In the comments to the Beacon's recent article about the highlights of the ASCO 2013 conference,
https://myelomabeacon.org/news/2013/06/11/asco-2013-multiple-myeloma-highlights/
Beacon reader Mark asked:
"I have a question about the antibody studies [presented at ASCO] and in particular why they use them with a steroid like dex. Dex is an immunosuppressive steroid. Why would they use dex with an antibody if the purpose of an antibody is to try and give your immune system a target to attack? It would seem that it would be helpful to stimulate the immune system when using antibody therapy, not suppress it. I would be interested in how lenalidomide and an antibody would perform without DEX or any other steroid. Fortunately I only needed DEX for 4 cycles during my induction and no steroids since. I think the Doctors should consider a patients QOL as well and try to find some effective combos that avoid using DEX. It would seem that the antibodies give them an opportunity to try and accomplish that."
We've reached out to Beacon Medical Advisor Dr. Ken Shain in regard to Mark's question, and are posting it below in this thread.
If others have questions on the issue, or further contributions they'd like to make, please feel free to make additional postings to the thread.
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Re: Why use dexamethasone with antibody therapies?
Monoclonal antibody therapy in myeloma is in the midst of a time of burgeoning success. For a period of time this type of immune therapy was not believed to be effective myeloma in wake of clinical failures and other theoretical reasons. However, persistence and the identification of appropriate targets is again moving this field forward with exciting anti-CD38 and anti-CS1 among others-these are antibodies that bind to specific cell surface markers/proteins of myeloma cells (CD38 and CS-1, respectively). These represent only two target of antibody therapy in multiple myeloma, but the two with the most clinical success.
Regarding the efficacy if monoclonal antibody therapy in face of steroids there are a number of things to consider. The mechanisms of action mediating myeloma cell death by these antibodies are termed:: antibody dependent cellular cytotoxicity (ADCC), and complement dependent cytotoxicity (CDC). It is important to note that specific antibody therapies may preferentially mediate myeloma cell death by one pathway over the other or even by direct killing.
Regardless, ADCC and CDC are mediated by the specific aspects of the immune system- not the antibody producing cells (B cells or plasma cells-cells very sensitive to steroids). ADCC involves the targeting of myeloma cells by elotuzumab binding to CS-1 and recruitment of immune effector cells including Natural Killer Cells, macrophages and neutrophils that in turn destroy the myeloma cells. In contrast, CDC involves complement mediated destruction of cells (without additional cellular components). These cellular responses are not as sensitive to steroids.
Preclinical evidence shows that monoclonal antibodies are, in fact, synergistic (multiply the effects of each agent when used together) with current drugs including dex, lenalidomide [Revlimid], and bortezomib [Velcade] that activate the cellular components of the immune response (ADCC, see references for more detail).
Not all antibodies are the same- some may be successful as single agents some are not. Again, using elotuzumab as an example. Phase 1 studies demonstrated best response to single agent elotuzumab to be stable disease and in only 26% of patients. However, following up on excellent preclinical activity in combination with lenalidomide, phase 2 trial examining elotuzumab with len/dex demonstrated significant efficacy achieving 84% ORR rates in relapsed myeloma patients and corresponding excellent disease modifying behavior with time to progression “not reached” for the lower dose of elotuzumab (Moreau et al EHA 2012; Lonial S et al. Proc ASH 2011;Abstract 303). These results led to ongoing phase 3 studies comparing elotuzumab with len/dex vs len/dex in the newly diagnosed and relapsed settings.
The anti-CD38 antibodies being studied (e.g. daratumumab and SAR650984) appear to have single agent activities in early phase studies and will hopefully also translate preclinical synergy with other compounds in ongoing early phase combination studies in the clinic.
There also more pragmatic reasons including the requirement premedication with steroids to prevent infusion reactions. Generally we would like to have a historical controls to make general (not specific) comments on efficacy (e.g. elotuzumab studied in combination with len/dex; the high efficacy in phase 2 clinical trials relative to historic len/dex as discussed above).
I hope that this gives an idea to the promise of monoclonal antibodies in myeloma and a brief discussion of why these therapies may have enhanced activities when combined with “immunosuppressive” therapies used in myeloma. It is not a simple question to answer and I would suggest we are still elucidating the true mechanisms of activity and enhanced efficacy in combination with monoclonal antibodies.
