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. 2025 Jun;132(10):922-936.
doi: 10.1038/s41416-025-02987-6. Epub 2025 Apr 1.

Individualized dynamic risk assessment and treatment selection for multiple myeloma

Carl Murie  1 , Serdar Turkarslan  1 , Anoop P Patel  2 , David G Coffey  3 , Pamela S Becker  4   5 , Nitin S Baliga  6   7   8   9   10
Affiliations

Individualized dynamic risk assessment and treatment selection for multiple myeloma

Carl Murie et al. Br J Cancer. 2025 Jun.

Abstract

Background: Individualized treatment decisions for multiple myeloma (MM) patients require accurate risk stratification that accounts for patient-specific consequences of cytogenetic abnormalities on disease progression.

Methods: Previously, SYstems Genetic Network AnaLysis (SYGNAL) of multi-omics tumor profiles from 881 MM patients generated a mmSYGNAL network of transcriptional programs underlying disease progression across MM subtypes. Here, through machine learning on activity profiles of mmSYGNAL programs we have generated a unified framework of cytogenetic subtype-specific models for individualized risk classifications and prediction of treatment response.

Results: Testing on 1,367 patients across five independent cohorts demonstrated that the framework of mmSYGNAL risk models significantly outperformed cytogenetics, International Staging System, and multi-gene biomarker panels in predicting PFS at primary diagnosis, pre- and post-transplant and even after multiple relapses, making it useful for individualized risk assessment throughout the disease trajectory. Further, treatment response predictions were significantly concordant with efficacy of 67 drugs in killing myeloma cells from eight relapsed refractory patients. The model also provided new insights into matching MM patients to drugs used in standard of care, at relapse, and in clinical trials.

Conclusion: Activities of transcriptional programs offer significantly better prognostic and predictive assessments of treatments across different stages of MM in an individual patient.

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Conflict of interest statement

Competing interests: NB is a co-founder and member of the Board of Directors of Sygnomics, Inc., which will commercialize the SYGNAL technology. AP and ST have equity stakes in Sygnomics, Inc. The terms of these arrangements have been reviewed and approved by ISB and Duke University in accordance with their conflict-of-interest policies. PB received institutional research support from Glycomimetics, Pfizer, Notable labs, and is an advisor to Accordant Health Services (CVS Caremark). Ethics approval and consent to participate: This study utilizes publicly available human RNA sequencing datasets (GSE19784, GSE24080, GSE136337) from the Gene Expression Omnibus (GEO) repository, a previously published study on ex vivo drug sensitivity profiles of CD138+ cells from bone marrow aspirates from 8 patients [28] and the CoMMpass study. The data used in this study is considered not human subjects research, as it is publicly available open-access data [15, 33, 80]. All data were originally collected with appropriate ethical approval from their respective original studies and made publicly available in accordance with relevant guidelines and regulations. Informed consent was obtained from all participants by the original authors as documented in the previously published studies. The CoMMpass study (NCT01454297, dbGaP: phs000748.v7.p4) was conducted in accordance with recognized ethical guidelines in the United States and European Union and the Institutional Review Board at each participating center approved the study protocol. The CoMMpass trial is in accordance with the Declaration of Helsinki. Ex vivo drug sensitivity profiles for CD138+ cells from bone marrow aspirates of 8 (Patient IDs 9944-01, 9944-02, 9944-04, 9944-10, 9944-14, 9944-20, 9944-21, 9944-25) of the 23 patients, obtained at the Seattle Cancer Care Alliance (SCCA) on a Fred Hutchinson Cancer Center-approved IRB protocol (9944), were previously published [28]. The remaining 15 patients (IDs: MM26, MM48, MM59, MM68, MM80, MM83, MM84, MM137, MM144, MM154, MM160, MM173, MM184, MM194, MM209) were enrolled under a Fred Hutchinson Cancer Center-approved IRB protocol (1757). Informed consent was obtained from all participants, and all data were collected in accordance with recognized ethical guidelines. All methods in this study were conducted in accordance with the relevant guidelines and regulations (e.g., 45 CFR 46). Ethical approval for the use of data in this research was granted by the Institute of Systems Biology Compliance Manager, with the data designated as not human subjects research, as all data is de-identified and publicly accessible for the relevant datasets. Appropriate data use agreements were established for any data classified as controlled access.

Update of

References

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