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

• Clinical diagnostic DNA sequencing can be used to identify resistance to immunotherapies, allowing for effective treatment management

Here we present the case for next generation sequencing of MM patient samples to not only identify high-risk markers, but also mutations and deletions relating to immunomodulatory drugs (IMiDs), and more importantly to guide the sequencing of immunotherapy regimens in response to intrinsic antigen escape as a means of treatment resistance and relapse. A single-center study of CD138+ cell selected samples (n=134) which included bone marrow aspirates from patients with smoldering multiple myeloma (n=11) and multiple myeloma (newly diagnosed n=38 and relapsed n=79) 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% of newly diagnosed myeloma patient samples. 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=0.03) which were mostly monoallelic. Deletions and mutations were detected in TNFRSF17 encoding BCMA in patients treated with anti-BCMA regimens, and the information was used to change the treatment of the patients. Targeted sequencing of multiple myeloma patient diagnostic samples can be used for risk stratification and also to monitor and adjust treatments as resistance mechanisms evolve.