Influence of genomic and clinical high-risk features on outcomes after BCMA-directed bispecific antibody therapy in relapsed/refractory multiple myeloma.

Abstract

7534 Background: The definition of high-risk (HR) multiple myeloma (MM) is broad and encompasses established molecular features such as gain(1q) and del(17p), and the presence of extramedullary disease (EMD), plasma cell leukemia (PCL), and focal lesions (FLs), particularly when located in the humeri and femora. While the prognostic relevance of these factors has been widely studied, most data were generated in the pre–T-cell–redirecting therapy era. Their role in patients treated with bispecific antibodies (bsAb) remains poorly defined. Here, we investigated the prognostic value of FL and other high-risk features in relapsed/refractory (RR) MM patients receiving BCMA-directed bsAB therapy. Methods: We included 152 RRMM patients (59% male) with a median age of 72 years at bsAb initiation, and a median of 5 (2-12) prior lines of therapy. All patients received at least one full cycle of BCMA targeting bsAb therapy. Functional imaging (PET and/or DWI) was performed within 3 months of bsAb initiation. HR status was defined according to the IMS/IMWG consensus. Progression free (PFS) and overall survival (OS) were estimated using Kaplan Meier analysis. To address the combined impact of prognostic factors, we calculated conditional inference trees. Results: Patients with FLs involving the appendicular skeleton (humeri/femora/ribs/shoulders, n=85) showed a trend toward shorter median PFS (20 months, p=0.061) and significantly shorter median OS (20 months, p=0.01), compared to patients without FLs (n=54) or with FLs confined to the spine and/or pelvis (n=13, median PFS and OS not reached [NR]). EMD and PCL were observed in 41 (27%) and 10 (7%) patients, respectively. Patients with PCL had the poorest outcomes, with both median PFS and OS <2 months. EMD was also strongly prognostic, with significantly shorter PFS (11 vs 28 months) and OS (17 months vs NR) compared to patients without EMD. Similarly, HR disease as defined by IMS/IMWG criteria was associated with worse outcomes (PFS 14 months, OS 19 months). Conditional inference tree analyses for PFS identified PCL, EMD and del(17p) as the most relevant prognostic variables. For OS, PCL again emerged as the strongest predictor, whereas EMD was only prognostic in the presence of gain(1q). Notably, gain(1q) also modified the impact of other clinical parameters: both a higher number of prior therapy lines (>5) and prior BCMA exposure were prognostic only in patients without gain(1q). Conclusions: Here, we show that EMD, PCL, and FLs of the appendicular skeleton are associated with inferior outcomes in RRMM patients treated with BCMA-directed bsAbs. Notably, the prognostic impact of these tumor growth patterns appears to be strongly influenced by the presence of genomic HR features, underscoring the central role of chromosomal aberrations as key modifiers of clinical risk even in the era of T-cell–redirecting immunotherapies.