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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
Maintenance lenalidomide in newly diagnosed transplant eligible and non-eligible myeloma patients; profiling second primary malignancies in 4358 patients treated in the Myeloma XI Trial
Jones, John R; Cairns, David A; Menzies, Tom; Pawlyn, Charlotte; Davies, Faith E; Sigsworth, Rachel; Brioli, Annamaria; Jenner, Matthew W; Kaiser, Martin F; Olivier, Catherine; Reed, Molly; Drayson, Mark T; Owen, Roger G; Boyd, Kevin D; Cook, Gordon; Morgan, Gareth J; Jackson, Graham H; ,
BACKGROUND/UNASSIGNED:Early trials of long-term lenalidomide use reported an increased incidence of second primary malignancy (SPM), including acute myeloid leukaemia and myelodysplastic syndrome. Later, meta-analysis suggested the link to be secondary to lenalidomide in combination with melphalan. METHODS/UNASSIGNED:Myeloma XI is a large, phase III randomised trial in-which lenalidomide was used at induction and maintenance, in transplant eligible (TE) and non-eligible (TNE) newly diagnosed patients (NCT01554852). Here we present an analysis of SPM incidence and profile the SPM type to determine the impact of autologous stem cell transplantation (ASCT) and lenalidomide exposure in 4358 patients treated on study. Data collection took place from the start of the trial in May 2010, to May 2019, as per the protocol timeline. The Median follow-up following maintenance randomisation was 54.5 and 46.1 months for TE and TNE patients, respectively. FINDINGS/UNASSIGNED:In the TE pathway, the overall SPM incidence was 7.7% in lenalidomide maintenance patients compared to 3.2% in those being observed (p = 0.006). Although the TNE lenalidomide maintenance patients had the greatest SPM incidence (15.4%), this was not statistically significant when compared to the observed patients (10%, p = 0.10).The SPM incidence was higher in patients who received lenalidomide at induction and maintenance (double exposure), when compared to those treated with lenalidomide at one time point (single exposure). Again, this was most marked in TNE patients where the overall SPM incidence was 16.9% in double exposed patients, compared to 11.7% in single exposed patients, and 11.2% in patients who did not receive lenalidomide (p = 0.04). This is likely an effect of treatment duration, with the median number of cycles being 27 in the TNE double exposed patients, vs 6 in the single exposure patients.Haematological SPMs were uncommon, diagnosed in 50 patients (incidence 1.1%). The majority of cases were diagnosed in TE patients treated with lenalidomide maintenance (n = 25, incidence 2.8%), suggesting a possible link with melphalan. Non-melanoma skin cancer incidence was highest in patients receiving lenalidomide maintenance, particularly in TNE patients, where squamous cell carcinoma and basal cell carcinoma were diagnosed in 5.5% and 2.6% of patients, respectively. The incidence of most solid tumour types was higher in lenalidomide maintenance patients.Mortality due to progressive myeloma was reduced in patients receiving lenalidomide maintenance, noted to be 16.6% compared 22.6% in those observed in TE patients and 32.7% compared to 41.5% in TNE patients. SPM related mortality was low, 1.8% and 6.1% in TE and TNE lenalidomide maintenance patients, respectively, compared to 0.4% and 2.8% in those being observed. INTERPRETATION/UNASSIGNED:This provides reassurance that long-term lenalidomide treatment is safe and associated with improved outcomes in TE and TNE populations, although monitoring for SPM development should be incorporated into clinic review processes. FUNDING/UNASSIGNED:Primary financial support was from Cancer Research UK [C1298/A10410].
