An Amplicon-Targeted Ultra-Deep Sequencing Approach Reveals the Presence at the Onset of Multiple Myeloma and the Selection over Time of TP53 Sub-Clonal Variants, Which Adversely Influence Patients' Overall Survival

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 24-24
Author(s):  
Carolina Terragna ◽  
Marina Martello ◽  
Mauro Procacci ◽  
Flavio Mignone ◽  
Annalisa Pezzi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Deep Sequencing ◽  
High Rate ◽  
Mutational Load ◽  
Newly Diagnosed ◽  
Mutational Status ◽  
Clonal Variant ◽  
Chromosome 17P13 ◽  
Wide Range ◽  
Over Time

Abstract INTRODUCTION In newly diagnosed Multiple Myeloma (MM) patients (pts), Copy Number (CN) losses of chromosome 17p13, carrying the TP53 tumor-suppressor gene, are strong predictors of poor outcomes. On the contrary, the prognostic relevance of TP53 mutations at the onset of the disease is less clear, due to the very limited frequency of clonal lesions, as revealed by Sanger sequencing. To address this poorly investigated issue, we used an ultra-deep sequencing (UDS) approach to characterize the TP53 structural architecture in both newly diagnosed and relapsed MM pts and to assess the prognostic role and evolution over time of small TP53 mutated sub-clones. SAMPLES AND METHODS A cohort of 99 newly diagnosed MM pts treated up-front with bortezomib-based regimens and autologous stem cell transplantation, was included in this molecular study. In 29 cases, samples were collected both at diagnosis and at relapse(s). DNA was obtained from CD138+ highly purified plasma cells. TP53 gene mutational status was analysed by using an amplicon-targeted UDS approach (GSJ, 454 Roche Life Sciences). In order to discriminate between low frequency sub-clonal TP53 variants and sequencing errors, sequencing raw data were filtered according to cut-off values based on different ranges of sequences' coverage depth. Additional filters were also applied, based on both quality and biological cut-offs, to obtain a final confident list of variants. Analysis of CN alterations (CNAs) was performed by SNPs array and results analysed with ChAS software. RESULTS With a median coverage of 1386X, a list of 129 correctly called TP53 variants (either missense, or nonsense or splice ones), including 20 INDELs, was detected. Only deleterious and N/A variants (according to SIFT classification) were included in the list. Most newly diagnosed MM pts (55%) carried at least one TP53 sub-clonal variant (on average 1.08 variants per pts), with 45/99 (45%) carrying non-mutated TP53. Pts carrying TP53 sub-clonal variants bared also TP53 CN hemizygous losses (20%), CKS1B gains (56%) and cdkn2c losses (14%). According to TP53 sub-clonal mutational load, pts were stratified in two sub-groups, including 28 pts with ≥2 (high load) and 71 with <2 variants (low load), respectively. Eleven out of 129 variants were recurrent (RVs), as being detected in at least 3% of pts, with Variants Allele Frequencies (VAFs) ranging from 0.24 to 70.1% (median 0,53%); RVs were observed in 29 pts. The clinical impact of the TP53 sub-clonal mutational load, as well as of variants recurrence, was evaluated in 90/99 MM (median follow up = 70 months). Results of statistical analysis are summarized in Table 1. Pts carrying either high TP53 sub-clonal mutational load or RVs had significantly shorter OS and OS after relapse, as compared to the others, while no difference between these two groups was seen regarding PFS and TTP. Multivariate analysis showed that high TP53 mutational load, as well as the presence of TP53 RVs, both resulted independent factors adversely affecting OS and OS after relapse (Table 2). Of note, none of the detected genomic aberrations significantly influenced the response to front-line induction therapy. The distribution of both TP53 sub-clonal variants and genomic CNAs was overall modified in samples collected at relapse(s): 90% of relapsed pts carried at least one sub-clonal variant (on average 1.63 variants per pts) with 3/29 (10%) relapsed MM carrying non-mutated TP53. Moreover, 5 different sub-clonal lesions proved a linear increment of both TP53 VAFs (from 29.4% to 54.6%; from 7.8% to 12.4%; from 0.5% to 4.3%) and TP53 CN loss smooth signal (from 7% to 89% and from 50% to 100%), as evaluated in longitudinally collected samples. CONCLUSIONS The UDS analysis of TP53 coding sequence in newly diagnosed MM highlighted for the first time a high rate of variants, recurring with a wide range of frequencies among samples. The increased number of TP53 sub-clonal variants per pts in samples collected at relapse(s), compared to that seen at the onset of the disease, suggests a sub-clonal dynamics over time. This finding might explain the adverse impact of high TP53 sub-clonal mutational load and TP53 RVs on OS, due to a shorter OS after relapse. Acknowledgments: Roche Diagnostics for applicationsupport in the realization of this project. Disclosures Zamagni: Celgene Corporation: Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Ariad: Consultancy; AMGEN: Consultancy; ROCHE: Consultancy; Pfizer: Consultancy; MSD: Consultancy. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria.

