(Guest Lecture): March 2024 - The Bounty of Treatments for Early Relapsed Myeloma

Good morning. Thank you all for coming. I'm COVID negative, but getting over a cold. So I've been wearing a mask. Let's see here. And I actually have a poll for you, which is how many of you know who Mr. Beast is? Okay. So very see, I think we all learn all the time. So I learned this morning who Mr. Beast is. And the reason that came up is I don't know if you're in the, you know, Cindy, you're in the presence of social media royalty. Cindy has I think over 10,000 followers. All right. So she's very influential. Yeah. And if you don't follow her, follow her. Right. My Loma teacher. But Mr. Beast apparently is, I learned from the kids in the back. Thank you to the crew back there making this all happen. That he's apparently has 240 million social media followers and the most YouTube subscribed person and he's actually a philanthropist. So I learned something new. But anyway, so, you know, I actually have a lot of affiliation with California. I did my undergrad here in Palo Alto and med school and I did my fellowship here. So when I left fellowship at UCSF, this is kind of what we had when I started. And I always think it's good to put a little history. I guess it's reflecting age. But did you know that every monoclonal antibody that's used in human beings today is actually owes its legacy to my Loma? Because in 1984, the Nobel Prize was given for fusing my Loma cells to spleen cells. And then the antibodies that came out were then harvested. And now you manipulate that. So whether it's for autoimmune disease, COVID, anything, everything owes its legacy to the my Loma cell over. Oops. What happened? I think I hit the wrong button. All right, there we go. Yeah. So these my Loma cells, when you fuse them with spleen, you get these antibody factories. And by the way, to the tech folks, Leo, the screen here is not working in the front. But thank you. All right. So that same table now looks like this, right? Which is dramatic in 20 years or so to have IMIDs, proteasome inhibitors, immunologic approaches, and the XPO inhibitor. So a lot of new categories of drugs. But this also, which is great for options, but it also presents a different problem. What's the right combination? What's the right sequence? So this is good and bad. And what I think we have to keep in mind, what's remarkable about this is that how long does it normally take a drug to go from the lab to the patient? And you might think it's a quick process based on the table you saw, but it's really not. Right? First, you check a compound in the laboratory to see if it works and kills the cancer cell. Then you go to animal models. Then you go to the humans in phase one. What's the right dose? Then when you find the dose, does it work? Then you compare it to, so phase one, two, and three studies. So normally that takes eight and a half years just in, and the fact that we've had so much progress is quite remarkable. And you might ask, how did that happen? Especially when you keep in mind that myeloma is not even common. Right? So compared to the big cancers, it's only number 14. So for an uncommon cancer to have so much drug development, it's a testament to all of these components. And why do we do these kinds of programs from academia? Obviously we work collaboratively across the world to advance myeloma. We need philanthropy. We need government. Because if the government does not approve drugs quickly, then you can't get all those drugs to patients. Right? We need these advocacy groups, which is why we're here. Because programs like Health Tree educate patients, get you access to academic centers, clinical trials. And then we need industry too. Because these clinical trials are really expensive. And so collectively, but you know who's at the center of it all is you all. Right? The patients and caregivers. And it takes really a village to make this happen. So when we talk about relapsed myeloma, there's a lot of factors to consider. And this is true of all of oncology. There's patient factors. I would in particular, for example, age, your other medical problems like kidney function, diabetes. So these are going to affect what treatments you pick. Then there's the disease. What stage did you present with? Do you have symptoms or are you just a biochemical relapse? What's your genetics of your myeloma? So there's disease. And then there's treatment issues. Right? How well does the treatment work? What have you had before? What are the side effects? Is it convenient? Cost, which we don't talk about enough. Access. A lot of factors. And I'd like to add yet another variable, which I think as we get more choices, your experience matters more. Right? So what we call patient-reported outcomes. And that's are you able to function? Are you able to work? How much time are you taking away from life to get your therapy? So what this table highlights is there's not going to be one size fits all. And every patient is unique. And that's our job. You know, I always tell patients, why do we need oncology? Why can't any of your drugs from myeloma be prescribed by your primary care? Because you've got to keep all of this in