摘要：

INTRODUCTION: Multiple myeloma (MM) is the second most prevalent blood cancer, representing approximately 1% of all cancers. Although overall survival has improved in recent years due to new approved agents, the vast majority of MM patients ultimately stop responding to treatment. Whereas current therapeutic approaches have focused mostly on the plasma cell biology of the disease, seminal genomic sequencing research efforts, such as the MMRF CoMMpass study, have highlighted that a large number of MM cases harbor potentially actionable oncogenic molecular alterations. Published reports on small numbers of cases suggest that Precision Medicine (PM) interventions clinically targeting such actionable alterations might be of benefit to MM patients who are running out of options. In order to study on a larger scale the potential and clinical utility of PM approaches in myeloma, the MMRF Molecular Profiling Protocol (NCT02884102) was opened in 2016 across the entire Multiple Myeloma Research Consortium (MMRC) with the goal of enrolling and following 500 relapsed patients that would be molecularly profiled using clinical-grade sequencing performed on the Michigan Oncology Sequencing (MI-ONCOSEQ) platform. METHODS: Bone marrow aspirates (BMAs) and matched normal peripheral blood (PB) are shipped overnight to the Michigan Center for Translational Pathology (MCTP) Clinical Sequencing Lab where CD138 enrichment is carried out. The MCTP sequencing lab is CLIA-CAP certified. DNA and RNA are isolated from MM cells and matched normal. Libraries are generated and subjected to the Oncoseq1500 gene exome capture. Deep targeted re-sequencing (>600x) is carried out on HiSeq2500 run in rapid mode. Data is computationally analyzed for mutation status. A molecular report highlighting actionable findings is produced, reviewed internally by a genomic Tumor Board and returned within 10 days. RESULTS: We are reporting on 228 consecutive cases analyzed with 84% of the sequenced samples (192) showing a very good tumor content. Importantly, 76% of cases were found to harbor at least one potentially actionable alteration. Of those cases, 53% had alterations in the MAPK pathway, 14% in the CCND1 and cyclin-dependent kinase (CDK) pathways, 6% had activating FGFR3 mutations followed by a group of events at 3% or less. In this cohort (n>2 priors on average), 16% of cases presented with TP53 mutations of which 1/4 could also be detected in blood. A search for other genes where a significant percentage of mutations were also detected in PB identified a small number of those including, among others, SF3B1, TET2, ASLX1, ASLX2 and DNMT3A with such mutations (typically subclonal) often co-occurring in the same specimen. In all, 10% of all cases presented with this mutational signature in both BMAs and PB of genes generally associated with MDS, AML and other myeloid disorders. With regards to actionability, in 10% of cases the treating clinician acted upon the information with the indicated targeted agent. Examples of the responses obtained will be presented. Analysis of progression-free survival and overall benefit for this cohort is ongoing. CONCLUSION: Actionable alterations were identified in over three quarter of cases analyzed. Deep sequencing of both BMAs and normal blood could also identify events that would have been missed had sequencing been only performed on the marrow. Although clinical applicability has been limited so far by the lack of availability of targeted agents for myeloma patients, the results suggest that Precision Medicine approaches in MM are possible and should be further studied clinically. To that end, we are launching MyDRUG, a master protocol aimed at developing new myeloma regimens based on individual patient's genomics.

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