Sustaining Research-Based Practices in Reading

1999 ◽  
Vol 20 (5) ◽  
pp. 263-287 ◽  
Author(s):  
Janette K. Klingner ◽  
Sharon Vaughn ◽  
Marie Tejero Hughes ◽  
Maria Elena Arguelles
Keyword(s):  
Instructional Practices ◽  
High Rate ◽  
Strategic Reading ◽  
School Year ◽  
Wide Range ◽  
Sustained Use ◽  
Development Experience ◽  
Collaborative Strategic Reading ◽  
Research Based Practices ◽  
Over Time

This study examined the extent to which the reading instructional practices learned by a cohort of teachers who participated in an intensive, yearlong professional development experience during the 1994-1995 school year have been sustained and modified over time. Teachers learned three multileveled practices—partner reading, collaborative strategic reading, and making words—that promote gains in reading for students from a wide range of achievement levels. Teachers were observed and interviewed 3 years later to determine the extent to which they continued to implement the practices, the ways in which they modified them, and factors that influenced their sustained use of the practices. With the exception of one teacher, all the teachers sustained one or more of the three practices at a high rate.

Abstract 4248: A long tail of sub-clonal TP53 mutations emerged by ultra-deep sequencing of newly diagnosed multiple myeloma (MM)

2015 ◽  
Author(s):  
Marina Martello ◽  
Giovanni Martinelli ◽  
Angela Flores Dico ◽  
Barbara Santacroce ◽  
Enrica Borsi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Deep Sequencing ◽  
Newly Diagnosed ◽  
Long Tail ◽  
Tp53 Mutations

Patterns of Total Costs of Care for Newly Diagnosed Multiple Myeloma (MM) Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2656-2656
Author(s):  
Steven R. Arikian ◽  
Dejan Milentijevic ◽  
Gary Binder ◽  
Mara Silvia Monzini ◽  
X Henry Hu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Direct Costs ◽  
Drug Costs ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Monthly Total ◽  
Equity Ownership ◽  
The Cost ◽  
Over Time

