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Multiple myeloma gammopathies

Prediction of immunomodulatory drugs (IMiDs) sensitivity in myeloma via determination of baseline anti-oxidative stress capacity

Leukemia volume 34, pages 3060–3063 (2020)Cite this article

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Multiple myeloma (MM) is a plasma cell neoplasm that produces and secretes monoclonal immunoglobulins. Immunoglobulin synthesis leads to the production of disulfide bonds during protein folding, a reaction catalyzed by the Ero1 flavoprotein in the endoplasmic reticulum (ER), which consumes oxygen and generates hydrogen peroxide (H2O2) [1, 2]. H2O2 production beyond the detoxifying capacity of the cell has been shown to increase cell apoptosis via activation of the oxidative stress response, and plasma cell survival is dependent upon a robust antioxidative system [3, 4]. Immunomodulatory drugs (IMiDs) like lenalidomide, thalidomide, and pomalidomide form a key component for the treatment of patients with MM. These therapies require the presence of cereblon (CRBN), leading to selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3 [5, 6].

Another mechanism of action of IMiDs is inhibition of intracellular peroxidase-mediated H2O2 decomposition by increasing intracellular oxidative stress, thereby inducing cell apoptosis [7]. MM cells with lower antioxidative capacity have shown increased vulnerability to lenalidomide-mediated apoptosis. Oxidized flavin adenine dinucleotide (FAD) can be used as an indirect measure of plasma cell antioxidative capacity. FAD has auto-fluorescent properties amenable to measurement via flow cytometry. In addition, samples with high antioxidative capacities have been shown to generate higher amounts of oxygen species when exposed to H2O2, due to its processing to water and soluble oxygen [7]. Understanding of these mechanisms has allowed for the development of assay that has the potential to evaluate IMiD resistance in MM cells. While in vitro testing has shown promise in assessing for IMiD resistance, it is unclear if this translates into clinical relevance. Currently, resistances to IMiDs can only be determined post hoc, and as defined by clinical assessments via imaging and serum protein studies. In the modern era, multi-agent anti-MM therapies have become the standard of care in effectively all patients with MM as recommended by multiple societies [8,9,10]. This has made identifying IMiD resistance more challenging as there is no definitive way to assess which of the agents is failing when disease progression is identified. We aimed to assess if there is a correlation between clinical patterns of MM progression on IMiD-based regimens and flow cytometry testing of IMiD resistance.

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Fig. 1: MM cells with lower antioxidative capacity are vulnerable to IMiD-mediated cytotoxicity.

References

  1. Sevier CS, Qu H, Heldman N, Gross E, Fass D, Kaiser CA. Modulation of cellular disulfide-bond formation and the ER redox environment by feedback regulation of Ero1. Cell. 2007;129:333–44.

    Article  CAS  Google Scholar 

  2. Ramming T, Appenzeller-Herzog C. Destroy and exploit: catalyzed removal of hydroperoxides from the endoplasmic reticulum. Int J Cell Biol. 2013;2013:13.

    Article  Google Scholar 

  3. Veal EA, Day AM, Morgan BA. Hydrogen peroxide sensing and signaling. Mol Cell. 2007;26:1–14.

    Article  CAS  Google Scholar 

  4. Ray PD, Huang B-W, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012;24:981–90.

    Article  CAS  Google Scholar 

  5. Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;343:301–5.

    Article  Google Scholar 

  6. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014;343:305–9.

    Article  CAS  Google Scholar 

  7. Sebastian S, Zhu YX, Braggio E, Shi C-X, Panchabhai SC, Van Wier SA, et al. Multiple myeloma cells’ capacity to decompose H2O2 determines lenalidomide sensitivity. Blood. 2017;129:991–1007.

    Article  CAS  Google Scholar 

  8. Network NCC Multiple Myeloma (Version 3.2019). 2019; available from: https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf.

  9. Moreau P, San Miguel J, Sonneveld P, Mateos MV, Zamagni E, Avet-Loiseau H, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2017;28(suppl_4):iv52–iv61.

    Article  CAS  Google Scholar 

  10. Mikhael J, Ismaila N, Cheung MC, Costello C, Dhodapkar MV, Kumar S, et al. Treatment of multiple myeloma: ASCO and CCO Joint Clinical Practice Guideline. J Clin Oncol. 2019;37:1228–63.

    Article  Google Scholar 

  11. Kumar SK, Mikhael JR, Buadi FK, Dingli D, Dispenzieri A, Fonseca R, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo stratification of myeloma and risk-adapted therapy (mSMART) Consensus Guidelines. Mayo Clin Proc. 2009;84:1095–110.

    Article  CAS  Google Scholar 

  12. Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24:1934.

    Article  CAS  Google Scholar 

  13. Zhu YX, Braggio E, Shi C-X, Bruins LA, Schmidt JE, Van Wier S, et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011;118:4771–9.

    Article  CAS  Google Scholar 

  14. Kortüm KM, Mai EK, Hanafiah NH, Shi C-X, Zhu Y-X, Bruins L, et al. Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes. Blood. 2016;128:1226–33.

    Article  Google Scholar 

  15. Eichner R, Heider M, Fernández-Sáiz V, van Bebber F, Garz A-K, Lemeer S, et al. Immunomodulatory drugs disrupt the cereblon–CD147–MCT1 axis to exert antitumor activity and teratogenicity. Nat Med. 2016;22:735–43.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Hematology and Medical Oncology, Department of Medicine, Mayo Clinic, Phoenix, AZ, USA

    Luke Mountjoy, Sinto Sebastian, Miguel Gonzalez-Velez, Greg Ahmann, Jeremy Larsen, Leif Bergsagel & Rafael Fonseca

  2. Hematologic Malignancies and Bone Marrow Transplantation Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Tania Jain

  3. Division of Hematology and Medical Oncology, University of Mississippi Medical Center, Jackson, MS, USA

    Talal Hilal

  4. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Phoenix, AZ, USA

    Marlene Girardo

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Contributions

Concept and design: SS, RF, and LM. Acquisition, analysis, or interpretation of the data: RF, SS, LM, and MG. Drafting of the paper: all authors. Statistical analysis: LM, MG, and RF. Administrative, technical, or material support: LM, RF, and SS. Supervision: RF.

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Correspondence to Rafael Fonseca.

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Conflict of interest

TJ: consultancy for Takeda oncology. LB: consultant for Jannsen, GSK. RF: consulting: Amgen, BMS, Celgene, Takeda, Bayer, Janssen, Novartis, Pharmacyclics, Sanofi, Merck, Juno, Kite, Aduro, and AbbVie. Scientific Advisory Board Adaptive Biotechnologies. The remaining authors declare no conflict of interest.

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Mountjoy, L., Sebastian, S., Jain, T. et al. Prediction of immunomodulatory drugs (IMiDs) sensitivity in myeloma via determination of baseline anti-oxidative stress capacity. Leukemia 34, 3060–3063 (2020). https://doi.org/10.1038/s41375-020-0881-2

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