What is the future of doing clinical trials more efficiently?

[Music] What is the future of doing clinical trials more efficiently? This is a huge challenge because we have an abundance of relatively new agents that have been approved. If you think about the last 15 years in myeloma, we have something like 17 drug approvals. We have a wealth of new therapies that are very close to approval. We've had new combination therapies that have been approved within the last few years. So we've had great progress and we're having better outcome. We know that patients are living longer with myeloma, but we also have to recognize we have not reached a point where we have curative therapy that we can apply to the majority of myloma patients. And I think it's important to remember how we got to where we are now because for most patients, if you're newly diagnosed with myeloma and you're eligible for transplant, you get your induction chemotherapy and it's usually some variation of a proteasome inhibitor anemia, drug and steroids. Now we're introducing quadruplet therapy up front. And then when patients go into remission, we harvest their stem cells. They have a stem cell transplant for consolidation therapy, and then they usually go on maintenance therapy with REVLIMID. But that didn't come out whole cloth in a single clinical trial. You know, we had transplant was introduced in the late nineties. You know, REVLIMID and Velcade came into care in the early 2000s. RVD became a common induction therapy in the late 2000s, and then the sequencing of RVD transplant and maintenance really was not fully validated until and in some respects until the mid two tens. Right. But that's the standard now. And interestingly, if you think about that, our standard therapy is not giving everything all at once. It's sequence therapy. We do induction therapy, we do consolidation therapy, we do maintenance therapy. So the real challenge now is to understand how do we combine the new agents we have so that we can achieve greater effectiveness. And the other part of that is should we be treating certain patients differently than other patients? Because if everybody's giving induction consolidation or maintenance, we already know that there's a subset of those patients between 15 and 20% who don't do as well as the others. And we have to understand that biology, maybe we should be treating them differently, right, so that we're not giving everybody the same sort of cookie cutter approach. And that's an approach that is broadly described as personalized medicine. In other words, can we identify characteristics in patients when they're diagnosed or when they relapse that will tell us they're going to do better on this therapy or we should try this type of therapy? And so things like basket trials and umbrella trials are a building block. To accomplish that, we need to understand which therapies we can apply to which patient population. Is there a biomarker or a mutation or whatever that can guide us? This set of drugs is going to be better for these patients or will be effective in these patients. So that's one part. The second part is the history of oncology drug development is more is better, right? There's 50, 60 years of history where a new drug is introduced. You put it together with another drug, you put three drugs together, you know, and that results in a lot of confusing acronyms. But it also means that, you know, you give a lot of different treatments altogether and you're trying to max out your impact on the disease. And in some diseases, that's been very effective. You know, certain types of lymphoma that works very well. But that approach has sort of gotten to a limited, limited maximum in myeloma. So we've gotten a lot of good results with increasing the upfront treatment. But I think some of the quad combination upfront data suggests that we're getting incrementally better results, but it's not clear whether that's going to translate into long term better outcomes. So I think another approach that we really need to think about, particularly with these new immune therapies, are should we be sequencing them, in other words, giving one set of treatments upfront, another set of treatments to promote immunity, and another set of treatments to maintain immunity. Right? The immune system is it's a highly orchestrated, complex machine. Right? So if you think about conventional chemotherapy, you're just dropping the big bomb and you're hoping to minimize the damage to normal tissue while maximizing the damage to the cancer and then targeted therapies, which are also drugs, but they're going after a particular biomarker or something like that. That's kind of like a guided missile. And you're just trying to hone as much of the effect into the cancer cells as you can. Immune therapy is really different because, remember, we're not poisoning the cells. We're not introducing toxins. We're trying to redirect the patient's own immune system to effectively identify and kill cancer cells and to develop the same kind of memory you get to infectious diseases so that they remember what the tumor looks like and they can still kill it. And guard the body against relapse disease. The demand on us as researchers is to understand that biology and then intelligently apply all these great new tools that we have so that we can craft sequential regimens that will, that will mimic like if you get sick, if you get a disease, you get a virus or a cold or bacteria, you know, there's a sort of a sequence of events that occurs that allows your immune system to effectively fight it. And remember, and we want to try to recreate that kind of effect in myeloma so that your immune system can see the myeloma as being bad, kill it and then remember it. So that's a real challenge for us. And I think that we are working to find the right combinations and sequences of immune agents, of targeted agents of chemotherapy agents that will accomplish this. And we hope that that that can be done. But to be to be frank, you know, we know that immune therapy can do this because the only published effective curative therapy to date is is allogeneic transparent. So we know that immune therapy in the form of an allogenic transplant can in fact induce long term disease free remissions. It's just that it's it's very dangerous and toxic. We can't use it for most myeloma patients because of their age and including co-morbidities with this disease. But nature has already showed us that the immune system can do this. Now it's now we need to figure out how to take all these fantastic new immune agents that we have at our disposal, figure out how to put them together to recreate that effect but without obviously the the toxicity and risks of allogeneic transplant. [Music]