Purpose: Molecular diagnostics for the risk stratification of patients with multiple myeloma (MM) have languished in the area of cytogenetics and fluorescence in situ hybidization (FISH). However, 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. Experimental design: <a href="https://www.ncbi.nlm.nih.gov/gene/6382">CD138</a>+ cell selected samples (n=134) from bone marrow aspirates from patients with multiple myeloma 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. Results: High-risk markers including t(4;14), t(14;16), t(14;20), gain or amplification 1q, deletion of <a href="https://www.ncbi.nlm.nih.gov/gene/1031">CDKN2C</a>, and deletion or mutation of <a href="https://www.ncbi.nlm.nih.gov/gene/7157">TP53</a> 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 (<a href="https://www.ncbi.nlm.nih.gov/gene/952">CD38</a>) were also enriched in patients who received anti-CD38 treatment (P=0.03) which were mostly monoallelic. Deletions and mutations were detected in <a href="https://www.ncbi.nlm.nih.gov/gene/608">TNFRSF17</a> encoding BCMA in patients treated with anti-BCMA regimens, and the information was used to change the treatment of the patients. Conclusions: 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.

Multiple Myeloma Clinical Targeted Sequencing of Patient Samples

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