Diagnostic sequencing identifies high-risk markers and mechanisms of resistance to guide immunotherapy selection.

abstractHere, we present the case for next-generation sequencing of samples from patients with multiple myeloma (MM), not only identify high-risk markers but also mutations and deletions relating to immunomodulatory drugs (IMiD), and more importantly to guide the sequencing of immunotherapy regimens in response to intrinsic antigen escape as a means of treatment resistance and relapse. This is a single-center study of CD138+ selected (n = 134) bone marrow aspirate samples from patients with smoldering MM (n = 11) and MM (newly diagnosed, n = 38; relapsed, n = 79). Samples were sequenced using a targeted panel in a clinical diagnostics laboratory. Data were analyzed for high-risk markers, treatment-related resistance mechanisms, and precision medicine targets to guide the future treatment of patients in the clinic. High-risk markers, including t(4;14), t(14;16), t(14;20), gain or amplification 1q, deletion of CDKN2C, and deletion or mutation of TP53, were identified in 15% samples from patients with newly diagnosed. At relapse, alterations in the cereblon degradation pathway were found in 24.3% of IMiD-treated patients. Deletions of 4p (CD38) were also enriched in patients who received anti-CD38 treatment (P = .03), which were mostly monoallelic. Deletions and mutations were detected in TNFRSF17-encoding B-cell maturation antigen (BCMA) in patients treated with anti-BCMA regimens, and the information was used to change the treatment of the patients. Targeted sequencing of diagnostic samples of patients with MM can be used for risk stratification and to monitor and adjust treatments as resistance mechanisms evolve.