How have checkpoint inhibitors been used in myeloma?

How have checkpoint inhibitors been used in myeloma? Checkpoint inhibition has been explored in multiple myeloma. There were some early studies that appeared to be quite promising with a drug called Pembrolizumab in the phase two studies. However, when that was done in phase three trials, both the trials actually showed that the survival was decreased with the use of checkpoint inhibition. Now, we don't understand all the mechanisms of that. Is it something unique to that particular checkpoint inhibitor or is it something to do with the fact that it was combined with immunomodulatory drugs like lenalidomide and pomalidomide? So, there's still interest in that mechanism and there are ongoing clinical trials trying to see if that would work in a subgroup of patients or whether it would work better in combination with another drug. As single agents used by themselves, they have not shown a lot of activity. Anti-PD1 showed some promising activities in earlier trials in combination with lenalidomide or Revlimid, but then in a randomized phase three trial, the studies were closed because of increased mortality. I think it's unfortunate that many of these things have actually been closed because there is probably significant efficacy in there. The story in multiple myeloma got a little bit more complicated. The early trials for checkpoint inhibitors were done with immune modulators combination. Immune modulators are pills, right, like lenalidomide, pomalidomide, telidomide, this class of drugs. Those drugs, they modulate our immune system and we know that sometimes they even activate some of the components of the immune system. For multiple myeloma, when it was combined with immune checkpoint inhibitors, the results were not as good as we wished for it to be and therefore the clinical trials were placed on hold. There's more to this story. We're thinking that maybe the design of those clinical trials, maybe the combination with IMIDs, might have been the reason why we got bad results. What is the future role of checkpoint inhibitors in myeloma? The general thinking is immune checkpoint inhibitors has still place in multiple myeloma. We just have to use it in the right clinical setting. More clinical trials are building on that now with the different combinations and hopefully we'll learn some more good news in the near future. Now we're looking at the immune therapies with other agents. I'm opening a trial next month with daratumumab and pembrolizumab. There's some people are looking at the combination of immune therapies with proteasome inhibitors, immune therapies as a sort of a maintenance-based agent after you get CAR T therapy to try to keep that immune system functioning and continue to be vigilant. The way that these cancer cells evade the immune system is by down regulating the proteins that cause our immune system to recognize them as foreign. So we try to decrease that from happening. I think what needs to happen at some point is for them to be restudied in different settings. It may also be that there is a situation which in myeloma that the use of checkpoint inhibitors could also increase the overall growth of the myeloma cells themselves and maybe PD-1 is not the right one to use. There are however a variety of other checkpoint inhibitors that are currently being explored and I think integrating these in combination potentially with chemotherapy with other agents can show promise and I would predict that in the next several years we'll probably see these coming into light and being studied more extensively. Regarding combining checkpoint inhibitors with other treatments, multiple clinical trials are going on. We have one of those clinical trials where it's testing combining the checkpoint inhibitors with different classes of checkpoint inhibitors together and comparing it with a standard of care. You might get two different types of checkpoint inhibitors with dexamethasone and add to that deratumumab as a backbone which is also an immune therapy and compare that with a standard of care treatment also it's going to be an immune therapy for example elutuzumab with pamalidomide which is an immune modulator with dexamethasone and then see what the results show there. Very promising area I have to say, very excited about it. It showed efficacy in other cancers. It's difficult to imagine why wouldn't be effective in multiple myeloma as well.