Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Multiple myeloma, gammopathies

Limited efficacy of daratumumab in multiple myeloma with extramedullary disease

Leukemia volume 36, pages 288–291 (2022)Cite this article

Subjects

The treatment of multiple myeloma (MM) has changed substantially during the past two decades. The incorporation of novel agents into therapeutic strategies has resulted in prolonged overall survival of MM patients with approximately 15% of them being considered operationally cured [1]. Extramedullary myeloma disease (EMD) is a less frequent manifestation of MM occurring either at the time of diagnosis (11.0–23.7%) or, more often, during the course of the disease (24–37%), where myeloma plasma cells (PCs) become independent of the bone marrow (BM) microenvironment and infiltrate distant tissues and organs [2]. There are two generally accepted subtypes of EMD: (i) soft tissue masses in extraosseous locations and (ii) bone-related masses that remain connected to the bone [3]. The presence of soft tissue EMD is always considered a high-risk feature with an aggressive phenotype, drug resistance and short survival [4], whereas the prognostic relevance of bone-related EMD remains controversial with discordant results from several analyses [5]. The incidence of EMD is increasing as the survival of MM patients is prolonged. The treatment options are the same for EMD as for MM patients without EMD and the outcome remains unsatisfactory. Daratumumab, the IgG kappa monoclonal antibody targeting CD38 antigen, has been rapidly incorporated as a backbone agent of the standard of care regimens in practically all MM stages due to its unprecedented efficacy [6]. Nevertheless, there are currently no data available regarding the activity of daratumumab in EMD.

After demonstrating lower efficacy of daratumumab in EMD patients compared to those without EMD we sought to shed light on the underlying mechanism. Daratumumab kills myeloma cells via multiple mechanisms of action: (i) Fc-dependent immune effector pathways including complement-dependent cytotoxicity (CDC), (ii) antibody-dependent cell-mediated cytotoxicity (ADCC) with NK cells serving as the main effector cells, and, (iii) antibody-dependent cellular phagocytosis (ADCP) [7]. Because all these mechanisms are dependent on the surface expression level of the target antigen CD38 [8, 9], we decided to quantify a relative amount of CD38 molecules on the surface of PCs isolated from extramedullary mass (EM) by multicolor flow cytometry. In total, we identified 15 archived samples of EM tumors (collected between May 2011 and November 2018) from patients previously untreated with any anti-CD38 antibodies (Table S1). CD38 expression level on EM PCs (EMD; n = 15) was compared with the BM PCs from unpaired newly diagnosed myeloma (NDMM) (n = 20) and RRMM patients (n = 20) using MFI (mean fluorescence intensity). We observed decreased expression of CD38 on EM PCs which was approximately 2 times lower compared to BM PCs from NDMM (n = 20) (median MFI 15 946 vs. 34 958; p = 0.03). CD38 expression was also significantly decreased on EM PCs compared to BM PCs from RRMM (n = 20) (median MFI 15 946 vs. 32 500; p = 0.0068). Interestingly, similar drop of CD38 expression was observed also on paired BM PCs from EMD patients (EMD-BM) harvested at the time of biopsy (Fig. 1D).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Limited efficacy of daratumumab and selected differentially expressed genes in EMD.

References

  1. Dimopoulos MA, Moreau P, Terpos E, Mateos M-V, Zweegman S, Cook G, et al. Multiple myeloma: EHA-ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Hemasphere. 2021;5:e528.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Bhutani M, Foureau DM, Atrash S, Voorhees PM, Usmani SZ. Extramedullary multiple myeloma. Leukemia. 2020;34:1–20.

    Article  CAS  PubMed  Google Scholar 

  3. Sevcikova S, Minarik J, Stork M, Jelinek T, Pour L, Hajek R. Extramedullary disease in multiple myeloma—controversies and future directions. Blood Rev. 2019;36:32–39.

    Article  PubMed  Google Scholar 

  4. Pour L, Sevcikova S, Greslikova H, Kupska R, Majkova P, Zahradova L, et al. Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse. Haematologica. 2014;99:360–4.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gagelmann N, Eikema D-J, Iacobelli S, Koster L, Nahi H, Stoppa A-M, et al. Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: a study from the Chronic Malignancies Working Party of the EBMT. Haematologica. 2018;103:890–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. van de Donk NWCJ, Pawlyn C, Yong KL. Multiple myeloma. Lancet. 2021;397:410–27.

    Article  PubMed  Google Scholar 

  7. Jelinek T, Hajek R. Monoclonal antibodies—A new era in the treatment of multiple myeloma. Blood Rev. 2016;30:101–10.

    Article  CAS  PubMed  Google Scholar 

  8. Nijhof IS, Casneuf T, van Velzen J, van Kessel B, Axel AE, Syed K, et al. CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma. Blood. 2016;128:959–70.

    Article  CAS  PubMed  Google Scholar 

  9. Moreno L, Perez C, Zabaleta A, Manrique I, Alignani D, Ajona D, et al. The mechanism of action of the anti-CD38 monoclonal antibody isatuximab in multiple myeloma. Clinical Cancer Res. 2019;25:3176–87.

