Efficacy of Idecabtagene Vicleucel (ide-cel) in Patients with Relapsed/Refractory Multiple Myeloma and Prior Central Nervous System Manifestation: A Retrospective Real-World Analysis
Authors: Maulhardt Markus , Berning Philipp , Hanoun Christine , Boyadzhiev Hristo , Albici Anca Maria , Janjetovic Snjezana , Ossami Saidy Anna , Call Simon , Schub Natalie , Aydilek Enver , Daskalakis Michael , Jung Wolfram , Hasenkamp Justin , Krekeler Carolin , Khandanpour Cyrus , Bacher Ulrike , Reinhardt Hans Christian , Lenz Georg , Stölzel Friedrich , Wulf Gerald , Pabst Thomas , von Tresckow Bastian , Shumilov Evgenii 
Published: December 2024

Introduction
Relapsed/refractory (r/r) multiple myeloma (MM) with central nervous system (CNS) manifestation represents a significant therapeutic challenge, characterized by a poor prognosis with a median overall survival (mOS) of two months (mo). Concurrently, BCMA-directed chimeric antigen receptor (CAR)-T cell therapies have emerged as a standard of care treatment in r/r MM. However, real-world evidence regarding the efficacy and safety profile of CAR-T cell therapy in MM patients (pts) with a history of CNS disease (MM-CNS) is limited, as these were excluded from the pivotal studies. We therefore evaluated the outcomes of MM-CNS pts undergoing ide-cel and compared them to MM pts without CNS disease (non-MM-CNS) in a real-world setting.
Methods
We conducted a multicenter retrospective study including r/r MM pts undergoing ide-cel treatment between March 2022 and May 2024 at seven German tertiary care centers. Pts were grouped by presence of CNS disease prior to ide-cel infusion.Only pts with intradural and/or intraparenchymal lesions or detection of myeloma cells in the cerebrospinal fluid (CSF) were regarded as MM-CNS pts. Subsequently, descriptive and survival analyses, including propensity score matching between MM-CNS and non-MM-CNS pts (nearest neighbor 1:1 matching with R-ISS stage, number of therapy lines, triple- and penta-class refractoriness, and remission status as co-variates) were performed.
Results
In total,we identified 153 r/r MM pts undergoing ide-cel therapy during the specified period. Seventeen (11%) pts met the criteria of CNS disease prior to CAR-T treatment. The median age for MM-CNS pts at CAR-T infusion and the median number of therapy lines prior to ide-cel was 62 years (range: 32-81 years) and 5 (range: 3-11), respectively. Penta-refractoriness was documented in 12 (71%) cases. CNS manifestation prior to ide-cel occurred in two pts (12%) at initial diagnosis, while the remaining cases (15/17; 88%) developed secondary CNS involvement during the disease course and after a median of three therapy lines. Median time from first CNS myeloma detection to CAR-T therapy was 10 mo. One pt experienced CNS manifestation after indication to ide-cel. CNS manifestations were parenchymal lesions (50%), leptomeningeal manifestations (44%) and/or central nerve lesions (31%). CNS myeloma was commonly detected by MRI (20%), CT (27%), or both (47%) as well as imaging plus CSF diagnostics (7%). Regarding CNS myeloma status immediately before CAR-T cell therapy and defined by imaging +/- CSF diagnostics, complete remission (CR) was achieved in 20%, partial remission (PR) in 27%, stable disease (SD) in 20% and 33% of pts presented with progressive disease (PD) at CAR-T application. Serologic response at ide-cel infusion showed CR and VGPR/PR in 31% of MM-CNS pts each, respectively, while 13% had SD and 25% PD at CAR-T treatment.
Best radiologic response for CNS manifestation following ide-cel treatment was CR (69%) followed by PR (23%) and SD (8%) while PD did not occur. The best serologic response was: CR (47%), VGPR/PR in (35%) and PD in 18%. Overall, seven (41%) pts experienced relapse post-CAR-T. Of these, two (12%) pts experienced relapse or progression of CNS disease after ide-cel, while the remaining five pts developed serologic progression. Cytokine-release syndrome (CRS) grade &gt;2 occurred in 19% (gr.3: 13%; gr.4: 6%). Notably, there were no cases of high-grade (3-4) immune effector cell-associated neurotoxicity syndrome (ICANS). With a median follow-up of 4.4 months, estimated median progression-free survival (mPFS) for MM-CNS pts was 10.5 mo while mOS was not reached; 1-year OS was 88%. Survival outcomes as well as serologic response rates were consistent after applying propensity score matching identifying a cohort of 17 pts without CNS myeloma undergoing ide-cel therapy: mPFS 10.5 vs. 8.5 mo (p=0.59), mOS 13 vs. 10.6 mo (p=0.92); CR/VGPR/PR rates 82% and 80%, for MM-CNS and non-MM-CNS pts, respectively.
Conclusions
We here report for the first time that CAR-T cell therapy is an effective and feasible treatment option in MM-CNS pts,showing comparable outcomes to those without a history of CNS myeloma. Our data showed a high remission rate for CNS manifestations after ide-cel treatment. Therefore, CAR-T cell therapy can be considered for eligible r/r MM patients with a history of CNS involvement.