The unparalleled scale of this recent study is therefore an important break from the past in the fight against a highly incurable cancer. On top of clarifying differences in treatment response from patient to patient, the screening platform also makes it possible to monitor differences in 1 patient over time. As a patient’s disease state changes, clinicians will have a better framework for adjusting or switching medication.
“The underlying hypothesis for functional precision medicine approaches is that every patient has a unique mosaic of genetic alterations, leading to a unique combination of drug sensitivities at a given time during the course of disease,” explained Dr Meurice. “This strategy can be applied over time, and drug sensitivities monitored as patients relapse.”
The assay requires a short turnaround time, and was designed with clinical utility in mind: the faster it provides results, the more easily it could be incorporated into routine clinical screening. One limitation is that it’s unable to screen immune therapies, such as monoclonal antibodies and checkpoint inhibitors. These types of therapies have had promising results in stymying multiple myeloma, and could be even more useful in an individualized therapy.
However, among the 76 drugs that the panel did include, some of the main takeaways included: cells with IRF4 mutations, which tend to be linked to a favorable survival rate as is, are particularly sensitive to MAPK and ALK inhibitors; samples with 17p deletions may benefit particularly from CDK and DNA synthesis inhibitors that can target the cell cycle; and deeper insight into venetoclax, for which patients with a more specific profile are most sensitive — those who are “newly diagnosed, standard risk, with low plasma cell S-phase, harboring t(11;14), and lacking Gain(1q) or t(4;14).” For venetoclax, this adds additional insight on top of reaffirming that patients expressing the BCL2 gene family is a good predictor of response to the drug.
The findings also offer a cautionary, contextual go-ahead for selinexor: while the drug’s adverse side effects have tended to make it more clinically limiting, in the context of a direct-to-drug screening assay, it’s possible to see which patients might really benefit from it, saving other patients from unnecessary toxicity. The researchers assert in the study that selinexor is best used in patients with biomarkers for a poor prognosis who are heavily pretreated.
The screening platform “is of particular interest to understand and identify exceptional responders,” says Dr Meurice.
Drs Meurice, de Campos, and Bergsagel agreed that one of the benefits of this screening program is how flexible it is. These data put a microscope on what outcomes can be expected when pairing specific drugs with specific patients. Further, as the broader understanding of multiple myeloma’s underlying biology grows and some drugs fall out of favor while new ones emerge, the screen can change with the times. Ultimately, the researchers hope that this flexible screening resource will not only personalize therapeutic care but will also help make clinical trials more informative.
Bonolo de Campos, C., Meurice, N., Petit, J.L. et al. “Direct to Drug” screening as a precision medicine tool in multiple myeloma. Blood Cancer J. 2020;10(5):54.