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PHILLIP MCCARTHY: So these are my disclosures, consulting from these companies, honoraria, institutional support. And I will be discussing non-EMA and FDA approved indications turning my talk. So auto transplants, as Saad pointed out-- rescue really-- following induction therapy, standard for transplant eligible newly diagnosed myeloma patients even with novel drug availability. Transplant can be delayed but not all relapsing patients are able to go to transplant after progression with upfront induction therapy.

I'll talk a little bit about maintenance and consolidation, deepen and prolong response, and continuous maintenances and approved approach. However, the majority of patients who have progressive disease have multiple choices and [INAUDIBLE]. So studies are ongoing to test new strategies to improve outcome.

We have to develop early surrogate endpoints for long term outcome because, as Saad pointed out, some of these studies may have to stay open for 10 years if we're going to look at an overall survival endpoint. This might include minimal residual disease immune profiling. Finally, I should add on here also, imaging. That's another important thing that needs to be incorporated into endpoints.

So I got this from a colleague in Oman. Before the new drugs, treating myeloma was like waiting for a taxi and none would come. Then all of a sudden, five come at once. I'm not going to go through all the therapies. But I'm going to point out that high dose therapy with stem cell support has been around since the mid '80s. And first with bone marrow, Bart Barlogie had a lot to do with that, and the French with using mobilized peripheral blood. This is back when VAD stood for vincristine and not for bortezomib or Velcade.

And since then, we've had a whole series of drugs. I won't go into them in great detail, the [INAUDIBLE] and then now the CELMoDs in clinical trial, the proteasome inhibitors, some in trial, panobinostat, HDAC inhibitor, the two monoclonals that were developed. Selinexor just came out this past year, or this year, I should say. And a variety of different strategies that are being developed, checkpoint inhibition, which Saad published recently, was actually not a good thing. It's a very interesting problem. And so there's a lot of things that we don't understand completely about the biology of myeloma, nor how to manage it long term. so that we cure everyone.

These are all some of the things that are being developed. Kelvin's going to talk about a lot of this. And so I'm going to talk a bit about the cellular therapy. And there's a whole series of things coming down the pike. So for the transplant eligible, there's induction, transplant, maintenance for a fixed time or if not in CR, or maintenance until PD. I'd make the argument for maintenance until PD.

Infectious disease prophylaxis is incredibly important. Antivirals, DVT prophylaxis, bisphosphonate, and mitigation of steroid effects. Andrew Spencer loaned me this slide. And so now we're talking about maintenance until PD with the consolidation. Sometimes that consolidation could be a second transplant. It's more popular in Europe.

This is from the CIBMTR. This is the number of transplants back in 2017. They wait for the data to mature then they publish it. And you can see the most common indication in the US was transplant from multiple myeloma autologous, which is in green, rarely allogeneic, won't talk too much about that, and then lymphoma.

And this is also showing that age is really not an issue. It's fitness. So you can see back from 2000 up to 2017, the bluer people who are less than 60 years of age, the green are 60 to 69, and greater than 70 in orange. In Europe, the cut off used to be 65. They're starting to look at that differently.

And here in the US, again, it's fitness that matters more than anything else. The oldest we've done is 83. And he did just fine.

So this is the-- Saad mentioned this so I thought I'd better put it in quick. I'll talk about the transplant versus no transplant. This is consolidation. It's after a VCD induction, chemotherapy versus high dose melphalen. And this is looking at chemotherapy versus transplant. I'll show it in the next slide as well.

And this is looking at one transplant in blue versus two transplants. And they found a benefit, in particular, in high risk patients. But then we did something similar here in the US. Ed Stadtmauer led this, high dose melphalen then followed by a consolidation, a second transplant, or going on to maintenance. All arms went on to maintenance. And this is the overall survival, no difference. Progression free survival, no difference.

And McKelly [INAUDIBLE] always shows these slides. And Ed Stadtmauer always shows McKelly's slides. And we sort of look at them and go, I guess it's different from Europe to the US. This is the transplant versus no transplant. This is transplant up at the top. And this is transplant, usually a progression. But you can see the inferior PFS.

This is a French study that looked at an RVD induction and then a randomization to high dose melphalen versus continued RVD. And you can see the transplant had a superior progression free survival, about 14 months. But the overall survival is the same. And there's a whole bunch of follow up that needs to be done on this. There's also a difference in maintenance. In the US, the maintenance is until progression. In this study, it was only for one year.

