Eighty-eight percent of patients with relapsed or refractory multiple myeloma responded to the therapy.

  • Major Finding: Eighty-eight percent of patients with relapsed or refractory multiple myeloma responded to the therapy.

  • Concept: Single-cell RNA-sequencing analyses pinpointed the protein folding enzyme PPIA as a possible target.

  • Impact: This study shows the promise of the combination and identifies an additional druggable vulnerability.

Primary treatment resistance or relapse following treatment response is common in multiple myeloma, and much remains to be known about the mechanisms underlying resistance and relapse. In a multicenter, single-arm, phase II clinical, Cohen, Zada, Wang, and colleagues evaluated the safety, tolerability, and efficacy of combination treatment with daratumumab, carfilzomib, lenalidomide, and dexamethasone in 41 patients with newly diagnosed multiple myeloma whose disease was resistant to or relapsed early (within less than 18 months) after treatment with a bortezomib-containing induction regimen. Additionally, single-cell RNA-sequencing (scRNA-seq) experiments using longitudinally collected patient samples along with samples from 11 healthy subjects and 15 patients with newly diagnosed multiple myeloma were conducted as prespecified exploratory analyses. Thirteen percent of patients experienced complete responses, the overall response rate was 88%, and the median progression-free survival was 14.7 months; the median overall survival was not reached after a median follow-up period of 14.6 months. Treatment-emergent adverse events—most commonly fatigue, diarrhea, or hematologic abnormalities—occurred in 98% of patients, and 10% of patients discontinued the study treatment due to treatment-emergent adverse events. Interestingly, the scRNA-seq analyses revealed perturbation of pathways related to hypoxia adaptation, protein folding, and mitochondrial respiration in the samples from patients with relapsed or refractory disease. Deletion of PPIA (encoding peptidylprolyl isomerase A, important for protein folding), one of the genes implicated by the scRNA-seq analyses, or inhibition of PPIA with a small-molecule drug led to increased multiple myeloma–cell sensitivity to proteasome inhibitors in vitro. Collectively, the results of this trial not only demonstrate the potential of combination treatment with daratumumab, carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma but also implicate PPIA as a possible target of interest in this disease.

Cohen YC, Zada M, Wang SY, Bornstein C, David E, Moshe A, et al. Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing. Nat Med 2021 Feb 22 [Epub ahead of print].

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