Faculty Bibliography
Searched for:
in-biosketch:true
person:morgag04
Total Results:
675
Antibody-based targeting of BCMA in multiple myeloma
PMID: 32007191
ISSN: 1474-5488
CID: 4301132
Long-term outcomes after autologous stem cell transplantation for multiple myeloma
As multiple myeloma (MM) treatments evolve, frequent updates are required to monitor the long-term effect of changes in approach. Traditionally, MM is considered an incurable disease, with most patients eventually relapsing. However, improvements in treatments has raised the possibility that MM might be functionally curable. To examine improvements in long-term survival, we followed 4329 patients with newly diagnosed MM treated with autologous stem cell transplantation (ASCT) at the University of Arkansas for Medical Sciences from 1989 through 2018. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier analysis, Cox proportional hazards models, relative survival analysis, and cure modeling among different time periods, risk groups, and demographic traits. Steady improvements in OS were found, with patients treated in 2014 or later having superior OS (hazard ratio, 0.35; 95% confidence interval [CI], 0.27-0.45) and reduced excess risk for MM death (relative excess risk, 0.30; 95% CI, 0.22-0.41) compared with patients treated in 1997 or earlier. Patients treated during intervening time periods often had intermediate survival, but trends in OS, PFS, and landmarked analyses were inconsistent. Cure models support the potential for cure, ranging from 6.3% to 31.3%, depending on the year of treatment, with 10.0% to 18.6% of patients achieving their normal life expectancy across multiple periods. There was some evidence of reductions in early mortality within 3 years of diagnosis, longer complete response (CR) duration, and reductions in relapse after achieving CR. However, results differed depending on age, risk group, and cytogenetic characteristics.
PMCID:6988393
PMID: 31990333
ISSN: 2473-9537
CID: 4294052
BRAF and DIS3 Mutations Associate with Adverse Outcome in a Long-term Follow-up of Patients with Multiple Myeloma
PURPOSE/OBJECTIVE:Copy number changes and translocations have been studied extensively in many datasets with long term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets. METHODS:we performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the Total Therapy Trials (TT). RESULTS:As expected, the most commonly mutated genes were NRAS, KRAS, and BRAF making up 44% of patients. Double-Hit, BRAF and DIS3 mutations had an impact on outcome alongside classical risk factors in the context of an intensive treatment approach. We were able to identify both V600E and non-V600E BRAF mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead BRAF mutated patients showed co-occurring alterations in KRAS, NRAS or activating BRAF mutations suggesting they play a role in the oncogenesis of multiple myeloma (MM) by facilitating MAPK activation and may lead to chemo resistance. CONCLUSION/CONCLUSIONS:Overall, these data highlight the importance of mutational screening to better understand newly diagnosed MM (NDMM) and may lead to patient specific mutation-driven treatment approaches.
PMID: 31988198
ISSN: 1078-0432
CID: 4294002
Role of AID in the temporal pattern of acquisition of driver mutations in multiple myeloma [Letter]
PMID: 31836853
ISSN: 1476-5551
CID: 4250282
The relative importance of factors predicting outcome for myeloma patients at different ages: results from 3894 patients in the Myeloma XI trial
Disease factors such as tumor burden and molecular risk affect myeloma patient outcomes as well as patient factors that impact the capacity to deliver treatment. How the relative importance of these factors changes with patient age has not previously been investigated comprehensively. We analyzed data from 3894 patients of all ages uniformly treated in a large clinical trial of myeloma patients, Myeloma XI. Even with novel therapeutic approaches progression-free survival (PFS) and overall survival (OS) are affected by age with a stepwise reduction in PFS and OS with each decade increase. Renal function deteriorated with increasing age whilst the frequency of t(4;14) and del(17p) decreased and gain(1q) increased. The relative contribution of performance status, international staging score and molecular risk to progression-free and overall survival varied by age group. Molecular events have a larger effect on outcome in younger patients with their relative contribution diminishing in the elderly. Performance status is important for patient outcome at all ages suggesting that physical frailty may be a more important predictor of outcome than age itself. Significant differences in the factors driving patient outcomes at different ages are important to consider as we design disease segmentation strategies to deliver personalized treatment approaches.
PMID: 31611625
ISSN: 1476-5551
CID: 4140312
Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
BACKGROUND:We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS:Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS:The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS:Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
PMCID:6820948
PMID: 31664920
ISSN: 1471-2261
CID: 5478742
Long-term Analysis Of Multiple Sequential Samples Reveals Patterns Of Progression In Smoldering Myeloma [Meeting Abstract]
ISI:000491229800091
ISSN: 2152-2650
CID: 5389082
Blood. 2019:134.DOI:
Analysis of the Sub-Clonal Structure of Smoldering Myeloma over Time Provides a New Means of Disease Monitoring and Highlights Evolutionary Trajectories Leading to Myeloma [Meeting Abstract]
ISI:000577164603065
ISSN: 0006-4971
CID: 5389112
Blood. 2019:134.DOI:
The Spectrum of Exomic Mutation in Elderly Myeloma Differs Substantially from Patients at Younger Ages Consistent with a Different Evolutionary Trajectory to Full Blown Disease Based on Age of Onset [Meeting Abstract]
ISI:000577164603078
ISSN: 0006-4971
CID: 5389122
Enrichment for copy number alterations and a unique pattern of gene mutations characterize multiple myeloma in elderly patients [Meeting Abstract]
ISI:000491229800129
ISSN: 2152-2650
CID: 5389092
