Skip to main content

Advertisement

Log in

Dosimetry results suggest feasibility of radioimmunotherapy using anti-CD138 (B-B4) antibody in multiple myeloma patients

  • Research Article
  • Published:
Tumor Biology

Abstract

Syndecan-1 (CD138), a heparan sulfate proteoglycan, is constantly expressed on tumor cells in multiple myeloma (MM). This surface antigen is an attractive candidate for targeted therapy, especially radioimmunotherapy (RAIT). We report preliminary biodistribution and dosimetry results obtained in refractory MM patients in a phase I/II RAIT study using iodine-131-labeled anti-CD138 (B-B4) monoclonal antibody (mAb). Four patients with progressive disease were enrolled after three lines of therapy. They received 370 MBq (20 mg/m2) of 131I-B-B4 for the dosimetry study. Each patient underwent a whole body (WB) CT and four WB emission scans at days D0, D1, and D3–4. Images were corrected for attenuation and scatter to assess doses absorbed by organs and bone marrow (BM). Blood and urine samples were additionally collected. Dosimetry was conducted using the MIRD method. Images obtained 1 h after 131I-B-B4 injection showed high BM and liver uptake without kidney uptake. The BM uptake confirmed BM involvement as detected by pre-inclusion FDG PET/CT. Absorbed doses were calculated at 2.03 ± 0.3 mGy/MBq for the liver, 1.10 ± 0.9 mGy/MBq for the kidneys, and 0.52 ± 0.20 mGy/MBq for the BM. Grade III thrombocytopenia was documented in two cases (highest BM-absorbed doses), and no grade IV hematological toxicity was observed. Therefore, autologous stem cells were not infused. One patient out of four experienced partial response, with 60% reduction of M-spike on serum electrophoresis, and total relief of pain, lasting for 1 year. This patient was able to go back to work. In this proof of concept study based on dosimetry, we show that MM RAIT is feasible using the anti-CD138 antibody. It would be of great interest to perform a RAIT phase I/II trial with a humanized anti-CD138 mAb with increased doses and systematic autologous stem cell infusions to overcome hematological toxicity and achieve efficacy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351(18):1860–73.

    Article  PubMed  CAS  Google Scholar 

  2. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23(1):3–9.

    Article  PubMed  CAS  Google Scholar 

  3. Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007;370(9594):1209–18.

    Article  PubMed  CAS  Google Scholar 

  4. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906–17.

    Article  PubMed  CAS  Google Scholar 

  5. Anderson KC. Targeted therapy of multiple myeloma based upon tumor-microenvironmental interactions. Exp Hematol. 2007;35(4 Suppl 1):155–62.

    Article  PubMed  CAS  Google Scholar 

  6. Caers J, Van Valckenborgh E, Menu E, Van Camp B, Vanderkerken K. Unraveling the biology of multiple myeloma disease: cancer stem cells, acquired intracellular changes and interactions with the surrounding micro-environment. Bull Cancer. 2008;95(3):301–13.

    PubMed  CAS  Google Scholar 

  7. Perez LE, Parquet N, Shain K, Nimmanapalli R, Alsina M, Anasetti C, et al. Bone marrow stroma confers resistance to Apo2 ligand/TRAIL in multiple myeloma in part by regulating c-FLIP. J Immunol. 2008;180(3):1545–55.

    PubMed  CAS  Google Scholar 

  8. Sanderson RD, Yang Y. Syndecan-1: a dynamic regulator of the myeloma microenvironment. Clin Exp Metastasis. 2008;25(2):149–59.

    Article  PubMed  CAS  Google Scholar 

  9. Ridley RC, Xiao H, Hata H, Woodliff J, Epstein J, Sanderson RD. Expression of syndecan regulates human myeloma plasma cell adhesion to type I collagen. Blood. 1993;81(3):767–74.

    PubMed  CAS  Google Scholar 

  10. Saunders S, Bernfield M. Cell surface proteoglycan binds mouse mammary epithelial cells to fibronectin and behaves as a receptor for interstitial matrix. J Cell Biol. 1988;106(2):423–30.

