Targeted Capture and Sequencing of Immunoglobulin Rearrangements in Multiple Myeloma to Enable Detection of Minimal Residual Diseas

Multiple Myeloma (MM) is an incurable plasma cell dyscrasia characterized by recurrent translocations into immunoglobulin loci and a unique V(D)J rearrangement signature that can be used to track disease over time. Modern myeloma therapy results in high response rates, however the majority of patients still relapse, suggesting persistence of minimal residual disease (MRD) beyond current limits of detection. We developed a targeted-capture approach to detect V(D)J rearrangements and recurrent immunoglobulin translocations to enable MRD assessment. We validated this assay in 69 human myeloma cell lines and established a limit of detection of 1/1000 DNA fragments. Our methods agree with MRD measured by multi-parameter flow cytometry in 11/14 patient samples. One sample was MRD positive by MFC and negative by targeted-capture sequencing, two were positive by sequencing and negative by MFC. Targetedcapture sequencing is an alternative strategy to MRD detection and has potential applications for disease monitoring and immune repertoire profiling.