Advertisement

Clinical and biological characteristics of myeloma patients influence response to elotuzumab combination therapy

  • Sophia Danhof
  • Susanne Strifler
  • Dorothea Hose
  • Martin Kortüm
  • Max Bittrich
  • Jochen Hefner
  • Hermann Einsele
  • Stefan Knop
  • Martin Schreder
Original Article – Cancer Research

Abstract

Based on ELOQUENT-2, combination therapy with the monoclonal antibody elotuzumab was approved for relapsed/refractory multiple myeloma in the US and Europe. However, outside clinical trials, the optimal integration of elotuzumab into the sequence of treatment lines remains to be determined. Therefore, we analyzed safety and efficacy of elotuzumab/immunomodulatory drug combinations in a real-life cohort of 33 patients from our institution. The most frequent grade 3/4 adverse event was lymphopenia which did not increase the incidence of viral reactivations. After a median of four prior treatment lines, an overall response rate of 60% and a median progression-free survival (PFS) of 8 months were observed. The presence of cytogenetic high-risk status had no impact on PFS while low disease burden and high numbers of natural killer (NK)-cells at treatment initiation were associated with longer PFS. We observed an extramedullary relapse in three patients, associated with reduced expression of the elotuzumab target antigen SLAMF7 on extramedullary myeloma cells in one patient. Thus, biomarkers like disease burden, NK-cell count and SLAMF7 expression on myeloma cells may help to define myeloma patients with high likelihood to respond to elotuzumab treatment. Prospective trials investigating these biomarkers in larger patient cohorts are highly warranted.

Keywords

Multiple myeloma SLAMF7 Immunotherapy Natural killer cells Extramedullary disease 

Notes

Author contributions

SD, SK and MS designed the research study; SD, SS, DH and MS performed the research; SS, MB, HE and MS contributed essential research material; SD, MK, MB and JH analyzed the data; HE supervised the project; SD drafted the manuscript; SS, DH, MK, MB, JH, HE, SK and MS carefully revised the manuscript; all authors approved the final version of the manuscript.

Funding

SD was supported by the Else Kröner-Forschungskolleg Würzburg, Germany.

Compliance with ethical standards

Conflict of interest

SK: honoraria from Celgene GmbH and Bristol-Myers Squibb GmbH. SD, MS: Advisory Board for Bristol-Myers Squibb GmbH.

Ethical Approval for Research involving Human Biospecimens

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants for whom biospecimens were included in the study.

Ethical approval for research involving animals

This article does not contain any studies with animals performed by any of the authors.

Supplementary material

432_2018_2807_MOESM1_ESM.docx (217 kb)
Supplementary material 1 (DOCX 218 KB)