    Article  PubMed  CAS  Google Scholar 

  11. Jourdan M, Ferlin M, Legouffe E, Horvathova M, Liautard J, Rossi JF, et al. The myeloma cell antigen syndecan-1 is lost by apoptotic myeloma cells. Br J Haematol. 1998;100(4):637–46.

    Article  PubMed  CAS  Google Scholar 

  12. Vooijs WC, Post J, Wijdenes J, Schuurman HJ, Bolognesi A, Polito L, et al. Efficacy and toxicity of plasma-cell-reactive monoclonal antibodies B-B2 and B-B4 and their immunotoxins. Cancer Immunol Immunother. 1996;42(6):319–28.

    Article  PubMed  CAS  Google Scholar 

  13. Jego G, Bataille R, Pellat-Deceunynck C. IL-6 is a growth factor for nonmalignant human plasmablasts. Blood. 2001;97:1817–22.

    Article  PubMed  CAS  Google Scholar 

  14. Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y, et al. Characterization of clonogenic multiple myeloma cells. Blood. 2004;103:2332–6.

    Article  PubMed  CAS  Google Scholar 

  15. Rasmussen T, Haaber J, Dahl IM, Knudsen LM, Kerndrup G, Lodahl M, et al. Identification of translocation products but not K-RAS mutations in memory B cells from multiple myeloma patients. Haematologica. 2010;95:1730–7.

    Article  PubMed  CAS  Google Scholar 

  16. Jakubikova J, Adamia S, Kost-Alimova M, Klippel S, Cervi D, Daley JF, et al. Lenalidomide targets clonogenic side population in multiple myeloma: pathophysiologic and clinical implications. Blood. 2011;117:4409–19.

    Article  PubMed  CAS  Google Scholar 

  17. Chiron D, Surget S, Maïga S, Bataille R, Moreau P, Le Gouill S, et al. The peripheral CD138+ population but not the CD138− population contains myeloma clonogenic cells in plasma cell leukemia patients. Br J Haematol. 2011. doi:10.1111/j.1365-2141.2011.08904.x.

  18. Seidel C, Sundan A, Hjorth M, Turesson I, Dahl IM, Abildgaard N, Waage A, Borset M. Serum syndecan-1: a new independent prognostic marker in multiple myeloma. Blood. 2000;95(2):388–92.

    PubMed  CAS  Google Scholar 

  19. Bartlett AH, Hayashida K, Park PW. Molecular and cellular mechanisms of syndecans in tissue injury and inflammation. Mol Cells. 2007;24(2):153–66.

    PubMed  CAS  Google Scholar 

  20. Yang Y, Yaccoby S, Liu W, Langford JK, Pumphrey CY, Theus A, Epstein J, Sanderson RD. Soluble syndecan-1 promotes growth of myeloma tumors in vivo. Blood. 2002;100(2):610–7.

    Article  PubMed  CAS  Google Scholar 

  21. Wijdenes J, Dore JM, Clement C, Vermot-Desroches C. CD138. J Biol Regul Homeost Agents. 2002;16(2):152–5.

    PubMed  CAS  Google Scholar 

  22. Wijdenes J, Vooijs WC, Clement C, Post J, Morard F, Vita N, et al. A plasmocyte selective monoclonal antibody (B-B4) recognizes syndecan-1. Br J Haematol. 1996;94(2):318–23.

    Article  PubMed  CAS  Google Scholar 

  23. Govindan SV, Goldenberg DM. New antibody conjugates in cancer therapy. Scientific World J. 2010;10:2070–89.

    Article  CAS  Google Scholar 

  24. Kraeber-Bodere F, Rousseau C, Bodet-Milin C, Ferrer L, Faivre-Chauvet A, Campion L, et al. Targeting, toxicity, and efficacy of 2-step, pretargeted radioimmunotherapy using a chimeric bispecific antibody and 131I-labeled bivalent hapten in a phase I optimization clinical trial. J Nucl Med. 2006;47(2):247–55.

    PubMed  CAS  Google Scholar 

  25. Williams T, Kelley C. gnuplot 4.2.6. (2009) Available from URL: http://www.gnuplot.info. Accessed 18 Feb 2009.

  26. Ogawa K, Harata Y, Ichihara T, Kubo A, Hashimoto S. A practical method for position-dependent Compton-scatter correction in single photon emission CT. IEEE Trans Med Imaging. 1991;10(3):408–12.

