Latest CARTITUDE-4 Data Highlight the Benefits of Cilta-Cel in Multiple Myeloma

In an interview with Pharmacy Times, Binod Dhakal, MD, discussed the latest data from the CARTITUDE-4 trial presented at the International Myeloma Society (IMS) 2024 Annual Meeting, taking place September 25 through 29 in Rio de Janeiro, Brazil. The trial is evaluating ciltacabtagene autoleucel (cilta-cel, Carvykti; Johnson & Johnson) in patients with relapsed and lenalidomide-refractory multiple myeloma.

Q: What are the latest data from CARTITUDE-4 being presented at IMS 2024?

Binod Dhakal, MD: So, as you know, CARTITUDE-4 is a phase 3 randomized study comparing cilta-cel versus standard of care in patients with 1, 2, or 3 prior lines of therapy and were lenalidomide-refractory. In the initial presentation of the primary analysis we showed that cilta-cel has significant benefit in progressive-free survival compared to standard of care with the hazard ratio .26, so that was about 15.9 months of follow-up. Now, in this meeting at IMS, we are presenting at a median follow up of 33.6 months the pre-specified analysis of overall survival and updated overall survival, efficacy, and safety outcomes, with cilta-cel vs standard of care. And what we saw is that, with the use of cilta-cel, there are 419 patients randomized, 208 to cilta-cel and 211 to standard of care, which is one of the either daratumumab, pomalidomide, and dexamethasone, or pomalidomide, bortezomib, and dexamethasone. At a median follow-up of 33.6 months, we showed that the median overall survival was not reached in either arm with cilta-cel or standard of care, and overall survival significantly improved with cilta-cel vs standard of care, with the hazard ratio .55 and significant P value. The 30-month overall survival rates were 76% in the cilta-cel arm versus 64% in the standard of care arm. And overall survival benefited all subgroups in the cilta-cel arm compared to standard of care. In terms of median progression free survival, that was still not reached at that follow up with cilta-cel, versus it was 11.8 months in the standard of care arm, and the hazard ratio is .29.

And in terms of safety, that was consistent with previous interim analyses. There were deaths occurring, with 50 patients in the cilta-cel arm, 82 patients in the standard of care arm, [and] 21 patients and 51, respectively, died of progressive disease. So, this study is the first study in myeloma that showed a survival benefit with the CAR T, BCMA CAR T in this case, using cilta-cel, and significantly reduced the risk of death by about 45% in those patients who received cilta-cel as early as first relapse.

Q: What previous data have been presented from the CARTITUDE-4 study, and how do these new data build on those?

Dhakal: So, as I said, in the median follow up of 15.9 months in CARTITUDE-4, in that time there was significant benefit in the PFS with cilta-cel, where the median PFS was not reached in the cilta-cel arm and was 11.8 months in the standard of care arm. The overall survival was not matured there [and] there was no difference in the overall survival. And here we see significant difference in the overall survival at that follow up of 33.6 months, I think that is quite significant.

Now, another thing that I think needs to be looked at, in terms of safety, is whether we are seeing new safety signals. And with the follow up data at this meeting, we saw that there is no added new safety signal, in terms of there is no delayed neurotoxicities, no increases for cytopenias, and there are no added grade 3 and 4 adverse reactions. In terms of second primary malignancies, that occurred in 13% in the celta-cil group and 11.5% in the standard of care group, so they were pretty comparable. But in terms of hematological malignancies, it was reported in 7 patients in the cilta-cel group and only 1 patient in the standard care group. And out of 7, 5 patients with MDS and AML were found to have pre-existing mutations at baseline prior to the cilta-cel infusion. So, in terms of the new safety signal, it's kind of promising to see that there is no new added grade 3 and 4 adverse events. There are no new delayed neurotoxicities, including Parkinson-like syndromes, and dosing is very encouraging as well.

Q: Why are these findings so significant, particularly for patients with lenalidomide-refractory multiple myeloma?

Badros: The findings are very significant for number of reasons. One is in the US, you know, most of the patients are on lenalidomide therapy as early as first line, because they’re either in maintenance or some form of therapy, and the data show that there is no prospective study looking at the outcomes of patients who are lenalidomide-refractory, how they do. But in general, if you look at all the retrospective data, including the pooled data from different trials, the patients who are lenalidomide-refractory, the median survival and progressive survival is very low, around 12 months. So, I think this is an unmet need patient population. You know, for patients who are lenalidomide refractory as early as first line, what is the next effective therapy as early as second line that could be used, that can really kind of change the outcome of these patients. So, I think in that aspect, cilta-cel showing significant improvement in both progressive survival and overall survival. It’s quite remarkable and can be a very important piece of data to inform the practice.

Q: How do you consider the risk/benefit profile for cilta-cel in this patient population?

Badros: So, as I said, in terms of efficacy, there is no question it is significant. It is significant to both progression-free survival and overall survival. We’ve really kind of established the impressive efficacy of this product. I think the concern about the safety, especially with the long-term follow-up, is how this is going to pan out when you follow these patients for the long term. And I think there is no added new toxicity in terms of grade 3 cytopenias, grade 3/4 cytopenias, no new neurotoxicities. You know, there are very low rates of Parkinson-like syndromes, and in terms of secondary malignancies, it was seen in both the groups, no major difference in the cilta-cel group. There are a little bit more [myelodysplastic syndromes] and AML in the cilta-cel group compared to the standard-of-care group, but even in that, I think overall, the benefit is much higher than the risks. The risk/benefit profile for the patients.

Q: If you have 1 key takeaway, what would it be?

Badros: [Cilta-cel] is a product that was approved in patients with 4 prior lines of therapy, for patients triple class exposed, showing the mean PFS is almost 33.4 months, or almost 3 years at a 3-year follow up. And in CARTITUDE-4, we tested if that highly effective product can be used in earlier lines, especially in patients with lenalidomide-refractory disease. And with the CARTITUDE-4 data, with the updated follow-up at almost 3 years, we saw that it not only improves the PFS, but also improves the overall survival. I think that is very, very important information to share with the patient.

And the other thing is about the safety. I think looking at the safety, it also looks like the safety profile is consistent with what has been observed with cilta-cel, and it's quite manageable. There is still some work to be done in terms of second primary malignancies, especially the MDS and AML, but at this point in time the data is quite encouraging and suggestive of having a high risk/benefit profile in favor of cilta-cel.