EHA 2023 | Results from CARTITUDE-4: cilta-cel for lenalidomide-refractory multiple myeloma

CARTITUDE-4 uses cilta-cel, which is a dual binding BCMA-directed CAR-T cell product and that was used in the CARTITUDE-1 study, in which heavily pretreated patients with a median of six lines of prior therapy were included. And at the ASCO and EHA, the median progression free survival for this patient cohort was recorded to be, amazingly, 34.9 months. Now the idea is if we use CAR-T cell therapy earlier in the treatment of multiple myeloma, it might be even more effective and maybe less toxic. And, in CARTITUDE-4, actually patients were included that were lenalidomide refractory because more and more patients are going out of the first line therapy being lenalidomide refractory. And in addition, they had to have received one to three prior lines of therapy. Then patients were randomized between standard of care, which at that time when the study was designed for lenalidomide for refractory patients, was PVd or Dara-Pd, and in the experimental arm patients also receive PVd and Dara-Pd until cilta-cel infusion and then patients were analyzed for safety and efficacy.

208 patients were randomized to cilta-cel and 208 received standard of care. The patients were fairly well matched between the two arms – so we had about 6% patients ISS stage three and about 20% of patients in both arms with a soft tissue plasmacytoma. And one third of patients had received one prior line of therapy, two thirds: two or three prior lines of therapy. In both arms, about 60% were high-risk patients, including patients with gain or amplification 1Q, and if we go for patients with two or more high-risk cytogenetic features, about 21% in both arms had two or more high-risk cytogenetics features. Triple-class refractory patients – about 15% in both arms and about 22% of patients were daratumumab refractory.

The primary endpoint was clearly met. Progression-free survival in the standard of care arm, as expected in this patient cohort, about 11.8 months. Median progression free survival not reached in the cilta-cel arm. And the hazard ratio for progression-free survival was, amazingly, 0.26% – the best ever recorded in patients with relapsed refractory multiple myeloma. And actually, looking at all key subgroups – like patients with one or two or three lines of therapy, ISS staging presence of soft tissue, plasmacytomas, tumor burden, cytogenetic high-risk, refractoriness or prior exposure – all subgroups benefited by an improves progression-free survival in favor of the cilta-cel arm. Now if we look at PFS by prior line of therapy: cilta-cel improved progression-free survival versus standard of care, whether patients had one or two to three prior lines of therapy. And actually comparing patients with one prior line of therapy and two and three prior lines of therapy, at least there is a trend to improved progression-free survival of patients that only received one prior line of therapy, but longer follow-up is clearly needed.

If we look at secondary endpoints – response rate: 84.6 versus 67.3% in favor of cilta-cel for the ITT patient population; CR rate: 73.1 versus 21.8% in favor of cilta-cel in the ITT population; MRD-negativity in patients that were actually evaluable: 87.5% in the cilta-cel versus 32.7% in the standard of care arm. And when actually patients were analyzed that received cilta-cel, this was 172 patients, the overall response rate was 99.4% and the complete remission rate 86.4%. And this patient cohort, the one-year progression-free survival rate was 90%. So really impressive results.

What about toxicity? Hematologic toxicity evenly distributed between both arms. Cytopenias in the silver cell arm resolved to grade two. By day 30, grade three and four infections similar between the two arms. Also a similar rate of second primary malignancies. There were more deaths in the cilta-cel arm due to the fact that more patients had developed a severe COVID-19 infection and died due to COVID-19. And so strict prevention measures and aggressive treatment of COVID-19 was introduced, and with this, no further death due to COVID-19 was observed in the silver cell arm. What about typical CAR-T cell toxicities? About 76% CRS any grade, 1.1% Grade three and four; neurotoxicity, 20.5% any grade, 2.8% grade three and four. 30 patients had a non-ICANS neurotoxicity, of which 16 had a cranial nerve palsy –  mainly involving Bell’s Palsy – and 14 of them completely recovered, two are already recovering. Five peripheral neuropathies and one case of movement neurocognitive treatment emergent adverse events or a kind of Parkinsonian-like syndrome. But when compared to the CARTITUDE-1 when patients after six lines of therapy were included, versus CARTITUDE-4 with 1.3 prior lines of therapy, there was clearly a lower incidence and severity of CRS, ICANS and (inaudible) and some cytopenias indicating that cilta-cel is better tolerated when used earlier in treatment and that effective bridging therapy enables better control of tumor burden prior to CAR-T cell infusion.

So in conclusion, cilta-cel significantly prolonged progression-free survival versus standard of care in patients with lenalidomide refractory multiple myeloma and one to three prior lines of therapy. The progression-free survival benefit was seen across all subgroups and all the CAR-T cell specific adverse events were manageable, and when compared to the CARTITUDE-1, so with more heavily pretreated patients, CARTITUDE-4 indicates an improve tolerability of cilta-cel when used earlier in treatment.  And with this the conclusion can be that cilta-cel has clearly the potential to become a new standard of care for patients with lenalidomide refractory myeloma after first relapse.