Speaking of maintenance, I know someone else-- did Ola talk about this? Sorry, I was late. Not yet. Oh, he is going to talk about it. All right. Good. I'll go through it fast. This is just PFS from the BMT CTN trial showing that if you're MRD negative, you do better than if you're MRD positive in terms of PFS OS. Same thing with the Myeloma 11 trial.

But the interesting thing that just came out for a transplant versus no transplant, this is the FORTE trial from Francesca Gay. There were three arms but she presented two. This is KRD times 12 versus KRD followed by transplant. And the transplant arm managed to have a higher MRD negativity at one year when compared to KRD 12. And in particular, the best benefit was seen in the high risk disease patient population. So we're beginning to see that the more intensive therapy may be superior in terms of driving a higher risk disease, a higher burden disease into a deeper response.

This is the maintenance, which I'll go through briefly. This is from the US, France, Italy. And this is the meta analysis showing a superior overall survival when you combine all three studies. And the median overall survival for the lenalidomide maintenance arm is approaching 10 years. And it's about seven years for the patients who did not get maintenance.

And as Saad mentioned, there is a second primary malignancy signal. We don't understand that quite well. It's down here. It's hard to see. I apologize. This line here is the cumulative incidence risk of getting multiple myeloma. And this is cumulative incidence risk of dying of it. And these are the placebo arms versus the len arms, which had a much lower risk.

So what this shows is that there is definitely a risk. But we don't understand yet how to identify those patients. And we're doing some work on that.

This is also showing that you can get changes in a response over time, as Saad also mentioned. Ixa was a little less enthusiastic about that for maintenance. This is looking at upgrade of response at any time up to two years. And it's 12% in the ixa arm going from MRD positive to MRD negative. It's 7% for the placebo arm.

This is Myeloma 11, a len land maintenance versus no maintenance. And there was a 32% upgrade from MRD positivity to negativity at six months. And then the EMN 02 is a single arm study. But they showed at anytime up to two years, you had a 48% conversion of the positive patients into negative. And then lastly BMT CTN, which I just showed you on the previous slide, 37% conversion rate at one year, showing that maintenance therapy has a benefit in particular for those who are MRD positive.

Now this is a cross trial comparison which you're not supposed to do. So what I'm doing, though, is showing them up there so that you can at least get a rough idea. This salmon colored thing, this is thalidomide. So this is Myeloma 9. And this is the Australian trial, the progression free survival in 30 and 31 months. The gray bars are the control arms.

These are the various proteasome inhibitor based studies. The HOVON which is bortezomib versus thalidomide. The German group which is no-- it was a consolidation versus no consolidation, same thing with Nordic. The Spanish group, pretty robust. This was a triplet VTD versus TD. And then GIMEMA, same thing. Tourmaline, relatively modest with the ixa.

This is IFM0502, which was an average of two years of maintenance. They stopped it due to the second cancer signal. And it's 41 months when you look at the entire population. But again, it was truncated. And this is the CLGB, the Italian study, the meta analysis in Myeloma 11, all showing a prolonged years worth of-- essentially approaching five years worth of progression free survival benefit.

So high risk, that was mentioned earlier by Saad. The HOVON trial looked at bortezomib. And at two years, bortezomib had 26 months progression free survival versus thalidomide. And this is for deletion 17p, which is sort of the worst.

The Emory Group has an RBD light approach for three years, then len until progression. That's 32 months progression free survival. They didn't have a control for that. And then this is courtesy of Sarah Holstein and also a fellow named [INAUDIBLE] who was a discussant at ASCO. And this is also showing that even in ultra high risk, it's very similar to the bortezomib. This is len until progression.

And then if you look at the 4;14s or deletion 17, it's 30 months. So people have talked about, oh, if you have deletion 17, you can only get bortezomib. That probably is not necessarily the case. We know that both of them are inadequate. You probably need a combination approach.

Kelvin's going to talk a lot about immunotherapy. So I'm going to focus on CAR T-cells. There's a variety of different strategies to attack the myeloma cell. And this is an overview of CAR T-cell therapies commercial, because we have the most experience with that. Although we have done protocol patients as well.

And I was told I had to take out all the brand names. So tisagenlecleucel, which is Kymriah, that's the CD19 from Novartis. And axicabtagene ciloleucel is Yescarta. And that's from [INAUDIBLE]. And it took me a month to learn how to say both of those things.

