"Direct to Drug" screening as a precision medicine tool in multiple myeloma

Area of Science:

• Oncology
• Pharmacology
• Genomics

Background:

• Multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) are hematologic malignancies with diverse therapeutic responses.
• Identifying predictive biomarkers for drug sensitivity is crucial for personalized medicine in these cancers.

Purpose of the Study:

• To evaluate ex vivo drug sensitivities of FDA-approved and emerging oncology therapeutics in MM and NHL models.
• To correlate drug responses with clinical, cytogenetic, genetic, and transcriptional profiles for biomarker discovery.

Main Methods:

• Screening of 76 oncology drugs against 25 MM and 15 NHL cell lines, and 113 primary MM samples.
• Analysis of ex vivo drug sensitivities against clinical phenotype, cytogenetics, genetic mutations, and transcriptional profiles.
• Clustering analysis to identify groups of drug sensitivity associated with genomic biomarkers and clinical outcomes.

Main Results:

• Proteasome inhibitors, dinaciclib, selinexor, venetoclax, auranofin, and histone deacetylating agents showed broad cytotoxicity in primary MM samples.
• Newly diagnosed MM samples were less sensitive to bromodomain inhibitors, RTK/non-RTK inhibitors, and DNA synthesis inhibitors.
• Drug sensitivity clusters correlated with genomic biomarkers; venetoclax sensitivity linked to t(11;14), while selinexor sensitivity associated with poor prognosis markers.

Conclusions:

• Ex vivo drug screening combined with functional genomics can guide individualized MM therapy.
• This approach has potential to enrich clinical trials by identifying likely responders.
• Specific drug sensitivities are associated with distinct molecular and clinical features in multiple myeloma.