mind. If you don't give enough drug, you don't kill the cancer. If you give too much, you get side effects. And that's our job as the oncology team to help navigate that rope. So when we go to the relapse setting, when you take that same table and narrow it down, there's basically six drugs that we tend to use. Cyclofosmide, lenalidomide or Revlimid, pomalidomide or pomelist, bortezomib or Velcade, carfilzomib or Kyprolis, and then the two CD38s, daratumumab or Darzalex, and esotuximab. And so right now, we're going to talk about lines of therapy. Many of you are so interested in CAR-Ts and bispecifics. Currently, they're approved for four or more lines of therapy. So if you're, let's say you got the treatments Dr. Kumar just outlined, and it's your first relapse, you don't qualify yet for those therapies. But stay tuned, that may change. So the question is, when do you start treatment? And so obviously, if you're having crab symptoms, calcium, renal, anemia, bone, you need new therapy. If your disease becomes detectable and you're a high-risk patient, maybe even before the crab symptoms, it might be prudent to start if you have aggressive genetics. And finally, if you don't have symptoms, nor are you high risk, but if your disease is growing quickly, that may be another reason to start therapy. So those are general principles. And some definitions, I just alluded to this, what is a line of therapy? So currently, as I said, CAR-Ts and bispecifics are approved for four or more lines of therapy. A line of therapy means more than one cycle of a planned treatment. And a new line is when you start either because of progression, relapse, or toxicity. So one kind of nuance is that induction or initial therapy followed by transplant, followed by maintenance, is currently just one line of therapy. So other than that, everything else would start being new lines of therapy. Relapse myeloma means myeloma that has come back after previous treatment. And refractory means not responsive, which means either while you're getting therapy or within 60 days of the last treatment. So for example, if somebody was getting Revlimid and they stopped it, but their disease progressed within 60 days, they'd be considered refractory to Revlimid. But if they relapsed after 60 days, say like in six months, they'd be considered relapse. So that's the difference between these terms. OK, so I kind of alluded to the top part. The other thing that we talk about is what makes somebody measurable. So for clinical trials, usually these are definitions. M-spike of more than 0.5 to 1, 24-hour urine shows more than 200 milligrams per day. We know everybody's favorite thing is to collect that 24-hour urine jug, right? Free light chains greater than 100 or 10, depending on the units of your lab. Or if you have a measurable plasma cytoma, which is myeloma that's coming out of the bone. So now I'm going to show you the data. And I think talking to these kinds of audiences is always a balanced act, right? Because there's some who have seen this data for the first time, and some of you who go to support groups who know this like the back of your hand. So at each slide, I'm going to do the myeloma kind of 101 basic and then the 202. So the 202 will always come at the end. But the 101 part is the exact, these are the studies that compared Revlimid and dexamethasone to another arm, right? So you could add exazomib, which is a pill. You could add carfilzomib, elotuzumab, or dara. And so those are triplets versus the doublet of Revlimid. So these are all randomized phase three studies, all published in high impact publications, New England Journal. And then these are what happened. So in the blue is what happened with the three drugs and the pink is the two drugs. And you can see across the board, three is better than two. Not really surprising. But the question is, is there one that you should be using? How do you pick? We're always taught in medical school not to compare across studies. Why is that? Because outcomes depend, as we said in that slide, it depends on the patients you're picking. Are these older patients? Do they have good kidney function? Depends on their stage of disease, depends on their genetics, depends on how they tolerate it. So you can see, for example, the control arms, PFS, or progression for survival can be anywhere from 15 months to 17 months. And that's just the same Revlimid dex. So that's why we really can't compare these across. But what we do is this percentage increase. And so what's the percentage benefit? This is what's the value add with that third drug. And you can see it's strikingly similar. 