Abstract Introduction: As clinical evidence has mounted in support of novel agents and longer treatment (Tx) durations for patients (pts) with newly diagnosed multiple myeloma (NDMM), questions have arisen regarding the economic impact of extending time to progression (TTP) in these pts, and the cost consequences once pts relapse and move to a second line of Tx. Previous analysis showed that relapsed myeloma pts incurred higher monthly costs once they advanced to later lines of Tx (Gaultney, 2013). There is limited information on the cost patterns of MM pts before and after their first relapse. A claims analysis was performed to evaluate the patterns of total direct costs of care, from Tx initiation until progression, for NDMM patients and for newly relapsed patients treated with novel agents, utilizing time to next therapy (TTNT) as a proxy measure for progression. Methods: A retrospective study was conducted using a large US medical and pharmacy claims database, covering > 25 million lives annually. NDMM patients were identified with at least 2 outpatient claims or 1 inpatient medical claim associated with a diagnosis of MM (ICD-9-CM] code 203.0X), with the first such claim used to define the index date. Inclusion criteria required a minimum of 12 months' pre-index enrollment and 6 months' post-index continuous enrollment between 2006 and 2012. Pts with claims for stem cell transplantation (SCT) were excluded, to avoid confounding results from various factors based on timing, costs, and site of care of SCT. The analysis focused on NDMM and relapsed MM pts receiving lenalidomide (LEN)- or bortezomib (BORT)- based Tx, where complete claim history was available from Tx onset to initiation of subsequent Tx. Using methods similar to those described by Gaultney, patients' average monthly costs were determined, including medical (inpatient, ambulatory, and emergency room) and pharmacy (index and other drugs) costs, and total cost patterns over quarterly time periods were calculated. Average Charlson comorbidity scores were determined to compare baseline measures between pt groups. Results: 897 NDMM pts and 280 relapsed MM pts were identified with complete data through initiation of subsequent Tx. Monthly total direct costs for NDMM pts were $15,400 in the first 3 months (mos) of Tx, and declined each quarter, reaching approximately $5,000/mo at 18+ mos. At relapse, monthly costs increased to over $12,000 for the first 3 mos and followed a quarterly pattern of reduction similar to that seen for NDMM pts (Fig 1). Quarterly cost reduction patterns were consistent for patients treated with LEN or BORT for both NDMM and relapsed pts. Pts' total monthly NDMM costs over the full TTNT period averaged $8,942 with LEN vs. $11,139 for BORT (due to 54% higher monthly medical costs for BORT), while monthly drug costs were nearly identical (Table 1). The baseline Charlson comorbidity index was similar between Tx groups in both lines of Tx. Figure 1: Direct monthly costs (medical and pharmacy) for LEN- and BORT-based treatments Figure 1:. Direct monthly costs (medical and pharmacy) for LEN- and BORT-based treatments Table 1: Direct monthly costs for NDMM pts Table 1 Table 1. Conclusions: For a population of NDMM pts receiving either LEN- or BORT-based Tx without SCT, followed until TTNT, total direct monthly costs per pt declined steadily over time, decreasing by 68% from the initial quarter to the period post 18 mos. Costs spiked when pts began 2nd-line therapy, then followed a similar pattern of decline over time. This pattern may suggest that further extending the TTP for NDMM pts may also yield economic benefits for each month extended before relapse. Patterns of cost decline were similar between the LEN and BORT groups, for NDMM and for relapsed patients, although mean monthly total costs were lower for NDMM pts receiving LEN-based Tx due to lower medical costs and similar drug costs. Disclosures Arikian: Genesis Research: Consultancy. Off Label Use: Lenalidomide in newly diagnosed multiple myeloma patients . Milentijevic:Celgene Corporation: Consultancy. Binder:Celgene Corporation: Employment, Equity Ownership. Monzini:Celgene Corporation: Employment, Equity Ownership. Hu:Celgene Corporation: Employment. Nagarwala:Celgene Corporation: Employment. Hussein:Celgene Corporation: Employment. Corvino:Genesis Research LLC: Consultancy. Surinach:Genesis Research LLC: Consultancy. Usmani:Celgene Corporation: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Array BioPharma: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding.

Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma

2021 ◽  
Author(s):  
Luciano J. Costa ◽  
Saurabh Chhabra ◽  
Eva Medvedova ◽  
Bhagirathbhai R. Dholaria ◽  
Timothy M. Schmidt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Progression Free Survival ◽  
High Rate ◽  
Newly Diagnosed ◽  
Serious Adverse Events ◽  
Disease Response ◽  
Minimal Residual

PURPOSE The MASTER trial combined daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) in newly diagnosed multiple myeloma (NDMM), using minimal residual disease (MRD) by next-generation sequencing (NGS) to inform the use and duration of Dara-KRd post-autologous hematopoietic cell transplantation (AHCT) and treatment cessation in patients with two consecutive MRD-negative assessments. METHODS This multicenter, single-arm, phase II trial enrolled patients with NDMM with planed enrichment for high-risk cytogenetic abnormalities (HRCAs). Patients received Dara-KRd induction, AHCT, and Dara-KRd consolidation, according to MRD status. MRD was evaluated by NGS at the end of induction, post-AHCT, and every four cycles (maximum of eight cycles) of consolidation. Primary end point was achievement of MRD negativity (< 10–5). Patients with two consecutive MRD-negative assessments entered treatment-free MRD surveillance. RESULTS Among 123 participants, 43% had none, 37% had 1, and 20% had 2+ HRCA. Median age was 60 years (range, 36-79 years), and 96% had MRD trackable by NGS. Median follow-up was 25.1 months. Overall, 80% of patients reached MRD negativity (78%, 82%, and 79% for patients with 0, 1, and 2+ HRCA, respectively), 66% reached MRD < 10–6, and 71% reached two consecutive MRD-negative assessments during therapy, entering treatment-free surveillance. Two-year progression-free survival was 87% (91%, 97%, and 58% for patients with 0, 1, and 2+ HRCA, respectively). Cumulative incidence of MRD resurgence or progression 12 months after cessation of therapy was 4%, 0%, and 27% for patients with 0, 1, or 2+ HRCA, respectively. Most common serious adverse events were pneumonia (6%) and venous thromboembolism (3%). CONCLUSION Dara-KRd, AHCT, and MRD response-adapted consolidation leads to high rate of MRD negativity in NDMM. For patients with 0 or 1 HRCA, this strategy creates the opportunity of MRD surveillance as an alternative to indefinite maintenance.

