A roundtable discussion, moderated by Sagar Lonial, MD, FACP, Blood Cancers Today Editor-in-Chief, of the Winship Cancer Institute at Emory University School of Medicine, focused on the latest updates in CAR T-cell therapy for multiple myeloma. Dr. Lonial was joined by Noopur Raje, MD, and Krina Patel, MD, MSc.
In the first segment of the roundtable series, the panel discussed the latest CAR-T data, including KarMMa-3 and CARTITUDE-4.
Dr. Lonial: Let’s get started with some general updates that we’ve seen at ASCO and EHA around both phase II as well as phase III randomized trials with chimeric antigen receptors (CARs).
Dr. Raje: We’ve seen really exciting data, Sagar, and it keeps getting better. We’ve had two CAR products already FDA-approved, and this is based on phase II data. We have ide-cel (idecabtagene vicleucel) approved after four prior lines of treatment. We have cilta-cel (ciltacabtagene autoleucel) also approved in a similar patient population.
What was interesting in our ASCO and EHA meetings this year was data from earlier lines of treatment. You have ide-cel in KarMMa-3, which was used in patients of between two and four lines of treatment, so a little bit earlier than the KarMMa phase II trial. What was interesting to me is that the data was able to kind of reproduce itself. In my mind, the KarMMa data is very similar to the phase II data. Although it seems like it’s an earlier indication, it’s going to include patients beyond two lines. Then we saw data from CARTITUDE-4, which is the earlier line cilta-cel data after one to three lines, which is truly, truly an earlier line treatment data. Again, more data to come, but the idea here is to try and open up the indications for myeloma therapies.
Dr. Patel: Yeah, I think the early-line trials were great. They are different patient populations, so I think when people try to compare them, you really can’t. As Noopur said, the cilta-cel was really lenalidomide-refractory patients, and most had not seen a CD38, so a different patient population compared to the KarMMa where they were triple-class exposed at least.
I think what we found is that most of these patients would fit some type of high-risk profile in the KarMMa-3. Almost 85% of patients would fit some type of high-risk feature. It really tells us these patients, we would love to have it before fourth line, but it was great access for our patients who do have higher-risk disease and seeing that difference in that PFS [progression-free survival].
For KarMMa-3, it was like 13.3 months versus 4.4 months. To have five different standard of care options and you get 4.4 months in that a little bit earlier line, that tells us these patients as they’re getting these novel therapies earlier, they still have refractory myeloma already. I think that urgency of, “Let’s keep going”, is there, but still a great option.
I think the other thing was the phase II studies, they had some of the long-term data. For cilta-cel, the PFS of 33 months, almost three years, for a relapsed/refractory patient, I didn’t expect that. It was great to see that patients could have no therapy during that time. I think the other one was the LCAR, the original LEGEND study, that actually showed about 16% of patients greater than five years out are still in remission. Those were a little bit earlier line and maybe not as refractory, but that gives us hope that hopefully patients getting it earlier will get a long period of therapy and maybe one day a true cure.
Dr. Lonial: I wanted to ask you both to put some of that data in context, and you touched on some of these issues about comparisons between trials, comparisons between products. I actually wonder a little bit about the control arms in both of those. Do you think they performed as you would have expected, better or worse, or were there unique aspects of those trials that I think make them incomparable amongst each other?
Dr. Raje: I think Krina brought up some really interesting differences. I think it’s really hard to compare KarMMa-3 with CARTITUDE-4, and I think we need to understand and appreciate that. Everybody throws that hazard ratio out, right? One is 0.4-something and the other is 0.26.
Well, the hazard ratio depends on your control arm, correct? What we’re seeing with the KarMMa-3 control arm, it was basically investigator choice and you were allowed to use carfilzomib in that patient population. It was a slightly later patient population, which is why the control arm had a PFS of about four months, which is very similar to what we saw with some of our real-world data. We can speak to that, and Krina, you can speak to that lot better.
If you look at the CARTITUDE-4 study, Sagar, what you saw there was an earlier line of treatment, the control arms were very restricted to a dara-Pd or a PVd-containing arm. There was no carfilzomib. You saw how the control arm performed. They did much better, which is in keeping with the number of lines of treatment they’ve had.
Dr. Patel: Agreed—4.4 months for KarMMa, 11.8 for … And I think they’re doing better because they’re earlier-line patients. But again, carfilzomib I think was a big one that we would use in the real world. Looking at our control retrospective studies like MAMMOTH and LocoMMotion, the response rates are 30% for those patients who are triple-class exposed, and PFS is usually six months, depending on refractory status of course, or less than a year at least for even just exposed patients rather than refractory.
I think the standard of care arms did similarly to what we would expect. The 4.4 in KarMMa was a little bit lower than what we had sort of thought it would be. But I think the patient population, again, 85% having some type of high-risk feature, shows that the investigators were really trying to get this access for their high-risk patients that weren’t going to have really other options left even earlier.
Dr. Lonial: I think this is sort of a great introduction to the controversies as well as the data that’s been coming out in the last six months.