And then CAR T is very different from-- it's like an auto transplant in that most the toxicity is over with at 30 days. It could be given as an out patient and in hospitalized. But it's very different from an auto because it's very expensive to obtain the product. We'll talk about that. There's a risk evaluation mitigation strategy. There's also lymphodepletion regimen, cytokine release syndrome which is one of the weirdest things I've ever seen, as well as CNS toxicity.

You treat with tociluzumab, which is a drug used for rheumatoid arthritis, other immunologicatory drugs. And there can be some patients with long term significant CNS toxicity as well as long term cytopenias, B cell aplasia, weird viral infection. So it's kind of like an allotransplant without GBHD. Or is I also like to say, when you've seen one CAR T-cell patient, you've seen one CAR T-cell patient. They're very complicated.

So this is a courtesy slide from David Porter who's at Penn. This is taking advantage of the gene transfer technology CAR T-cells. Then essentially hijack the T-cell machinery. And I'll show you how that gets done. And they persist.

The one thing that is just being undertaken or figured out is what cells do you need. Do you need memory cells, affector cells, CD4s, CD8s? And that's all sort of an ongoing research effort. The first successful use of this was in CLL patients published in 2011. And the other thing is these are non-cross resistant to chemotherapy.

So here is our lentivirus that comes in. Do you know what this lentivirus used to be originally? Anyone? It's HIV. It's disabled. And so if you will look at some of these patients and do an HIV test on them, it might be a false positive. Because there is a little bit of viral product in there. Again, it's disabled.

So then the virus sends out through its vector an antiCD19 molecules. So this is, again, B cell and ALL. Do you know where that CD19 is? Anyone? Fellows, you can-- you should speak up. It's an immunoglobulin. And do you know what animal it came from? A mouse. So this is a mouse antiCD19. There are now ones being humanized and a variety of other efforts.

So this goes, it hits the CD19, kills the cell. Nice demonstration. And for myeloma, the target of choice right now is BCMA. I'll talk about that in a sec. As mentioned earlier, there is this tremendous toxicity that may or may not occur. I have some patients just sail and walk out of here and go home back to the Syracuse area by day 26. And I have others who stay in the hospital for weeks.

And there's this whole cytokine release syndrome, which is thought to be due to the interaction and the-- there's a tumor lysis syndrome that can occur. But there's some type of activation, probably through interferon gamma IL-2 where you probably activate the reticular endothelial system. And you can generate fever, neurotoxicity, shock, and acute phase reaction production. We're actually going to be doing an anti-GM CSF antibody to see if we can mitigate some of that toxicity. It works in mice. We're going to see if it works in humans.

So this is the target for myeloma. It's BCMA. And it's expressed on maturing plasma cells and [INAUDIBLE] plasma cells. And it's expressed on the cell surface. It's activated through B-cell activating factor. Or my favorite here is APRIL A Proliferation Inducing Ligand.

And the other thing that's kind of interesting, it's also cleaved and shed off the surface. So it makes it a little more complicated. Because theoretically you could gum up the T-cell that's against BCMA with all this protein. It's going to stay away from the cells. So there's a bunch of strategies to try and mitigate this and understand it more.

This is the paper from Noopur Raje which was published in New England Journal earlier this year. She looked at 33 patients. The objective response rate was about 85%. And there were 15 patients who attained CR. And six of them had relapsed. So attaining CR does not necessarily mean that you're going to do well. And the medium PFS was just about a year.

And all 16 patients who were greater than a PR and it could be evaluated for minimal residual disease were negative. However it's only 10 to the minus fourth. And as Dr. Longren will tell you, there's a variety of different depths of response. And that's not a very low level. You want to be closer to 10 to the minus sixth.

And here are all the relapses. The other thing is, this is not a drug. Because you can see that at the lower doses, the patients had a higher degree of progression. Those are the red circles. But at 150 times 10 to the sixth, there's still some patients who are doing well. At a higher dose level, 450 times 10 of the sixth, you have still a fair amount of progressions. And at the highest dose level, 800, two out of three is bad, to paraphrase Meatloaf.

And those patients progressed. And yet they got the highest cell dose. So there's a large we don't understand yet about how this all works. And you can see that some of these lower dose patients still did pretty well.