Circulating Mir-130a in Multiple Myeloma and Extramedullary Myeloma Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2043-2043 ◽  
Author(s):  
Lenka Kubiczkova-Besse ◽  
Lenka Sedlarikova ◽  
Fedor Kryukov ◽  
Lenka Radova ◽  
Jana Nekvindova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Area Under The Curve ◽  
Newly Diagnosed ◽  
Circulating Mirnas ◽  
Serum Samples ◽  
Reactive Protein ◽  
Specificity And Sensitivity ◽  
Healthy Donors ◽  
Wide Range

Abstract Background MicroRNAs (miRNAs) are a class of short, non-coding, single stranded RNAs regulating a broad spectrum of processes. Circulating miRNAs are an important emerging biomarker in cancer as well as a possible non-invasive diagnostic solution for a wide range of clinical disorders due to their high stability and association with disease state, although their source still remains uncertain. In multiple myeloma (MM), a plasma cell malignancy, circulating miRNAs have been reported to have a diagnostic and prognostic potential. It is therefore plausible to assume that they are involved in pathogenesis of this disease and thus could be used as diagnostic tool not only for MM, its extramedullary (EM) form but also for monitoring the clinical course of the disease. Therefore, in this study, we aimed to identify such miRNAs. Methods Screening analysis of 667 miRNAs was performed on 5 EM serum samples, 5 newly diagnosed MM samples and 6 healthy donors (HD) serum samples using TaqMan Low Density Arrays (TLDA) from Life Technologies. QPCR was performed for miR-130a on 118 serum samples obtained in Brno from newly diagnosed MM patients (pts) (35 pts), primary and secondary EM (35 pts), relapsed MM (18 pts) and HD (30). Further, 45 serum samples (12 diagnostic and 33 follow-up) of pts reaching VGPR/better response, enrolled in Italian CRD/MEL-200 and EMN-02 studies were used for circulating miRNA estimation. Receiver Operating Characteristic (ROC) analysis was used to calculate specificity and sensitivity of the miRNA as a biomarker. Biochemical characteristics were also available for EM and MM pts from Brno. P values <0.05 were considered as significant. Results TLDA profiling revealed 14 deregulated miRNAs (all p<0.05, adjusted p<0.41) between MM pts and EM pts, and 20 miRNAs were on the top of the list of deregulated miRNAs between EM and HD serum samples (all p<0.05, adjusted p<0.40). MiR-130a was chosen for further verification by qPCR as it was on the top of the list of deregulated miRNAs between the groups. qPCR revealed that level of miR-130a was significantly decreased in MM and EM samples when compared with HD (all p<0.005); moreover, level of miR-130a was decreased also in EM when compared with MM sera (p<0.06). To discriminate EM pts from other groups, ROC curve was calculated. It revealed that miR-130a is potent to distinguish EM pts from HD with area under the curve (AUC) = 0.805, specificity of 86.7% and sensitivity of 65.7% using cut-off value = 3377 copies/1ng of miRNA/RNA. Most importantly, miR-130a was able to distinguish EM pts from newly diagnosed MM pts with AUC = 0.628, specificity of 94.3% and sensitivity of 28.6% using cut-off value = 1438 copies/1ng of miRNA/RNA, and EM pts from MM pts in relapse with AUC = 0.702, specificity of 94.4% and sensitivity of 28.6% using cut-off value = 1438 copies/1ng of miRNA/RNA. In the cohort of EM pts, miR-130a significantly correlated with most of clinically relevant parameters; there was a positive correlation with level of hemoglobin and thrombocytes count (rs=0.397 and 0.439, all p<0.05) and a negative correlation with levels of monoclonal immunoglobulin, β2-microglobulin and C-reactive protein (rs=-0.398, -0.427 and -0.488, all p<0.05) and it was also associated with higher ISS stage (p=0.017). Further, in the analysis of miR-130a dynamics in follow-up samples from Italy, we observed increase of miR-130a levels in 8/12 MM pts during the follow-up sampling (p<0.06) in comparison with diagnostic samples, whereas in remaining 4 MM pts it remained stable or decreased. Conclusions In this study, miR-130a was decreased in serum samples of pts developing EM disease and distinguished EM pts from newly diagnosed MM pts and relapsed/progressed MM pts with specificity over 90%. Further, we observed increased level of miR-130a in the follow-up samples of MM pts. It suggests that miR-130a could be associated with EM disease; however, underlying biology and origin of miR-130a still remains to be explored. Work was supported by grants IGA NT 12130, NT 14575 and NT 13190. Disclosures Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Array BioPharma: Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Sanofi Aventis: Honoraria.

