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Cited by 34Multiple Myeloma Research and TreatmentsExtracellular vesicles in diseaseChronic Lymphocytic Leukemia Research

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A liquid biopsy to detect multidrug resistance and disease burden in multiple myeloma

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Rajeev Krishnan, Sabna, De Rubis, Gabriele, Suen, Hayley, Joshua, Douglas, Lam Kwan, Yiu, Bebawy, Mary·2020·Blood Cancer Journal
DOI 10.1038/s41408-020-0304-7PMC PMC7070076
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Abstract

Multiple myeloma is an incurable cancer of bone marrow plasma cells, with a 5-year survival rate of 43%. Its incidence has increased by 126% since 1990. Treatment typically involves high-dose combination chemotherapy, but therapeutic response and patient survival are unpredictable and highly variable—attributed largely to the development of multidrug resistance (MDR). MDR is the simultaneous cross-resistance to a range of unrelated chemotherapeutic agents and is associated with poor prognosis and survival. Currently, no clinical procedures allow for a direct, continuous monitoring of MDR. We identified circulating large extracellular vesicles (specifically microparticles (MPs)) that can be used to monitor disease burden, disease progression and development of MDR in myeloma. These MPs differ phenotypically in the expression of four protein biomarkers: a plasma-cell marker (CD138), the MDR protein, P-glycoprotein (P-gp), the stem-cell marker (CD34); and phosphatidylserine (PS), an MP marker and mediator of cancer spread. Elevated levels of P-gp+and PS+MPs correlate with disease progression and treatment unresponsiveness. Furthermore, P-gp, PS and CD34 are predominantly expressed in CD138−MPs in advanced disease. In particular, a dual-positive (CD138−P-gp+CD34+) population is elevated in aggressive/unresponsive disease. Our test provides a personalised liquid biopsy with potential to address the unmet clinical need of monitoring MDR and treatment failure in myeloma.

