Retrospective Study Provides Real-World Insight on Ide-cel in R/R Multiple Myeloma With Renal Impairment

Surbhi Sidana, MD

Real-world data from a retrospective study revealed that the CAR T-cell therapy idecabtagene vicleucel (Abecma; ide-cel) is safe and effective in patients with relapsed or refractory multiple myeloma who have renal impairment, according to lead study author Surbhi Sidana, MD.

In March 2021, ide-cel gained FDA approvalfor patients with relapsed/refractory multiple myeloma who had progressed on 4 or more prior lines of therapy. The regulatory decision was based on findings from the phase 2 KarMMa trial (NCT03361748), which showed that patients who received ide-cel achieved an overall response rate (ORR) of 72% (95% CI, 62%-81%).¹

Although these data support the use of ide-cel as a standard-of-care (SOC) treatment option in multiple myeloma, the trial did not include those with renal impairment, according to Sidana, who is a hematologist/oncologist in the Division of Blood and Marrow Transplantation and Cellular Therapy in the Department of Medicine at Stanford University School of Medicine, Stanford, CA

To address this unmet need, a multicenter, retrospective analysis was launched.² Real-world data from the analysis were presented at the 2023 Transplantation and Cellular Therapy Meetings and demonstrated that the agent elicited comparable ORRs of 96% and 83% in patients with and without renal impairment, respectively. The median progression-free survival (PFS) was 6.5 months vs 8.1 months, respectively, in these groups. Although safety was noted to be comparable between those with or without renal insufficiency, a higher prevalence of short-term high-grade cytopenias was observed in the former group.

“[We determined that] it’s feasible to give patients with renal impairment BCMA-directed CAR T-cell therapy, specifically ide-cel,” Sidana said. “If my colleagues take away anything from this research, I want them to consider patients with renal impairment for these novel therapies, and advocate for their inclusion in clinical trials [for multiple myeloma]. As a field, we must advocate to [include] these patients, because they comprise a significant proportion of those with [this disease].”

In an interview with OncLive^®, Sidana further discussed the real-world safety and efficacy of ide-cel in patients with multiple myeloma and renal impairment and emphasized the importance of including this population in future clinical trials examining novel therapies in this disease.

OncLive: Could you speak to the importance of evaluating real-world experience with CAR T-cell therapies in patients with relapsed/refractory multiple myeloma who have renal impairment?

Sidana: BCMA-directed CAR T-cell therapy is a very promising treatment option for patients with multiple myeloma. We have two FDA-approved products: ide-cel and ciltacabtagene autoleucel [Carvykti; cilta-cel]. Patients who had renal impairment were excluded from both trials. We know that renal impairment impacts a significant proportion of patients with multiple myeloma; [it impacts] up to one-fourth of patients at diagnosis and [an] even higher [number of patients] at the time of relapse.

As such, this is an area of huge unmet need. [Although] we don’t have data [quantifying this need], we see patients every day in clinic who are asking for, and are deserving of, these therapies. We [formed] the US Multiple Myeloma Car T-cell Consortium, and [combined] our data to look at outcomes [in] patients with reduced renal functions [who are] undergoing CAR T-cell therapy with ide-cel.

Why were patients with renal impairment excluded from the registrational KarMMa trial?

Patients in clinical trials are often highly selected. Patients were perhaps excluded from the trial because investigators were not sure of how the toxicity or efficacy of ide-cel would play out in this patient population. [Remember,] this was one of the first products to be evaluated. However, once we have established that the product works, we [know] that we need to include special cohorts of patients that are represented in the disease [in our analyses.] This includes patients with renal dysfunction, plasma-cell leukemia, etc. We must include these patients in trials going forward.

Could you expand on patients’ baseline characteristics in the study population?

[Data were collected] from 200 patients who were undergoing ide-cel therapy at 11 different centers across the country, which comprised the US Multiple Myeloma CAR T-cell Consortium. Out of these [200] patients, 28 had renal impairment, which was defined as a creatine clearance of less than 50 mL/min at the time of CAR T-cell therapy. Eleven patients had severe renal impairment, defined as a creatinine clearance of less than 30 mL/min, or being on dialysis at the [start of treatment].

What key findings from this retrospective analysis were presented at the meeting?

We found that we did have to adjust the dosage of lymphodepletion. That is a concern with fludarabine use in these patients. Since this is a retrospective analysis, there was no mandated [dose reduction], but a majority of these patients had a significant amount of dose reduction.

Importantly, [the incidence of] cytokine release syndrome and neurotoxicity was not [significantly] different in these patients compared with those who had normal renal function. We did note that these patients had longer hospital stays, and a higher [incidence of] grade 3 or greater cytopenias at day 30, but these [rates] tended to become similar across the 2 groups by day 90. There [may be a] slightly different toxicity signal, but no major safety concerns [were revealed].

[Most] importantly, these patients benefited from the CAR T-cell therapy. Efficacy was comparable in both groups; response rates and PFS were similar. We also did not see any differences in non-relapse mortality in the 2 groups. Did renal function change over time? Did CAR T-cell therapy make renal function worse in these patients? No. When we compared patients with renal impairment [at] baseline [vs] day 30, no new patients needed dialysis and there was not any worsening of renal function.

In our study cohort, [ide-cel’s] safety profile is similar [to toxicities in patients without renal impairment]. [There is] the slight exception of more short-term cytopenias, but by 3 months, it is similar across the board.

How might these findings affect the treatment of patients with renal impairment in clinical practice?

Our results have a few implications, but we also have more work to do. The implications are [that] it’s feasible to give BCMA-directed CAR T-cell therapy with appropriate adjustments in lymphodepletion doses to patients who have renal impairment. We should not limit the use of both SOC and investigational CAR T-cell therapies for these patients. We can continue to give them in the clinic but we should also include these patients in clinical trials going forward, perhaps in a special cohort or expansion cohort. [Regardless,] these patients should be included because we need to generate safety and efficacy data for different constructs.

What were some limitations of this analysis, and how might continued research address them?

One limitation of our study was that we did not mandate any particular decrease in dosage for fludarabine. We need to study this [systematically] in a clinical trial, where certain lymphodepletion dosing is required so we can assess the safety and efficacy [of ide-cel] in a uniform manner.

Editor’s Note: Dr Sidana disclosed serving as a consultant or in an advisory role for Oncopeptide, Bristol-Myers Squibb, Janssen, Sanofi: Prothena, Magenta Therapeutics; she reported receiving research funding from Bristol-Meyers Squibb, Allogene, Janssen, Magenta Therapeutics; she received honoraria from Prothena.

References

1. US Food and Drug Administration approves Bristol Myers Squibb’s and bluebird bio’s Abecma (idecabtagene vicleucel), the first anti-BCMA CAR T cell therapy for relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb and bluebird bio. March 26, 2021. Accessed March 10, 2023. https://news.bms.com/news/details/2021/
2. Sidana S, Peres LC, Hashmi H, et al. Idecabtagene vicleucel (Ide-cel) Chimeric Antigen Receptor T-cell therapy for relapsed/refractory multiple myeloma (RRMM) with renal impairment: real world experience. Presented at: 2023 Transplantation & Cellular Therapy Meetings of ASCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 42.