High-throughput drug screening and multi-omic analysis to guide individualized treatment for multiple myeloma

David G. Coffey, Andrew J. Cowan, Bret DeGraaff, Timothy J. Martins, Niall Curley, Damian J. Green, Edward N. Libby, Rebecca Silbermann, Sylvia Chien, Jin Dai, Alicia Morales, Ted A. Gooley, Edus H. Warren, Pamela S. Becker

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE Multiple myeloma (MM) is a genetically heterogeneous malignancy characterized by variable treatment responses. Although numerous drugs have been approved in recent years, the ability to predict treatment response and tailor individual therapy is limited by the absence of robust predictive biomarkers. The goal of this clinical trial was to use ex vivo, high-throughput screening (HTS) of 170 compounds to predict response among patients with relapsed or refractory MM and inform the next treatment decisions. Additionally, we integrated HTS with multi-omic analysis to uncover novel associations between in vitro drug sensitivity and gene expression and mutation profiles. MATERIALS AND METHODS Twenty-five patients with relapsed or refractory MM underwent a screening bone marrow or soft tissue biopsy. Sixteen patients were found to have sufficient plasma cells for HTS. Targeted nextgeneration sequencing was performed on plasma cell-free DNA from all patients who underwent HTS. RNA and whole-exome sequencing of bone marrow plasma cells were performed on eight and seven patients, respectively. RESULTS Results of HTS testing were made available to treating physicians within a median of 5 days from the biopsy. An actionable treatment result was identified in all 16 patients examined. Among the 13 patients who received assay-guided therapy, 92% achieved stable disease or better. The expression of 105 genes and mutations in 12 genes correlated with in vitro cytotoxicity. CONCLUSION In patients with relapsed or refractory MM, we demonstrate the feasibility of ex vivo drug sensitivity testing on isolated plasma cells from patient bone marrow biopsies or extramedullary plasmacytomas to inform the next line of therapy.

Original languageEnglish (US)
Pages (from-to)602-612
Number of pages11
JournalJCO Precision Oncology
Volume5
DOIs
StatePublished - 2021
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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