26, 34, 29, all kind of around that 30%. And it's kind of interesting standout of 56% with the addition of Dara. And you can see that goes from 17 to 45. So even though the doublet control arm was the best of the bunch, the addition of Dara got the best outcome. So I think the problem is you've got to throw out all four of these studies. Because Dr. Kumar just told you that older patients are getting Dara Revlimid dex. Younger patients are getting chemo, transplant, and Revlimid maintenance. So at first relapse, pretty much everybody is refractory to Revlimid or intolerant, which means it would have been unethical to randomize patients like that to getting more Revlimid dex. So if you're progressing on Revlimid, are you really going to assign somebody to get more Revlimid? So we throw out this entire table. Luckily, we have other options. We can use Bortezumib or Velcade index. And you can see that doublet. You can add pomalidomides, selenexer, daratumumab, carfilzomib, venetoclax. And I'll get to this study in a second. And again, same theme. Three drugs are better than two. Not shocking. But the percentage benefit at the top is, again, around that 30% to 40% with a notable standout of 69% for Dara. So these immunologic therapies really do seem to be adding quite a bit of value, 16.7 relative to 7.1. And some people criticize this study, though, because the control arm was discontinued. So in a way, it's like stacking odds in your favor, right? You're giving three drugs versus two drugs, but the two-drug arm stops, say, after eight months. Well, you kind of know what's going to happen. Three drugs is going to win. But the problem is that even if you try to give it till progression, it's hard because some of these other arms, you give it till progression. But Velcade, any of you who've had this, can I see how many people have had neuropathy from Velcade? Yeah, so you can see your colleagues here who've... It's not an easy drug to give. And when you give it twice weekly, it causes neuropathy. So it's not the best control arm. But the other thing that this study is highlight is what happens if you're Revlimid refractory, right? Because we said that's the unmet need. The previous slide was thrown out. And look what happens. Even a regimen that's really effective, Dara, Velcade, and Dex, now only gives you eight-month remission. And so there's something about becoming Revlimid resistant that makes your myeloma more difficult to treat. Thank you. And therefore, we need really better drugs than... I don't think any of us are happy with an eight-month remission duration, right? And so I'll show you some better strategies. But I think the take-home message, so the myeloma 101 from this slide, Velcade is hard to take twice weekly. And patients who are resistant to Revlimid need better. OK, so what about pomelist? Oh, and I forgot to talk about this. This is new slide. I think finally, we as a myeloma community realize that we need to go beyond three drugs versus two drugs. It's like a boxing match against a weak opponent, right? So of course three is going to be better than two. So now we're going to start seeing three versus three comparisons. And this is the first one that just got press release in February, actually. Bilantumab, which is an antibody drug conjugate that's given IV, Velcade and Dex versus Dara Velcade and Dex. And now you can see the control arm does do better. 13.4 is the best of any of these guys. But the triplet did even better, 36.6. So stay tuned for this. But I think one of the issues with this Bilantumab is, well, two issues. One is it can cause eye issues like blurry vision, decreased vision. But the other issue is that this targets BCMA, which is the same protein target as CAR-T and bispecific. So again, if we need to think about sequencing, using this early may have some downstream effects, which I'll show you a little bit later. So Velcade is OK, but we can do better. So what about pomalist? Pomalist, these are the pomalist backbones. And again, same theme, two drugs. But you can add cyclophosphamide, elotuzumab, Velcade, esotuximab, Dara, four drugs. And then I'll get to these two in a second. But basically, the pomdex as a doublet gives you about seven months, which again is not that great. But guess what? Most of these patients are Revlimid refractory. So I always joke that the imides are like cell phones. First came thalidomide, then Revlimid, then pom. And it feels like every new year you get a new iPhone update. And that's what these are doing. But they're strategic because each drug works when the other one stops working. So Revlimid works in thalidomide failures. Pomalist works in Revlimid failures. So you can use pomalist if Revlimid's no longer working. And the value add there is about 30 to 40%. But even then, you're getting about 12 months, say, if you add a Dara or esotuximab, you're getting about a 12-month remission. So pomdex does work in Revlimid-resistant myeloma. And it's oral. So that's nice to make it convenient. But an interesting story here in drug development. So because of this history, some of the newer drugs are trying to compare to pomalidomide and dex. So they're like, all right, pomdex, you get a four to seven-month remission. Why don't we try to just beat that to get our pivotal approval? Not so easy. Two studies that were negative, belantamab versus pomdex and melfloofin, which is a drug that was approved briefly, versus pomdex were actually negative studies. And so they did not get approved. So pomdex may not be the best, but it ain't that easy to beat either. So I think it's given people pause to do these kind of studies. And we need to be more thoughtful about how we do this. So what about carfilzomib or Kyprolis? So now we're seeing some really interesting