PMCID:10404862
PMID: 37554123
ISSN: 2589-5370
CID: 5727882
Maintenance lenalidomide in newly diagnosed transplant eligible and non-eligible myeloma patients; profiling second primary malignancies in 4358 patients treated in the Myeloma XI Trial
Jones, John R; Cairns, David A; Menzies, Tom; Pawlyn, Charlotte; Davies, Faith E; Sigsworth, Rachel; Brioli, Annamaria; Jenner, Matthew W; Kaiser, Martin F; Olivier, Catherine; Reed, Molly; Drayson, Mark T; Owen, Roger G; Boyd, Kevin D; Cook, Gordon; Morgan, Gareth J; Jackson, Graham H; ,
BACKGROUND/UNASSIGNED:Early trials of long-term lenalidomide use reported an increased incidence of second primary malignancy (SPM), including acute myeloid leukaemia and myelodysplastic syndrome. Later, meta-analysis suggested the link to be secondary to lenalidomide in combination with melphalan. METHODS/UNASSIGNED:Myeloma XI is a large, phase III randomised trial in-which lenalidomide was used at induction and maintenance, in transplant eligible (TE) and non-eligible (TNE) newly diagnosed patients (NCT01554852). Here we present an analysis of SPM incidence and profile the SPM type to determine the impact of autologous stem cell transplantation (ASCT) and lenalidomide exposure in 4358 patients treated on study. Data collection took place from the start of the trial in May 2010, to May 2019, as per the protocol timeline. The Median follow-up following maintenance randomisation was 54.5 and 46.1 months for TE and TNE patients, respectively. FINDINGS/UNASSIGNED:In the TE pathway, the overall SPM incidence was 7.7% in lenalidomide maintenance patients compared to 3.2% in those being observed (p = 0.006). Although the TNE lenalidomide maintenance patients had the greatest SPM incidence (15.4%), this was not statistically significant when compared to the observed patients (10%, p = 0.10).The SPM incidence was higher in patients who received lenalidomide at induction and maintenance (double exposure), when compared to those treated with lenalidomide at one time point (single exposure). Again, this was most marked in TNE patients where the overall SPM incidence was 16.9% in double exposed patients, compared to 11.7% in single exposed patients, and 11.2% in patients who did not receive lenalidomide (p = 0.04). This is likely an effect of treatment duration, with the median number of cycles being 27 in the TNE double exposed patients, vs 6 in the single exposure patients.Haematological SPMs were uncommon, diagnosed in 50 patients (incidence 1.1%). The majority of cases were diagnosed in TE patients treated with lenalidomide maintenance (n = 25, incidence 2.8%), suggesting a possible link with melphalan. Non-melanoma skin cancer incidence was highest in patients receiving lenalidomide maintenance, particularly in TNE patients, where squamous cell carcinoma and basal cell carcinoma were diagnosed in 5.5% and 2.6% of patients, respectively. The incidence of most solid tumour types was higher in lenalidomide maintenance patients.Mortality due to progressive myeloma was reduced in patients receiving lenalidomide maintenance, noted to be 16.6% compared 22.6% in those observed in TE patients and 32.7% compared to 41.5% in TNE patients. SPM related mortality was low, 1.8% and 6.1% in TE and TNE lenalidomide maintenance patients, respectively, compared to 0.4% and 2.8% in those being observed. INTERPRETATION/UNASSIGNED:This provides reassurance that long-term lenalidomide treatment is safe and associated with improved outcomes in TE and TNE populations, although monitoring for SPM development should be incorporated into clinic review processes. FUNDING/UNASSIGNED:Primary financial support was from Cancer Research UK [C1298/A10410].