References:
Richardson, P. G., Lonial, S., Jakubowiak, A. J., Harousseau, J.-L. and Anderson, K. C. (2011), Monoclonal antibodies in the treatment of multiple myeloma. British Journal of Haematology, 154: 745–754. doi: 10.1111/j.1365-2141.2011.08790.x
Allegra, A., Penna, G., Alonci, A., Russo, S., Greve, B., Innao, V., Minardi, V. and Musolino, C. (2013), Monoclonal antibodies: potential new therapeutic treatment against multiple myeloma. European Journal of Haematology, 90: 441–468. doi: 10.1111/ejh.12107
Regarding the efficacy if monoclonal antibody therapy in face of steroids there are a number of things to consider. The mechanisms of action mediating myeloma cell death by these antibodies are termed:: antibody dependent cellular cytotoxicity (ADCC), and complement dependent cytotoxicity (CDC). It is important to note that specific antibody therapies may preferentially mediate myeloma cell death by one pathway over the other or even by direct killing.
Regardless, ADCC and CDC are mediated by the specific aspects of the immune system- not the antibody producing cells (B cells or plasma cells-cells very sensitive to steroids). ADCC involves the targeting of myeloma cells by elotuzumab binding to CS-1 and recruitment of immune effector cells including Natural Killer Cells, macrophages and neutrophils that in turn destroy the myeloma cells. In contrast, CDC involves complement mediated destruction of cells (without additional cellular components). These cellular responses are not as sensitive to steroids.
Preclinical evidence shows that monoclonal antibodies are, in fact, synergistic (multiply the effects of each agent when used together) with current drugs including dex, lenalidomide [Revlimid], and bortezomib [Velcade] that activate the cellular components of the immune response (ADCC, see references for more detail).
Not all antibodies are the same- some may be successful as single agents some are not. Again, using elotuzumab as an example. Phase 1 studies demonstrated best response to single agent elotuzumab to be stable disease and in only 26% of patients. However, following up on excellent preclinical activity in combination with lenalidomide, phase 2 trial examining elotuzumab with len/dex demonstrated significant efficacy achieving 84% ORR rates in relapsed myeloma patients and corresponding excellent disease modifying behavior with time to progression “not reached” for the lower dose of elotuzumab (Moreau et al EHA 2012; Lonial S et al. Proc ASH 2011;Abstract 303). These results led to ongoing phase 3 studies comparing elotuzumab with len/dex vs len/dex in the newly diagnosed and relapsed settings.
The anti-CD38 antibodies being studied (e.g. daratumumab and SAR650984) appear to have single agent activities in early phase studies and will hopefully also translate preclinical synergy with other compounds in ongoing early phase combination studies in the clinic.
There also more pragmatic reasons including the requirement premedication with steroids to prevent infusion reactions. Generally we would like to have a historical controls to make general (not specific) comments on efficacy (e.g. elotuzumab studied in combination with len/dex; the high efficacy in phase 2 clinical trials relative to historic len/dex as discussed above).
I hope that this gives an idea to the promise of monoclonal antibodies in myeloma and a brief discussion of why these therapies may have enhanced activities when combined with “immunosuppressive” therapies used in myeloma. It is not a simple question to answer and I would suggest we are still elucidating the true mechanisms of activity and enhanced efficacy in combination with monoclonal antibodies.
References:
Richardson, P. G., Lonial, S., Jakubowiak, A. J., Harousseau, J.-L. and Anderson, K. C. (2011), Monoclonal antibodies in the treatment of multiple myeloma. British Journal of Haematology, 154: 745–754. doi: 10.1111/j.1365-2141.2011.08790.x
Allegra, A., Penna, G., Alonci, A., Russo, S., Greve, B., Innao, V., Minardi, V. and Musolino, C. (2013), Monoclonal antibodies: potential new therapeutic treatment against multiple myeloma. European Journal of Haematology, 90: 441–468. doi: 10.1111/ejh.12107
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Dr. Ken Shain - Name: Ken Shain, M.D., Ph.D.
Beacon Medical Advisor
Re: Why use dexamethasone with antibody therapies?
Thanks Dr Shain for clarifying the mechanisms involved in antibody therapies. It is greatly appreciated.
Libby
Libby
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LibbyC - Name: LibbyC
- Who do you know with myeloma?: myself
- When were you/they diagnosed?: 2009
- Age at diagnosis: 43
Re: Why use dexamethasone with antibody therapies?
Dr. Shain,
Thanks so much for taking the time to write such an informative response to my question.
Mark
Thanks so much for taking the time to write such an informative response to my question.
Mark
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Mark
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