What is the future of cellular and immune therapies in myeloma?

What is the future of cellular and immunotherapies in myeloma? So immunotherapy in myeloma I think is here to stay. There are very many different types of immunotherapy. There are bispecific therapies, there's CAR T cell therapies, there's vaccine therapies, there are potentially checkpoint inhibitor therapies. I think what we're probably going to end up figuring out is how to refine them to minimize the toxicities of a lot of these things, potentially to combine them and to potentially sequence them in a way to maximize the overall efficacy. But what I think we're going to see over the next 10 years is more of them available and a deeper understanding of how to get the maximum benefit of these. Another big aspect of this will likely be patient selection. If there's somebody that intrinsically we know will not respond to immunotherapy, then there's really no point putting that patient on an immunotherapeutic study. By the same token, if we know that somebody will respond, we can potentially treat them at regular intervals with the same therapy to prolong that overall response. Right now we don't know if somebody is going to respond to therapy. We do this empirically. We give the therapy and they respond or they don't respond. But I think there's a lot of work to try to understand if there's a way to prognostically determine that. And that I think is one of the areas that is being worked on and hopefully we will be more enlightened to what those outcomes are over the next decade. We are actually at the verge, in my view, of a major paradigm shift in how we're going to treat myeloma in the future. We've already seen very dramatic responses with immune-based approaches to myeloma therapy. Response rates exceeding 80 to 90 percent for each of those therapies with very durable and deep responses occurring in these patients that have received multiple prior lines of therapy. We think it is likely that as these therapies move proximately, before earlier lines of therapy, that the responses will actually improve. They may not be the solution by themselves, but they will certainly be part of the solution for trying to combine them with different approaches and likely become more, have a significant potential of becoming front-line therapies for a large number of our patients. So I think it is quite likely that immune-based approaches become the mainstay of therapy. I think the future for cellular therapy and immunotherapy in myeloma, in one short answer, is bright. There is great optimism about immune system and its ability to treat cancer across the cancer spectrum. Certain things that have worked for solid tumors, like checkpoint inhibitors, may not have worked for myeloma, but now we have bispecifics and CAR-Ts that are showing very impressive results. We certainly haven't hit a home run. I think we have great work to do. We have to expand on these with perhaps combinations and moving them earlier in the treatment course, as we said, but I think that they will provide the next big leap in outcomes for our patients. I think it sounds very promising based on what we have seen so far. I think the efficacy of the immune approaches, whether it be using a CAR-T cell or one of the bispecific antibodies to redirect the T cells to the cancer cells, both of them seem to be very effective. We can see responses upwards of 70-80% in patients whose myeloma has become refractory to all other standard therapies. Now what we don't know yet is how long will these responses last. Right now, though, they don't seem to last very long and doesn't seem to be curing any patients, but that could be just a function of the fact that these treatments are being used so late in the course of the disease. So there are trials looking at immunotherapies either alone or in combination with standard therapies in newly diagnosed myeloma, and that's where we might actually see a significant benefit and also in the context of potentially preventing the precursor disease to get to be myeloma. I think immunotherapy is finally coming to age. We started immunotherapy 25 years ago when allogeneic transplant was the only immunotherapy we have. I was at University of Arkansas and my first paper was the new concept of doing autotransplant followed by an allotransplant, expecting that that will cure multiple myeloma. And after treating 70 patients, if you look at 10-year outcome, only seven patients are in complete remission. Most of the patients do relapse. So the immunotherapy with allogeneic transplant has been abandoned in myeloma. And now we are talking about IMIDs, which is another form of immunotherapy. You probably talk about the monoclonal antibodies, which is another form of immunotherapy. And I think these are changing the paradigm of treatment. Daratumumab definitely has an impressive outcome on patients, especially when used upfront in combination with RVD or KRD. We are seeing MRD negativity up to 60, 70% of the transplant. And then you talk about the new antibodies coming, like bilentumab or the CAR T cells or the bispecifics. These are all newer therapies. I think immunotherapy is definitely the way to go. I personally think that immunotherapy is going to be the next frontier in myeloma. There are some unanswered questions about immunotherapy in general in oncology and in myeloma. The first in my mind is how do we measure efficacy of immunotherapy? I do not believe that looking at overall response rate is the way to measure efficacy of immunotherapy, because overall response rate immunotherapy is not an accurate measure of the efficacy of the immunotherapy. Immunotherapy can benefit 20% of the patients by having them in remission for two to three years. If you look at response at, let's say, bilentumab, bilentumab overall response rate is somewhere around 30%. However, the subset of patients that had achieved these deep responses do benefit from this treatment. And as I learned from a lot of my immunology colleagues, the whole market of immunotherapies, when you stop the immunotherapy, you see persistence of response. Immunotherapy is different than chemotherapy. It's not just suppressing cells. It's eliminating some of the malignant clones, like we see in lymphoma and in leukemia. And that's where we're headed with myeloma. Now we see patients on the CAR T cell trials remission up to two years. I know that people say progression-free survival is only nine months, but forget progression-free survival, forget overall response. Just look at the subset that have two plus years. And this is a subset that may be cured from immunotherapy. You probably know about our trial we've done here, combining this pomalidomide with PD-1 inhibitor. And PD-1 was a huge deal a couple of years ago. The problem was it was a toxicity. So it's a very toxic treatment. But when you treat patients and they achieve a response, we have seen those patients, even after you stop the treatment, stay in remission for up to a year. Some of them are remission two to three years on no maintenance. And that's immunotherapy in my mind. So immunotherapy is not like chemotherapy. You give it, you relapse, you give another. It's the durability of response. Two things I think we should look at in immunotherapy. What happens after you stop the treatment? Are you really curing subset of patients? And that's the holy grail of myeloma today. Can we cure subset of patients?