Idecabtagene Vicleucel Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Multiple Myeloma with Renal Insufficiency: Real World Experience

Introduction: Idecabtagene vicleucel (ide-cel) is an autologous BCMA directed chimeric antigen receptor therapy T (CAR-T) cell therapy approved for relapsed/refractory multiple myeloma (RRMM). However, patients with renal insufficiency (RI) were excluded from the registrational KarMMa clinical trial. RI impacts a significant proportion of patients with multiple myeloma and the safety and efficacy profile of CAR-T remains unknown in this patient population. We evaluated the real-world outcomes of patients with RI treated with standard of care ide-cel.

Methods: RI was defined as creatinine clearance (CrCl) < 50 ml/min at the time of CAR-T therapy. CrCl of < 30 ml/min or being on dialysis was defined as severe RI. Dosing of lymphodepletion chemotherapy and grading/management of toxicities was per institutional guidelines, while responses were graded based on the IMWG response criteria.

Results: The study cohort includes 211 patients receiving ide-cel from 11 medical centers, of which 28 (13%) patients had RI at the time of CAR-T therapy with CrCl < 50 ml/min. Among these, 11 (39%) patients had severe RI including one patient on dialysis. Table 1 describes baseline and treatment characteristics of patients with and without RI. Patients with RI were older (69 vs 63 years, p=0.003) and more likely to be female (68% vs 35%, p=0.001). They had lower albumin, higher beta-2-microglobulin (B2M) and higher likelihood of having revised ISS stage 3 disease, driven primarily by high B2M levels. Median prior lines of therapy in patients with and without RI was 8 vs 6, respectively. Fludarabine was dose reduced in 82% patients with RI and amongst this group 61% of patients had > 20% dose reduction. There was no difference in CAR-T cell dose infused (median: 416 vs 408 million cells).

Cytokine release syndrome (CRS) was seen in 89% vs 84%, p=0.7 of patients with and without RI, including grade ≥ 2 CRS in 14% vs 20%, p=0.6 of patients, respectively. Neurotoxicity was observed in 21% vs 19%, p=0.7 of patients, respectively. Patients with RI had a longer hospital stay (median 13 vs 9 days, p=0.05), although ICU admission rates were similar (14% vs 7%, p=0.3). Infections were seen in 43% vs 32%, p=0.2 of patients, respectively. At one month, any ≥ grade 3 cytopenia was more common in patients with RI (86% vs 55%, p=0.001), including grade ≥ 3 neutropenia (54% vs 33%, p=0.04) and grade ≥ 3 thrombocytopenia (75% vs 41%, p<0.001). By 90 days post CAR-T, there was no difference in > grade 3 cytopenias amongst the 2 groups. Renal function did not significantly change after CAR-T in most patients. Amongst patients with paired baseline and day 30 data, no patient with CrCl 30-49 ml/min experienced worsening of CrCl to < 30 ml/min at day 30. Amongst 10 patients with CrCl < 30 ml/min, 3 patients experienced improvement in CrCl to 30-49 ml/min, while 7 patients had similar CrCl at day 30. New need for dialysis post CAR-T was observed in two patients, both with baseline CrCl > 50 ml/min; in one patient at 1 week post CAR-T in the setting of critical illness/severe CRS and in another patient 8 months post CAR-T in the setting of salvage therapy for relapse and critical illness. 34 patients have died by last follow-up, of which 8 were due to CAR-T related toxicities including infections (1 patient with RI, 7 without RI, p=0.9).

189 patients were evaluable for response. Patients with RI had an overall response rate of 96% comparted to 83% in patients without RI, p=0.045. Complete response (58% vs 65%, p=0.1) and very good partial response rates (77% vs 65%, p=0.2) were similar. At a median follow-up of 6 months, the median progression-free survival (PFS) in the two groups was 6.5 vs 8.1 months, p=0.6 (Fig 1). On multivariable analysis incorporating RI, age, cytogenetics and prior BCMA-directed therapy, RI was not an independent predictor for PFS (HR 1.4, 95% CI: 0.7-2.7, p=0.4), while high-risk disease, prior BCMA therapy, and age < 65 years were independent adverse prognostic factors.

Conclusions: This multicenter retrospective study supports the feasibility of ide-cel CAR-T cell therapy in RRMM patients with RI. CRS, neurotoxicity and non-relapse mortality were comparable in patients with or without RI, although patients with RI had a longer hospital stay and were more likely to experience short-term high-grade cytopenias. Importantly, patients with RI experienced similar benefit in terms of response rates and PFS.

S.S & L.P: co-first authors. L.S, K.K.P & D.K.H: joint senior authors