Activity of CAR-T Cells and Bispecific Antibodies in Multiple Myeloma with Extramedullary Involvement
Authors: Steinhardt Maximilian J. , Schaefers Christoph , Leypoldt Lisa , Harzer Marie , Zhou Xiang , Riedhammer Christine , Kamili Abdulaziz , Kosch Ricardo , Arztenroth Jule , Al-Bazaz Maximilian , Alsdorf Winfried , Topp Max S. , Duell Johannes , Mersi Julia , Waldschmidt Johannes , Bokemeyer Carsten , Einsele Hermann , Kortüm K. Martin , Weisel Katja C. , Rasche Leo 
Published: December 2024

Background
Extramedullary disease (EMD) represents an aggressive variant of multiple myeloma (MM) associated with low response rates to conventional myeloma therapies, short progression-free survival (PFS) and high mortality. While CAR T cells and bispecific antibodies (bsABs) provide new opportunities in patients with relapsed/refractory MM (RRMM), their use in EMD is less clear. Furthermore, it remains uncertain whether one strategy is superior to the other in the setting of EMD and should therefore be preferred.
Methods
We retrospectively collected data of patients with EMD not adjacent to the bone treated with bsABs or CAR T cell therapies from two academic centers in Germany from 09/21 to 07/24. All patients had both serological assessment and EMD imaging prior to therapy initiation and follow-up after at least three months or at the point of progression. We analyzed demographics, outcomes, cytogenetics, and prior therapies.
Results
We enrolled all 78 RRMM patients with EMD treated with either cilta-cel (n=11), ide-cel (n=21), talquetamab (n=27), and teclistamab (n=18). Muscle (38%), skin (33%), pleural (30%) and retroperitoneal manifestations (22%) were the most common EMD localizations, and the median follow-up was 4.6 months.
The four cohorts were comparable with a median of 5 to 7 prior lines of therapy. EMD was diagnosed 2.5-4 years after MM diagnosis. All patients were triple-refractory and more than 64% were penta-refractory in each cohort. The population was enriched for high-risk cytogenetics (&gt;41% of patients with available FISH over all cohorts). The majority of CAR T cell patients received bridging therapy. Response to bridging therapy was not associated to PFS and 41/36% had extramedullary or serologic progressive disease at the time of cilta-cel or ide-cel cell infusion, respectively. The vast majority of patients receiving cilta-cel, ide-cel or teclistamab were BCMA-naive (&gt;91% in each cohort).
EMD response rates of patients receiving CAR T cells were significantly higher (93% for cilta-cel, 82% for ide-cel) than with bsABs (47% for talquetamab, 38% for teclistamab, p&lt;0.0001). Complete resolution of EMD was also significantly more frequent after CAR T cell therapies (50% and 41%) than after bsABs (16% and 14%, p=0.001). Median PFS was not reached in patients after cilta-cel and significantly longer in ide-cel with 11.2 months when compared to talquetamab and teclistamab (3.2 and 2.8 months, p=0.03). OS was not reached for patients receiving cilta-cel, 24.6 months for ide-cel, 18.4 months for teclistamab, and 15.1 months for Talquetamab (ns).
Serologic response ≥PR in patients with measurable serologic activity predicted EMD response (p&lt;0.0001).
Independent of treatment, visceral and soft tissue manifestations responded significantly less frequent than skin, mucosal, and lymph node lesions (p=0.02).
Conclusion
Both CAR T cells and bsABs show efficacy in EMD. However, CAR T cells appear to be superior to bsABs in this setting. With significantly higher response rates, deeper remissions and longer median PFS in our analysis, CAR T cells may provide a meaningful benefit in EMD and should be considered preferentially.