Impact of T-Cell Redirecting Therapies on Survival Outcomes in Ultra-High-Risk Multiple Myeloma and Plasma Cell Leukemia
Authors: Elmaleh Hassan , Li Hong , Raza Shahzad , Mazzoni Sandra , Samaras Christy J. , Faiman Beth M. , Khouri Jack , Valent Jason , Anwer Faiz , Williams Louis S 
Published: December 2024

Background:
T-cell redirecting therapies (TR), including bispecific antibodies (BsAbs) and CAR-T cells, have shown efficacy in patients with multiple myeloma (MM) undergoing fourth-line or later treatments. However, patients with ultra-high-risk multiple myeloma (ultra-HRMM) and plasma cell leukemia (PCL) were largely excluded from pivotal clinical trials. This study aims to present response data and survival outcomes for a cohort of ultra-HRMM patients who received TR at the fourth line of treatment (Tx) or beyond.
Methods:
This retrospective study included patients with either PCL or at least two of the following cytogenetic abnormalities (CAs) at diagnosis: t(4;14), t(14;16), t(14;20), del(17p), del(1p32), and gain or amplification of 1q. Overall survival (OS) from TR or last Tx was evaluated using the Kaplan-Meier method and a Cox proportional hazards model. A total of 69 ultra-HRMM patients were identified, of which 30 received TR therapies, either CAR-T cells and/or BsAbs.
Results:
The cohort (n=69) had a median (IQR) age of 62.1 (57.5, 68.1) years at TR or last Tx. The median treatment time for the entire cohort was 26.9 months (17.2 months for the non-TR group vs 42 months for the TR group). Median lines of therapy in the overall population was 5 (3 in the non-TR group vs 7 in the TR group). Patients who received TR were more likely to have extramedullary disease (EMD) and less likely to have PCL. They also had lower levels of LDH and B2M at diagnosis. The most common CAs were gain/amp of 1q (67.2%), del17p (41.2%), and t(4;14) (26.5%). Among the TR group (n=30), 100% were triple-refractory and 36.7% were penta-refractory, compared to 75% and 7.7%, respectively, in the non-TR group (n=39). The median (IQR) prior lines of therapy at the time of first TR treatment were 7 (5, 8). Sixteen pts received CAR-T cells (8 cilta-cel, 8 ide-cel), 23 BsAbs, and 10 pts received multiple TRs. The overall response rate (ORR) to the first TR was 40% (VGPR-10%, CR-23%), with a median duration of response (DOR) of 6.5 months. Cytokine release syndrome (CRS) occurred in 82% of pts, and immune effector cell-associated neurotoxicity syndrome (ICANS) in 35%, predominantly low grade. A detailed follow-up analysis revealed a median (IQR) follow-up time from first Tx (at initial diagnosis) of 35.4 (14.7-59.5) months, and from TR or last Tx of 4.0 (1.8-8.5) months. OS from first Tx was significantly better in patients receiving TR after multiple lines of treatment compared to those not receiving TR (median OS: 65.0 vs 32.2 months; 3-year OS: 85.2% vs 41.3%, p log-rank=0.03).
In comparing OS from TR or last Tx, a crossing hazard pattern was observed. More deaths occurred within the first month in the TR group (1-month OS: 80.0% vs 94.7%), 5 of 6 in TR died within 1 month had ECOG 2 or higher at TR. Survival curves crossed around 3 months, showing better OS in the TR group: OS: 63.9%, vs 45.6% at 6-month and 40.7% vs 25.6% at 12-months. Among those who survived 1 month or longer after last Tx, patients with TR had significant better OS than without TR (Median OS: 13.1 vs 5.7 months, 12-month OS 50.8% vs 27.1%). After adjusting for age, ECOG and penta-refractory at last Tx, patients who did not have TR were more than 3 times likely died earlier (Adjusted HR, 95% CI: 3.3, 1.2-9.4). ECOG ≥2 (2.9, 1.3-6.6) and penta-refractory (2.7, 0.9, 8.0) were also associated with treatment failure in multivariate analysis. The overall median OS (95% CI) from the time of diagnosis was 51.8 months (34.5-63.4), while OS from last Tx or TR therapy was 6.3 months (4.3-8.5).
Conclusion:
These data demonstrate that TR therapies may improve overall survival in selected patients with ultra-HRMM and PCL treated as fourth line or later. Rates of CRS and ICANS in this population align with clinical trial populations and real-world data sets. Response rates and survival outcomes in this population appear to be numerically inferior to comparable outcomes in non-UHRMM. Limitations include the retrospective nature of the study, variations in the efficacy of different TR products, and the confounding bias of indolent disease phenotype in those receiving TR Careful patient selection with attention to performance status will play a role in optimizing these outcomes. Future prospective clinical trials should include more ultra-HRMM and PCL patients to thoroughly evaluate and optimize these treatment strategies, with consideration toward the delivery of TR therapies in earlier lines of treatment.