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Fig. 1 P-gp+ MPs increase in MM. The P-gp+ MP counts in the total MP population in MM patients and healthy subjects are shown. a P-gp+ MP numbers were significantly greater in MM patients relative to healthy subjects (p = 0.0071, U = 516). b P-gp+ MP numbers were greater in de novo (p = 0.0032, U = 69) and progressive disease (p = 0.0096, U = 96) patients relative to healthy subjects. There was no significant difference in the P-gp+ MP numbers between patients in partial remission (PR) or complete remission (CR) and healthy subjects. Lines represent the mean values. p values were determined by Mann–Whitney U. **p < 0.01.
Fig. 1 P-gp+ MPs increase in MM. The P-gp+ MP counts in the total MP population in MM patients and healthy subjects are shown. a P-gp+ MP numbers were significantly greater in MM patients relative to healthy subjects (p = 0.0071, U = 516). b P-gp+ MP numbers were greater in de novo (p = 0.0032, U = 69) and progressive disease (p = 0.0096, U = 96) patients relative to healthy subjects. There was no significant difference in the P-gp+ MP numbers between patients in partial remission (PR) or complete remission (CR) and healthy subjects. Lines represent the mean values. p values were determined by Mann–Whitney U. **p < 0.01.CC BY · PubMed Central
Fig. 2 CD138 and P-gp are not coexpressed on MPs. The numbers of Pgp+ MPs in the context of CD138 expression are shown. a There was no significant difference in CD138+ P-gp+ MP numbers in MM patients relative to healthy subjects. b CD138+ P-gp+ MP numbers across de novo, PR, CR and PD were not significantly different in MM patients relative to healthy subjects. c CD138− P-gp+ MP numbers were significantly greater in MM patients relative to healthy subjects (p = 0.011, U = 541). d CD138− P-gp+ numbers were significantly greater in de novo (p = 0.001, U = 81) and PD (p = 0.0379, U = 104) patients compared to healthy volunteers and not significant for CR, PR patients. Lines represent the mean values. p values were determined by Mann–Whitney U. *p < 0.05; **p < 0.01.
Fig. 2 CD138 and P-gp are not coexpressed on MPs. The numbers of Pgp+ MPs in the context of CD138 expression are shown. a There was no significant difference in CD138+ P-gp+ MP numbers in MM patients relative to healthy subjects. b CD138+ P-gp+ MP numbers across de novo, PR, CR and PD were not significantly different in MM patients relative to healthy subjects. c CD138− P-gp+ MP numbers were significantly greater in MM patients relative to healthy subjects (p = 0.011, U = 541). d CD138− P-gp+ numbers were significantly greater in de novo (p = 0.001, U = 81) and PD (p = 0.0379, U = 104) patients compared to healthy volunteers and not significant for CR, PR patients. Lines represent the mean values. p values were determined by Mann–Whitney U. *p < 0.05; **p < 0.01.CC BY · PubMed Central
Fig. 3 PS+ MPs represents a more aggressive state in MM. The PS+ MP counts in MM patients and healthy subjects are shown. a PS+ MP counts were significantly greater in MM patients relative to healthy volunteers (p = 0.005, U = 433). b PS+ MP counts were greater in de novo (p = 0.0026, U = 60), PR (p = 0.03, U = 172), and PD (p = 0.005, U = 85) cohorts relative to healthy volunteers. No significant difference in PS+ MP counts was observed between the CR and healthy volunteers. PS+ MPs counts were significantly higher in the PD cohort compared to the CR cohort (p = 0.034, U = 54). p values were generated using Mann–Whitney U test and the lines represent mean values. *p < 0.05; **p < 0.01.
Fig. 3 PS+ MPs represents a more aggressive state in MM. The PS+ MP counts in MM patients and healthy subjects are shown. a PS+ MP counts were significantly greater in MM patients relative to healthy volunteers (p = 0.005, U = 433). b PS+ MP counts were greater in de novo (p = 0.0026, U = 60), PR (p = 0.03, U = 172), and PD (p = 0.005, U = 85) cohorts relative to healthy volunteers. No significant difference in PS+ MP counts was observed between the CR and healthy volunteers. PS+ MPs counts were significantly higher in the PD cohort compared to the CR cohort (p = 0.034, U = 54). p values were generated using Mann–Whitney U test and the lines represent mean values. *p < 0.05; **p < 0.01.CC BY · PubMed Central
Fig. 4 PS is enriched on CD138− MPs in progressive disease. The numbers of PS+ MPs in context to the expression of CD138 are shown. a PS+MPs in the CD138+ MP subset were significantly elevated in MM patients compared to the healthy volunteers (p = 0.0041, U = 405.5). b CD138+PS+MP levels in the de novo and PR (p = 0.007, U = 134) cohorts were significantly higher relative to healthy volunteers, while the differences between CR or PD and healthy volunteers were not significant. c PS+MPs in the CD138− MP subset were significantly elevated in MM patients relative to healthy volunteers (p = 0.001, U = 406). d CD138−PS+ MPs were significantly higher in de novo (p = 0.004, U = 80), PD (p = 0.001, U = 52) and PR (p = 0.043, U = 180) cohorts relative to healthy volunteers. There was no significant difference in CR cohort relative to healthy volunteers. Mann–Whitney U test was conducted to generate p values and the data are represented as mean. *p < 0.05; **p < 0.01.
Fig. 4 PS is enriched on CD138− MPs in progressive disease. The numbers of PS+ MPs in context to the expression of CD138 are shown. a PS+MPs in the CD138+ MP subset were significantly elevated in MM patients compared to the healthy volunteers (p = 0.0041, U = 405.5). b CD138+PS+MP levels in the de novo and PR (p = 0.007, U = 134) cohorts were significantly higher relative to healthy volunteers, while the differences between CR or PD and healthy volunteers were not significant. c PS+MPs in the CD138− MP subset were significantly elevated in MM patients relative to healthy volunteers (p = 0.001, U = 406). d CD138−PS+ MPs were significantly higher in de novo (p = 0.004, U = 80), PD (p = 0.001, U = 52) and PR (p = 0.043, U = 180) cohorts relative to healthy volunteers. There was no significant difference in CR cohort relative to healthy volunteers. Mann–Whitney U test was conducted to generate p values and the data are represented as mean. *p < 0.05; **p < 0.01.CC BY · PubMed Central
Fig. 5 P-gp+MPs in a 58-year-old female patient with aggressive disease (patient 1). The P-gp+ MP counts (Y-axis) and time of MP sampling post diagnosis (X-axis) are shown. a CD138−P-gp+ MP numbers during treatment (CyBorD, circle; BorD (Cyclophosphamide discontinued), filled circle; VTD, triangle; lenalidomide/dexamethasone, filled triangle; D-PACE and melphalan, diamond). b CD138+ P-gp+ MP numbers during treatment.
Fig. 5 P-gp+MPs in a 58-year-old female patient with aggressive disease (patient 1). The P-gp+ MP counts (Y-axis) and time of MP sampling post diagnosis (X-axis) are shown. a CD138−P-gp+ MP numbers during treatment (CyBorD, circle; BorD (Cyclophosphamide discontinued), filled circle; VTD, triangle; lenalidomide/dexamethasone, filled triangle; D-PACE and melphalan, diamond). b CD138+ P-gp+ MP numbers during treatment.CC BY · PubMed Central
Fig. 6 Increased ‘dual-positive’ MPs in aggressive disease (patient 1). P-gp+ and CD34+ MP counts in CD138− and CD138+ MP populations were determined using flow cytometry. a A sequential gating strategy using MP size (left panel) followed by CD41a expression (middle panel) and CD138 expression (right panel) was applied to the total MP population (left panel). The total MP population (CD41a−) was defined based on ± staining for anti-CD41a (middle panel). b The total MP population was gated based on CD138 expression. We phenotyped for the presence of CD138− P-gp+ CD34+ MPs (left panel, gate P1) and CD138+ P-gp+ CD34+ MPs (right panel, gate P4). c The CD138− P-gp+ CD34+ and CD138+ P-gp+ CD34+ MP subpopulations (gates P1 and P4 of left and right panel in b, respectively) were gated and phenotyped for PS+ events using annexin V (left panel, gate P11; right panel, gate P12), respectively.
Fig. 6 Increased ‘dual-positive’ MPs in aggressive disease (patient 1). P-gp+ and CD34+ MP counts in CD138− and CD138+ MP populations were determined using flow cytometry. a A sequential gating strategy using MP size (left panel) followed by CD41a expression (middle panel) and CD138 expression (right panel) was applied to the total MP population (left panel). The total MP population (CD41a−) was defined based on ± staining for anti-CD41a (middle panel). b The total MP population was gated based on CD138 expression. We phenotyped for the presence of CD138− P-gp+ CD34+ MPs (left panel, gate P1) and CD138+ P-gp+ CD34+ MPs (right panel, gate P4). c The CD138− P-gp+ CD34+ and CD138+ P-gp+ CD34+ MP subpopulations (gates P1 and P4 of left and right panel in b, respectively) were gated and phenotyped for PS+ events using annexin V (left panel, gate P11; right panel, gate P12), respectively.CC BY · PubMed Central
Fig. 7 62-year-old male patient in remission—long-term survivor (patient 5). The presence of P-gp+ and CD34+ MPs in CD138− (left panel) and CD138+ (right panel) MP populations was determined by flow cytometry for patient 5. a The total MP population was gated based on CD138 expression (left panel, CD138−; right panel, CD138+, respectively). We phenotyped for CD138− P-gp+ CD34+ MPs (left panel, gate P1) and CD138+ P-gp+ CD34+ MPs (right panel, gate P4). b The CD138 MP subpopulations (gates P1 and P4 of left and right panel, respectively) were also gated and phenotyped for the presence of PS using annexin V (left panel, gate P11, events; right panel, gate P12), respectively.
Fig. 7 62-year-old male patient in remission—long-term survivor (patient 5). The presence of P-gp+ and CD34+ MPs in CD138− (left panel) and CD138+ (right panel) MP populations was determined by flow cytometry for patient 5. a The total MP population was gated based on CD138 expression (left panel, CD138−; right panel, CD138+, respectively). We phenotyped for CD138− P-gp+ CD34+ MPs (left panel, gate P1) and CD138+ P-gp+ CD34+ MPs (right panel, gate P4). b The CD138 MP subpopulations (gates P1 and P4 of left and right panel, respectively) were also gated and phenotyped for the presence of PS using annexin V (left panel, gate P11, events; right panel, gate P12), respectively.CC BY · PubMed Central