PMCID:10404862
PMID: 37554123
ISSN: 2589-5370
CID: 5727892
Tracking the Evolution of Therapy-Related Myeloid Neoplasms Using Chemotherapy Signatures
Diamond, Benjamin T; Ziccheddu, Bachisio; Maclachlan, Kylee H; Taylor, Justin; Boyle, Eileen Mary; Arango Ossa, Juan Esteban; Jahn, Thomas Jacob; Affer, Maurizio; Totiger, Tulasigeri M; Coffey, David G; Chandhok, Namrata; Watts, Justin M; Cimmino, Luisa; Lu, Sydney X; Bolli, Niccolo; Bolton, Kelly L; Landau, Heather J; Park, Jae H; Ganesh, Karuna; McPherson, Andrew; Sekeres, Mikkael A; Lesokhin, Alexander M; Chung, David J; Zhang, Yanming; Ho, Caleb; Roshal, Mikhail; Tyner, Jeffrey W; Nimer, Stephen D; Papaemmanuil, Elli; Usmani, Saad Z; Morgan, Gareth J; Landgren, Ola; Maura, Francesco
Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Pre-leukemic clones (i.e., clonal hematopoiesis; CH) are detectable years before the development of these aggressive malignancies, though the genomic events leading to transformation and expansion are not well-defined. Here, leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of pre-chemotherapy samples, we reconstruct the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy is revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan are hypermutated and enriched for complex structural variants (i.e., chromothripsis) while neoplasms with non-mutagenic chemotherapy exposures are genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to a discrete clinical exposure in each patient's life, we estimate that several complex events and genomic drivers are acquired after chemotherapy is administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes melphalan exposure and is selected following reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA-damage. Overall, we reveal a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select pre-existing CH, but also promote the acquisition of recurrent genomic drivers.
PMID: 36626250
ISSN: 1528-0020
CID: 5434332
Optimizing the value of lenalidomide maintenance by genetic profiling - an analysis of 556 Myeloma XI trial patients
Panopoulou, Aikaterini; Cairns, David A; Holroyd, Amy Elizabeth; Nichols, Isabel; Cray, Nikita; Pawlyn, Charlotte; Cook, Gordon; Drayson, Mark T; Boyd, Kevin D; Davies, Faith E; Jenner, Matthew W; Morgan, Gareth J; Owen, Roger G; Houlston, Richard S; Jackson, Graham H; Kaiser, Martin F
Prediction of individual patient benefit from lenalidomide (Len) maintenance post autologous transplant (ASCT) remains challenging. We investigated here extended molecular profiling for outcome prediction in NCRI Myeloma XI (MyXI) trial patients. MyXI patients randomized to Len maintenance or observation post-ASCT were genetically profiled for t(4;14), t(14;16), t(14;20), del(1p), gain(1q) and del(17p) and co-occurrence of risk markers computed. PFS, PFS2 and OS were calculated from maintenance randomization, and groups compared using Cox proportional hazards regression. 556 MyXI patients, 17% with double hit MM (≥2 risk markers), 32% with single hit (1 risk marker) and 51% without risk marker, were analyzed. Single hit MM derived the highest PFS benefit from Len maintenance, specifically isolated del(1p), del(17p) and t(4;14), with approximately 40-fold (HR 0.02; 95% CI: 0.002-0.24; P=0.0012), 10-fold (HR 0.1; 95% CI: 0.02-0.58; P=0.0095) and 7-fold (HR 0.14; 95% CI: 0.04-0.45; P=0.0009) reduced risk of progression or death (PFS) compared to observation, respectively. This benefit translated into improved PFS2 HR 0.27 (95% CI: 0.13-0.54; P=0.0002) and OS HR 0.41 (95% CI: 0.18-0.93; P=0.03) for this group of patients over observation; median PFS was 10.9 vs. 57.3 months for observation vs. Len maintenance. Patients with isolated gain(1q) derived no benefit, and double hit MM limited benefit, regardless or risk lesions involved, from Len maintenance. Extended genetic profiling identifies patients deriving exceptional benefit from Len maintenance and should be considered for newly diagnosed patients to support management discussions along their treatment pathway.