numbers. The doublets are giving 15 to 19 months. And then the third drug, with the addition of the Dara-tumumab or esotuximab, you're now getting really impressive numbers, 40% improvement. The only issue here is we have to be cautious with elderly patients. As you get older, you have more high blood pressure, cardiac dysfunction. And so the likelihood of heart damage from this drug is quite low in most clinical trials. But most clinical trials cherry pick healthy patients. So if you look at probably broader data, the likelihood of heart failure in an older patient can be as high as 10%. And also those who have had heart history, like if you've had coronary artery disease, have a low heart function, this may not be the best drug. And a word of advice is always, and I see some of the folks in the audience, I always ask patients, if you're on this drug and we're seeing some high blood pressures at the cancer center, I ask people to do it at home. Because we all recognize that when you come to the cancer center, getting parking and stress and being late can increase your blood pressure. But it's really important to make your blood pressure as controlled on this drug. But this is, I think, the most important thing. What about those Revlimid refractory patients? Now you're seeing a really impressive number, 28.1 months, which is amongst the best that we've seen so far. So these triplets have now, I think, established that carfilzomib and a CD38 drug like Dara or ESA are really giving outstanding results. So this is kind of our go-to. So if you've gotten this treatment that Dr. Kumar mentioned and you're relapsing and first relapse, this would be an ideal triplet regimen to do. Okay, so when we compare, put all of those on the same slide, I can't put all of them because then the slide would be overtaken. And again, in a way, I'm doing what we're not supposed to, right, cross-study comparisons, because you can see that Revlimid refractory in the POM studies is almost 80 to 90 percent, whereas in the carfilzomib studies, it's only about a third of patients. So of course, these patients are not as heavily treated. But the take-home message here is that the CD38 carfilzomib decks are quite good. And they all add about 40 percent improvement. But the difference is it's easier to improve on 40 percent on seven months than it is on, say, 16 months. So what's in this gap? It's what you all want to know. What about CAR-Ts? And so currently, as I said, it's only approved for four or more lines of therapy. And just before I show you that, so I think up till now, what we've covered is that triplets are better than doublets. If possible, you want to switch classes from Revlimid to, say, carfilzomib type of regimen. And then we keep using up these three drug combinations till we get to that four lines of therapy where we have more options. OK, so now we have these T-cell redirections, which are, which my colleague Dr. Wolf is going to be talking to you about in much more detail. By specifics, there's TAL, TEC, and ELRA. And there's CAR-Ts, IDA cell, and CILTA cell. So again, just to orient you, CAR-Ts, you do collect your cells, genetically modify them and put them back. I call it waking up your immune system. Maybe you could say that myeloma might occur because we have lazy immune systems. Maybe we all have a little bit of myeloma in our body. But as our immune system gets lazy, those cells can expand. And that seems to be our leading hypothesis as to why it occurs in the late 60s and 70s, although I'll say I think my youngest patient was diagnosed at 18, and the oldest is over 100. So it's really heterogeneous disease. But CAR-Ts basically wake up that immune system. And then the other way to wake up the immune system is use double-sided tape, if you will. Use a bispecific antibody where one side binds to myeloma, the other side binds to your T-cell. And why are these so revolutionary? Take a look at what used to be the PFS for DERA, POM, CARF, CELI. These are all important advancements, but they got you about three to four months and lasting about four to eight months. And now we're seeing the remissions go from 11 to 35 months, which is really in patients who've actually had all of those drugs. So that's how revolutionary this is. And if I had to paint this picture for you in a story, I was in New York for 18 years, approximately, and I was privileged to have patients follow me around while I was in New York. And I said goodbye to many of those patients. And guess what? These patients had exhausted these therapies and we'd actually had hospice conversations because what do you do when you've exhausted all those therapies? And those same patients are now in some of their most deep and durable remissions thanks to these kinds of therapies. So patients literally, our lives are being changed because of these, and that's why there's so much excitement about these T-cell redirection therapies. Okay, so I've set it up now. How do these CAR-Ts compare to what we've talked about? So we have two clinical trials, CARMA 3 and CARD2T4. IDA cell was compared to standard of care and CILTA cell was compared to either DERA POMDEX or DERA VELCADE index. Again, randomized phase 3 studies. And here's the numbers. So 13.3 versus 4.4, not reached yet at the current follow-up. They haven't hit the median versus 12 months. And so again, I said let's not do the, and this is a great example of why we shouldn't do cross-study comparisons, right? Look at the control arm. 4 months versus 12 months. This study had sicker patients, right? So it's not appropriate to compare the CAR-T numbers directly because these are sicker patients, these are healthier patients. And so the benefit though, what's the percentage improvement? 