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Metadata

Authors
Rajeev Krishnan, S., De Rubis, G., Suen, H., Joshua, D., Lam Kwan, Y., & Bebawy, M.
Affiliations
  • Royal Prince Alfred Hospital (AU)
  • University of Technology Sydney (AU)
Corresponding author
Bebawy, Mary
ORCID
Venue
Blood Cancer Journal
Publisher
Springer Science and Business Media LLC
Published
2020-03-13
Volume
10
Issue
3
Pages
37-37
ISSN
2044-5385 (ISSN-L)
DOI
10.1038/s41408-020-0304-7
PMC
PMC7070076
OpenAlex
W3011733886
Cited by
34
References
0
Citations by year
2026: 1 · 2025: 7 · 2024: 2 · 2023: 3 · 2022: 7 · 2021: 10 · 2020: 4
FWCI
3.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Blood Cancer Journal (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RUNE (Research UNE) (submittedVersion, cc-by)
  • UTS ePRESS (University of Technology Sydney) (submittedVersion, other-oa)
Funders
NSW Health Pathology
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
Keywords
multiple myeloma, multidrug resistance, liquid biopsy, circulating microparticles, extracellular vesicles, P-glycoprotein, phosphatidylserine, syndecan-1, CD34, disease burden monitoring, treatment response, disease progression
MeSH terms
Liquid Biopsy, Humans, Multiple Myeloma, Drug Resistance, Multiple

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