Abstract 782: Circulating tumour DNA-based molecular response predicts treatment outcome in multiple myeloma
Authors: Mithraprabhu Sridurga , Khong Tiffany , Yuen Flora , Reynolds John , Durie Brian , Spencer Andrew 
Published: April 2023

Abstract
Background: Multiple myeloma (MM) is an incurable and multi-focal plasma cell malignancy manifesting predominantly within the bone marrow (BM). BM-based minimal residual disease (MRD) assessment utilising next generation flow (NGF - EuroFlowTM) has become an important measure of treatment response and a validated predictor of patient outcome. However, MRD is a single-site BM-derived assay and is conceptually limited due to the spatially heterogenous nature of MM and response to treatment.
Objective: We investigated if the evaluation of circulating tumour DNA (ctDNA) can be utilised as an adjunct to MRD analysis in predicting patient outcome.
Methods: Peripheral blood plasma was obtained at baseline (B), cycle 3 day 1 (C3D1) and end of study (EOS)/relapse from a phase II, multicentre single arm study of carfilzomib-thalidomide-dexamethasone (KTd) in 50 transplant-eligible newly diagnosed MM patients who were refractory to or had demonstrated a suboptimal response to first-line therapy. Extracted ctDNA was assessed utilising high-sensitivity targeted amplicon sequencing (TAS) of 22 MM-relevant genes. The variant allele frequency (VAF) of mutations at B was utilised to calculate a fold change in VAF at C3D1 and/or EOS. A negative fold change was defined as a decrease in VAF (ctDNA-) and a positive fold change an increase in VAF (ctDNA+) with the average fold change across all mutations calculated for each patient. EuroflowTM was performed on BM obtained pre and post-autologous stem cell transplant (ASCT) and at EOS and the ‘best MRD response’ achieved (MRD+ or MRD-) was recorded. The ctDNA and MRD responses were combined and correlated with progression-free survival (PFS) calculated using Kaplan-Meier estimates.
Results: A total of 45 patients had one or more mutations identified at B that could be tracked at C3D1 and/or EOS and 40 patients had one or more mutations that emerged at C3D1, EOS and/or relapse. Of these, 33 patients were evaluable for both MRD and ctDNA response. Patients that were MRD- and ctDNA- as best response for B mutations had a significantly longer PFS compared to those who were MRD+/ctDNA- or MRD-/ctDNA+ (p&lt;0.0001, Log-rank tests; 23.9 months vs not reached for MRD-ctDNA-, Log rank-tests). Patients that were MRD- and ctDNA- at C3D1 (as early response for B mutations) had a significantly longer PFS compared to those that were MRD+/ctDNA- or MRD-/ctDNA+ (p=0.0011, 26.4 months vs not reached in MRD-ctDNA-, Log-rank tests).
Conclusions: Our results demonstrate that treated MM patients manifesting a molecular response, as defined by a reduction in ctDNA mutational burden, and who are also MRD- have a superior outcome to those patients who are MRD- but without a molecular response. These results for the first time confirm the utility of ctDNA-based early molecular response as a predictor of patient outcome in MM.
Citation Format: Sridurga Mithraprabhu, Tiffany Khong, Flora Yuen, John Reynolds, Brian Durie, Andrew Spencer. Circulating tumour DNA-based molecular response predicts treatment outcome in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 782.