    Article  PubMed  CAS  Google Scholar 

  27. Buvat I, Benali H, Frouin F, Bazin JP, Di Paola R. Target apex-seeking in factor analysis of medical image sequences. Phys Med Biol. 1993;38(1):123–38.

    Article  PubMed  CAS  Google Scholar 

  28. Yushkevich PA, Piven J, Hazlett HC, Smith RG, Ho S, Gee JC, et al. User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage. 2006;31(3):1116–28.

    Article  PubMed  Google Scholar 

  29. Ferrer L, Kraeber-Bodere F, Bodet-Milin C, Rousseau C, Le Gouill S, Wegener WA, et al. Three methods assessing red marrow dosimetry in lymphoma patients treated with radioimmunotherapy. Cancer. 2010;116(4 Suppl):1093–100.

    Article  PubMed  CAS  Google Scholar 

  30. Stabin MG, Siegel JA. Physical models and dose factors for use in internal dose assessment. Health Phys. 2003;85(3):294–310.

    Article  PubMed  CAS  Google Scholar 

  31. Siegel JA, Thomas SR, Stubbs JB, Stabin MG, Hays MT, Koral KF, et al. MIRD pamphlet no. 16: techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med. 1999;40(2):37S–61S.

    PubMed  CAS  Google Scholar 

  32. Bartel TB, Haessler J, Brown TL, Shaughnessy Jr JD, van Rhee F, Anaissie E, et al. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood. 2009;114:2068–76.

    Article  PubMed  CAS  Google Scholar 

  33. Zamagni E, Nanni C, Patriarca F, Englaro E, Castellucci P, Geatti O, et al. A prospective comparison of 18F-fluorodeoxyglucose positron emission tomography-computed tomography, magnetic resonance imaging and whole-body planar radiographs in the assessment of bone disease in newly diagnosed multiple myeloma. Haematologica. 2007;92:50–5.

    Article  PubMed  Google Scholar 

  34. McDevitt MR, Sgouros G, Finn RD, Humm JL, Jurcic JG, Larson SM, et al. Radioimmunotherapy with alpha-emitting nuclides. Eur J Nucl Med. 1998;25(9):1341–51.

    Article  PubMed  CAS  Google Scholar 

  35. Couturier O, Faivre-Chauvet A, Filippovich IV, Thedrez P, Sai-Maurel C, Bardies M, et al. Validation of 213Bi-alpha radioimmunotherapy for multiple myeloma. Clin Cancer Res. 1999;5(10 Suppl):3165s–70s.

    PubMed  CAS  Google Scholar 

  36. Supiot S, Faivre-Chauvet A, Couturier O, Heymann MF, Robillard N, Kraeber-Bodere F, et al. Comparison of the biologic effects of MA5 and B-B4 monoclonal antibody labeled with iodine-131 and bismuth-213 on multiple myeloma. Cancer. 2002;94(4 Suppl):1202–9.

    Article  PubMed  CAS  Google Scholar 

  37. Cherel M, Gouard S, Gaignerie A, Gaschet J, Bigot-Corbel E, Faivre-Chauvet A, et al. Targeting the CD138 antigen for the treatment of multiple myeloma with Bismuth-213. Eur J Nucl Med Mol Imaging. 2009;36 Suppl 2:S194–233. abstract.

    Google Scholar 

  38. Liersch T, Meller J, Kulle B, Behr TM, Markus P, Langer C, et al. Phase II trial of carcinoembryonic antigen radioimmunotherapy with 131I-labetuzumab after salvage resection of colorectal metastases in the liver: five-year safety and efficacy results. J Clin Oncol. 2005;23:6763–70.

    Article  PubMed  CAS  Google Scholar 

  39. Devys A, Thedrez P, Gautherot E, Faivre-Chauvet A, Sai-Maurel C, Rouvier E, et al. Comparative targeting of human colon-carcinoma multicell spheroids using one- and two-step (bispecific antibody) techniques. Int J Cancer. 1996;67:883–91.

    Article  PubMed  CAS  Google Scholar 

  40. Mirallie E, Vuillez JP, Bardet S, Frampas E, Dupas B, Ferrer L, et al. High frequency of bone/bone marrow involvement in advanced medullary thyroid cancer. J Clin Endocrinol Metab. 2005;90:779–88.

