divergent evolutionary pathways within the different molecular subgroups

Boyle, Eileen M; Rosenthal, Adam; Ghamlouch, Hussein; Wang, Yan; Farmer, Phillip; Rutherford, Michael; Ashby, Cody; Bauer, Michael; Johnson, Sarah K; Wardell, Christopher P; Wang, Yubao; Hoering, Antje; Schinke, Carolina; Thanendrarajan, Sharmilan; Zangari, Maurizio; Barlogie, Bart; Dhodapkar, Madhav V; Davies, Faith E; Morgan, Gareth J; van Rhee, Frits; Walker, Brian A
Sequencing studies have shed some light on the pathogenesis of progression from smouldering multiple myeloma (SMM) and symptomatic multiple myeloma (MM). Given the scarcity of smouldering samples, little data are available to determine which translational programmes are dysregulated and whether the mechanisms of progression are uniform across the main molecular subgroups. In this work, we investigated 223 SMM and 1348 MM samples from the University of Arkansas for Medical Sciences (UAMS) for which we had gene expression profiling (GEP). Patients were analysed by TC-7 subgroup for gene expression changes between SMM and MM. Among the commonly dysregulated genes in each subgroup, PHF19 and EZH2 highlight the importance of the PRC2.1 complex. We show that subgroup specific differences exist even at the SMM stage of disease with different biological features driving progression within each TC molecular subgroup. These data suggest that MMSET SMM has already transformed, but that the other precursor diseases are distinct clinical entities from their symptomatic counterpart.
PMID: 34365473
ISSN: 1476-5551
CID: 5006072

Improving prognostic assignment in older adults with multiple myeloma using acquired genetic features, clonal hemopoiesis and telomere length

Boyle, Eileen M; Williams, Louis; Blaney, Patrick; Ashby, Cody; Bauer, Michael; Walker, Brian A; Ghamlouch, Hussein; Choi, Jinyoung; Perrial, Emeline; Wang, Yubao; Caro, Jessica; Stoeckle, James H; Arbini, Arnaldo; Kaminetzky, David; Braunstein, Marc; Bruno, Benedetto; Razzo, Beatrice; Diamond, Benjamin; Maclachlan, Kylee; Maura, Francesco; Landgren, Ola; Litke, Rachel; Fegan, Christopher D; Keats, Johnathan; Auclair, Daniel; Davies, Faith E; Morgan, Gareth J
PMID: 34148053
ISSN: 1476-5551
CID: 4918002

The impact of bortezomib-based induction in newly diagnosed multiple myeloma with chromosome 1q21 gain

Tang, Hoi Ki Karen; Fung, Chi Yeung; Morgan, Gareth J; Kumar, Shaji; Siu, Lisa; Ip, Ho Wan Alvin; Yip, Sze Fai; Lau, Ka Ngai Harry; Lau, Chi Kuen; Lee, Harold; Leung, Kwan Hung; Kho, Bonnie; Wong, Howard; Ngai, Cheong; Hwang, Yu Yan; Sim, Joycelyn; Kwong, Yok Lam; Chim, Chor Sang
Introduction/UNASSIGNED:(4;14) and del(17p) in multiple myeloma (MM), but its impact on gain 1q (+1q) is unknown. Methods/UNASSIGNED:(4;14), and +1q. Presence of +1q was defined as the presence of at least three copies of 1q21 at the cut off level of 20% of bone marrow plasma cells. Results/UNASSIGNED: = 0.000069). Conclusion/UNASSIGNED:+1q is an adverse factor for OS in MM uniformly treated with bortezomib-based induction but was partially mitigated by ASCT. A risk scoring system comprising +1q, LDH, high-risk FISH, and ISS is a potential tool for risk stratification in MM.
PMID: 35465644
ISSN: 2040-6207
CID: 5217272