Ciltacabtagene Autoleucel for Triple-Class Exposed Multiple Myeloma: Adjusted Comparisons of CARTITUDE-1 Patient Outcomes Versus Therapies from Real-World Clinical Practice from the LocoMMotion Prospective Study
Authors: Mateos Maria-Victoria , Weisel Katja , Martin Thomas , Berdeja Jesús G. , Jakubowiak Andrzej , Stewart A. Keith , Jagannath Sundar , Lin Yi , Diels Joris , Ghilotti Francesca , Perualila Nolen J , Cabrieto Jedelyn , Haefliger Benjamin , Erler-Yates Nichola , Hague Clare , Jackson Carolyn C. , Strulev Vadim , Nesheiwat Tonia , Pacaud Lida , Moreau Philippe , Einsele Hermann 
Published: November 2021

Abstract
Background: Patients with relapsed and refractory multiple myeloma (RRMM) who have triple class exposure to immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies (MoABs) have a poor prognosis and high unmet medical need. Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy which may offer long-term disease control for these patients. CARTITUDE-1 is an open-label, single arm phase 1b/2 clinical trial conducted to characterize the safety and efficacy of cilta-cel in adult patients with triple-class exposed RRMM. Since CARTITUDE-1 is a single-arm study, adjusted comparisons to other currently available therapies can provide valuable information on relative efficacy and safety benefits of cilta-cel over current real-world clinical practice (RWCP). LocoMMotion is the first prospective study of RWCP efficacy and safety outcomes in triple-class exposed patients with RRMM. It was designed a priori to serve as an external control cohort for CARTITUDE-1, using aligned inclusion criteria and endpoint definitions, to enable robust, high quality indirect comparisons vs. cilta-cel.
Objective: To compare patient outcomes of cilta-cel vs. RWCP, including overall response rate (ORR), complete response or better rate (≥CR rate), progression-free survival (PFS) as assessed by a review committee and overall survival (OS) in patients with triple-class exposed RRMM.
Methods: Individual patient level data available from both CARTITUDE-1 (clinical cut-off February 2021) and LocoMMotion (clinical cut-off March 2021) were pooled to conduct the comparative analyses. Imbalances between both cohorts on key prognostic baseline characteristics, including refractory status, ISS stage, time to progression on prior line, number of prior lines, average duration of prior lines, age, creatinine clearance, ECOG PS and MM type were adjusted for using inverse probability weighting. Average treatment effect on the treated (ATT) weights derived from propensity scores estimated using multivariable logistic regression modeling were applied to the LocoMMotion patients to have the weighted RWCP cohort reflecting the CARTITUDE-1 patient population. Balance between the ATT weighted RWCP cohort versus the CARTITUDE-1 population was evaluated based on reduction of standardized mean differences and overlap of propensity score distributions. Weighted logistic and Cox proportional hazards regression were used to estimate the relative treatment effects for cilta-cel vs. RWCP on binary endpoints (Odds ratios (OR), transformed into Response-rate Ratios (RR) and time to event endpoints (Hazard ratios (HR)), respectively. The base case analyses included all enrolled (apheresed) patients from CARTITUDE-1, reflecting an intention to treat approach. Additional analyses were conducted including only patients who received cilta-cel infusion compared to an aligned population of LocoMMotion where patients that progressed or died within 52 days were excluded from the LocoMMotion cohort.
Results: 113 patients were enrolled in CARTITUDE-1, of which 97 were infused with cilta-cel. 246 patients were enrolled in LocoMMotion receiving RWCP in Italy (24%), Germany (15%), France (14%), UK (11%), Spain (10%), USA (9%), Belgium (5%), Poland (5%), Netherlands (4%) and Russia (3%). Therapies within the RWCP cohort were diverse and &gt;90 unique treatment regimens were used. The most frequent regimens were Kd (13.8%), PCd (12.6%) and Pd (11.0%). The weighted LocoMMotion population was well balanced with the CARTITUDE-1 cohort. Adjusted comparisons (Table 1) showed statistically significant improvements for cilta-cel vs. RWCP for ORR (RR=4.43), ≥CR (RR=568.92), PFS (HR=0.15) and OS (HR=0.38), all comparisons with p&lt;0.001. All additional analyses were consistent with these findings (Table 1).
Conclusions: Outcomes for patients with triple-class exposed RRMM treated with RWPC observed in LocoMMotion are poor, illustrating the high unmet medical need. Adjusted comparisons vs. CARTITUDE-1 demonstrate significantly improved ORR, ≥CR, PFS and OS for cilta-cel compared to a diverse set of RWCP. These findings highlight cilta-cel's potential as a highly effective treatment option for patients with triple-class exposed RRMM.
Figure 1 Figure 1.

Disclosures
Mateos: Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weisel: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Martin: Sanofi: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; GlaxoSmithKline: Consultancy; Amgen: Research Funding. Berdeja: Celularity, CRISPR Therapeutics: Research Funding; Abbvie, Acetylon, Amgen: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; EMD Sorono, Genentech: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding. Jakubowiak: Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Stewart: Oncopeptides: Honoraria; Janssen: Honoraria; GSK: Honoraria; BMS: Honoraria; Amgen: Honoraria; Skyline diagnostics: Consultancy; Genomcs England: Membership on an entity's Board of Directors or advisory committees; Tempus Inc.: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; PikSci Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Sanofi Aventis: Honoraria. Jagannath: Legend Biotech: Consultancy; Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. Lin: Novartis: Consultancy; Bluebird Bio: Consultancy, Research Funding; Legend: Consultancy; Sorrento: Consultancy; Juno: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; Vineti: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Diels: Janssen: Current Employment. Ghilotti: Janssen-Cilag SpA, Cologno Monzese, Italy: Current Employment. Perualila: Janssen: Current Employment. Cabrieto: Janssen: Current Employment. Haefliger: Janssen-Cilag AG: Ended employment in the past 24 months; Cilag GmbH International: Current Employment. Erler-Yates: Janssen: Current Employment. Hague: Janssen: Current Employment, Current equity holder in publicly-traded company. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Strulev: Janssen Pharmaceutica NV: Current Employment. Nesheiwat: Legend Biotech USA: Current Employment. Pacaud: Legend Biotech: Current Employment. Moreau: Janssen: Honoraria; Celgene BMS: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Oncopeptides: Honoraria. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding.