Bridging Response Emerges as Key Predictor of Cilta-Cel Outcomes in CARTITUDE-4

In new findings presented at the American Society of Hematology (ASH) Annual Meeting, investigators highlight how patients’ responses to bridging therapy before cilta-cel infusion strongly influence both safety and long-term efficacy in relapsed, lenalidomide-refractory multiple myeloma.

In this Q&A, Binod Dhakal, MD, discusses how deeper responses prior to CAR-T were linked with markedly improved progression-free and overall survival in CARTITUDE-4, and what these data mean for clinicians—particularly pharmacists—optimizing bridging strategies to ensure patients reach CAR-T in the best possible condition.

Q: Could you give us a bit of background on the data that you'll be presenting at ASH?

Binod Dhakal, MD: Definitely. At the American Society of Hematology (ASH) Annual Meeting, we're going to present data looking at the effectiveness of bridging therapy, and how that corresponds to improved outcomes after cilta-cel, or ciltacabtagene autoleucel, which is a B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy in the phase 3 CARTITUDE-4 study of patients with relapsed lenalidomide-refractory multiple myeloma.

In this study, what we looked at is that, in the initial report, we have shown that the single infusion of cilta-cel has improved both progression-free survival and overall survival in patients with one to three prior lines of therapy who were lenalidomide-refractory. Now, in this study, we want to look at what would be the impact of the disease burden prior to this infusion.

Recently, we also reported that a 25% reduction in tumor burden after bridging correlated with longer progression-free survival after cilta-cel. Here, we are investigating further the correlation between response to bridging therapy and efficacy and safety outcomes after cilta-cel infusion.

One thing I would like to point out is that there were 419 patients randomized—208 in the cilta-cel arm and the remaining in the standard-of-care arm, which included two different regimens: daratumumab, pomalidomide, and dexamethasone (DPd), or pomalidomide, bortezomib, and dexamethasone (PVd). The initial report looked at 176 patients who were treated with cilta-cel as the study treatment, and then 20 patients were treated in a subsequent line of therapy because those patients progressed on bridging therapy. The bridging therapy allowed in the study was either DPd or PVd based on physician choice.

So here, we are reporting the safety and efficacy data in all patients who received cilta-cel infusion—that is, 176 patients who received it as study treatment and 20 patients who received it as a subsequent line of therapy. And we want to look at the response to bridging and also the subsequent outcomes of all these 196 patients.

Most of the patients received bridging with DPd as the bridging therapy. About one-fifth of the patients achieved a very good partial response or better; about one-third achieved a partial response; around 10% had progressive disease; and about 31% had either minimal response or stable disease.

What we showed is that patients who achieved partial response or better to bridging therapy experienced superior progression-free survival and overall survival compared with patients who had less than a partial response. Especially if you look at the patients who had a very good partial response or better to bridging, at 30 months, 76% of them were progression-free and 85% were alive. So that really tells you the effect of bridging therapy on efficacy outcomes.

And what about those 20 patients who progressed and received cilta-cel as a subsequent line of therapy? Eight first received salvage therapy after bridging, and nine would not have been eligible for the CARTITUDE-4 trial because they had more than four prior lines of therapy. Progression-free survival in this group was worse. Median progression-free survival in this group of patients was only 7.4 months, underscoring how disease burden and progression while waiting for CAR-T can impact outcomes. But it is also important to note that despite poorer outcomes, six of these patients—around 30%—remained progression-free at a median of 28.6 months (range, 25–35 months). So that is still a decent number of patients, over one-third, who exhibited benefit despite progression.

In terms of safety, it is important to know that in patients who achieved partial response or better, there were no cases of delayed neurotoxicity, especially delayed neurotoxicity with Parkinson-like features. In terms of non-relapse mortality, it was higher in patients who had poor response to bridging, especially infections in the first two months after cilta-cel. Similarly, grade 3/4 cytopenias were lower in patients who had a very good partial response to bridging before cilta-cel. The rate of cranial nerve palsy was higher in patients with a good response to bridging therapy, suggesting this is a different entity not related to disease burden.

So in conclusion, in 196 patients treated with cilta-cel in CARTITUDE-4, deeper response to bridging therapy correlated with better progression-free survival, overall survival, and better safety. There were no cases of immune-effector-cell–associated Parkinsonism in patients who achieved partial response to bridging, and patients with poor response to bridging were more likely to have fatal adverse events, including infections and prolonged cytopenia. Overall, this study highlights the significance of better bridging therapy before receiving cilta-cel infusion.

Q: How do these data reinforce the role of the pharmacist in selecting and optimizing these regimens to help patients achieve these better responses?

Dhakal: As you saw in the data, deeper pre-cilta-cel response has a win-win situation, both in safety and efficacy. So it is important to understand that and the significance of bridging in CARTITUDE-4. The only two bridging options allowed were DPd or PVd, but in the real world, there are many other options that could be used in patients with one to three prior lines of therapy.

So this definitely underscores the importance of optimizing regimen selection. The team can evaluate prior refractoriness and potential toxicity of bridging therapies and individualize the regimen, because many options are available and many patients in the one-to-three prior line setting are still sensitive to these regimens. You tailor the bridging therapy so the patient can at least get a partial response before pursuing CAR-T. That is probably the main role—selecting the right bridging therapy given the many options available in this patient cohort.

Q: Given the strong correlation between pre-cilta-cel response and post-infusion safety outcomes, what practical strategies can be used to monitor and manage patients during bridging therapy to reduce cytopenias or infections?

Dhakal: You saw in the data that patients who had a good response had better outcomes after cilta-cel in terms of both cytopenias and infections. Having said that, we also want to make sure that while patients are receiving bridging therapy, they are not having unnecessary toxicities such as cytopenias or infections.

So it underscores the significance of monitoring blood counts, making sure they are not having grade 3 or 4 cytopenia, and stopping the drug as needed. Giving growth factor support, adjusting the dose of medications— for example, for someone treated with DPd, adjusting pomalidomide—making sure they are on aggressive infection prophylaxis, including antiviral prophylaxis, bacterial prophylaxis in neutropenia, fungal prophylaxis, and supplementing intravenous immunoglobulin if needed.

Early and prompt evaluation of symptoms for infection is also essential. These strategies are important for all patients but especially for patients undergoing CAR-T, and while they are receiving bridging therapy, it is important to monitor so that they get the best response—at least a partial response—before cilta-cel.