DRiving STandard-of-care CAR T cells in real-world Germany Free

In this issue of Blood, Merz et al¹ report a nationwide registry analysis of real-world outcomes with chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma in Germany. Two CAR T-cell therapies targeting the B-cell maturation antigen (BCMA), idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) were initially approved by the US Food and Drug Administration and the European Medicines Agency for patients requiring fourth-line therapy and beyond based on the results of the KarMMa-1² and CARTITUDE-1³ studies, respectively. These latter-line patients are the focus of this report, although both products are now approved in early lines.

Real-world evidence is critical for evaluating the postapproval safety and efficacy of new therapies outside of the highly controlled environment of a clinical trial, in a broader patient population than were eligible for the pivotal trials. To date, real-world evidence for ide-cel⁴ and cilta-cel⁵ has been restricted to the United States and shows outcomes comparable with those in the pivotal trials, despite approximately half of patients not meeting the registrational trial eligibility criteria. The report by Merz et al is the first from a national registry, the German Registry for Hematopoietic Stem Cell Transplantation and Cell Therapy, the first from a universal health care environment, and includes patients who received both products. The population is relatively skewed toward ide-cel (n = 266) compared with cilta-cel (n = 77) because of its earlier availability in Germany. Median follow-up was 12 months for ide-cel, and 9 months for cilta-cel. All patients were triple-class exposed, with a median age in the mid 60s (years), and a median of 6 previous lines of therapy.

The turnaround time for cilta-cel (66 days) was longer than ide-cel (56 days), and all patients received bridging therapy during that time, reflecting growing physician experience and consensus that optimization of disease control at the time of infusion is important for improving both safety and effectiveness of CAR T-cell therapy. Unfortunately, data for patients who underwent apheresis but did not proceed to infusion are not reported. Intention-to-treat population studies are difficult to perform, because the entry point into a program is often unclear, but they provide important context for evaluating the therapeutic modality as a whole, taking into account important real-world variables such as the availability of effective bridging therapy.

Overall, the overall and complete response outcomes are reassuring and align with the pivotal trial data for both products. Follow-up was short, but the 10-month progression-free survival (PFS) was reported as 76% for cilta-cel and 47% for ide-cel, in line with expectations. The impact of disease control at time of infusion was stark, with a 10-month PFS of 79% for patients in complete response, 59% for patients in very good partial response, and 44% for patients in partial response or less (both products combined). Early CAR T-cell–associated toxicity was also comparable with that in the pivotal trials, with low-grade cytokine release syndrome seen in most (>80%) patients for both products, and more immune effector cell–associated neurotoxicity in cilta-cel patients (25%) compared with ide-cel patients (15%). Intriguingly, there were no cases reported of late-onset motor and neurocognitive toxicities that have been of concern with cilta-cel. This likely reflects treatment of latter-line patients with relatively good disease control at the time of infusion at centers with experience in early intensive management of emergent toxicities, early intervention in those patients with excessive CAR T-cell expansion, as well as the small numbers and short follow-up.

Finally, to address the potential impact of differences in baseline characteristics of patients that received the 2 products, a weighted multivariable analysis was performed after propensity score matching. In this analysis the hazard ratio for PFS was 0.48 for cilta-cel compared with ide-cel, confirming the apparent advantage of cilta-cel for disease control.

In summary, the registry-based analysis of Merz et al reflects the successful implementation of anti-BCMA CAR T-cell therapy as a standard-of-care option for patients with myeloma in a universal health care system outside of the United States. The data are supportive of the concept that effective bridging can improve both safety and response duration, as has been seen in several retrospective studies of anti-CD19 CAR T-cell therapy for aggressive lymphoma^6,7 and acute lymphoblastic leukemia,⁸ although with some conflicting reports.⁹ It seems likely that real-world outcomes will continue to improve, similar to the pattern seen after the introduction of CAR T cells for aggressive B-cell lymphoma,¹⁰ as physicians gain more experience with patient selection and aggressive management of toxicities and as more effective bridging therapies become available.

Conflict-of-interest disclosure: M.R.D. reports receiving royalties from AbbVie and honoraria from Kite/Gilead and Novartis. S.J.H. reports consultancy with AbbVie, Amgen, Bristol Myers Squibb (BMS)/Celgene, GlaxoSmithKline (GSK), Janssen Cilag, Novartis, Roche/Genetec, and Eusa; participation on advisory boards for AbbVie, Amgen, BMS/Celgene, GSK, Janssen Cilag, Novartis, and Roche/Genetec; investigator roles in studies for AbbVie, Amgen, BMS/Celgene, Janssen Cilag, Novartis, Roche/Genetec, and HaemaLogiX; receiving honoraria from Amgen, BMS/Celgene, Janssen Cilag, Novartis, and Roche/Genetec; receiving research funding from Amgen, BMS/Celgene, GSK, Janssen Cilag, Novartis, and HaemaLogiX; participation on a scientific advisory board for HaemaLogiX; and advisory work and expert testimony for Eusa.