New Target for Multiple Myeloma

A lot of progress has been made in myeloma, but there remains unmet need of patients who’ve exhausted many treatment options.

In a new prospective, prospective, multicenter, single-arm clinical trial study published in Nature Medicine, the researchers used longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. The main focus of the trial was to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination in newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen.

Prespecified exploratory analyses, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass).

The researchers found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM.

The researchers found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM.

CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors.

The authors concluded that integrating scRNA-seq in clinical trials can identify a signature of highly resistant MM patients and that PPIA is a potent therapeutic target for these tumors.

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