So very exciting. These are all heavily pre-treated, all DARA exposed, PI and [INAUDIBLE] exposed. So they were fairly far down the track. The FDA had mandated that when these studies were developed. So it's exciting. But it's not clear yet if it's going to be anywhere close to even a double, to use the baseball analogy.

These are some of the products that have been reported. There's others. I just see commercials. This is Bluebird. They partnered with Celgene. And of course Celgene had to have another BCMA so they partnered-- actually they bought Juno. And then BMS bought them. And then there's Legend, which is the Chinese company which partnered with Janssen.

So they're all slightly different in terms of mostly cell composition. They use the same costimulatory molecules. And they've all had an overall response rate in the 80% range. CR rate has ranged from 27% to 74%. They have toxicity. And the median progression free survival with the Bluebird, as I showed you, is about a year. It's about a year and three months. And it's not been reached for the Juno. But that's a little bit earlier. They'll update it soon.

So what's on the horizon for cellular therapy? Other BCMA directed therapies, other novel agents, combinations cellular therapy, novel targets. For myeloma, it's not ALL yet. ALL probably is a pretty durable 60% progression free survival. Lymphoma diffuse large B cell, both the commercial indications, 40%. And you've seen that we don't even have a plateau yet. So we're going to have to see more and develop this more before we get really excited about it.

So this is one of the developments. I have learned more about other animal antibodies with this technology. This is a human immunoglobulin there on the right with the light chain and the heavy chain. And this in the middle is a cameloid, or a llama or a camel. And llama and camels only have a single heavy chain for their binding.

The reason why this is kind of fun is that you can package more into the vector. So by using this type of binding, it allows you to put other things into the vector like something maybe to increase activity, downregulate it. Because the viruses, you can only put so much material into it.

This is a shark antibody. It has a very long FC receptor. But it also has a very small single variable heavy chain. So that also might be utilized as well. I'm waiting for the shark CAR T.

So this is what's some of the future holds. There's lots of studies undergoing. I'll summarize it towards the end. But this is for high risk disease. These are patients who have ISS-3, revised ISS-3. So high risk disease. They get a dealer's choice for an induction. They get enrolled. CAR T-cells are collected and made transplant. And they get their CAR T-cells afterwards.

This is a incomplete response at nine months. Then they get their cells collected, a lymphodepletion in the CAR T. And then they get len maintenance, as with the previous one. So this is a little bit different. These are for incomplete responders.

So to summarize, I'm not going to go through all of this. There's a whole series of targets that are being utilized besides BCMA, [INAUDIBLE] GRP, it's a G Protein Receptor, kappa chain, and NYESO-1. We're also doing NYESO-1 here. Decreased exhaustion, improved the activity of the T-cells, multiple infusions. If you go to clinicaltrials.gov there were 29 citations in May. There are now 35 with CAR T-cell myeloma USA. And if you substitute China, it's 27 citations. And now 31 in October. They're really very active in China with lots of interesting things being developed.

Does MRD mean the same thing? There's the whole cost of this. We'll have to see. So one thing that's interesting is there is a registry that we have to report to the CIDR. And there's also Data Management Resource, which is a center which is being done here at Roswell Park. A lot of the analytics for some of these trials that will be done here are led by Alan Hutson. There's the CIDR.

So I'd like to end with Carthage was the sworn enemy of Rome. Cato the Elder used to end all his speeches, regardless of topic, with Carthage must be destroyed Carthago delenda est. And in an era when median PFS is greater than five years and OS 10 years, surrogate endpoints for long term outcome must be tested to prevent studies that remain open for 10 years longer with an OS endpoint. And these are just some of the things that we would want to be thinking about in the future.

I'd like to thank all my colleagues here at Roswell, my colleagues around the world who loaned slides, all the co-operative group, and the NCI, NHLBI, the FDA, my wife puts up with me. And this is-- I've run over. Haven't I? All right. I'll be quick.

There is a workshop if you are interested. If you register for ASH you can go to it. It's Friday, December 6, 1:00 to 6:00 PM. We're going to have little 10-minute blasts of information which we're really excited with multiple presenters. If you go to this URL, well please go to the very bottom. Because we're at the very bottom. You might think, where are they? And so we're very excited because we're now part of the official ASH symposium. We're also going to be looking at various people will be presenting on immune profiling, MRD testing. Thank you very much.