Preliminary results of 3D telomeres profiling for myeloma MRD and evaluation of concordance between blood and marrow.

Abstract

e19560 Background: Recent meta-analyses have demonstrated the importance of minimal residual disease (MRD) as a prognostic factor in multiple myeloma (MM). As a result, the FDA has approved MRD as an accelerated end point in clinical trials of MM. Current MRD technologies recognized by the International Myeloma Working Group include next generation sequencing and next generation flow cytometry. These technologies are focused on detection and enumeration of MRD. Each of these technologies has its technical limitations that prevent its broader applicability to all MM patients. Furthermore, these technologies are predominantly applicable to bone marrow specimens, which compromises the ability to monitor patients repeatedly over time. Since MM is a patchy disease, sampling of one area of the bone marrow may not detect the true burden of the disease, whereas a blood-based assay may be more representative of the tumor burden. Given the heterogeneity of MM there is a need for technologies that go beyond enumeration to characterize residual MM clones and classify MRD positive cases as aggressive or MGUS-like. Genomic instability (GI) is an accepted sensitive indicator of disease progression in cancer. Telomere dysfunction is an early event in GI. The 3-dimensional (3D) profiling of telomeres was shown to inform on GI and predict disease progression in cancer including hematological disorders. Here we present a comparative analysis of the 3D telomere profiles from blood vs marrow of 8 transplant eligible MM patients enrolled in our MRD clinical trial at baseline. Methods: We developed a technology that allows for enumeration of myeloma MRD cells combined with 3D telomere profiling using the TeloView platform. 3D co-immuno-telomere FISH is conducted on myeloma plasma cells isolated from marrow samples or circulating myeloma plasma cells isolated from blood. MRD enumeration is conducted based on immunophenotyping of the MM plasma cells followed by 3D telomere profiling using TeloView. At least 2 independent samples (from marrow & from blood) were included in the analysis. Statistics was conducted to calculate standard error, standard deviation and co-efficient of variation (CV). Concordance was considered if the CV was less than 20%. Results: The assay was successfully conducted on marrow and blood equally. We report concordance between blood and marrow in 5 out of 6 telomere parameters quantified by TeloView across all 8 patients (>80%), and concordance of all 6 parameters in 6 out of the 8 patients. Conclusions: These results show that at time of diagnosis, the clones in the marrow can be identified in the blood thus allowing for the assessment of GI in the plasma cells which may then predict risk of relapse. As patients will enter MRD negative status, we will demonstrate if this assay compares to the current standard of care assays, and potentially show an assessment of the residual clones in those that remain MRD positive. Clinical trial information: NCT05530096 .