Clinical Implications of Circulating Tumor DNA in Multiple Myeloma and Its Precursor Diseases
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background: Genetic alterations play a pivotal role in multiple myeloma (MM) develop- ment and therapeutic resistance. Traditionally, the genetic profiling of MM requires inva- sive bone marrow (BM) procedures; however, these procedures are associated with patient discomfort and cannot fully capture the spatial and temporal heterogeneity of the disease. Therefore, we investigated the clinical implications of liquid biopsy using targeted deep se- quencing. Methods: We analyzed the genetic profiles of circulating tumor DNA (ctDNA) by targeted deep sequencing from 102 patients, including those with monoclonal gammopathy of un- determined significance (MGUS, N=7), smoldering MM (N=6), and symptomatic MM (N=89). Results: The number of ctDNA mutations increased with disease progression from MGUS to MM, with averages of 1.0 mutations in MGUS, 1.8 mutations in smoldering MM, and 1.9 mutations in MM, respectively. Shared mutations between BM and ctDNA were more prev- alent in MM (68.9%) than in MGUS (25.0%). RAS/RAF and TP53 mutations were signifi- cantly enriched in MM ctDNA. Specific mutations were associated with clinical features in patients with MM: hypercalcemia and TET2 (P =0.006), renal insufficiency and NRAS (P =0.012), paramedullary myeloma and TP53 (P =0.02), and extramedullary myeloma and NRAS (P =0.007). TET2 mutations significantly affected 2-yr progression-free survival (hazard ratio=7.11, P =0.003). Serial ctDNA profiling accurately predicted treatment re- sponse in patients with MM. Conclusions: Our findings highlight the potential of liquid biopsy for understanding MM progression and prognosis utilizing a minimally invasive approach, paving the way for its in- tegration into personalized treatment strategies and real-time disease monitoring.
Abstract
Background: Genetic alterations play a pivotal role in multiple myeloma (MM) develop- ment and therapeutic resistance. Traditionally, the genetic profiling of MM requires inva- sive bone marrow (BM) procedures; however, these procedures are associated with patient discomfort and cannot fully capture the spatial and temporal heterogeneity of the disease. Therefore, we investigated the clinical implications of liquid biopsy using targeted deep se- quencing. Methods: We analyzed the genetic profiles of circulating tumor DNA (ctDNA) by targeted deep sequencing from 102 patients, including those with monoclonal gammopathy of un- determined significance (MGUS, N=7), smoldering MM (N=6), and symptomatic MM (N=89). Results: The number of ctDNA mutations increased with disease progression from MGUS to MM, with averages of 1.0 mutations in MGUS, 1.8 mutations in smoldering MM, and 1.9 mutations in MM, respectively. Shared mutations between BM and ctDNA were more prev- alent in MM (68.9%) than in MGUS (25.0%). RAS/RAF and TP53 mutations were signifi- cantly enriched in MM ctDNA. Specific mutations were associated with clinical features in patients with MM: hypercalcemia and TET2 (P =0.006), renal insufficiency and NRAS (P =0.012), paramedullary myeloma and TP53 (P =0.02), and extramedullary myeloma and NRAS (P =0.007). TET2 mutations significantly affected 2-yr progression-free survival (hazard ratio=7.11, P =0.003). Serial ctDNA profiling accurately predicted treatment re- sponse in patients with MM. Conclusions: Our findings highlight the potential of liquid biopsy for understanding MM progression and prognosis utilizing a minimally invasive approach, paving the way for its in- tegration into personalized treatment strategies and real-time disease monitoring.