Blood cancers

Monoclonal antibodies in multiple myeloma: helping us to take back control of the immune system

Tuesday, 17 Sep 2019


Professor Saad Usmani from the Levine Cancer Institute in Charlotte, North Carolina gave delegates attending the Janssen H3 medical education symposium in Melbourne an overview of the diverse strategies by which monoclonal antibodies (MAbs) are helping to tackle multiple myeloma (MM).

“As our understanding of myeloma biology has expanded, we’re in a position where we can start to think the way the cancer does. The holy grail is manipulation of the immune system, which is what MM itself does. Aside from targeting the cancer cells themselves, what some MAbs can now offer is a means to manipulate the immune response towards cancer cells as well,” he began.1

An explosion of targets for MAbs in MM

“Today there are a lot of targets in development,” noted Prof. Usmani. At present, there are 11 targets in clinical development and another three targets which have demonstrated pre-clinical activity.2 Of those in clinical development there are two currently approved in Australia, elotuzumab and daratumumab.3,4

Each MAb acts in distinct ways

Daratumumab is a first‐in‐class, fully human IgG‐1k MAb directed against CD38, a transmembrane protein that is highly expressed on MM plasma cells and, at lower levels, on other immune‐competent cells.5 It is understood to have pleiotropic effects, but not all were understood until some of the monotherapy trials were undertaken, as Prof. Usmani explained.

 “We got a hint of a suprising mode of action (MOA) for daratumumab after looking at a patient from one of the monotherapy trials. In a case presented at the American Society of Hematology (ASH) conference in 2017, a 70 year-old male patient with 17p deletion and triple refractory myeloma achieved an sCR 194 days post the first dose of daratumumab 16 mg/kg, was MRD negative two years later and had T-cell expansion sustained for 32 months. He sustained clinical response and MRD negativity for more than 3.5 years without relapse. It turned out his CD8+ cell expansions were clonal,” he explained.6

It is now understood that daratumumab has both direct tumour and immunomodulatory effects. Direct on-tumour actions include antibody-dependent cell-mediated cytotoxicity (ADCC),  complement-dependent cytotoxicity (CDC), direct apoptosis and antibody-dependent cellular phagocytosis (ADCP).7 The immunomodulatory effects act through directly suppressing CD38+ immune regulatory cells (including Treg, CD8+ and Breg cells).8 In the CD8+ Tcell, this not only enhances the T-cell response, but also induces clonal T-cell expansion.8The effect of this is we see a superior depth of response to IMID or proteasome inhibitor-based therapies, but also responses that continue to deepen with longer follow-up,” noted Prof. Usmani.9 “Compared to lenalidomide-based therapy, we see an improved overall response rate of 93% with daratumumab-lenalidomide-dexamethasone vs 76% with lenalidomide-dexamethasone.9 Compared with bortezomib-based therapy we’re looking at 84% with daratumumab-bortezomib-dexamethasone vs 63% with bortezomib-dexamethasone.10 Plus, looking at MDR in high cytogenetic risk patients, only those who received daratumumab therapy achieved MRD negativity in either POLLUX or CASTOR.”11

The other MAb, elotuzumab is a first‐in‐class, humanized, IgG‐1k chimeric, immune‐stimulatory MAb that recognises CD319/SLAMF7, a cell surface glycoprotein that is highly expressed by MM cells, and across several hematopoietic cells, NK cells, but not by other normal tissue cells.12,13

“Elotuzumab has two mechanisms of action, but these are different to what you see with daratumumab. With elotuzumab you have direct activation of NK cells and you have tagging of the myeloma cell for antibody-dependent cell-mediated cytotoxicity (ADCC),”14 he explained.

The future of MAb targeting of MM is all about choosing the right MAb for the right patient

“In addition to the mechanisms leveraged by daratumumab and elotuzumab, there are additional areas of research into MAb mechanisms at the moment,” explained Prof. Usmani. They include:15

  • Antibody-drug conjugates delivery”of toxic payload (ADC), generally using a highly toxic, non-cell permeable drug
  • Bi-specific MAbs, which enable targeting of two unique targets, usually CD3 and another target.”

In conclusion, Prof. Usmani noted the benefit of the MAbs available today is that “they represent a class of drugs that are different from other treatments due to their ability to modulate the immune system as well as kill myeloma cells themselves. They may be combined with other agents to enhance both the depth and duration of response, which we hope translates to a curative approach rather than the disease control mentality we have today.”

 

This article was sponsored by Janssen, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Janssen.

 

References:

  1. Ghobrial I, et al. Clin Lymphoma Myeloma Leuk. 2019; 19(6):332-344.
  2. Lonial S, et al. Leukemia 2016;30(3):526-35.
  3. Empliciti Product Information. 22 September 2016. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2016-PI-02539-1 (Accessed 28 May 2019).
  4. Darzalex Product Information. 7 February 2019. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2017-PI-02146-1&d=201905281016933 (Accessed 28 May 2019).
  5. van de Donk NWCJ, et al. Blood 2018;131(1):13-29.
  6. Usmani SZ et al. Poster presentation at: 59th American Society of Hematology (ASH) Annual Meeting and Exposition; December 9-12 2017; Abstract 3107.
  7. Sanchez L, et al. J Hematol Oncol 2016;9(1):51.
  8. Krejcik J, et al. Blood 2016;128(3):384–94.
  9. Usmani SZ, et al. Presented at American Society of Hematology (ASH) Annual Meeting; December 3-6 2016; Abstract 1151.
  10. Dimopoulos MA, et al. Haematologica 2018; 103(12):2088-2096.
  11. Avet-Loiseau H, et al. American Society of Hematology (ASH) Annual Meeting; December 3-6 2016; Abstract 246.
  12. Gavriatopoulou  M, et al. Expert Opin Drug Saf 2017;16(2):237–245.
  13. Hsi ED, et al. Clin Cancer Res 2008;14(9):2775–784.
  14. Collins SM, et al. Cancer Immunol Immunother 2013;62(12):1841–9.
  15. Tai YT, Anderson KC. Bone Marrow Res 2011;2011:924058.

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