Ide-Cel Is Effective, Safe for Patients With R/R Multiple Myeloma and Renal Insufficiency

Surbhi Sidana, MD

Patients with relapsed or refractory multiple myeloma treated with the CAR T-cell agent idecabtagene vicleucel (ide-cel; Abecma) had comparable efficacy and safety outcomes regardless of whether they had renal impairment, according to findings from a real-world study presented at the 2023 Transplantation & Cellular Therapy Meetings.¹

Findings from the multicenter retrospective study showed that efficacy-evaluable patients with renal insufficiency (n = 26), defined as a creatine clearance (CrCl) of less than 50 mL/min, experienced an overall response rate (ORR) of 96% compared with 83% among 163 patients with preserved renal function (CrCl ≥ 50 mL/min; P = .045). The very good partial response (VGPR) rates were 77% vs 65%, respectively (P = .20), and the complete response (CR) rates were 58% vs 42%, respectively (P = .10).

Moreover, at a median follow-up of 6 months, the median progression-free survival (PFS) in the preserved renal function group was 8.1 months compared with 6.5 months in the renal insufficiency arm (P = .60). A multivariable PFS analysis that used age, cytogenetics, and prior BCMA therapy as covariates in the model showed that renal insufficiency was not an independent predictor in terms of PFS (HR, 1.4; 95% CI, 0.7-2.7; P = .40). High-risk disease, prior BCMA therapy, and an age of less than 65 years were independent adverse prognostic factors.

“We know ide-cel has resulted in unprecedented response rates in patients with myeloma,” Surbhi Sidana, MD, assistant professor of medicine, blood and marrow transplantation and cellular therapy at Stanford University School of Medicine in Palo Alto, California, said in a presentation of the findings. “However, clinical trials set stringent eligibility criteria and patients with renal impairment were excluded from the KarMMa clinical trial [NCT03361748]. Renal impairment is a hallmark feature of myeloma; [one-fourth] of patients are diagnosed with renal impairment. As time goes on, that number increases. Therefore, in this very critical population, [in which] we still don’t know the safety and efficacy profile of CAR T-cell therapy.”

The retrospective study examined a total of 211 patients from 11 cancer centers who were receiving standard-of-care ide-cel for relapsed or refractory multiple myeloma in the United States. Patients were stratified by preserved renal function (n = 183) and renal insufficiency (n = 28); there was also a severe renal insufficiency subgroup (CrCl < 30 mL/min or dialysis; n = 11). All patients received fludarabine and cyclophosphamide lymphodepletion. The dosing of chemotherapy and management of subsequent toxicities was performed per institutional guidelines.

The baseline characteristics between the renal insufficiency and preserved renal function groups were well-balanced; the median ages were 69 years and 63 years, respectively. Patients in the renal insufficiency arm were mostly women (68%) and had a median albumin level of 3.4 g/dL, a median β2-microglobulin of 4.3 mg/L, and revised International Staging System stage 3 disease at a rate of 44%. In the preserved renal function arm, these figures were 35%, 3.7 g/dL, 2.9 mg/L, and 25%, respectively.

Most patients in the renal insufficiency and the preserved renal function arms received bridging therapy (93% vs 75%). Dose reductions of fludarabine occurred for 82% of patients with renal insufficiency compared with 22% for those without (P < .001).

In terms of safety, patients in the renal-insufficiency arm experienced any-grade cytokine release syndrome at a rate of 89% compared with 84% in the preserved renal function arm (P = .70). Immune effector cell–associated neurotoxicity syndrome was present in 21% and 19% of patients (P = .70), respectively, and the median duration of hospital stay was 13 days vs 9 days (P = .05).

Eighty-six patients in the renal insufficiency arm experienced cytopenia of grade 3 or greater at day 30. In the preserved renal function arm, 170 patients were evaluable at day 30 and 55% of patients had cytopenia grade 3 or higher. Neutropenia of at least grade 3 was observed in 54% vs 33% of patients, respectively (P = .04), and thrombocytopenia of grade 3 or greater was present in 75% vs 41%, respectively (P < .001).

At day 90, 19 patients in the renal insufficiency arm and 122 patients in the preserved renal function arm were evaluable for safety. Grade 3 or greater cytopenia, neutropenia, and thrombocytopenia occurred at a rate of 36%, 16%, and 16%, respectively, in the renal insufficiency arm. In the preserved renal function arm, these figures were 27%, 9%, and 21%, respectively.

Overall, 4 patients in the insufficiency arm died compared with 32 in the preserved renal function arm. Death due to CAR-T toxicity occurred at a rate of 25% vs 23%, respectively.

Additional findings from the study showed that patients in the severe renal insufficiency subgroup experienced a median PFS of 6.5 months compared with 8.5 months among the 200 other patients. The ORR in the 10 response-evaluable patients in the severe renal insufficiency subgroup was 100% (n = 10/10), including a 90% VGPR rate and a 70% CR rate. Among the other 179 response-evaluable patients, these figures were 84%, 65%, and 43%, respectively. One of 2 deaths in the severe renal insufficiency subgroup was due to CAR-T toxicity.

“Importantly, [patients] had a similar clinical benefit in terms of response rates and PFS,” Sidana said. “Of course, this is a retrospective study and there are limitations. Specifically, there was no mandatory dose reduction and there was no uniform dose reduction. Going forward, we are planning a phase 2 multicenter study to evaluate [ide-cel] in this population.”

Ide-cel is also under evaluation for patients with relapsed or refractory multiple myeloma in the ongoing phase 3 KarMMa-3 trial (NCT03651128). However, patients withrenal impairment were not included as part of this trial, underscoring the importance of the retrospective study in determining the agent’s safety and efficacy in this subgroup.²

Ide-cel became the first FDA-approved cell-based gene therapy for multiple myeloma when the agency gave the agent the go-ahead for the treatment of adult patients with relapsed or refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, on March 26, 2021.³

References

1. Sidana S, Peres L, 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; February 15-19, 2023; Orlando, FL. Abstract 42.
2. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. Published online February 10, 2023. doi:10.1056/NEJMoa2213614
3. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. March 26, 2021. Accessed February 16, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/