Outcomes after CAR T Cells in Multiple Myeloma Patients with Extramedullary and Paramedullary Disease
Authors: Pan Darren , Mouhieddine Tarek H. , Fu Weijia , Moshier Erin , Parekh Samir , Jagannath Sundar , Rossi Adriana C , Richter Joshua , Rodriguez Cesar , Sanchez Larysa J , Thibaud Santiago , Cho Hearn Jay , Richard Shambavi 
Published: December 2023

Background: Extramedullary disease (EMD) is a poor prognostic factor for multiple myeloma patients even in the era of novel therapies, while patients with paramedullary disease (PMD) have historically fared better. We sought to characterize EMD and PMD in the peri-CAR T period, assess their effects on outcomes after CAR T, and evaluate the ability of CAR T-cell therapy to clear EMD.

Methods: We retrospectively analyzed patients with relapsed/refractory multiple myeloma (RRMM) treated with CAR T-cell therapy in a clinical trial or with a commercially approved product at The Mount Sinai Hospital who had at least 3 months of follow-up. EMD was defined as the presence of soft tissue lesions not contiguous with bone and was quantified by measuring the sum of the product of the two longest perpendicular diameters (SPD) of each lesion. PMD was defined as the presence of soft tissue lesions contiguous with bone.

Results: A total of 134 patients received CAR T-cell therapy for RRMM between April 2017 and February 2023 and were followed for a median of 18.6 months, with 59 patients treated with ciltacabtagene autoleucel, 52 with idecabtagene vicleucel, and 23 with other products on clinical trials. Thirty-four patients (25.4%) had EMD at baseline (EMD+), while patients without EMD were further subdivided into those with PMD (PMD-only, 25 patients, 18.7%) and those with neither EMD nor PMD (75 patients, 56.0%). Among patients with measurable EMD, median SPD was 11.15 cm 2 (range 0.25-200.10 cm 2). Patients were heavily pretreated with triple-class refractory status present in 94.1% of EMD+ patients, 96.0% of PMD-only patients, and 74.7% of patients with neither.

Compared to patients with neither EMD nor PMD, PMD-only patients had similar PFS (HR 0.98, 95% CI 0.51-1.87) and OS (HR 1.34, 95% CI 0.48-3.76), while EMD+ patients exhibited significantly worse PFS (HR 1.87, 95% CI 1.13-3.09) and OS (HR 3.78, 95% CI 1.81-7.92). Overall response rates (ORR) were 76.5% in EMD+, 92.0% in PMD-only, and 88.0% in patients with neither. Among EMD+ patients, those with the highest tumor burdens (SPD ≥50 cm 2, n = 7) had ORR of 57.1% with no complete responses (3 PD, 3 PR, 1 VGPR). Conversely, EMD+ patients with SPD &lt;50 cm 2 (n = 27) had 81.5% ORR and deeper responses (66.7% complete response).

Of the 134 patients, 69 patients relapsed including 34 with EMD at relapse. Among the 34 patients with baseline EMD, 23 (67.6%) relapsed including 21 (61.8%) who relapsed with EMD. EMD was present in its prior location for 13 patients, while EMD cleared in prior locations and was present in new locations for 8 patients. Of 100 patients who had no EMD at baseline, only 13 (13.0%) relapsed with EMD. All patients with bulky EMD (SPD ≥50 cm 2) relapsed with EMD.

Among the 34 patients with EMD at relapse, 28 were assessed for MRD status in the bone marrow at the time of relapse, of which 12 (42.9%) remained MRD negative by next generation flow (sensitivity 10 -5). EMD post-BCMA CAR T was biopsied and stained for BCMA in 7 relapsing patients, of which 6 were BCMA positive and 1 was BCMA negative.

Conclusion: EMD is a well-recognized poor prognostic factor in multiple myeloma. In our single-center retrospective analysis, the presence of EMD but not PMD was associated with significantly worse PFS and OS following CAR T-cell therapy. EMD+ patients with SPD &lt;50 cm 2 experienced high response rates and deep responses following CAR T-cell therapy (with two-thirds of patients clearing EMD), while patients with the highest extramedullary tumor burdens (SPD ≥50 cm 2) did not. This shows the ability of CAR T-cell therapy to benefit patients in this high-risk group when extramedullary tumor burden is lower. We contend that controlling extramedullary sites of disease prior to CAR T-cell therapy with optimal bridging chemotherapy and/or radiation therapy may be an effective strategy for improving outcomes. Half of patients relapsing after CAR T-cell therapy had EMD, and the majority of patients with baseline EMD ultimately relapsed with EMD despite having been radiographically EMD negative following CAR T treatment. Finally, 42.9% of patients relapsing with EMD after CAR T-cell therapy remained MRD negative in the marrow, showing bone marrow MRD does not adequately represent overall disease control post-CAR T.