Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing
Open accessAbstract
Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We 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. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.
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MM, a plasma cell malignancy, remains incurable until now.
“MM, plasma cell malignancy, remains incurable until now, so anti-myeloma drugs should improve its prognosis.”
From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [233]
Despite progress in disease treatment, resistance to therapy and relapse has occurred.
“Despite progress in disease treatment, resistance to therapy and relapse has occurred [233].”
From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [233]
BMSCs activate NF-κB, PI3K/Akt, and MAPK signaling pathways, which in turn suppress caspase cleavage and apoptosis in myeloma cells caused by chemotherapy.
“Additionally, they activate the nuclear factor kappa B (NF-κB), phosphoinositide 3 kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) signaling pathways, which in turn suppresses caspase cleavage and apoptosis in myeloma cells caused by chemotherapy [233, 239].”
From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [233]
The Results section on PPIA reports apoptosis after carfilzomib treatment and increased apoptosis when ciclosporin is added, but does not address whether BMSCs suppress it. Searches for BMSCs, NF-κB/PI3K/Akt/MAPK signaling, and caspase cleavage found no passage in our copy describing the claimed mechanism. (LLM, conf=0.76)
Experimental — accuracy not yet measuredHypoxia is a major driver of multiple drug resistance (MDR) to chemotherapeutic drugs.
“Hypoxia is considered to be a major driver of multiple drug resistance (MDR) to chemotherapeutic drugs. 378 , 379”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [379]
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Single cell clonotypic and transcriptional evolution of multiple myeloma precursor disease
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Clonal Evolution of Multiple Myeloma—Clinical and Diagnostic Implications
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Metabolic Alterations in Multiple Myeloma: From Oncogenesis to Proteasome Inhibitor Resistance
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Current Novel Targeted Therapeutic Strategies in Multiple Myeloma
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- Authors
- Cohen, Y. C., Zada, M., Wang, S.-Y., Bornstein, C., David, E., Moshe, A., Li, B., Shlomi-Loubaton, S., Gatt, M. E., Gur, C., Lavi, N., Ganzel, C., Luttwak, E., Chubar, E., Rouvio, O., Vaxman, I., Pasvolsky, O., Ballan, M., Tadmor, T., Nemets, A., Jarchowcky-Dolberg, O., Shvetz, O., Laiba, M., Shpilberg, O., Dally, N., Avivi, I., Weiner, A., & Amit, I.
- Affiliations
- Tel Aviv University (IL)
- Weizmann Institute of Science (IL)
- Hebrew University of Jerusalem (IL)
- Rambam Health Care Campus (IL)
- Shaare Zedek Medical Center (IL)
- Emek Medical Center (IL)
- Soroka Medical Center (IL)
- Carmel Medical Center (IL)
- Bnai Zion Medical Center (IL)
- Barzilai Medical Center (IL)
- Meir Medical Center (IL)
- Kaplan Medical Center (IL)
- Assuta Medical Center (IL)
- Rebecca Sieff Hospital (IL)
- Corresponding author
- Weiner, Assaf
- Amit, Ido
- ORCID
- Venue
- Nature Medicine
- Published
- 2021-02-22
- Volume
- 27
- Issue
- 3
- Pages
- 491-503
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC7612793
- OpenAlex
- W3133251387
- Cited by
- 235
- References
- 55
- Citations by year
- 2026: 30 · 2025: 33 · 2024: 51 · 2023: 58 · 2022: 48 · 2021: 15
- FWCI
- 29.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Amgen
- European Molecular Biology Organization (ALTF 263‐2018)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- relapsed multiple myeloma, treatment resistance, resistance mechanisms, single-cell RNA sequencing, daratumumab, carfilzomib, lenalidomide, dexamethasone, bortezomib, proteasome inhibitors, PPIA, hypoxia tolerance, mitochondrial respiration, therapeutic target, CRISPR/Cas9 gene deletion, cyclosporine
- MeSH terms
- Lenalidomide, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Dexamethasone, Female, Humans, Male, Middle Aged, Multiple Myeloma, Neoplasm Recurrence, Local, Oligopeptides, Case-Control Studies, Treatment Outcome, Drug Resistance, Neoplasm, Single-Cell Analysis
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