The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
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, 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]
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“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]
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“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]
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“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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Cites
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Massively parallel single-cell RNA-seq for marker-free decomposition of tissues into cell types
Jaitin, D. A., Kenigsberg, E., Keren-Shaul, H., Elefant, N., Paul, F., Zaretsky, I., Mildner, A., Cohen, N., Jung, S., Tanay, A., et al. (2014) · Science · doi:10.1126/science.1247651 · Cited by 1,795
Self-citationThe molecular classification of multiple myeloma
Zhan, F., Huang, Y., Colla, S., Stewart, P., Hanamura, I., Gupta, S. K., Epstein, J., Yaccoby, S., Sawyer, J. R., Burington, B. E., et al. (2006) · Blood · doi:10.1182/blood-2005-11-013458 · Cited by 1,147
Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors
Paul, F., Arkin, Y., Giladi, A., Jaitin, D. A., Kenigsberg, E., Keren-Shaul, H., Winter, D., Lara-Astiaso, D., Gury, M., Weiner, A., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.013 · Cited by 1,082
Self-citationKrejcik, J., Casneuf, T., Nijhof, I. S., Verbist, B. M. P., Bald, J., Plesner, T., Syed, K. W., Liu, K., van de Donk, N. W. C. J., Weiss, B. M., et al. (2016) · Blood · doi:10.1182/blood-2015-12-687749 · Cited by 981
Shaughnessy, J. D., Zhan, F., Burington, B. E., Huang, Y., Colla, S., Hanamura, I., Stewart, P., Kordsmeier, B., Randolph, C. E., Williams, D. R., et al. (2006) · Blood · doi:10.1182/blood-2006-07-038430 · Cited by 916
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Metadata
- 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 › Hematology › Chronic Lymphocytic Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › 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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