Bone Marrow Microenvironment–Driven Resistance in Multiple Myeloma: A Prospective Clinical and Molecular Correlation Study

RESEARCH ARTICLE
Open Access

Bone Marrow Microenvironment–Driven Resistance in Multiple Myeloma: A Prospective Clinical and Molecular Correlation Study

Pierre Laurent1, Sophie Martin2, Julien Moreau3  

1Department of Thoracic Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay
Villejuif, France
2Department of Medical Oncology, Hôpital Bichat–Claude Bernard, Assistance Publique–
Hôpitaux de Paris (AP-HP), Université Paris Cité, Paris, France
3Department of Molecular Oncology and Liquid Biopsy, Centre Léon Bérard, Université Claude
Bernard Lyon, Lyon, France
Copyright: © 2026 Moreau, et al. This is an open-access article under a Creative Commons license (CC BY 4.0).

[crossmark doi="10.18081/ajbm.2026.1.57"]

ABSTRACT

Background

The optimal sequencing of targeted therapy and immunotherapy in advanced lung cancer remains a major clinical challenge due to evolving tumor heterogeneity and acquired resistance. Circulating tumor DNA (ctDNA) has emerged as a minimally invasive biomarker capable of capturing real-time tumor dynamics. This study aimed to evaluate the clinical utility of dynamic ctDNA monitoring in guiding treatment sequencing in a real-world prospective cohort of patients with advanced lung cancer.

Methods

In this prospective multicenter study conducted across five tertiary oncology centers in France, 174 patients with advanced lung cancer were enrolled between January 2021 and June 2024. Serial plasma samples were collected at baseline, early during treatment (week 4), at radiologic assessment, and at progression. ctDNA analysis was performed using high-depth next-generation sequencing and digital PCR. Early molecular response was defined as ctDNA clearance or ≥80% reduction at week 4. Associations between ctDNA dynamics, resistance mechanisms, treatment sequencing, and clinical outcomes were evaluated.

Results

Baseline ctDNA was detectable in 85.6% of patients. Early ctDNA clearance occurred in 52.3% and was strongly associated with improved progression-free survival (14.6 vs 6.1 months; HR 0.48; 95% CI, 0.34–0.67; P < .001) and overall survival (26.3 vs 13.9 months; HR 0.52; P < .001). ctDNA-based molecular progression preceded radiologic progression by a median of 6.4 weeks. Resistance mechanisms were identified in 47.9% of patients receiving targeted therapy, with EGFR C797S mutation and MET amplification being the most frequent. ctDNA-informed treatment adaptations were implemented in 35.1% of patients and were associated with improved post-progression outcomes (8.7 vs 5.2 months; HR 0.66; P = .01).

Conclusion

Baseline ctDNA was detectable in 85.6% of patients. Early ctDNA clearance occurred in 52.3% and was strongly associated with improved progression-free survival (14.6 vs 6.1 months; HR 0.48; 95% CI, 0.34–0.67; P < .001) and overall survival (26.3 vs 13.9 months; HR 0.52; P < .001). ctDNA-based molecular progression preceded radiologic progression by a median of 6.4 weeks. Resistance mechanisms were identified in 47.9% of patients receiving targeted therapy, with EGFR C797S mutation and MET amplification being the most frequent. ctDNA-informed treatment adaptations were implemented in 35.1% of patients and were associated with improved post-progression outcomes (8.7 vs 5.2 months; HR 0.66; P = .01).

Keywords: Circulating tumor DNA; Liquid biopsy; Non–small cell lung cancer; Treatment sequencing; Targeted therapy; Immunotherapy.

Recommended Citation

Laurent P, Martin S, Moreau J. Dynamic Monitoring of Circulating Tumor DNA to Guide Targeted and Immunotherapy Sequencing in Advanced Lung Cancer: A Real-World Prospective Analysis. Advanced Journal of Biomedicine & Medicine. 2026;14(1):57-81. doi:10.18081/ajbm.2026.1.57

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Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

[citeby doi="10.18081/ajbm.2026.1.57" refresh="true" interval="3600000"]

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Article details

  • Article type: Research Article
  • Journal: Journal of Global Hematology
  • Volume: 2
  • Issue: 1
  • Pages: 12–23
  • Published: 14 April 2021
  • DOI: 10.18081/JGH/2021.2/12

How to cite

El Harrak Y, Berrada S, Touhami A. Molecular Profiling of TP53 Mutations in Acute Myeloid Leukemia: A Prognostic and Therapeutic Insight. Journal of Global Hematology. 2021;2(1):12–23. doi:10.18081/JGH/2021.2/12

Corresponding author

Amina Touhami
Department of Clinical Oncology, National Institute of Oncology, Rabat, Morocco.
editor@globalhematology.com

Article timeline
  • Received: 24 January 2021
  • Revised: 25 March 2021
  • Accepted: 30 March 2021
  • Published: 14 April 2021
Post Views: 48