Outcomes of BCMA-Directed Chimeric Antigen Receptor T-Cell (CART) Therapy in Patients with Relapse-Refractory Multiple Myeloma with Extramedullary Disease
Authors: Dima Danai , Davis James A , Rashid Aliya , Rice Mikhaila , DeJarnette Shaun , Shune Leyla , Khouri Jack , Raza Shahzad , McGuirk Joseph P , Anwer Faiz , Ahmed Nausheen , Abdallah Al-Ola , Hashmi Hamza 
Published: December 2023

Background: Presence of extramedullary disease (EMD) is associated with poor outcomes for patients with relapsed-refractory multiple myeloma (RRMM) and has been identified as a major risk factor for early progression (≤ 3 months) after CAR T-cell therapy. Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are B-cell maturation antigen (BCMA) targeting CAR T-cell therapies approved for patients with RRMM who have received ≥4 prior lines of therapy (LOT). This is a multicenter retrospective study on the real-world safety and efficacy of commercially available ide-cel and cilta-cel in heavily pretreated RRMM patients with EMD.
Methods: Three U.S. academic centers, part of the U.S. Myeloma Innovations Research Collaborative (USMIRC), contributed data to this analysis, which included patients with RRMM who had received an ide-cel or cilta-cel infusion ≥30 days prior to data-cut off (7/1/2023). Baseline patient characteristics were outlined by descriptive analyses. Responses including overall response (ORR), and complete response or better (≥CR) rates were evaluated using the International Myeloma Working Group (IMWG) criteria. Statistical analysis was done with the Fisher's exact test and Kaplan Meier method for progression free (PFS) and overall survival (OS) calculations.
Results: A total of 132 patients who received commercial (standard of care) BCMA-directed CAR T-cell therapy between 5/1/2021 and 5/30/2023 were included in this study. Out of these, 64 (48%) patients had a previous history or existing EMD prior to CART infusion. Table 1 summarizes the main patient characteristics and outcomes stratified as EMD and non-EMD groups. Both groups had comparable baseline patient and disease characteristics including median age, ECOG performance status, median bone marrow plasma cell percentage, high-risk cytogenetics, number of prior LOT, refractoriness status prior to CART and type of CAR T-cell product received. CART-related toxicities were comparable between the EMD and the non EMD groups. Cytokine release syndrome (CRS) was seen in 73% (≥ grade 3: 5%) of EMD patients vs 79% (≥ grade 3: 4%) of non-EMD patients (p=0.79). Likewise, immune effector cell-associated neurotoxicity syndrome (ICANS) was noted in 28% (≥ grade 3: 5%) of EMD patients vs 32% (≥ grade 3: 9%) of non-EMD patients (p=0.72). Infections were seen in 39% of the EMD group vs 28% of the non-EMD group (p=0.38). Response rates were also similar between the EMD vs non EMD cohorts: ORR 78% vs 96% (p=0.44); and ≥CR rate 42% vs 51% (p=0.54), respectively. With a median follow up of 7.2 (range 0.5-22.8) months for the entire patient cohort, the estimated median PFS was inferior for the EMD group (6.5 months [95% CI, 5.1-9.6]) compared to the non-EMD group (9.8 months [95% CI, 8.2-16.4]) (p=0.017) (Figure 1). At the time of data cut-off, 43 patients had died, 77% from disease progression, 11.5% from CART-related complications and 11.5% from unrelated causes. The estimated median OS was significantly worse for the EMD group (12.9 months [95% CI, 9.5-NA]) compared to the non-EMD group (19.4 months [95% CI, 1.2-NA]) (p=0.031).
Conclusions: This is the largest multicenter retrospective study delineating the real-world outcomes of ide-cel and cilta-cel CAR T-cell therapies in RRMM patients with the high-risk disease feature of EMD. Based on our results, patients with prior history or presence of existing EMD at the time of CART infusion did not have any excessive treatment-related toxicities. However, these patients did experience shorter PFS and OS compared to patients without EMD highlighting the presence of EMD as a risk factor for poor outcomes after CART. Therefore, this group of patients should be considered for pre- and post-CART risk mitigation strategies aiming to prevent disease progression and improve survival outcomes.