Dataset Information

A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis.

ABSTRACT: Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R² = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R² of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.

SUBMITTER: Walker BA

PROVIDER: S-EPMC6326953 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis.

Walker Brian A BA Mavrommatis Konstantinos K Wardell Christopher P CP Ashby T Cody TC Bauer Michael M Davies Faith F Rosenthal Adam A Wang Hongwei H Qu Pingping P Hoering Antje A Samur Mehmet M Towfic Fadi F Ortiz Maria M Flynt Erin E Yu Zhinuan Z Yang Zhihong Z Rozelle Dan D Obenauer John J Trotter Matthew M Auclair Daniel D Keats Jonathan J Bolli Niccolo N Fulciniti Mariateresa M Szalat Raphael R Moreau Phillipe P Durie Brian B Stewart A Keith AK Goldschmidt Hartmut H Raab Marc S MS Einsele Hermann H Sonneveld Pieter P San Miguel Jesus J Lonial Sagar S Jackson Graham H GH Anderson Kenneth C KC Avet-Loiseau Herve H Munshi Nikhil N Thakurta Anjan A Morgan Gareth G

Leukemia 20180702 1

Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part ...[more]

PMID: 29967379

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Project description:PurposeThe GMMG-CONCEPT trial investigated isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in transplant-eligible (TE) and transplant-noneligible (TNE) patients with newly diagnosed multiple myeloma (NDMM) with exclusively high-risk disease for whom prospective trials are limited, aiming to induce minimal residual disease (MRD) negativity.MethodsThis academic, investigator-initiated, multicenter, phase II trial enrolled patients with high-risk NDMM (HRNDMM) defined by mandatory International Staging System stage II/III combined with del17p, t(4;14), t(14;16), or more than three 1q21 copies as high-risk cytogenetic aberrations (HRCAs). Patients received Isa-KRd induction/consolidation and Isa-KR maintenance. TE patients received high-dose melphalan. TNE patients received two additional Isa-KRd cycles postinduction. This prespecified interim analysis (IA) reports the primary end point, MRD negativity (<10-5, next-generation flow), at the end of consolidation. The secondary end point was progression-free survival (PFS).ResultsAmong 125 patients with HRNDMM (TE-intention-to-treat [ITT]-IA, 99; TNE-ITT, 26) of the IA population for the primary end point, the median age was 58 (TE-ITT-IA) and 74 (TNE-ITT) years. Del17p was the most common HRCA (TE, 44.4%; TNE, 42.3%); about one third of evaluable TE/TNE patients presented two or more HRCAs, respectively. The trial met its primary end point with MRD negativity rates after consolidation of 67.7% (TE) and 54.2% (TNE) of patients. Eighty-one of 99 TE-ITT-IA patients reached MRD negativity at any time point (81.8%). MRD negativity was sustained for ≥1 year in 62.6% of patients. With a median follow-up of 44 (TE) and 33 (TNE) months, median PFS was not reached in either arm.ConclusionIsa-KRd effectively induces high rates of sustainable MRD negativity in the difficult-to-treat HRNDMM population, regardless of transplant status, translating into a median PFS that was not yet reached after 44/33 months.

Project description:1q gain/amplification (1q+) is the most common cytogenetic abnormality (CA), with a frequency of 30-50% in patients with newly diagnosed multiple myeloma (NDMM). Although accumulating evidence supports 1q+ as a "high-risk" CA (HRCA), several issues remain to be addressed to understand its true prognostic property. We retrospectively analyzed a cohort of 934 patients with NDMM from three centers in China, who had baseline data available for 1q+ [including 1q21 gain (3 copies) and amplification (> 3 copies)] detected by fluorescence in situ hybridization in isolated CD138+ cells, and who received first-line treatment with novel agents including proteasome inhibitors, immunomodulatory drugs, or both. Minimal residue disease (MRD) was assessed using next-generation flow cytometry. In this cohort, 1q+ patients accounted for 53% of all patients. 1q+ patients were characterized by larger tumor burden, more advanced diseases, adverse complications, and frequent concurrence of other CAs (particularly HRCAs) at diagnosis. Concurrence of HRCAs [del(17p), t(4;14), and t(14;16); known as double-hit MM], but not standard-risk CA, markedly worsened the outcome of 1q+ patients, compared to those with 1q+ only (progression-free survival/PFS: hazard ratio/HR 1.63, 95% confidence interval/CI 1.21-2.20, P = 0.0013; overall survival/OS: HR 1.96, 95% CI 1.40-2.74, P < 0.0001). 1q+ modulated the risk levels defined by the Revised International Staging System (R-ISS). Although the overall response rate was not significantly different between patients with or without 1q+, fewer 1q+ patients achieved complete response or better and minimal residue disease negativity (MRD-). MRD- attainment substantially prolonged PFS (HR 4.03, 95% CI 2.59-6.29, P < 0.0001) and OS (HR 3.72, 95% CI 2.24-6.19, P < 0.0001) of 1q+ patients. While 1q+ patients had relatively shorter MRD- duration, sustained MRD- significantly improved the PFS and OS of 1q+ patients. Together, 1q+ is an HRCA and a major component of double-hit MM, while the risk-adapted and MRD-tailored therapy may best help manage this high-risk population.

Dataset Information

A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis.

Publications

A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis.

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