PMID: 36564045
ISSN: 1528-0020
CID: 5418912
The addition of vorinostat to lenalidomide maintenance for patients with newly diagnosed multiple myeloma of all ages: results from 'Myeloma XI', a multicentre, open-label, randomised, phase III trial
Jenner, Matthew W; Pawlyn, Charlotte; Davies, Faith E; Menzies, Tom; Hockaday, Anna; Olivier, Catherine; Jones, John R; Karunanithi, Kamuraj; Lindsay, Jindriska; Kishore, Bhuvan; Cook, Gordon; Drayson, Mark T; Kaiser, Martin F; Owen, Roger G; Gregory, Walter; Cairns, David A; Morgan, Gareth J; Jackson, Graham H
Lenalidomide is an effective maintenance agent for patients with myeloma, prolonging first remission and, in transplant eligible patients, improving overall survival (OS) compared to observation. The 'Myeloma XI' trial, for newly diagnosed patients, aimed to evaluate whether the addition of the histone deacetylase inhibitor vorinostat to the lenalidomide maintenance backbone could improve outcomes further. Patients included in this analysis were randomised to maintenance therapy with lenalidomide alone (10 mg/day on days 1-21 of each 28-day cycle), or in combination with vorinostat (300 mg/day on day 1-7 and 15-21 of each 28-day cycle) with treatment continuing until unacceptable toxicity or progressive disease. There was no significant difference in median progression-free survival between those receiving lenalidomide-vorinostat or lenalidomide alone, 34 and 40 months respectively (hazard ratio [HR] 1.18, 95% confidence interval [CI] 0.96-1.44, p = 0.109). There was also no significant difference in median OS, not estimable and 75 months respectively (HR 0.99, 95% CI 0.76-1.29, p = 0.929). Subgroup analysis demonstrated no statistically significant heterogeneity in outcomes. Combination lenalidomide-vorinostat appeared to be poorly tolerated with more dose modifications, fewer cycles of maintenance therapy delivered and higher rates of discontinuation due to toxicity than lenalidomide alone. The trial did not meet its primary end-point, there was no benefit from the addition of vorinostat to lenalidomide maintenance.
PMID: 36541152
ISSN: 1365-2141
CID: 5394992
A phase I/II open-label study of molibresib for the treatment of relapsed/refractory hematologic malignancies
Dawson, Mark A; Borthakur, Gautam; Huntly, Brian; Karadimitris, Anastasios; Alegre, Adrian; Chaidos, Aristeidis; Vogl, Dan T; Pollyea, Daniel A; Davies, Faith E; Morgan, Gareth J; Glass, Jacob; Kamdar, Manali; Mateos Manteca, Maria-Victoria; Tovar, Natalia; Yeh, Paul; GarcÃa Delgado, Regina; Basheer, Faisal; Marando, Ludovica; Gallipoli, Paolo; Wyce, Anastasia; Krishnatry, Anu Shilpa; Barbash, Olena; Bakirtzi, Evi; Ferron-Brady, Geraldine; Karpinich, Natalie O; McCabe, Michael T; Foley, Shawn W; Horner, Thierry; Dhar, Arindam; Kremer, Brandon E; Dickinson, Michael
PURPOSE/OBJECTIVE:Molibresib is a selective, small molecule inhibitor of the BET protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851). EXPERIMENTAL DESIGN/METHODS:Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS; as well as AML evolved from antecedent MDS) or cutaneous T cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR). RESULTS:There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg QD (for MDS) and 60 mg QD (for CTCL) were selected. Most common Grade 3+ AEs included thrombocytopenia (37%), anemia (15%) and febrile neutropenia (15%). Six patients achieved complete responses (three in Part 1 [two AML, one NHL], three in Part 2 [MDS]), and seven patients achieved partial responses (six in Part 1 [four AML, two NHL], one in Part 2 [MDS]). The ORRs for Part 1, Part 2, and the total study population were 10% (95% CI: 4.8-18.7), 25% (95% CI: 7.3-52.4), and 13% (95% CI: 6.9-20.6), respectively. CONCLUSIONS:While anti-tumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted.
PMID: 36350312
ISSN: 1557-3265
CID: 5357332