Sensitivity, specificity, and accuracy of molecular profiling on circulating cell-free DNA in refractory or relapsed multiple myeloma patients, results of MM-EP1 study

Abstract

As a promising alternative to bone marrow aspiration (BMA), mutational profiling on blood-derived circulating cell-free tumor DNA (cfDNA) is a harmless and simple technique to monitor molecular response and treatment resistance of patients with refractory/relapsed multiple myeloma (R/R MM). We evaluated the sensitivity and specificity of cfDNA compared to BMA CD138 positive myeloma plasma cells (PCs) in a series of 45 R/R MM patients using the 29-gene targeted panel (AmpliSeq) NGS. KRAS, NRAS, FAM46C, DIS3, and TP53 were the most frequently mutated genes. The average sensitivity and specificity of cfDNA detection were 65% and 97%, respectively. The concordance per gene between the two samples was good to excellent according to Cohen’s κ coefficients interpretation. An increased number of mutations detected in cfDNA were associated with a decreased overall survival. In conclusion, we demonstrated cfDNA NGS analysis feasibility and accuracy in R/R MM patients who may benefit from early phase clinical trial.

Keywords:

• Refractory/relapsed multiple myeloma
• precision medicine
• liquid biopsy
• tumor-derived
• circulating cell-free DNA
• targeted next-generation sequencing

Ethical approval statement

The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in conformity with good clinical practice described in the E6 guidelines of the International Council for Harmonization. The protocol was reviewed and approved by Gustave Roussy Institutional Review Board and Independent Ethics Board. All the patients included in the study signed a written informed consent before the start of the study.

Disclosure statement

Jean-Marie Michot: Principal/sub-Investigator of Clinical Trials for: Abbvie, Agios, Amgen, Argen-x, Astex, AstraZeneca, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Seattle Genetics, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor; Personal fees (Monies paid to you for services rendered, generally honoraria, royalties or fees for consulting, lectures, speakers bureaus, expert testimony, employment, ad-boards, etc.): Roche, AstraZeneca, Amgen, Ideogen; Non-financial support (Drugs, equipment supplied by the entity, travel paid by the entity, writing assistance, administrative support, etc.): Celgene, Bristol-Myers Squibb, and GSK. Alina Danu: Membership on a Board or Advisory Committee: Amgen. Vincent Ribrag: Speakers Bureau: Abvie; Research Funding: Astex, Epizyme, GSK; Membership on a Board or Advisory Committee: AZ, BMS, Gilead, Incyte, Infinity, MSD, Nanostring, Pharmamar, Roche, Servier; Honoraria: Epizyme, Pharmamar; Consultancy: Servier.

The remaining authors have no potential conflict of interest to declare.

Author contributions

CQ, AD, and VR designed the research study; JMM, AD, VS, KS, VV, SC, and VR managed patients; HL performed NGS experiments; CQ performed data analysis; CQ and JMM wrote the manuscript; CQ, JMM, VS, HL, OAB, and VR reviewed and edited the manuscript; CQ, JMM, AD, and VR supervised the study. All authors reviewed and approved the manuscript.

Data availability statement

All the data supporting the findings of this study are available in Supplementary material. Any further request may be addressed to corresponding author upon reasonable request.

Additional information

Funding

This work was funded by GlaxoSmithKline LLC and by the research program in personalized medicine of the Translational Hematology Laboratory.