Computer generated transcript

Warning!
The following transcript was generated automatically from the content and has not been checked or corrected manually.

Hello, my name is Sadusmani. I'm the chief of the myeloma service at the Memorial Sloan Kettering Cancer Center in New York, and today I'm going to be talking about managing relapsed myeloma and choice of immunotherapies. There has been a lot of data that's been recently presented this year, and I'd like to put that in context, uh, in terms of how we're making those choices. These are my disclosures. When we think about selecting treatment options for relapse disease, we've uh kind of uh put certain factors in buckets, um, you know, these are, uh, patient-related factors, disease-related factors, and prior therapies or treatment-related factors. And when we talk about patient-related factors, it's got to do with age, comorbidities, um, um, any organ damage that patients have had, um, and then at the time of relapse, where patients have high-risk features or. More pronounced clinical uh relapse picture that includes circulating plasma cells or extramedullary disease and how burdensome the relapse is, it is bio, is it biochemical or is it, uh, you know, a lot of clinical disease burden with symptoms. Then prior therapies, prior lines of, um, uh, treatment, uh, prior, uh, classes of drugs that have been utilized, all of those, uh, factor into our decision making as well. And historically in the last 10 odd years. We've seen, uh, advancements in therapies, going for triplets to quadruplet induction treatment. So, our frontline treatment landscape is changing and that's, uh, influencing the options at the time of relapse. Lenidomide refractorness is becoming highly common at the time of first, uh, relapse. Um, even anti-C38 refractoryness is starting to become more common after first-line treatment. And then primary refractory disease, even though it makes up a small proportion of patients, but at least at the academic centers, we're seeing more, more of it, especially in the first two years of diagnosis, what we call functional high risk. And CARDs and bio-specifics are moving into early lines, and we'll go over some of that data. Historically, we've had several options with triplet regimens for that lenidomide refractory, uh, patient population, um, uh, with no prior anti-C38, um. Uh, monoclonal antibody exposure, so, you know, we had the proteosome inhibitor combinations and um imid, uh, pomalidomide-based combinations. So with datumumab we had the Castor clinical trial, the Candor and the Apollo trials that looked at data VD, data KD, and Dara PD, um, but you can see that, uh, you know, a smaller proportion of patients, uh, with the PI combinations, um, uh, were len refractory. And then of course these patients were anti-C38 um uh uh naive as well. Same story with iscetuximab being combined with carfilzomib and pomalidomide in the Ikema and Araria clinical trials, um, showing that, um, you know, you have a low, at least with the PI combination, you have a low proportion of only a third of the patients with len refractors, and then when you get to a higher proportion of patients. Len refractors, the PFS, uh, is, uh, generally shorter for those patients for about, you know, 12 odd months. So, you know, this appears to be an area of unmet need and if you start looking at previous options of triplet combinations with both L LN and anti-C38 exposure, you see that the median PFS across these clinical trials is less than 12 months, whether it's, you know, pomalidomide being combined with porttizumab, elotuzumab. Or with carfilzomib or exazomib. This brings us to the beentumab combination. So beentumab mofootin is uh a BCMA directed antibody drug conjugate. Um, there were two randomized phase 3 clinical trials that read out, um, one that compared uh beentumab mefootin with, uh, bortezomib dexamethasone with daratumumabborzomib dexamethasone. Um, that was the DREAM 7 trial, and the DREAM 8 looked at the Bella combination with Palmdex and compared that to PALM BD. Now both clinical trials were in the relapse setting, but, uh, the devil is in the detail. Look at the prior histories and prior drug exposures. The Bella PD, uh, trial had both LEN, and anti-C38 exposed and refractory patients, whereas, um, you know, the Bella VD or potizumab dexamethasone was primarily LEN. Um, refractory and aimed exposed patient population but no prior anti-C38s. So, you know, both these clinical trials read out positively depending on the jurisdiction. Um, you had, um, the approval for either the Dream 7, or the Dream 8 or both, uh, in the, you know, you know, in the UK as an example, both Dream 7 and 8 led to the regular. Story approval and availability of both