    Article  CAS  Google Scholar 

  10. Choudhry P, Mariano MC, Geng H, Martin TG, Wolf JL, Wong SW, et al. DNA methyltransferase inhibitors upregulate CD38 protein expression and enhance daratumumab efficacy in multiple myeloma. Leukemia. 2020;34:938–41.

    Article  PubMed  Google Scholar 

  11. Emran AA, Chatterjee A, Rodger EJ, Tiffen JC, Gallagher SJ, Eccles MR, et al. Targeting DNA methylation and EZH2 activity to overcome melanoma resistance to immunotherapy. Trends Immunol. 2019;40:328–44.

    Article  CAS  PubMed  Google Scholar 

  12. Varlet E, Ovejero S, Martinez A-M, Cavalli G, Moreaux J. Role of polycomb complexes in normal and malignant plasma cells. Int J Mol Sci. 2020;21:8047.

    Article  CAS  PubMed Central  Google Scholar 

  13. Piedra-Quintero Z. L., Wilson Z., Nava P., Guerau-de-Arellano M. CD38: an immunomodulatory molecule in inflammation and autoimmunity. Front Immunol. 2020; 11. https://doi.org/10.3389/fimmu.2020.597959.

  14. Beksac M. Isatuximab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma and soft-tissue plasmacytomas: Icaria-MM Subgroup Analysis. ASH, 2020 https://ash.confex.com/ash/2020/webprogram/Paper134727.html (accessed 11 Mar2021).

  15. Bahlis NJ, Dimopoulos MA, White DJ, Benboubker L, Cook G, Leiba M, et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia. 2020;34:1875–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to give thanks to Dr. Shira Timilsina Godfrey for editing the article. This work has been supported the European Regional Development Fund—Project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868), and the Ministry of Health of the Czech Republic (AZV 17-30089 A; AZV 17-29343A.), Institutional Support by MH CZ—DRO—FNOs/2019, MH CZ—DRO—FNOs/2020 Student’s grant system SGS15/PrF/2021 University of Ostrava and by The Ministry of Education, Youth and Sports from the Large Infrastructures for Research, Experimental Development and Innovations project e-Infrastructure “CZ—LM2018140“.

Author information

Authors and Affiliations

  1. Department of Hematooncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic

    Tomas Jelinek, Tereza Sevcikova, David Zihala, Tereza Popkova, Veronika Kapustova, Lucie Broskevicova, Hana Plonkova, Michal Simicek & Roman Hajek

  2. Department of Biology and Ecology, Faculty of Science, University of Ostrava, Ostrava, Czech Republic

    Veronika Kapustova

  3. Institute of Biostatistics and Analyses, Ltd, Brno, Czech Republic

    Lenka Capkova

  4. Department of Clinical Hematology, University Hospital Brno, Brno, Czech Republic

    Lucie Rihova & Renata Bezdekova

  5. Babak Myeloma Group, Department of Pathofysiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic

    Sabina Sevcikova

  6. Department of Pathology, University Hospital Ostrava, Ostrava, Czech Republic

    Vladimir Zidlik

  7. Department of Nuclear Medicine, University Hospital Ostrava, Ostrava, Czech Republic

    Martin Havel

  8. Hematology and Oncology Department, Charles University Hospital Pilsen, Czechia, Czech Republic

    Alexandra Jungova

  9. Department of Hematooncology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czechia, Czech Republic

    Jiri Minarik

  10. Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine Masaryk University, Czechia, Czech Republic

    Martin Stork & Ludek Pour

  11. Department of Internal Medicine and Hematology, University Hospital Kralovske Vinohrady, Prague, Czech Republic

    Petr Pavlicek

  12. 1st Medical Department—Clinical Department of Haematology of the First Faculty of Medicine and General Teaching Hospital Charles University, Prague, Czech Republic

    Ivan Spicka

  13. 4th Department of Internal Medicine—Hematology, University Hospital Hradec Kralove, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic

    Vladimir Maisnar & Jakub Radocha

Authors
  1. Tomas Jelinek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tereza Sevcikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Zihala
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tereza Popkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Veronika Kapustova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lucie Broskevicova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lenka Capkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lucie Rihova
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Renata Bezdekova
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sabina Sevcikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Vladimir Zidlik
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Martin Havel
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hana Plonkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Alexandra Jungova
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jiri Minarik
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Martin Stork
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Ludek Pour
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Petr Pavlicek
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Ivan Spicka
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Vladimir Maisnar
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Jakub Radocha
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Michal Simicek
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Roman Hajek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tomas Jelinek.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jelinek, T., Sevcikova, T., Zihala, D. et al. Limited efficacy of daratumumab in multiple myeloma with extramedullary disease. Leukemia 36, 288–291 (2022). https://doi.org/10.1038/s41375-021-01343-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-021-01343-w

This article is cited by

Search

Advanced search

Quick links