Insights From:Jatin P. Shah, MD, MD Anderson Cancer Center;Ivan Marques Borrello, MD, Johns Hopkins University;James R. Berenson, MD, Institute for Myeloma and Bone Cancer Research
Ivan Marques Borrello, MD: The antibody of development in multiple myeloma to date has focused on a variety of different targets. The two that have gotten FDA approval thus far have been daratumumab that targets CD38, and elotuzumab that targets SLAMF7. There are several other anti-CD38 antibodies that are currently being developed. And I think the interesting thing about CD38 is that it’s not a target that’s necessarily unique to plasma cells. It’s also expressed on activated T cells, as well as a variety of other immune cells. And so, how this all fits into the paradigm needs to be considered when coming up with therapies.
Another interesting target that is being looked at is BCMA (B-cell maturation antigen). BCMA, in contrast to something like CD38, is primarily expressed on the late stage of plasma cell differentiation—so, for the most part, primarily on the mature plasma cells and malignant plasma cells. And, certainly, we’re seeing some very early CAR-T cell therapy with BCMA-targeted CARs that are looking very promising. And I know that bispecific antibodies are currently being developed to BCMA, and also monoclonal antibodies with a toxin associated to it are being developed. That’s another target that I think is interesting and we’ll probably be seeing a lot of.
Another completely different class of monoclonal antibodies that has globally shown promise across a vast number of diseases, in which they’re being tested, are the checkpoint inhibitors and, more specifically, PD-1 and PD-L1 antibodies. I think, similarly to the data with elotuzumab, what we’ve seen is that a single-agent, PD-1 blockade does not seem to be very effective. These are data that are being published and are scheduled to come up very soon.
But, at ASH in 2015, what we saw was, surprisingly, that combining pembrolizumab, a PD-1 antibody, with Revlimid/dexamethasone in Revlimid relapsed patients, and also in Revlimid refractory patients, was able to elicit up to a 70% response rate and approximately a 50% response rate in the Revlimid refractory patients. And this has really generated a huge interest of the role of checkpoint inhibitors in multiple myeloma. Clearly, just like with other malignancies, there are a variety of other checkpoints that can be targeted and CTLA4 is one, TIM-3 is another. Another target, which is actively being studied right now in multiple myeloma, is PD-L1. There’s an antibody called durvalumab that is being tested by Celgene right now. It’s a combination with pomalidomide/dexamethasone. And I think, again, the idea is that checkpoint inhibition is critical to the overall development of an anti-tumor response. But, it’s the presence of an IMiD that can potentially augment this overall efficacy.
Jatin P. Shah, MD: Excitingly, now we have two monoclonal antibodies with elotuzumab and daratumumab, which are important immunotherapies that we can use in myeloma. However, if we start thinking about checkpoint inhibitors, I think that’s another exciting wave that we see coming down the road. So, in addition to CAR T-cells, which is another new emerging therapy as well, again, targeting or using the immune system, checkpoint inhibitors are going to be very important as well. We see now checkpoint inhibitors proven as a valuable therapy in other solid tumors. We’ve seen drugs like nivolumab just recently approved in Hodgkin’s Lymphoma with very impressive response rates in the relapsed/refractory setting for Hodgkin’s Lymphoma. And, importantly, now we’re starting to see that transition or activity in myeloma.
Initially, when we looked at drugs like PD-1 inhibitors in myeloma as a single agent, they were not active. And so, there was waning interest in checkpoint inhibitors by itself as a single agent. However, importantly, when we look at the combination with pembrolizumab/lenalidomide/dexamethasone, when we add it to lenalidomide/dexamethasone, there are very impressive response rates. Completely different story that we see here, where we see very nice high response rates, even in patients who are lenalidomide refractory, or bortezomib refractory, with a combination. I’ve seen some very exciting science and very exciting data when you look at, for example, pembrolizumab/lenalidomide/dexamethasone. Importantly, if you look at pembrolizumab/pomalidomide/dexamethasone, again, there were also very high response rates, including in pomalidomide refractory patients as well. I think that when you look at checkpoint inhibitors, really, the future is going to be in combination with various backbone therapies that we have now. So, very exciting now that multiple phase III studies have been launched with pembrolizumab, both with pomalidomide in relapsed as well as lenalidomide in newly-diagnosed myeloma. And a number of other companies as well now are starting to look at checkpoint inhibitors in combination in myeloma.
James R. Berenson, MD: Newer data emerging are certainly suggesting that the antibodies can be combined safely and effectively with about anything. And they are suggesting that the antibodies alone are not very active, but they are really great partners for other drugs and they can do this long-term without added toxicity. I think that’s a big home run. And whether the partner’s Revlimid, Kyprolis, bortezomib, Ninlaro, or hopefully chemotherapy, which we’re forgetting about, I don’t really know. I think the other thing we’ve got to be able to get our hands around is that maybe you can start slowly with these antibodies and start adding other things in if, indeed, your less complicated regimen isn’t working early on. It’s a real advantage of the antibodies.