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Patient similarity network of newly diagnosed multiple myeloma identifies patient subgroups with distinct genetic features and clinical implications.

ABSTRACT: The remarkable genetic heterogeneity of multiple myeloma poses a substantial challenge for proper prognostication and clinical management of patients. Here, we introduce MM-PSN, the first multiomics patient similarity network of myeloma. MM-PSN enabled accurate dissection of the genetic and molecular landscape of the disease and determined 12 distinct subgroups defined by five data types generated from genomic and transcriptomic profiling of 655 patients. MM-PSN identified patient subgroups not previously described defined by specific patterns of alterations, enriched for specific gene vulnerabilities, and associated with potential therapeutic options. Our analysis revealed that co-occurrence of t(4;14) and 1q gain identified patients at significantly higher risk of relapse and shorter survival as compared to t(4;14) as a single lesion. Furthermore, our results show that 1q gain is the most important single lesion conferring high risk of relapse and that it can improve on the current International Staging Systems (ISS and R-ISS).

SUBMITTER: Bhalla S

PROVIDER: S-EPMC8598000 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Patient similarity network of newly diagnosed multiple myeloma identifies patient subgroups with distinct genetic features and clinical implications.

Bhalla Sherry S Melnekoff David T DT Aleman Adolfo A Leshchenko Violetta V Restrepo Paula P Keats Jonathan J Onel Kenan K Sawyer Jeffrey R JR Madduri Deepu D Richter Joshua J Richard Shambavi S Chari Ajai A Cho Hearn Jay HJ Dudley Joel T JT Jagannath Sundar S Laganà Alessandro A Parekh Samir S

Science advances 20211117 47

The remarkable genetic heterogeneity of multiple myeloma poses a substantial challenge for proper prognostication and clinical management of patients. Here, we introduce MM-PSN, the first multiomics patient similarity network of myeloma. MM-PSN enabled accurate dissection of the genetic and molecular landscape of the disease and determined 12 distinct subgroups defined by five data types generated from genomic and transcriptomic profiling of 655 patients. MM-PSN identified patient subgroups not ...[more]

PMID: 34788103

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Project description:Mass spectrometry (MS) is a promising tool for monitoring monoclonal protein in plasma cell dyscrasias. We included 480 transplant-eligible newly-diagnosed multiple myeloma (MM) patients from the GMMG-MM5 trial (EudraCT No. 2010-019173-16) and performed a retrospective MS analysis at baseline (480 patients) and at the pre-defined, consecutive time points after induction (444 patients), prior to maintenance (305 patients) and after one year of maintenance (227 patients). We found that MS negativity was significantly associated with improved progression-free survival (PFS) even in patients with complete response (CR) at all investigated follow-up time points. The prognostic impact was independent of established risk factors, such as the revised International Staging System. Combining MS and baseline cytogenetics improved the prediction of outcome: MS-positive patients with high-risk cytogenetics had a dismal PFS of 1.9 years (95% confidence interval [CI]: 1.6-2.3 years) from the start of maintenance. Testing the value of sequential MS prior to and after one year of maintenance, patients converting from MS positivity to negativity had an excellent PFS (median not reached) while patients converting from MS negativity to positivity progressed early (median 0.6 years, 95% CI: 0.3-not reached). Among patients with sustained MS positivity, the baseline high-risk cytogenetic status had a significant impact and defined a group with poor PFS. Combining minimal residual disease (MRD) in the bone marrow and MS allowed the identification of double negative patients with a favorable PFS (median 3.33 years, 95% CI: 3.08-not reached) and no overall survival events. Our study provides strong evidence that MS is superior to conventional response monitoring, highlighting the potential of MS to become a new standard. Our data indicate that MS should be performed sequentially and combined with baseline disease features and MRD to improve its clinical value.Clinical Trials Register: EudraCT No. 2010-019173-16.

Project description:BackgroundSecondary myelofibrosis (SMF) is characterized by the excessive deposition of fibrous tissue on top of the primary disease, often causing clinical manifestations to be overshadowed by the primary disease. Unfortunately, current staging systems do not incorporate myelofibrosis, leading to potential treatment delays for SMF.ObjectivesTo evaluate the prognosis of patients with multiple myeloma (MM) complicated with myelofibrosis.DesignThe study included the clinical data and treatment results of 208 newly diagnosed multiple myeloma (NDMM) patients who were treated in the Affiliated Hospital of Qingdao University from January 2014 to August 2020, and performed a retrospective analysis.MethodsAll patients underwent bone marrow biopsy, and MF severity was classified into grades 0-3 according to the 2016 WHO criteria. Treatment efficacy was evaluated based on the International Myeloma Working Group (IMWG) standard and SPSS was used for analysis.ResultsThe MM patients without SMF exhibited better treatment response (p < 0.05). Importantly, increasing degrees of myelofibrosis were associated with a significant reduction in median progression-free survival (PFS; p < 0.05). MM-SMF patients exhibited significantly shorter median PFS and overall survival (OS; p < 0.05). In the MM-SMF group, neutrophil-lymphocyte ratio >2.39, monocyte-lymphocyte ratio ⩽0.18, and platelet-lymphocyte ratio ⩽61.6 were associated with significantly reduced median PFS and OS (p < 0.05). Notably, the use of bortezomib-based regimens did not significantly impact prognosis in MM-SMF patients, while lenalidomide-based regimens significantly extended median OS but did not significantly affect median PFS.ConclusionMyelofibrosis emerges as an important prognostic indicator for predicting the survival outcomes of NDMM patients. In the era of new therapeutics, there is a pressing need to explore novel treatment strategies in order to improve the prognosis of patients with multiple myeloma complicated by myelofibrosis.

Dataset Information

Patient similarity network of newly diagnosed multiple myeloma identifies patient subgroups with distinct genetic features and clinical implications.

Publications

Patient similarity network of newly diagnosed multiple myeloma identifies patient subgroups with distinct genetic features and clinical implications.

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