51 and 74. So clearly, these are the best that we have. They're even better than the KD backbones. Now, of course, a lot of people criticize these studies like, oh, well, why didn't you pick, why didn't you pick these against these two regimens which have 28, 35 months? We have to keep in mind how studies are developed, right? These studies are designed well before these read out. So the way that the research is progressing, you have to kind of pick your best partner when you design the study and then let the results go. Otherwise, we'll always be criticizing everybody for not picking the most up-to-date therapy. But I think this is what's super exciting, that these are the best value add in early VLAPS myeloma. And these studies have both been submitted to the FDA. And if these get approved, we would then have access to CAR-Ts and one to three lines of therapy. So that would be really great, game changing for all of us, obviously. But remember, in some ways, we know what the side effects of these are. These are newer products. And so we got it, if you're going to move a product earlier, you can't do it without thinking about safety, right? So what are the safety issues with CAR-Ts? These are from the original studies that Dr. Wolf will go into more detail. And I'm not going to go through this in detail. But the main things I want to call your attention to are this delayed neurotoxicity, which was in silt to cell 12% all grade and 8% high grade. So all patients, about 10%, and many of those were severe. What are we talking about? We're talking about Parkinson's disease, right? So people who are healthy, who now have cognitive slowing, difficulty walking. And these are really big deal, right? So but there's, before I get back to that, I want to also address some press releases that have created a lot of concern in this space. So there was an FDA warning about CAR-Ts associated T cell cancer. So why is this? Remember, you're taking T cells and genetically modifying them and putting them back. And there's a possibility that any time you manipulate a cell, you can have adverse unintended consequences like that T cell expands and becomes a cancer. So the FDA was aware as of December that there were 22 cases in over 27,000 patients who had been dosed with CAR-Ts. These are obviously not just myeloma. We don't have 27,000 myeloma cases. But of those 22 cases, 14 had adequate data. And these T cell cancers occurred within two years of the CAR-T. In the three cases who had genetic sequencing data, the CAR-T gene was detected in the cancer. So suggesting that there is a causal relationship that those T cells that were genetically modified did then lead to the T cell cancer. OK. That's important to know about. But what we all care about in this room is what about myeloma? Well, let's drill down. And this was, again, this is how quickly the field moves. This is not a publication or peer review journal. This is a press release from a biopharma or some investing company. Because that's the only publicly available data. In this data set, CARVIC-D had one case of a T cell lymphoma and ABECMA had zero. So this signal seems to be much less of an issue in myeloma. And this case was actually presented at ASH. And who is this patient? It's a 51-year-old male who, five months after getting Silt-to-cell, had a rapidly growing mass on his nose and neck. Both were positive for T cell lymphoma. But that patient had that clone even in the aphoresis product, which means those cells that were taken out of the patient and sent to the lab already had that T cell problem. So you can't blame the CAR T for this, right? This is a preexisting. And this is why, when you have these rare side effects, you really need more numbers and mechanisms to really understand that. So I think for myeloma, we can just say this is rare. This is not as big a deal. But there's another one that raised some concern. And there was an update from the FDA regarding CARVIC-D's secondary blood cancers. This was on the Phase I study, where they found that MDS, or myeloid neoplasm, myelodysplastic syndrome, or acute myeloid leukemia. Myelo is the Latin or Greek term for bone marrow. These are bone marrow failure syndromes. MDS is basically, literally means funny-looking marrow. And this is the leukemia coming from the bone marrow. So this occurred in 10% of patients. And the median time was about a little over a year after getting CAR T. Nine of these 10 patients went on to die from these cancers. Four of those occurred after they started a new therapy. So in other words, they got the CAR T, the myeloma came back, and then they started a new therapy. And at that