Anderson, Larry D

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 Improved understanding of how chimeric antigen receptor (CAR) and endogenous T‐cell phenotypes associate with progression‐free survival (PFS) is needed to individualize and improve immunotherapy outcomes in multiple myeloma (MM). We characterized and investigated the prognostic value of immune dynamics defined with multidimensional and computational flow cytometry in 258 bone marrow aspirates from 107 MM patients treated with idecabtagene vicleucel in the KarMMa trial. At screening, there was an association between longer PFS and increased percentages of PD1 + cytotoxic T cells and ICOS − TIGIT + Tregs. At Month 1 after infusion, the presence of >1% CAR‐T cells, a CD4/CD8 CAR‐T‐cell ratio >0.09, and greater abundance of non‐activated non‐cytolytic CAR‐T cells identified patients with longer PFS. Notably, 47 of the 115 endogenous T‐cell clusters were prognostic at the latest assessment performed after CAR‐T infusion. Lower percentages of ICOS + TIGIT − Tregs showed the strongest association with longer PFS. Altogether, this large dataset of dynamic immune profiling throughout treatment with anti‐B‐cell maturation antigen (anti‐BCMA) CAR‐T cells uncovered that the T‐cell composition prior to apheresis as well as CAR‐T and endogenous T‐cell phenotypes after infusion associates with PFS. These findings have potential for translation into routine laboratory practice for improved understanding of response and resistance to CAR‐T cells in relapsed/refractory MM.

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 Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), 2 B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell (CAR-T) therapies, have transformed outcomes for relapsed/refractory multiple myeloma; however, the 6 to 8 weeks manufacturing time risks disease progression or death in up to 10% of patients. Talquetamab, a G-protein–coupled receptor, family C, group 5, member D (GPRC5D)–targeting bispecific antibody, represents a promising option. We performed a multi-institutional retrospective analysis across 20 centers (18 United States, 2 Germany) evaluating talquetamab as a bridging therapy prior to cilta-cel or ide-cel. Among 134 patients receiving talquetamab, 119 proceeded to CAR-T (n = 98 cilta-cel, n = 21 ide-cel). Reasons for not proceeding (n = 15) included progression (n = 7), manufacturing failure (n = 6), or patient decision (n = 2). Median age was 65 years and had median 5 prior lines of therapy. Notably, 85% would not have met CARTITUDE-1/KarMMa eligibility criteria. Talquetamab was administered for a median 23 days. Toxicity was manageable: no grade ≥3 cytokine release syndrome (CRS), 2% grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS) and grade 1 to 2 talquetamab unique toxicities (70% oral, 38% skin, and 17% nail; 60% resolved). Talquetamab achieved 71% response rate. After CAR-T, 88% responded (54% complete response), with low-grade toxicities (2 grade ≥3 CRS, 1 grade 3 ICANS, and 5% grade ≥3 infections). Two cases of facial palsy and 1 acute myeloid leukemia occurred. Talquetamab correlated with sustained soluble BCMA decline and peak CAR-T expansion around day 14. Talquetamab bridging appears safe, enabling the majority of difficult-to-treat patients to successfully proceed to BCMA CAR-T therapy.

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

The NCCN Guidelines for Multiple Myeloma (MM) provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with MM. These NCCN Guidelines Insights highlight the important updates and changes specific to systemic therapy for patients with newly diagnosed as well as previously treated MM included in Version 1.2025 of the NCCN Guidelines for MM.

Abstract Outcomes of bispecific antibodies in patients with renal impairment (RI) are not well characterized, given the exclusion of these patients from clinical trials. Herein, we evaluated patients with relapsed/refractory multiple myeloma and RI treated with standard-of-care teclistamab. RI was defined as creatinine clearance (CrCl) <40 mL/min. CrCl <30 mL/min or dialysis dependence was defined as severe RI. Of the 384 included patients, 81 (21%) had RI, including 45 (18%) with severe RI, and 18 (5%) on dialysis. Patients with RI were more likely to be older (median age, 71 vs 67 years; P = .002) and have a higher median number of previous lines of therapy (7 vs 6; P = .04). Rates and severity of cytokine release syndrome (51% vs 59%; grade ≥3: 1.2% vs 1%) and immune effector cell–associated neurotoxicity syndrome (16% vs 13%; grade ≥3: 2.5% vs 2.6%) were similar in patients with and without RI, respectively. Patients with RI had higher baseline and day 30 post-teclistamab grade ≥3 anemia and grade ≥3 thrombocytopenia. Renal function did not worsen after teclistamab initiation in most patients with RI outside of the context of disease progression. Overall response rate (52% vs 56%; P = .61) and survival outcomes (median progression-free survival, 4.6 vs 6.5 months; P = .62) were comparable in patients with and without RI, respectively, after a median follow-up of 9.9 months. No differences in overall survival or non-relapse mortality were noted. Our findings suggest that treatment with teclistamab is feasible in patients with RI, including those on dialysis, with a similar safety and efficacy profile to patients without RI.