combinations, whereas in the US only Bella VD is available but good options to have and, and you can see with the hazard ratio and the median PFS, uh, of about 3 odd years, the, at the end of this combination may be a good option. It's for land refractory, um, and even for land refractory and I see 38 exposed refractory patient population. This brings us to the BCMA directed T cell redirection strategies with CAR Ts and bio-specific, so. So this is, uh, you know, um, has been a game changer for us, um, in the relapse refractory myeloma situation. The BCMA directed autologous scars, um, are kind of like trained assassins. You actually introduce the BCMA chimeric antigen receptor in autologous T cells, expand them, um, you know, ex vivo, and then patients are given lymphode depleting chemotherapy and infused with the product, and these, um, cells go and, and attack the myeloma cells and leading to cell kill, whereas the bio-specific antibodies. Uh, one part of the antibody can recognize the BCMA on the cancer cell, um, and the other part recognizes CD3 on the T cell and brings the T cell, uh, to do the myeloma cell kill. So, highly effective treatments, uh, you know, in this slide, we're, we're talking about BCMA as an option, but I'll also touch upon, uh, GPRC5D, which is another, uh, target that we are employing for relapse refractory multiple myeloma. So, um, I'll start with the Silta cell BCMA directed CART construct, uh, the CARtitude 4 study, um, uh, looked at infusing Silta cell to patients compared with standard of care triplet regimens of either PVD or. DPD in patients with 1 to 3 prior lines of treatment, um, you know, patients had to be BCM and naive. The PFS was primary endpoint. Secondary endpoints were complete response, overall response rate, MRD negativity, as well as overall survival, and of course looking at the AES. The study met its primary endpoint, the median PFS, um, you know, at the time of the original report about 3 years ago. Um, was standard of care reaching a median PFS of about 12 months, whereas that well, you know, for the silter cell arm was not reached and the hazard ratio was 0.26, and, um, um, this, uh, did lead to a regulatory approval across the world in different, uh, geographic areas for this particular product. Um, some, um, you know, some comparison was subsequently made, uh, to the late relapse Cartitude one clinical trial and looking at patients with standard risk features, uh, on karyotypic abnormalities with or without 1Q, um, uh, abnormalities, and, and, uh, the real comparison here was, can you give the CAR T cell early, um, and will it result in better. Better outcomes and, and that is kind of the punch punchline here. The deeper responses were seen in terms of MRD negativity and as well as overall response rates when you give cell to cell in early relapse, when you look at the standard risk disease, um, and both the median PFS and OS was better for those patients, um, and quite impressive actually when you compare. With the original CARTI21, uh, clinical trial experience where patients were given, uh, CARTs and 4+ lines of treatment. So the survival rates are better if you employ CART early for eligible patients regardless of whether it's standard risk or high risk. But here, you know, the point was being made that this is probably the best single agent therapy we have, um, you know, and there is, um, Uh, while logistics are involved with giving CAR T cell therapy, um, um, you know, once patients recover, the quality of life, being off therapy, um, uh, or treatment-free, you know, it's something of value for, for many patients. So with this in mind, let's switch over to the two bis specifics we're going to talk about, uh, teclistumab, which targets BCMA and telketumab, which targets GPRC 5D, um, and some important clinical trials that have recently read out changing, um, um, our options and practices, uh, um, you know, across the world. The first clinical trial was Majestic 3. This was presented at Ash, um, late last. Year, um, this is the combination of telistumab, which is the BCM directed, um, bi-specific antibody being combined with daratumumab and comparing it, um, in a one is to one randomized fashion with either DPD or DVD, uh, as the triplets of choice. Um, you can see that, um, the arms of the study in terms of patient characteristics were evenly matched. The primary endpoint for this trial was progression-free survival. Um, and, um, let's take a look at, uh, all the important endpoints. So, number one. We talked about depth of response as being important and helping translate to better progression fee and overall survivals. Um, the MRD negativity in this clinical trial, uh, with the tech data combination, uh, was, um, uh, far superior, 58.4%.