point, they died. Ten of these patients, we know all of these patients in that initial CAR Titude 1 were heavily treated. They had seven and a half lines of therapy. What that means is many of these patients had one or more stem cell transplants. They had DNA damaging agents. of the patients who are, these are older patients getting lots of therapies. So there's a substrate for getting these kinds of problems. But the link between the CAR T and the myeloid cancers where it's not linked, there's been post-marketing as well. So I actually did my undergrad here. One of my majors here was psychology. And one of the things I remember from that, because in the harder sciences, you can kind of try to make these causal inferences. But there's a term in social psychology that correlation does not equal causation. What that means is just because you're getting these secondary cancers after CAR T doesn't mean that the CAR T necessarily caused it. Because we said these are older patients getting beaten up with lots of therapies. To truly answer this question, you need a randomized Phase 3. Well guess what? We just had one. So what do we know about that one? So here's the CAR Titude 4 where silt to cell was compared to standard of care, 200 patients in each arm. And the secondary cancers, all secondary cancers, 9 versus 14. So that's 4.3% versus 6.7%. We're not as concerned about these cutaneous skin. Many of you know like basal cells, it's part of aging, those are treatable. What we really want to zoom in on is these blood cancers, 3 versus 0. So it's much less than we saw. That other study showed it was 10% in heavily, heavily treated patients who had had medium of six lines of therapy. In less heavily treated patients, we're seeing it's 1.4%. This is with 16 month follow up with 200 patients. So that's why we need a little bit more data. But it looks reassuring, right? It doesn't look as bad as 10%, but I think we need a little bit longer follow up. What about the other CAR T? I just saw it was also compared to standard of care. Any cancer is 6% versus 4% when we drill down into blood cancers, 1% versus 0. So 3 patients versus 0. So really low numbers, but we need to keep an eye on that. So the other thing I mentioned about moving CAR T's earlier will be neurotoxicity. What did the randomized studies tell us about that? So again, because we don't have the initial CAR T's, didn't have a control arm. But here, the control arm of course is not going to have any of these neurotoxicity. So what was the signal here for CAR T? So good news is there was only one Parkinson patient out of 208. So the other study had anywhere from 8% to 12%. And that patient was in a male patient who had a high grade CRS and had refractory disease. And so what this is getting at is we think one of the reasons Parkinsonism is going down in earlier lines of therapy is you're able to control the disease better going into CAR T. So imagine in the first CAR Titude 1, we had six lines of therapy. If you've exhausted all your therapies and then you're going to CAR T, many of those patients went into CAR T with a lot of disease. When you go into CAR T with a lot of disease, that's going to generate more immune chaos and cytokines, and that may be part of the linkage. So the signal looks better. But there were some other neurotoxicities that we do need to talk about. So in this randomized study that we talked about, there were a total of 30 patients that had neurotoxicity, 17%. Very few were at high grade, 2.3%. But one of the categories that is worth highlighting is cranial nerve palsy. So these are basically nerves that come out of the brain that can be affected by the CAR T or the post-CAR T side effects that can create palsies. Many of you may have heard of Bell's palsy where part of your face freezes. That's an example of these cranial nerve palsies. So that happened in 9%. It occurred about three weeks after the CAR T. The biggest one was cranial nerve 7, which is the facial Bell's palsy like. It lasted about 77 days and recovered in about 14 of those patients out of 16. So this is generally reversible, but it is a hassle. And the way we treat these is with steroids and IVIG. So the other side effect is peripheral neuropathy. So five patients, primarily low grade, occurring about two months after CAR T, resolved in most of those. So I think the take home message here is that CAR T is super effective. We're not worried about T cell cancers, but this blood cancer issue is a question mark. The Parkinson's and cranial neuropathy is a question mark. All of that seems to be less and less heavily treated patients, but how do we put that all together? So this is like my take home message for relapsed myeloma. First is we have to ask what does the patient want, right? What's your goals of care? Do you want IV therapy or not? Can you come to the cancer center? What are your previous therapies? If you're not yet eligible for commercial products because of that four lines of therapy, but you have high risk disease, consider clinical trial. These are the patients CAR T's and bispecifics should be moved up earlier. If you have good organ function and there's a CAR T slot available and you have kind of slow growing disease, no neurologic issues, consider CAR T study or Cilta cell or IDA cell. If you're rapidly progressing, closer to an academic center, consider the bispecifics with Dr. Wolf to talk about more. And then if you have low blood counts, you may need more aggressive therapy to get rid of the myeloma. One important message which is here, and I'll show you why, is if you're at all thinking about CAR T down the road, try to avoid doing BCMA targeting therapies to prevent that. And here's why. So CAR T1 was probably the product with single best response that we've ever had in myeloma. 