References

  1. Barlogie B, Alexanian R, Gehan EA, Smallwood L, Smith T, Drewinko B (1983) Marrow cytometry and prognosis in myeloma. J Clin Invest 72:853–861.  https://doi.org/10.1172/JCI111056 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Boles KS, Stepp SE, Bennett M, Kumar V, Mathew PA (2001) 2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes. Immunol Rev 181:234–249CrossRefGoogle Scholar
  3. Chim CS et al (2017) Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia.  https://doi.org/10.1038/leu.2017.329 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Chng WJ et al (2014) IMWG consensus on risk stratification in multiple myeloma. Leukemia 28:269–277.  https://doi.org/10.1038/leu.2013.247 CrossRefPubMedGoogle Scholar
  5. Clave E et al (2014) Lenalidomide consolidation and maintenance therapy after autologous stem cell transplant for multiple myeloma induces persistent changes in T-cell homeostasis. Leuk Lymphoma 55:1788–1795.  https://doi.org/10.3109/10428194.2013.865182 CrossRefPubMedGoogle Scholar
  6. Collins SM et al (2013) Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing. ADCC Cancer Immunol Immunother 62:1841–1849.  https://doi.org/10.1007/s00262-013-1493-8 CrossRefPubMedGoogle Scholar
  7. Danhof S et al (2017) Expression of programmed death-1 on lymphocytes in myeloma patients is lowered during lenalidomide maintenance. Haematologica.  https://doi.org/10.3324/haematol.2017.178947 CrossRefPubMedGoogle Scholar
  8. Davies FE et al (2001) Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 98:210–216CrossRefGoogle Scholar
  9. Dimopoulos MA et al (2016a) Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol 17:27–38.  https://doi.org/10.1016/S1470-2045(15)00464-7 CrossRefPubMedGoogle Scholar
  10. Dimopoulos MA et al (2016b) Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 375:1319–1331.  https://doi.org/10.1056/NEJMoa1607751 CrossRefPubMedGoogle Scholar
  11. Dimopoulos MA et al (2017a) Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol 178:896–905.  https://doi.org/10.1111/bjh.14787 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Dimopoulos MA et al (2017b) Carfilzomib, lenalidomide, and dexamethasone in patients with relapsed multiple myeloma categorised by age: secondary analysis from the phase 3 ASPIRE study. Br J Haematol 177:404–413.  https://doi.org/10.1111/bjh.14549 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Dimopoulos MA et al (2018) Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med 379:1811–1822.  https://doi.org/10.1056/NEJMoa1805762 CrossRefPubMedGoogle Scholar
  14. Durie BG, Salmon SE (1975) A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment. and survival. Cancer 36:842–854CrossRefGoogle Scholar
  15. Gogishvili T et al (2017) SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7(+) normal lymphocytes. Blood 130:2838–2847.  https://doi.org/10.1182/blood-2017-04-778423 CrossRefPubMedGoogle Scholar
  16. Hofmeister CC, Lonial S (2016) How to integrate elotuzumab and daratumumab into therapy for multiple myeloma. J Clin Oncol 34:4421–4430.  https://doi.org/10.1200/JCO.2016.69.5908 CrossRefPubMedGoogle Scholar
  17. Hsi ED et al (2008) CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res 14:2775–2784.  https://doi.org/10.1158/1078-0432.CCR-07-4246 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hsu AK et al (2011) The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy. Blood 117:1605–1613.  https://doi.org/10.1182/blood-2010-04-278432 CrossRefPubMedGoogle Scholar
  19. Jimenez-Zepeda VH et al (2015) Absolute lymphocyte count as predictor of overall survival for patients with multiple myeloma treated with single autologous stem cell transplant. Leuk Lymphoma 56:2668–2673.  https://doi.org/10.3109/10428194.2014.1003057 CrossRefPubMedGoogle Scholar
  20. Krejcik J et al (2016) Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 128:384–394.  https://doi.org/10.1182/blood-2015-12-687749 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Kumar S et al (2016) International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 17:e328–e346.  https://doi.org/10.1016/S1470-2045(16)30206-6 CrossRefPubMedGoogle Scholar
  22. Laubach JP, Paba Prada CE, Richardson PG, Longo DL (2017) Daratumumab, elotuzumab, and the development of therapeutic monoclonal antibodies in multiple myeloma. Clin Pharmacol Ther 101:81–88.  https://doi.org/10.1002/cpt.550 CrossRefPubMedGoogle Scholar
  23. Lonial S et al (2015) Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 373:621–631.  https://doi.org/10.1056/NEJMoa1505654 CrossRefPubMedGoogle Scholar
  24. Lonial S et al (2016) Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet 387:1551–1560.  https://doi.org/10.1016/S0140-6736(15)01120-4 CrossRefPubMedGoogle Scholar
  25. McCarthy PL et al (2012) Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1770–1781.  https://doi.org/10.1056/NEJMoa1114083 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Moreau P et al (2016) Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 374:1621–1634.  https://doi.org/10.1056/NEJMoa1516282 CrossRefPubMedGoogle Scholar
  27. Paiva B et al (2016) Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis. Blood 127:1151–1162.  https://doi.org/10.1182/blood-2015-10-662320 CrossRefPubMedGoogle Scholar
  28. Palumbo A et al (2016) Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 375:754–766.  https://doi.org/10.1056/NEJMoa1606038 CrossRefPubMedGoogle Scholar
  29. Richardson PG et al (2015) Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol 2:e516–e527.  https://doi.org/10.1016/S2352-3026(15)00197-0 CrossRefPubMedGoogle Scholar
  30. Salmon SE, Smith BA (1970) Immunoglobulin synthesis and total body tumor cell number in IgG multiple myeloma. J Clin Invest 49:1114–1121.  https://doi.org/10.1172/JCI106327 CrossRefPubMedPubMedCentralGoogle Scholar
  31. San Miguel J et al (2013) Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol 14:1055–1066.  https://doi.org/10.1016/S1470-2045(13)70380-2 CrossRefGoogle Scholar
  32. San-Miguel JF et al (2014) Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 15:1195–1206.  https://doi.org/10.1016/S1470-2045(14)70440-1 CrossRefPubMedGoogle Scholar
  33. Tai YT et al (2008) Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood 112:1329–1337.  https://doi.org/10.1182/blood-2007-08-107292 CrossRefPubMedPubMedCentralGoogle Scholar
  34. van de Donk NW et al (2016) Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma. Blood 127:681–695.  https://doi.org/10.1182/blood-2015-10-646810 CrossRefPubMedGoogle Scholar
  35. Zonder JA et al (2012) A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood 120:552–559.  https://doi.org/10.1182/blood-2011-06-360552 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Hematology and Medical Oncology, Department of Internal Medicine IIUniversity Hospital WürzburgWürzburgGermany

Personalised recommendations