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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

Progression-Free Survival of Daratumumab Versus Bortezomib Triplet Combination With Lenalidomide and Dexamethasone in Transplant Ineligible Patients With Newly Diagnosed Multiple Myeloma: TAURUS Chart Review Study

Gordan, Lucio Navarro; Tan, Carlyn Rose; Vescio, Robert; Ye, Jing Christine; Schinke, Carolina; Medhekar, Rohan; Fu, Alex Z; Lafeuille, Marie-Hélène; Thompson-Leduc, Philippe; Khare, Vipin; Reitan, John; Milkovich, Gary; Kaila, Shuchita; Davies, Faith; Usmani, Saad Z
BACKGROUND:Daratumumab, lenalidomide and dexamethasone (DRd) and bortezomib, lenalidomide and dexamethasone (VRd) are preferred regimens for transplant ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). Both DRd and VRd demonstrated superior efficacy versus Rd in the MAIA and SWOG S0777 trials, respectively, but there is no head-to-head (H2H) clinical trial comparing their efficacy. Differing populations in the MAIA and S0777 trials make an unadjusted comparison of outcomes challenging and biased. The current TAURUS study is the first real-world H2H study comparing progression-free survival (PFS) among TIE NDMM patients treated with DRd or VRd as first-line (1L) in similar clinical settings. MATERIALS AND METHODS/METHODS:A multicenter chart review study was conducted at nine sites across the United States. All TIE patients treated with DRd and a randomly selected population of VRd patients were included. TIE NDMM patients aged ≥65 were included if they initiated 1L DRd/VRd between January 2019 and September 2021. PFS was defined as the time from DRd/VRd initiation until disease progression or death. A doubly-robust multivariable Cox regression model combined with inverse probability of treatment weighting (IPTW) methodology was used to compare PFS between cohorts. RESULTS:Weighted cohorts comprised 91 DRd and 87 VRd patients. Thirteen DRd and 24 VRd patients experienced progression/death. Patients treated with DRd had a lower risk of progression/death versus VRd (adjusted hazard ratio: 0.35, 95% confidence interval: [0.17; 0.73]). CONCLUSION/CONCLUSIONS:DRd is associated with a significantly lower risk of disease progression or death compared to VRd as 1L treatment for TIE NDMM patients.
PMID: 37838502
ISSN: 2152-2669
CID: 5604652

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

A Meta-Analysis of the Efficacy of Pomalidomide-Based Regimens for the Treatment of Relapsed/Refractory Multiple Myeloma After Lenalidomide Exposure

Davies, Faith E; Leleu, Xavier; Vogel, Prisca; Dhanasiri, Sujith; Le Nouveau, Pauline; Weisel, Katja
INTRODUCTION:The objective was to assess the benefit of pomalidomide-based combination regimens in patients with relapsed/refractory multiple myeloma (RRMM) previously treated with lenalidomide. A pooled estimate was obtained for efficacy outcomes including overall response rate (ORR), complete response (CR) rate, and progression-free survival (PFS) based on multiple trials conducted in this patient population. PATIENTS AND METHODS:A literature search was conducted on March 22, 2022 for relevant trials published between January 1, 2016 and the search date. The search identified 12 eligible trials with publications dated between 2016 and 2021. The meta-analyses were conducted among the intention-to-treat (ITT) population (patients treated in all lines of therapy) and 2 subpopulations: 2L (only patients treated in the second line [2L]) and ≥2L (patients treated in the 2L and beyond). RESULTS:From the meta-analyses, ORR was 69.9% for ITT, 74.4% for ≥2L, and 87.2% for 2L. CR rate was 12.1% for ITT, 17.6% for ≥2L, and 29.7% for 2L. One-year PFS rates were 55.1% for ITT, 59.1% for ≥2L, and 74.0% for 2L. Two-year PFS rates were 29.3% for ITT, 36.0% for ≥2L, and 41.9% for 2L. CONCLUSION:Pomalidomide-based combination regimens were effective in patients with RRMM previously treated with lenalidomide and tended to be associated with better outcomes when used earlier in the treatment pathway. A drug class switch may not always be necessary when making treatment decisions for patients with RRMM for whom the benefits of lenalidomide have been exhausted, although this must be supported by comparative studies.
PMID: 37684184
ISSN: 2152-2669
CID: 5609402

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: 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: 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: 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: 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: Primary financial support was from Cancer Research UK [ C1298/A10410].
SCOPUS:85165885225
ISSN: 2589-5370
CID: 5567862

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 new isoelectric focusing (IEF) based technique to diagnose and monitor non-secretory multiple myeloma [Meeting Abstract]

Chan, T; Jeewa, B; Fairweather-Tipping, D; Karim, A; Goodall, M; Plant, T; Davies, F; Jackson, G; Child, J A; Morgan, G; Drayson, M; Heaney, J L J
In most patients with myeloma, the tumour cell produces a unique monoclonal immunoglobulin (Mig), which serves as a quantitative surrogate biomarker for tumour burden. Patients with non-secretory myeloma (NSM) represent 1%-3% of patients and do not produce a Mig suitable for standard monitoring. Therefore, clinicians rely on bone marrow biopsies and CT-PET/ WB MRI scans, which are challenging for patients/clinicians, especially when required regularly for monitoring. Consequently, there is an unmet need for a blood-based biomarker in this patient group to determine remission induction and disease relapse. We have developed a new method to detect monoclonal light chains in this series of patients with NSM, (negative on immunofixation and no measurable disease marker (sFLC <100 mg/L)). Isoelectric focusing (IEF) is well-established for detecting IgG oligoclonal banding in cerebrospinal fluid to diagnose multiple sclerosis. Using IEF, any monoclonal immunoglobulin displays a highly reproducible unique spectrotype of bands. We have developed serum IEF to identify monoclonal sFLCs using highly specific and sensitive monoclonal antibodies. Study patients were identified from the MRC Myeloma IX, CRUK Myeloma XI or NIHR TEAMM trials. Overall, serum IEF detected monoclonal FLC in 28/32 patients (88%): 14 patients with kappa FLC and 10 lambda FLC. One patient had both kappa and lambda FLC bands detected, likely reflecting bi-clonality with both active myeloma clone and secondary MGUS clone picked up by the sensitive IEF assay. Follow-up samples were available in 27/32 patients. Serum IEF identified response to therapy (disappearance of band) and relapse (reappearance of band). The method also allows serial sample dilution to determine percentage reduction in monoclonal protein and provide semi-quantitative results in response to therapy. The IEF method identified monoclonal FLC in 86% of NSM patients studied, indicating that most are low-level secretors rather than true non-producers. Although their Mig cannot be monitored using standard techniques, our highly sensitive IEF assay allows NSM patients to be diagnosed and monitored using blood samples. This approach could reduce reliance on bone marrow biopsy and imaging in this patient cohort. Mass spectrometry (MS) is emerging as another exciting blood-based option for Mig detection. However, the limit of detection for MS is <10 mg/L compared to IEF sensitivity <1 mg/L. Further, the IEF assay utilises a low-cost electrophoresis platform available in many laboratories that conduct myeloma testing, enabling easier integration into clinical practice. Future clinical studies are required to validate IEF and should include comparison to other technologies, including MS
EMBASE:641392969
ISSN: 1365-2141
CID: 5514432