Role of CAR T Therapies in Newly Diagnosed Multiple Myeloma

Nina Shah, MD: Ola, I wanted to go back to you, because in both of the studies of these exciting T-cell therapies, both cilta-cel [ciltacabtagene autoleucel] and ide-cel [idecabtagene vicleucel] had a median of 6 prior lines of treatment. Getting a person to 6 prior lines of treatment and then using CAR [chimeric antigen receptor] T-cell therapy in the seventh line seems crazy when we’re having all these nice responses. I want to talk about moving this therapy earlier, and potentially in patients with newly diagnosed myeloma. There are some studies looking at this. I was wondering if you might be able to tell us about the design of studies like CARTITUDE-5 (NCT03248492), which is using cilta-cel plus VRd [bortezomib, lenalidomide, dexamethasone] for transplant-ineligible patients, and KarMMa-4 [NCT04196491], a study of ide-cel in patients with newly diagnosed, transplant-ineligible, high-risk myeloma .

Ola Landgren, MD, PhD: I’m happy to briefly go over that. There aren’t any data out; it’s too early. But based on all the exciting results we have in the relapsed/refractory setting—we talked about Thomas Martin’s presentation at this ASH [American Society of Hematology Annual Meeting]—the logical thing is we need to see whether this could be even better if we go in earlier lines. At ASCO [American Society of Clinical Oncology Annual Meeting] earlier this year, we heard that the KarMMa-4 study with ide-cel, the bb2121, is now being designed in an upfront setting for patients with high-risk disease, so newly diagnosed high-risk disease. High-risk disease in this study is based on the ISS [International Staging System], the Revised-ISS criteria, and cytogenetic abnormalities, including 4;14, 17p, and 14;16 translocations. There’s also inclusion for ISS-3 with LDH [lactate dehydrogenase] over the upper limit of normal.

This is a phase 1 multicenter study. The primary end point in any phase 1 study is to look for safety signal. Secondary end points include overall responses. Patients will be allowed to get up to 3 prior lines of therapy with the standard drugs. During the fourth cycle they’re given, that’s when the cells will be manufactured. You do up to 3 cycles, you collect, then you can get another cycle, and then you get the CAR T cells.

CARTITUDE-5 is a very large study developed by the European group. This is a large, randomized phase 3 trial that is taking on the big task. It’s targeting 650 patients. This is going to be open for patients who are newly diagnosed where transplant isn’t intended. In this study, patients are screened, then they go on for VRd and can get 5 to 6 cycles. Then they’re randomized to 1 of the 2 arms. In the first arm, you go for an additional 2 cycles of VRd and then you go to Rd [lenalidomide, dexamethasone] maintenance and stay on that until disease progression. In the other arm, after the 5 to 6 cycles and randomization, you get your 2 additional VRd cycles—similar to the first arm—but you also collect and make the cells, and then you get your single cilta-cel infusion. Then the therapy is stopped and the patient is observed. The primary end point in this study is PFS [progression-free survival]. This is a very exciting study. This has potential to change the field.

Nina Shah, MD: Yes. And I agree that if we can do better later, maybe we can do better earlier. Katja, in thinking about that point, what do you think is the optimal place that we should use BCMA-targeting T-cell therapy? In what position in the myeloma continuum should we use it for patients who have this long disease course?

Katja Weisel, MD: Whether it comes into front line will depend on the head-to-head phase 3 first-line comparisons. We learned that we have to give each patient with myeloma the best things first. For me, it’s also a question of whether we’ll have a signal for cure in a substantial proportion of patients. If this occurs, then we have to rethink many things. If not, it’s the question of how to sequence, the availability, and long-term outcome and superiority in PFS and OS [overall survival]. And then we have still to wait. We probably also come to the point where we tailor and treat high-risk patients differently, or translocation 11;14 patients different from standard-risk patients without this distinct abnormality. At the end, we should never prevent the patient from a high potential treatment. I’d very much like to see it in front. I want to see the results, and then we can rethink.

Nina Shah, MD: Yes, there a lot of things going on as far as trying to position this in the right direction or in the position for our patients who have a long course of therapy.

Transcript Edited for Clarity