Precision medicine holds great promise to improve outcomes in cancer, including haematological malignancies. However, there are few biomarkers that influence choice of chemotherapy in clinical practice. In particular, multiple myeloma requires an individualized approach as there exist several active therapies, but little agreement on how and when they should be used and combined. We have previously shown that a transcriptomic signature can identify specific bortezomib- and lenalidomide-sensitivity. However, gene expression signatures are challenging to implement clinically. We reasoned that signatures based on the presence or absence of gene mutations would be more tractable in the clinical setting, though examples of such signatures are rare. We performed whole exome sequencing as part of the CARDAMON trial, which employed carfilzomib-based therapy. We applied advanced machine learning approaches to discover mutational patterns predictive of treatment outcome. The resulting model accurately predicted progression-free survival (PFS) both in CARDAMON patients and in an external validation set of patients from the CoMMpass study who had received carfilzomib. The signature was specific for carfilzomib therapy and was strongly driven by genes on chromosome 1p36. Importantly, patients predicted to be carfilzomib-sensitive had a longer PFS when treated with carfilzomib/lenadlidomide/dexamethasone than with bortezomib/carfilzomib/dexamethasone. However, in those predicted to be carfilzomib-insensitive, the latter therapy may have been capable of eradicating carfilzomib-resistant clones. We propose that the signature can be used to make rational therapeutic decisions and could be incorporated into future clinical trials.

Walker: Abbvie & Janssen: Honoraria. Popat: Takeda: Research Funding; GSK: Honoraria, Research Funding; Janssen, Takeda, Celgene, and GSK: Honoraria; Janssen, Takeda, GSK: Other: Travel expenses from Janssen, Takeda GSK; Roche:Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda, AbbVie, GlaxoSmithKline, and Celgene: Consultancy. Benjamin:Bristol Myers Squibb/Celgene: Research Funding; Amgen: Research Funding. Clifton-Hadley: Astra Zeneca, GSK, Pfizer, MSD, BMS, Amgen, Millennium Takeda: Other: CRUK and UCL CTC have received research funding in the past 24 months, Research Funding. Owen: Astra Zeneca: Honoraria; Janssen: Honoraria Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria ;Membership on an entity's Board of Directors or advisory committees. Chapman:Sanofi: Honoraria.

https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(22)00350-7/fulltext

IGW is supported by the Kay Kendall Leukaemia Fund KKL1442 also received support from the UK Myeloma Society UKMS, VdA has received support from the UKMS. MAC is supported by the Medical Research Council Toxicology Unit MC UU 00025 10. KY and RP are supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The Cardamon trial was funded by Amgen and endorsed by Cancer Research UK C9203 A17750 .

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Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The London City and East Research Ethics Committee London, UK gave full approval of study.

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All data produced in the present study are available upon reasonable request to the authors. Data and code will be made publicly available on acceptance in a peer reviewed journal