Prospective predictors of toxicity of BCMA‑directed CART therapy in multiple myeloma

Abstract

Abstract Background: Anti–B cell maturation antigen (BCMA) chimeric antigen receptor T cell (CART) therapy has become a standard for relapsed/refractory (R/R) multiple myeloma (MM), achieving unprecedented responses and durable remissions. However, CART is associated with unique and potentially life-threatening inflammatory toxicities, including cytokine release syndrome (CRS), immune cell-associated neurotoxicity syndrome (ICANS), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), as well as prolonged cytopenias and increased infection risk. While risk factors for these toxicities are established in lymphoma, often reflecting high tumor burden and pro-inflammatory status, their relevance in MM is unclear, and current evidence is largely limited to retrospective series. Identifying MM-specific predictors may inform patient selection, mitigate toxicity, and aid next-generation CART design. Methods: We included all patients with R/R MM enrolled in the NCT04720313 phase 1a/b study using the academic anti-BCMA CART product HBI0101 who received the target dose of 800×10⁶ CART cells. Patients had ≥3 prior therapy lines, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody. We evaluated the association between baseline patient and disease factors (prior to apheresis and bridging therapy) and CART toxicity outcomes, using univariate and multivariable (MV) models. We also evaluated the effect of CART product characteristics. “Any severe inflammatory toxicity” (SIT) was defined as CRS grade ≥3 or ICANS or IEC-HS of any grade. Secondary outcomes included early severe infections (≤30 days post-infusion) and persistent severe cytopenias (grade ≥3 neutropenia, anemia, or thrombocytopenia lasting or recurring >30 days). Results: We analyzed 119 patients (117 on study and 2 who received the same CART dose in a compassionate program). The median age was 65 years (range 35–84) and patients received median of 4 prior lines (range 3–13). Any SIT occurred in 25 patients (21%): CRS of grade ≥3 in 20 (17%), ICANS in 6 (5%), and IEC-HS in 6 (5%). SIT was strongly associated with baseline performance status; no events occurred in patients with ECOG 0 (0/23) versus 25/96 (26%) in those with ECOG 1/2 (Fisher p=0.003). In MV analysis, older age (odds ratio (OR)=1.17/year, 95% confidence interval (CI) 1.07–1.31, p<0.0001), hemoglobin <9 g/dL (OR=58.5, 95% CI 7–903, p<0.0001), and higher involved free light chain (FLC) levels (OR=1.002/mg/L, 95% CI 1.001–1.003, p=0.005) were also predictive of SIT. Interestingly, prior anti-BCMA therapy was inversely associated with SIT in MV analysis (OR=0.08, 95% CI 0.05–0.58, p=0.009), with only 2 SIT events occurring among 24 patients previously treated with anti-BCMA therapy (8%) compared with 23/95 (24%) without prior exposure (p=0.049). CD4/CD8 ratio in the CART product was also associated with SIT in univariate analysis (OR=1.43, 95% CI 1.07–2.39, p=0.01) and also MV models. The CAR-HEMATOTOX score in its original design (“high” vs. “low”) was not predictive of SIT, while its numeric sum trended toward significance in univariate (OR=1.36/point, 95% CI 0.99–1.89, p=0.053) but not in MV models. Early severe infections occurred in 14 patients (12%) and were associated with higher baseline beta-2 microglobulin (OR=1.53/mg/l, 95% CI 1.2–2.0, p=0.0004). Persistent severe cytopenias occurred in 16 patients (14%) and were associated with lower baseline platelet count (OR=0.98/10⁹/l, 95% CI 0.97–0.99, p=0.0003) and later CART peak (OR=1.12/day, 95% CI 1.004–2.9, p=0.04). Conclusion: ECOG >0, older age, anemia, and high involved FLC levels predicted severe inflammatory toxicities after anti-BCMA CART. Prior anti-BCMA therapy (mostly belantamab mafodotin in our cohort) appeared protective, an observation that may reflect differences in immune milieu or CART expansion kinetics and warrants further investigation. These predictors outperformed the CAR-HEMATOTOX score, and appear to have some similarities to what is known in lymphoma (burden of disease) but are not identical. This research supports the development of myeloma-specific CART toxicity risk tools to improve patient selection and management.