    Article  PubMed  CAS  Google Scholar 

  41. Tassone P, Goldmacher VS, Neri P, Gozzini A, Shammas MA, Whiteman KR, et al. Cytotoxic activity of the maytansinoid immunoconjugate B-B4-DM1 against CD138+ multiple myeloma cells. Blood. 2004;104(12):3688–96.

    Article  PubMed  CAS  Google Scholar 

  42. Vanderkerken K, De Raeve H, Goes E, Van Meirvenne S, Radl J, Van Riet I, Thielemans K, Van Camp B. Organ involvement and phenotypic adhesion profile of 5T2 and 5T33 myeloma cells in the C57BL/KaLwRij mouse. Br J Cancer. 1997;76(4):451–60.

    Article  PubMed  CAS  Google Scholar 

  43. Sjögreen-Gleisner K, Dewaraja YK, Chiesa C, Tennvall J, Lindén O, Strand SE, Ljungberg M. Dosimetry in patients with B-cell lymphoma treated with [(90)Y]ibritumomab tiuxetan or [(131)I]tositumomab. Q J Nucl Med Mol Imaging. 2011;55(2):126–54.

    PubMed  Google Scholar 

  44. Meredith RF, Shen S, Forero A, LoBuglio A. A method to correct for radioactivity in large vessels that overlap the spine in imaging-based marrow dosimetry of lumbar vertebrae. J Nucl Med. 2008;49(2):279–84.

    Article  PubMed  Google Scholar 

  45. Juweid M, Sharkey RM, Siegel JA, Behr T, Goldenberg DM. Estimates of red marrow dose by sacral scintigraphy in radioimmunotherapy patients having non-Hodgkin’s lymphoma and diffuse bone marrow uptake. Cancer Res. 1995;55(23 Suppl):5827s–31s.

    PubMed  CAS  Google Scholar 

  46. Siegel JA. Establishing a clinically meaningful predictive model of hematologic toxicity in nonmyeloablative targeted radiotherapy: practical aspects and limitations of red marrow dosimetry. Cancer Biother Radiopharm. 2005;20:126–40.

    Article  PubMed  CAS  Google Scholar 

  47. DeNardo DA, DeNardo GL, O’Donnell RT, et al. Imaging for improved prediction of myelotoxicity after radioimmunotherapy. Cancer. 1997;80:2558s–66s.

    Article  Google Scholar 

  48. Sgouros G, Stabin M, Erdi Y, et al. Red marrow dosimetry for radiolabeled antibodies that bind to marrow, bone, or blood components. Med Phys. 2000;27:2150–64.

    Article  PubMed  CAS  Google Scholar 

  49. Research Triangle Park, NC: GlaxoSmithKline. Bexxar prescribing information [package insert]. 2005. Available at: http://us.gsk.com/products/assets/us_bexxar.pdf

  50. Chatterjee M, Chakraborty T, Tassone P. Multiple myeloma: monoclonal antibodies-based immunotherapeutic strategies and targeted radiotherapy. Eur J Cancer. 2006;42(11):1640–52.

    Article  PubMed  CAS  Google Scholar 

  51. Zalutsky MR, Bigner DD. Radioimmunotherapy with alpha-particle emitting radioimmunoconjugates. Acta Oncol. 1996;35(3):373–9.

    Article  PubMed  CAS  Google Scholar 

  52. Couturier O, Supiot S, Degraef-Mougin M, Faivre-Chauvet A, Carlier T, Chatal JF, et al. Cancer radioimmunotherapy with alpha-emitting nuclides. Eur J Nucl Med Mol Imaging. 2005;32(5):601–6s14.

    Article  PubMed  CAS  Google Scholar 

Download references

Conflicts of interest

None

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Caroline Rousseau.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rousseau, C., Ferrer, L., Supiot, S. et al. Dosimetry results suggest feasibility of radioimmunotherapy using anti-CD138 (B-B4) antibody in multiple myeloma patients. Tumor Biol. 33, 679–688 (2012). https://doi.org/10.1007/s13277-012-0362-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-012-0362-y

Keywords

Navigation