scholarly journals The Role of Monoclonal Antibodies in the First-Line Treatment of Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma

2020 ◽  
Vol 14 (1) ◽  
pp. 20
Author(s):  
Francesca Bonello ◽  
Mariella Grasso ◽  
Mattia D’Agostino ◽  
Ivana Celeghini ◽  
Alessia Castellino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Clinical Practice ◽  
Elderly Patients ◽  
Residual Disease ◽  
Real Life ◽  
Newly Diagnosed ◽  
First Line ◽  
Large Variability ◽  
Wide Range

Elderly transplant-ineligible (NTE) patients represent the majority of patients affected by multiple myeloma (MM). Elderly patients are a highly heterogeneous population, with large variability in health and functional status. Thus, choosing their optimal treatment is challenging. A wide range of first-line treatments is available, and novel-agent combinations, including monoclonal antibodies (mAbs), have recently entered clinical practice. The combination of the anti-CD38 mAb daratumumab with bortezomib, melphalan and prednisone (Dara-VMP) or lenalidomide and dexamethasone (Dara-Rd) demonstrated impressive advantages in terms of progression-free survival and minimal residual disease negativity, as compared to VMP and Rd, without safety concerns. Another anti-CD38 mAb, isatuximab, is showing encouraging results, and new isatuximab-based combinations might enter clinical practice in the future. Nevertheless, available data come from clinical trials with selected patient populations and, to date, the manageability of these regimens in real-life patients or in frail patients remains unknown. Frailty-tailored treatments, including mAbs, are under evaluation in preliminary studies. In this review, we analyze recently approved mAb-based treatments for NTE newly diagnosed MM patients and new combinations under evaluation, focusing on the efficacy and safety of these regimens and on open issues regarding the choice of therapy for elderly patients.

scholarly journals Defining Genomic Probability of Progression to Identify Low-Risk Smoldering Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 545-545
Author(s):  
Anil Aktas-Samur ◽  
Mariateresa Fulciniti ◽  
Sanika Derebail ◽  
Raphael Szalat ◽  
Giovanni Parmigiani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
High Sensitivity ◽  
Mutational Load ◽  
Newly Diagnosed ◽  
Genomic Features ◽  
Genomic Deletions ◽  
Smoldering Multiple Myeloma ◽  
Short Period