98% response rate in about 100 patients, remissions lasting about three years. If you got a bispecific or an antibody drug conjugate, that three years drops to five to nine months. So this is really very important to remember and that's why we really need to think about sequencing. It's not just what you're doing today, but what you're doing later. So my final conclusion slide here is at each treatment stage, we need to consider the patient, disease, and treatment factors. Sorry, Cindy, I do have a couple brief UCSF stuff, so last topic on this one. We need to consider all the patient disease and treatment factor. No one size fits all. Fortunately, the treatment options keep increasing. Most patients at first relapse will be revlimid resistance or intolerant and Velcade is not really well tolerated. So if you have a patient who has a cell that's not in a good condition, you can't just take the cell and send it off. You can't just take the cell and send it back. So there's logistical constraints to this. So I think as we're waiting for longer follow-up, the patients who definitely should be considered first for these would be high risk and maybe also we talked about revlimid resistance, but as Dr. Kumar outlined, there's going to be a lot of risk. So we need to consider the patient's risk. Also, we talked about revlimid resistance, but as Dr. Kumar outlined, there's going to be an extra group of patients who now will be not only revlimid resistant, but DERA or esotoxin-mab resistant. So those might be the patients that we want to do this the first in just because we're going to have to triage people. There are patients who can get CD38, carfilzomib, DEX, who are going to have a three-year remission, but there's patients who won't be able to get that. So where does that leave us? I always say we have lymphoma envy in myeloma, right? Because our lymphoma colleagues, the pathologists tell us what kind of lymphoma they have, they're treated differently, and their survival curves are outstanding. This is myeloma. We need to narrow this gap. These are those survival curves that Dr. Kumar showed you. What are the unmet needs right now? I would say they're frail elderly, patients with persistent kidney disease, high stage myeloma that comes out of the bone marrow, high risk disease, and multi-drug refractory. And so fortunately, you're seeing we're getting amazing products like CAR-Ts and bispecifics that are working a lot of these, but I think to truly get to cure, I think our goal at UCSF is to put ourselves out of business, right? We don't want to keep treating patients over time. We just want to be done and move on. And that's what our lymphoma colleagues do, right? So lymphoma envy. So how are we going to do that? Yes, we need new therapeutics, and you've heard a lot about that today. We need to bank specimens. We need clinical trials. We need to study your genomics. We need to study your immune microenvironment, because studies have shown that what's differentiating patients who are cured from non-cured are not just the myeloma, but the bone marrow microenvironment. There's actually a difference in myeloma patients who've been treatment-free without relapse. Bone marrow looks like a normal person. So that's where we need to get to. It's not just the myeloma part. We're going to need artificial intelligence, right? This is a lot of data to put together. No human being is going to be able to keep track of all this. And fortunately, at UCSF, we have really working on each one of these components. We're actually approaching recruitment of a really great investigator studying the microenvironment that's going to fill in that missing piece. And so finally, this is really my last slide, Cindy. I really want to thank our entire team. It takes a village. You guys are at the center of it. But I really want to highlight first, part of the reason why I went into myeloma is Dr. Martin. And unfortunately, we were both asked to go to a conference. He said yes. I said no. So he's in Southern Cal right now. But he's the reason I went into myeloma. And I think this would not have been possible. We have this amazing team. Health Tree normally invites people from lots of institutions. I begged and pleaded with Jenny to make it just UCSF. And that's because we have such a great team. You've met Dr. Kumar. You'll be hearing from Dr. Wolff and Dr. Chung. And you're going to meet here some in-years breakout groups from our outstanding advanced practitioners, both Nancy Wong and Grace Savilla right here. So super excited. And thank you for your attention. And back to Cindy.