De Menezes Silva Corraes, Andre

Patients with plasma cell leukemia (PCL) are generally excluded from pivotal T-cell redirecting bispecific antibody (BsAb) trials. We evaluated real-world outcomes in a multicenter retrospective study of 122 patients with primary or secondary PCL across 15 academic centers, categorized as 'active' (≥5% circulating plasma cells within 30 days of BsAb initiation) or 'historical'. In a heavily pretreated population, patients received teclistamab (37%), elranatamab (11%), talquetamab as a line of therapy (Tal LOT, 42%), or talquetamab as bridging therapy to CAR-T (Tal Bridge, 11%). Cytokine release syndrome (CRS) was grade 1-2 in 56% and grade 3-4 in 4%, whereas neurotoxicity was grade 1-2 in 16% and grade 3-4 in 5%. Among 110 evaluable patients, the overall response rate (ORR) was 55%, including 61% with Tal LOT, 58% with Tal Bridge, 46% with elranatamab, and 33% with teclistamab. With a median follow-up of 8.3 months, talquetamab demonstrated superior survival. Tal LOT showed a median progression-free survival (mPFS) of 5.5 months and a median overall survival (mOS) of 11.5 months, and both were unreached in the Tal Bridge cohort. In contrast, teclistamab and elranatamab showed a mPFS of 1.2 and 1.6 months and mOS of 8.1 and 3.6 months, respectively (P=0.007, P=0.023). In active PCL, Tal LOT achieved mPFS/mOS of 6.9/12.2 months versus 0.7/1.4 months with teclistamab and 1.0/3.1 months with elranatamab, respectively (P<0.001, P=0.002). Multivariable analysis associated active PCL with worse survival and Tal LOT with improved outcomes. BsAbs were safe in PCL, with talquetamab showing superior outcomes compared with BCMA-directed BsAbs.

Abstract Immune effector cell–associated enterocolitis (IEC-EC) has been observed after ciltacabtagene autoleucel (cilta-cel [Carvykti]) chimeric antigen receptor T-cell (CAR-T) therapy. It is associated with dismal outcomes and is poorly characterized. Here, we examined its clinical features, risk factors, and proposed management strategies. Among the 229 consecutive patients who received cilta-cel at Mayo Clinic, 9 (3.9%) presented with a nonresolving, nonbloody, grade 3 diarrhea, often requiring prolonged total parenteral nutrition. Gastrointestinal coinfections were seen in most patients. Median time from CAR-T infusion to symptom onset was 85 days (range, 35-166), and there appeared to be a latency from symptom onset to endoscopic evaluation. Histopathology findings resembling a graft-versus-host disease pattern of mucosal injury were most seen on duodenal biopsies, whereas 2 cases had patterns akin to a T-cell lymphoproliferative disorder (1 CD4+ and 1 CD8+). Independent associated factors for IEC-EC included high-risk disease as defined by the International Myeloma Society and International Myeloma Working Group, prolonged cytokine release syndrome, and antecedent delayed neurotoxicity. Response to first-line therapy comprising IV or oral corticosteroids, bile acid sequestrants, IV immunoglobulin, and antimicrobial-directed therapy was poor, with no durable responses. Biologic therapy appeared to induce durable responses in 3 of the 5 patients (2/2 vedolizumab; 1/3 infliximab); none of the responders had gastrointestinal coinfection. Early gastroenterology input for endoscopic evaluation with the inclusion of duodenal biopsy is a key component for diagnosis. Early institution of biologic therapy after failure of a short course of corticosteroids should be considered.

Abstract Despite significant therapeutic advances in multiple myeloma (MM), outcomes in patients with plasma cell leukemia (PCL) remain dismal. We conducted a multicenter retrospective analysis of patients with PCL who were treated with the B-cell maturation antigen–directed chimeric antigen receptor T-cell (CAR-T) products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). We identified 34 patients; 19 patients received ide-cel and 15 received cilta-cel. With a median follow-up of 11.9 months, the overall median progression-free survival (mPFS) was 9.0 months (95% confidence interval [CI], 4-15) and the median overall survival (mOS) was 13.0 months (95% CI, 8 to not estimable [NE]). The 1-year cumulative incidence of progression or death was 72%, and the 1-year cumulative incidence of death was 47%. Patients who received cilta-cel had a longer mPFS (19.0 months vs 6.0 months) and mOS (>23 months [NE] vs 9.0 months) when compared with those treated with ide-cel. Similarly, the 1-year cumulative incidence of disease progression or death was 37.5% (95% CI, 17.4-68.5) with cilta-cel, whereas all patients treated with ide-cel progressed or died within 12 months of infusion. The rates of hematologic and nonhematologic toxicities were similar between patients treated with cilta-cel and those treated with ide-cel and were consistent with those reported in patients with MM. In this first multicenter study that evaluated patients with PCL who were treated with standard-of-care CAR-T products, we show that CAR-T is safe, feasible, and associated with improved outcomes when compared with historic standards.

Abstract Teclistamab is an anti-CD3-/B-cell maturation antigen (BCMA) bispecific antibody approved for use in relapsed/refractory multiple myeloma. We undertook a retrospective study of post-approval, real-world outcomes with teclistamab in the US Multiple Myeloma Immunotherapy Consortium. Among 509 patients, 89% would have been ineligible for the MajesTEC-1 trial, primarily due to prior BCMA-directed therapy, cytopenias, or diminished performance status. Cytokine release syndrome occurred in 54% (1.4% grade ≥3) and immune effector cell–associated neurotoxicity syndrome in 11% (2.2% grade ≥3), with no fatal events. Infections occurred in 42% and contributed to death in 5%. Partial response (PR) or better was achieved in 53% and very good PR or better in 45%. With 10.1 months of median follow-up, the estimated median progression-free survival (PFS) was 5.8 months and 12-month overall survival was 61%. Independent predictors of less than very good PR and shorter PFS included BCMA-directed chimeric antigen receptor T-cell therapy in the previous 9 months, high disease burden, lymphopenia, and elevated ferritin. Significance: T cell–engaging bispecific antibodies such as teclistamab represent an important new treatment modality for multiple myeloma and other blood cancers. This study evaluates the real-world safety and efficacy of teclistamab, including its activity in populations not represented in the initial phase I/II study, and identifies clinical variables associated with treatment response. See related commentary by Zweegman et al., p. 542