Abstract On an average, 1% of monoclonal gammopathy of undermined significance (MGUS) and 10% of smoldering Multiple Myeloma (SMM) progress to symptomatic MM every year within the first five years of diagnosis. The probability of progression significantly decreases for SMM patients after first 5 years. However, a distinct subset of SMM patients progress within 2 years and are re-classified as high-risk patients based on risk markers such as 20/2/20 or certain genomic features. Although recent studies have evaluated the high-risk genomic features for SMM but genomic background of SMM patients who do not progress to MM after long-term follow-up (&gt;= 5 years) has not been described. Here, we evaluated transcriptomic and genomic changes enriched in non-progressor (NP) (no progression after 5 years of follow-up) precursor conditions (N=31) with those progressed within short period of time (N=71) and compared them with changes observed in newly diagnosed MM (N=192). Additionally, using transcriptome, epigenome and whole genome profiling we also studied additional unique samples from 18 patients at their precursor stage as well as when progressed to MM. Overall, we have observed significantly lower mutational load for NP SMM from progressor SMM (median SNV 4900 vs. 7881 p &lt; 3e-04) with high sensitivity (0.83) and specificity (0.65) to separate NP from progressors. We have further developed a deep learning model by using more than 4500 genome wide features using ten-fold cross validation. This model indicated that not only the load but also the patterns of mutations (type, location, frequency) are different between two conditions. We also found that NP samples have significantly lower heterogeneity (p &lt; 0.05). However, progressed samples showed similar mutational load and heterogeneity at precursor stage and MM. Among CNA differences, absence of gain or deletion of chr8 (not involving MYC region) were strong predictor of NP (OR=7.2 95% CI 2.2-24). Focal genomic loss was also significantly lower for NP (p=0.004) which was also reflected by low genome scar score (GSS) (p=0.07). Structural variant and copy number signature analysis also showed that NPs were showing significantly low exposure to non-clustered variable size genomic deletions. We observed similar frequency of primary translocations [t(11;14), t(4;14), and t(14;16)] in both progressor and NP samples as well as newly diagnosed MM. MYC translocation with any partner was not observed in NP samples, whereas 37% of progressor samples had a MYC translocations (OR=12.8). Adding all these differences including chr8 CNAs, MYC translocations, mutation burden, GSS, focal deletions, all driver mutations as well as primary translocations into recursive partitioning model to predict non-progressor SMM, we have identified a simple genomic model only involving chr8 CN changes and overall mutational burden to achieve a high sensitivity (0.82) and specificity (74%). Our transcriptomic analysis measured the distance between progressor and NP SMM as well as MM and found that NP SMM has greater difference with MM which is closer to progressor SMM. We quantified transcriptomic heterogeneity by using molecular degree of perturbation. This analysis showed that consistent with DNA changes, DNA repair pathway and MYC target genes are expressed similarly in NP SMM as in normal plasma cells compared to progressor SMM. Epigenomic analysis yielded 75 SEs regions differentially utilized between precursor and symptomatic MM stage using paired samples. The targeted genes included BMP6, PRDM1, STAT1, SERTAD2 and RAB21 and possibly regulating genes related to oncogenic KRAS activities. In conclusion, we define genomic characterization of non-progressor SMM and our results now provide the basis to develop molecular definition of SMM as well as risk driving features. Disclosures Munshi: Janssen: Consultancy; Pfizer: Consultancy; Legend: Consultancy; Novartis: Consultancy; Adaptive Biotechnology: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Takeda: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy.

scholarly journals Genome-Wide Somatic Alterations in Multiple Myeloma Reveal a Superior Outcome Group

2020 ◽  
Vol 38 (27) ◽  
pp. 3107-3118 ◽  
Author(s):  
Mehmet Kemal Samur ◽  
Anil Aktas Samur ◽  
Mariateresa Fulciniti ◽  
Raphael Szalat ◽  
Tessa Han ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Chromosome 9 ◽  
Cell Transplant ◽  
Mutational Load ◽  
Newly Diagnosed ◽  
Therapeutic Algorithms ◽  
Genomic Markers ◽  
Somatic Alterations

PURPOSE Multiple myeloma (MM) is accompanied by heterogeneous somatic alterations. The overall goal of this study was to describe the genomic landscape of myeloma using deep whole-genome sequencing (WGS) and develop a model that identifies patients with long survival. METHODS We analyzed deep WGS data from 183 newly diagnosed patients with MM treated with lenalidomide, bortezomib, and dexamethasone (RVD) alone or RVD + autologous stem cell transplant (ASCT) in the IFM/DFCI 2009 study (ClinicalTrials.gov identifier: NCT01191060 ). We integrated genomic markers with clinical data. RESULTS We report significant variability in mutational load and processes within MM subgroups. The timeline of observed activation of mutational processes provides the basis for 2 distinct models of acquisition of mutational changes detected at the time of diagnosis of myeloma. Virtually all MM subgroups have activated DNA repair–associated signature as a prominent late mutational process, whereas APOBEC signature targeting C>G is activated in the intermediate phase of disease progression in high-risk MM. Importantly, we identify a genomically defined MM subgroup (17% of newly diagnosed patients) with low DNA damage (low genomic scar score with chromosome 9 gain) and a superior outcome (100% overall survival at 69 months), which was validated in a large independent cohort. This subgroup allowed us to distinguish patients with low- and high-risk hyperdiploid MM and identify patients with prolongation of progression-free survival. Genomic characteristics of this subgroup included lower mutational load with significant contribution from age-related mutations as well as frequent NRAS mutation. Surprisingly, their overall survival was independent of International Staging System and minimal residual disease status. CONCLUSION This is a comprehensive study identifying genomic markers of a good-risk group with prolonged survival. Identification of this patient subgroup will affect future therapeutic algorithms and research planning.

