Can Circulating Tumor DNA Improve Identification of High-Risk Myeloma Patients?
Dr. Sridurga Mithraprabhu presents the results of a study to find out if circulating RAS/RAF and DNA-Repair gene mutations associates with high-Risk/treatment resistance in primary refractory multiple myeloma.
Abstract title:
Circulating RAS/RAF and DNA-Repair Gene Mutations Associates with High-Risk/Treatment Resistance in Primary Refractory Multiple Myeloma
Purpose of the trial:
Multiple myeloma (MM) is an incurable plasma cell malignancy with a median overall survival (OS) of 5 years in newly diagnosed (ND) patients. Real-world data reveals that 23% of transplant eligible newly diagnosed MM patients relapse within 12 months of starting first-line bortezomib (1LB) based therapy and of these ~50% will fail secondary therapy and die within 18 months of diagnosis. It is currently impossible to identify these high-risk patients and genomic studies could potentially inform alternative secondary therapeutic options. We propose that circulating tumour DNA (ctDNA) analysis could provide a more holistic approach to gain an insight into the genomics of high-risk patients than bone marrow (BM) tumour DNA analysis in this genetically heterogenous multi-site malignancy.
Video summary:
A total of 186 paired peripheral blood plasma and BM samples were obtained at baseline, cycle 3 day 1 (C3D1), end of study (EOS) and/or relapse, whichever appeared earlier, from a Phase II single arm study of carfilzomib-thalidomide-dexamethasone (KTd) in 50 transplant-eligible ND MM patients who were refractory or had a suboptimal response to 1LB (Australasian Leukaemia and Lymphoma Group MM17 trial). Somatic variants were identified with ultra-sensitive targeted amplicon sequencing of BM and plasma for 22-genes known to be mutated in MM. The mutational profiles were combined with the International Staging System (ISS), SKY92 MMProfilerTM risk profile - standard-risk (SR) or high-risk (HR) or EuroFlow minimal residual disease (MRD) status and correlated to progression-free survival (PFS). Longitudinal monitoring of ctDNA variant allele frequency was also plotted to observe alterations in ctDNA kinetics at relapse compared to baseline and C3D1.
Conclusions:
These data demonstrate that combining ctDNA mutational profiling with available platforms for MM risk-stratification significantly enhances the identification of high-risk patients. Moreover, the impact in this context of RAS/RAF and DDR mutations provides a rationale for the design and implementation of novel treatment paradigms utilising RAS/RAF inhibitors or DNA-repair modulators in these high-risk MM patients.
Trial information:
ASH 2022: Abstract #4460
Authors:
Sridurga Mithraprabhu, PhD, MSc, John Reynolds, PhD, Rose Turner, Hang Quach, Noemi Horvath, MB ChB FRACP FRCPA, Ian H Kerridge, BA, BMed(Hons), MPhil(Cantab), FRACP, FRCPA, Flora Yuen, BBiomedSc, Tiffany Khong, BSc, PhD, Brian G.M. Durie, MD and Andrew Spencer
Doctor Bio:
Dr. Sridurga Mithraprabhu of Monash University joined Professor Andrew Spencer’s Myeloma Research Group (MRG) at the Australian Centre for Blood Diseases as a postdoctoral scientist in 2010. Her work on histone deacetylases (HDAC) in multiple myeloma (MM) and the utilisation of HDAC inhibitors (HDACi)/novel drugs for MM therapy resulted in 11 manuscripts, 6 conference abstracts, initiated a fully funded Phase I clinical trial at the Alfred Hospital and attracted significant research funding ($180K); she was subsequently promoted to Senior Research Fellow at the MRG.
