Comparative Safety and Efficacy of Ciltacabtagene Autoleucel and Idecabtagene Vicleucel CAR T-Cell Therapies in Relapsed or Refractory Multiple Myeloma
Authors: Hansen Doris K. , Peres Lauren C. , Dima Danai , Richards Alicia , Shune Leyla O. , Afrough Aimaz , Midha Shonali , Dhakal Binod , Kocoglu Mehmet H. , Atrash Shebli , Ferreri Chris , Castaneda Omar , Davis James A , Ouchveridze Evguenia , McGuirk Joseph P. , Wagner Charlotte B , Bansal Radhika , Costello Patrick , Smith Kinaya , Lieberman-Cribbin Alex , De Avila Gabriel , Purvey Sneha , Hosoya Hitomi , Mikkilineni Lekha , Oswald Laura B. , Kaur Gurbakhash , Pasvolsky Oren , Gaballa Mahmoud R. , Herr Megan M , Forsberg Peter A. , Janakiram Murali , Htut Myo , Asoori Sireesha , Kalariya Nilesh , Hashmi Hamza , Reshef Ran , Sborov Douglas W , Nadeem Omar , Anwer Faiz , Khouri Jack , Raza Shahzad , Atanackovic Djordje , Alsina Melissa , Freeman Ciara Louise , Locke Frederick L. , Voorhees Peter M. , Anderson Larry D , Richard Shambavi , Martin Thomas , Lin Yi , Patel Krina K. , Sidana Surbhi 
Published: December 2024

Introduction. Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), two anti-B-cell maturation antigen (BCMA) CAR T therapies, have demonstrated remarkable responses and improved survival among patients with relapsed/refractory multiple myeloma (RRMM) in the clinical trials and standard of care (SOC) setting. Here, we compare safety, efficacy, and survival for patients treated with SOC ide-cel and cilta-cel.

Methods. Data were from a retrospective chart review of RRMM patients leukapheresed by 12/31/2022 with the intent to receive SOC ide- or cilta-cel at 19 institutions in the US Multiple Myeloma Immunotherapy Consortium. An inverse probability of treatment weighting (IPTW) approach was used to compare outcomes by therapy type (cilta- vs. ide-cel), balancing on age, sex, race and ethnicity, performance status, extramedullary disease, high-risk cytogenetics, prior BCMA therapy, bone marrow plasma cells, penta-refractory status, lymphodepleting chemotherapy, baseline ferritin, low cell dose, and bridging therapy response. Logistic regression and Cox proportional hazard models were used to examine the association of treatment type with safety, efficacy, and survival accordingly, while adjusting for IPTW weights. We employed propensity score matching utilizing the same covariates to identify the association of treatment type with progression-free survival (PFS) within relevant patient sub-groups.

Results. A total of 641 patients were leukapheresed by 12/31/2022 with ide-cel (n=386) and cilta-cel (n=255). 586 patients were infused (n=350 for ide-cel; n=236 for cilta-cel) with a median follow-up of 13.0 and 12.6 months, respectively. After IPTW, patient characteristics were well-balanced. Patients treated with cilta-cel were more likely to have grade ≥ 3 cytokine release syndrome (CRS) (OR=5.52, 95% CI=1.76-17.30, p=0.004), infections (OR=2.07, 95% CI=1.44-2.97, p&lt;0.001), and delayed neurotoxicity (NT) (OR=20.97, 95% CI=4.75-92.42, p&lt;0.001) compared to patients treated with ide-cel. In the cilta-cel cohort, 24 patients (10%) experienced delayed NT compared to 2 patients (1%) in the ide-cel cohort. Although not statistically significant, patients treated with cilta-cel were more likely to have any second primary malignancies (SPMs) (OR=1.87, 95% CI=0.94-3.71, p=0.08) and any SPMs excluding non-melanoma skin cancers (OR=1.78, 95% CI=0.78-4.10, p=0.2) but no association was observed for odds of hematologic SPMs (OR=0.98, 95% CI=0.26-3.61). No association was observed for therapy type with any or severe immune effector cell-associated neurotoxicity syndrome, any CRS, severe cytopenias, and non-relapse mortality.

Compared to ide-cel, cilta-cel was associated with better treatment responses of ≥ complete response (OR=2.38, 95% CI=1.61-3.51, p&lt;0.001) and ≥ partial response (OR=1.74, 95% CI=0.99-3.05, p=0.06). Patients treated with cilta-cel had a longer PFS and overall survival (OS) than ide-cel (HR=0.47, 95% CI=0.35-0.62, p&lt;0.001 and HR=0.63, 95% CI=0.42-0.93, p=0.02, respectively), and these findings were similar in the intention to treat cohort (PFS: HR=0.44, 95% CI=0.34-0.55, p&lt;0.001; OS: HR=0.55, 95% CI=0.41-0.73, p&lt;0.001, respectively). We observed consistent findings when repeating the analyses restricting the ide-cel cohort to patients infused during the same time-period as FDA approval for cilta-cel (≥ March 2022), restricting to patients with data on all covariates, and restricting to sites that contributed data for both products. In a propensity matched population, (n=380; n=190 for cilta-cel and n=190 for ide-cel), patients treated with cilta-cel had superior PFS compared to those treated with ide-cel in most subgroups with respect to age and disease characteristics including extramedullary disease, high-risk cytogenetics, and elevated baseline ferritin (p&lt;0.05).

Conclusion. Our results suggest superior efficacy of cilta-cel with a higher incidence of certain toxicities compared to ide-cel in the SOC setting. This study provides valuable information for patient counseling and guiding the selection of CAR T-cell therapy for specific patient populations. Further validation through similar large-scale real-world experiences or prospective studies is needed to confirm our results and enhance applicability in the clinical setting.

*DH, LP, & DD are co-first authors

* YL, KP, & SS are co-last authors