Prognostic Implication of Somatic Mutations By Next Generation Sequencing: An Analysis from the Mmrf Commpass Study in Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2079-2079
Author(s):  
Mattia D'Agostino ◽  
Stefania Oliva ◽  
Alessandra Larocca ◽  
Stefano Spada ◽  
Manuela Gambella ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Cox Model ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Group Iii ◽  
Mutational Status ◽  
Group I ◽  
Group Ii

Abstract Introduction: High throughput techniques, such as massively parallel sequencing, are becoming an attractive approach to characterize multiple myeloma (MM) genomic profiles. However, the clinical relevance and contribution to risk assessment of such approaches need to be established. The Multiple Myeloma Research Foundation (MMRF)CoMMpass trial (NCT01454297) has collected data from 1000 newly-diagnosed MM patients enrolled worldwide and observed through an expected follow-up of up to eight-years. Comprehensive analysis of somatic mutations detected in purified MM cells could reveal disease features with prognostic value, which may not have been detected using traditional approaches. Materials and methods: We analyzed data from the interim analysis 8 cohort. CD138+ purified MM specimens from bone marrow aspirates and mononuclear cells from peripheral blood were collected at diagnosis. Whole exome libraries from both tumor and constitutional DNA samples were created. Somatic single nucleotide variants (SNV) were identified using three different variant callers (Seurat,Strelka andMutect), only nonsynonymous SNV calls made from at least two callers were included in the analysis. Patients were analyzed on an intention-to-treat basis. We evaluated the impact on progression free survival (PFS) of recurrently mutated genes (with at least a nonsynonymous SNV in more than 10 patients) in a Cox model adjusted for international staging system (ISS) and cytogenetic profile (high risk, standard risk and missing). An additive score related to mutated genes was calculated on the basis the level of each coefficient estimated using a Cox Model with backward selection based on theAkaikeInformation Criterion (AIC). Results: 517 patients with baseline somatic mutation data were included in the analysis. Median age at diagnosis was 64 years (range 27-93). All patients received novel agents as first line treatment; 236 (45.6%) received autologous stem cell transplantation (ASCT). Each patient showed a median number of 55 nonsynonymous somatic SNV (range 8-1970) in a median number of 47 genes (range 5-1741). Excluding immunoglobulin genes, the most recurrent mutated genes were KRAS (25%), NRAS (19.5%), TTN (12.1%), MUC16 (9.1%) and DIS3 (9.1%). Based on the results of a multivariable Cox model corrected for ISS and cytogeneticprofile, we created a scoring system determined by the mutational status of 9 genes identified in a nonbiased manner (Table 1). Three groups were identified: group I (score 0-2, 17%); group II (score=3, 51%), and group III (score >3, 32%). After a median follow-up of 371 days, the 18-month PFS rate was 93% for group I, 85% for group II, and 67% for group III. In a Cox model adjusted for ISS and cytogeneticprofile, the hazard ratio was 2.34 (p=0.112) for group II versus group I, and 5.96 (p<0.001) for group III versus I. The prognostic trend of the score was confirmed in different patient subgroups including ASCT/no ASCT, standard/high risk cytogenetic profile, ISS I, II, or III. Of note, 23.3% of patients in group I had an ISS III and 30.4% of patients in group III had an ISS I. Conclusion: The use of a prognostic model based on the mutational status of 9 recurrently mutated genes could improve risk assessment of newly-diagnosed MM patients. To our knowledge, this is the largest study correlating nonsynonymous somatic SNV with MM patients' outcome. Longer follow-up and validation in independent cohorts are needed to confirm our findings. Disclosures Larocca: Amgen, Celgene, BMS, Janssen-Cilag: Honoraria. Gay:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria.

Sign in / Sign up

Export Citation Format

Share Document