Noopur Raje, MD Sagar Lonial, MD Director, Multiple Myeloma Professor Program Vice Chair of Clinical Affairs Massachusetts General Hospital Department of Hematology and Medical Oncology Associate Professor of Medicine Winship Cancer Institute Harvard Medical School Emory University School of Medicine Boston, Massachusetts Atlanta, Georgia Advancements in Immunotherapeutics for Multiple Myeloma Raje: Hello, I am Noopur Raje, and I am here at the 50th Annual ASCO Meeting in Chicago. I am here with Dr. Sagar Lonial who is a professor at Emory University. Sagar, it is always a pleasure to have you. Lonial: Thank you. Raje: And, thank you for being here. You know, every year we kind of do this for myeloma, and it is amazing that every year I am more enthusiastic about the next year, which I think is fantastic. We have interesting data at this meeting, but what I was hoping you would be able to do was talk us through. Obviously monoclonal antibodies have been huge for myeloma. We have been trying to study them for years, but I think in the last couple of years we are actually now beginning to see some impact of these. You have done a lot of work with elotuzumab. There are a couple of others. Do you want to speak a little bit to where we are and where we are going with monoclonal antibodies? Lonial: You are right. I think both on investigator side, we are very excited and on the patient side, I know patients are very excited about the idea of immune-based therapy or monoclonal, which is probably the closest place we are right now. The challenge I think we have had for a long time is that we either did not have the right antibody, or immune function in myeloma patients was never adequate enough to really support an effective monoclonal antibody, and that is sort of the story we learned with elotuzumab a few years ago. By itself, it did not seem to do a whole lot, but that is because we learned that ELO is actually most effective when you have lots of NK cells and is ADCC dependent.1 So the addition of lenalidomide to elotuzumab gave us pretty neat data that said 33 months of progression-free survival in an early relapsed setting.2 We now have antibodies that appear to be less dependent on ADCC alone, have some CDC as an alternative mechanism, antibodies like daratumumab or the Sanofi monoclonal targeting CD38 (SAR650984), and both of those at this meeting appear to have single-agent activity, somewhere in the 30-40% range,3,4 and both of those antibodies are doing what ELO did which is combine with lenalidomide, and appears to again show a higher response rate in the combination, presumably because they have ©2014 MediCom Worldwide, Inc. some level of ADCC that is activated by NK cells.5,6 There are also other monoclonals that I think we are excited about that we are looking at either things in the microenvironment like the BAFF work that you have done.7,8 The denosumab (anti- RANL) is another antibody again targeting microenvironment9 and then things targeting CD138 for instance that are not unconjugated antibodies but are targeted with chemotherapy attached to them (eg, Indatuximab Ravtansine; GSK2857916), 10,11 much like gemtuzumab ozogamicin (Mylotarg) was years ago in leukemia. Those are actually showing synergy with lenalidomide as well.10 The field as we have it now with daratumumab, the Sanofi 38 antibody, elotuzumab, and others that are I think in early development really says that we are going to have exciting trials down the road, and the challenge is how do we incorporate these into our treatment paradigms? Raje: I think what is also very interesting are these monoclonal antibodies. The good news here is the frequency of how often we have to give them. What we have been able to learn over the last couple years is how to better treat some of those infusion-related reactions, and that has made a big difference, and incorporating them even in the upfront setting as we all are doing trials with say ELO for sure now has come up front, especially for the high-risk patient population.12 Talking about immune strategies, Sagar, this is something I think we have learned from our solid tumor colleagues. There is obviously a lot of interest in the PD-1 and PD-L1 pathway, situations or diseases like colon cancer and lung cancer have actually seen nice responses when you interfere with this pathway.13,14 What do you think or how do you think we are going to be able to study this pathway in the context of myeloma? Lonial: I think in all of oncology, it is really exciting area to work in, and that is because much of what we have done to try and modulate immune function through vaccines or through other cell-based approaches to treat cancer has likely been limited in some way by the tumor’s ability to hijack the immune system to protect itself, and these PD-1 and PD-L1 based approaches are attempts to reverse that hijacking, to no longer have the tumor under a cloaking device if you will, to unmask it and allow it to be susceptible to the things that we normally use. So, I think it is a very exciting time. Those trials are ongoing right now.15,16 The question is when is the best time to do that? At an end-stage refractory relapse patient, they may not have immune function or receptor density to really warrant that kind of an approach, whereas in a newly diagnosed or smoldering stage they may, and so I think we need to learn a little bit about this biology in myeloma, how it relates to genetic risk, which probably has something to do with some of this as well, and that will teach us how to best do it as opposed to a broad ‘everybody is going to get PD-1 antibody and we are going to see what is going to happen.’ Raje: Sure. These are more kind of specific, the monoclonal antibodies tend to be a little more targeted. You know for myeloma we have been toying with the idea of vaccination strategies for years. We have a couple of them, one of them which you and I have used in the smoldering setting is a tripeptide vaccine.16 Another one which we 2 have used in the myeloma setting as a fusion vaccine.17 Any thoughts on where that kind of more designer-specific vaccines are going? Lonial: Yes, I mean the targets for those vaccines are validated targets in myeloma. I think the challenge is, even in the MGUS setting, and I think this is data from your institution as well, suggests that immune responses to vaccine in MGUS and smoldering are not as good as a normal patient’s, a normal person. So that tells us that even at the earliest stages of the disease, we have to do something to augment immune function to allow responses to vaccines, and in the next iteration of that vaccine trial that you just mentioned, we are adding lenalidomide to try and do that. So, I think it is not just a matter of giving the vaccine. It is giving the tools to allow the vaccine to be effective, whether that is PD-1, PD-L1, or lenalidomide, that is really the key. Raje: I think having the IMiDs has really made a big difference because based on a lot of data over a lot of years and like you talked about, it is combining it with elotuzumab upregulating the NK system has made a big difference. So incorporating IMiD-based strategies with these vaccine strategies is probably what we would be doing in the future. We have even more open IMiDs coming along now. Your thoughts on the latest greatest newest IMiD now, pomalidomide? Lonial:I think pomalidomide is a really exciting new drug because in many ways it has got the best of both preexisting agents, thalidomide and lenalidomide. I think its potency is really quite striking, and while there has been a lot of talk about potentially using cereblon as a biomarker to predict response and I think Keith has some of that very nice data,18,19 there is something about pomalidomide that works even when lenalidomide has not worked before, and that is a great option for our patients.20 Whether we can make even pom better by adding other drugs to it I think is really the next step and that is what the antibody I think offers. Raje: Ability to be able to combine drugs and largely because all of these drugs are fairly well tolerated. Well, on that note Sagar, thank you so much. This has been interesting. Thanks. Lonial: Thank you. References: 1. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008;14(9):2775- 2784. [PubMed/Full-Article] 3 2. Lonial S, Vij R, Harousseau JL, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30(16):1953-1959. [PubMed/Full-Article] 3. Martin TG, Hsu K, Strickland SA, et al. A phase I trial of SAR650984, a CD38 monoclonal antibody in relapsed or refractory multiple myeloma. J Clin Oncol. 2014;32:5s (suppl; abstr 8532). [Link to Abstract] 4.