Cell-free DNA for the detection of emerging treatment failure in relapsed/ refractory multiple myeloma

Abstract

Interrogation of cell-free DNA (cfDNA) represents an emerging approach to non-invasively estimate disease burden in multiple myeloma (MM). Here, we examined low-pass whole genome sequencing (LPWGS) of cfDNA for its predictive value in relapsed/refractory MM (RRMM). We observed that cfDNA positivity, defined as ≥10% tumor fraction by LPWGS, was associated with significantly shorter progression-free survival (PFS) in an exploratory test cohort of 16 patients who were actively treated on diverse regimens. We prospectively determined the predictive value of cfDNA in 86 samples from 45 RRMM patients treated with elotuzumab, pomalidomide, bortezomib and dexamethasone in a phase II clinical trial ( NCT02718833 ). PFS in patients with tumor-positive and -negative cfDNA after two cycles of treatment was 1.6 and 17.6 months, respectively (HR 7.6, P<0.0001). Multivariate hazard modelling confirmed cfDNA as independent risk factor (HR 96.6, P=6.92e-05). While correlating with serum-free light chains and bone marrow, cfDNA additionally discriminated patients with poor PFS among those with the same response by IMWG criteria. In summary, detectability of MM-derived cfDNA, as a measure of substantial tumor burden with therapy, independently predicts poor PFS and may provide refinement for standard-of-care response parameters to identify patients with poor response to treatment earlier than is currently feasible.

The level and integrity of plasma circulating cell-free DNA in patients with primary multiple myeloma

“…Mithraprabhu et al ( 16 ) found that patients with higher cfDNA levels had significantly poorer overall survival, and that reductions in cfDNA levels were associated with improvement after several days of chemotherapy cycles. Waldschmidt et al ( 17 ) prospectively enrolled 86 blood samples from 45 MM patients treated with drugs such as pomalidomide, bortezomib, and dexamethasone in a phase II clinical trial. After two cycles of treatment, higher levels of cfDNA were found to be associated with worse PFS (1.6 vs. 17.6 months).…”

Liquid biopsy by analysis of circulating myeloma cells and cell-free nucleic acids: a novel noninvasive approach of disease evaluation in multiple myeloma

“…However, the ctDNA level only showed a conditional correlation with myeloma cell infiltration in the BM. Although some studies found that patients with a high ctDNA level had more BM infiltrations [47,48,57,73], no quantificational correlation was found between the VAF of tumor-related mutations in cfDNA and BM MM cell infiltration [10], which could be explained by BM heterogeneity and the presence of EM lesions. According to a previous report, patients with short progression-free survival (PFS) and high tumor burden by cfDNA were observed to have inconsistently low BM infiltration.…”

“…A previous study found that the TF in cfDNA from MM was 4.5 times higher than that in cfDNA from MGUS and SMM [56]. The cfDNA levels were observed to be significant predictors of clinical scores or markers of high disease burden, including advanced ISS stage [9,57,73] and R-ISS stage [46,73], elevated levels of LDH [3,9,47,73] and β2-MG in serum [9], more EM disease in positron emission tomography-computed tomography (PET-CT) [47,74], or osteolytic lesions [48,74]. Most patients showed a positive correlation between the frequencies and VAF of mutations [57,73,75,76], the TF based on CNAs [3,49,74,76], and the frequencies of MM clones (Ig rearrangements) [36] in paired myeloma cells in the BM and cfDNA.…”

“…According to a previous report, patients with short progression-free survival (PFS) and high tumor burden by cfDNA were observed to have inconsistently low BM infiltration. This suggests that cfDNA is less prone to spatial and technical bias than a BM biopsy and can assess a more thorough disease burden than a singlesite BM biopsy [47].…”

Advances in the molecular characterization of multiple myeloma and mechanism of therapeutic resistance

“…In the case of MM, ctDNA burden correlates with higher 70-GEP and prognosis, with patients with higher burden having worse PFS and OS ( 41 ). Furthermore, it has been proposed as a tool to detect treatment failure and subsequent relapse in the RRMM setting ( 42 ). As mentioned before, the integration of SNV’s, translocation, and copy number changes into defined molecular subgroups of SMM improve the performance of 2/20/20 model ( 34 ), but will lack of widespread access to this technology remains a limitation.…”