Most patients with multiple myeloma experience disease relapse after treatment with a B-cell maturation antigen-targeted therapy (BCMA-TT), and data describing outcomes for patients treated with sequential BCMA-TT are limited. We analyzed clinical outcomes for patients infused with standard-of-care idecabtagene vicleucel, an anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, at 11 US medical centers. A total of 50 patients with prior BCMA-TT exposure (38 antibody-drug conjugate, 7 bispecific, 5 CAR T) and 153 patients with no prior BCMA-TT were infused with ide-cel, with a median follow-up duration of 4.5 and 6.0 months, respectively. Safety outcomes between cohorts were comparable. The prior BCMA-TT cohort had a lower overall response rate (74% versus 88%; p = 0.021), median duration of response (7.4 versus 9.6 months; p = 0.03), and median progression-free survival (3.2 months versus 9.0 months; p = 0.0002) compared to the cohort without prior BCMA-TT. All five patients who received a prior anti-BCMA CAR T responded to ide-cel, and survival outcomes were best for this subgroup. In conclusion, treatment with ide-cel yielded meaningful clinical responses in real-world patients exposed to a prior BCMA-TT, though response rates and durability were suboptimal compared to those not treated with a prior BCMA-TT.

Idecabtagene vicleucel (ide-cel) was FDA-approved in March 2021 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. On the KarMMa trial, grade ≥ 3 cytopenias and infections were common. We sought to characterize cytopenias and infections within 100 days after ide-cel in the standard-of-care (SOC) setting. This multi-center retrospective study included 52 patients who received SOC ide-cel; 47 reached day-90 follow-up. Data were censored at day 100. Grade ≥ 3 cytopenia was present among 65% of patients at day 30 and 40% of patients at day 90. Granulocyte colony stimulating factor (G-CSF) was administered to 88%, packed red blood cell transfusions to 63%, platelet transfusions to 42%, thrombopoietin (TPO) agonists to 21%, intravenous immunoglobulin to 13%, and CD34+ stem cell boosts to 8%. At day 100, 19% and 13% of patients had ongoing use of TPO agonists and G-CSF, respectively. Infections occurred in 54% of patients and were grade ≥ 3 in 23%. Earlier infections in the first 30 days were typically bacterial (68%) and severe (50%). Later infections between days 31 and 100 were 50% bacterial and 42% viral; only 13% were grade ≥ 3. On univariate analysis, high pre-CAR-T marrow myeloma burden (≥ 50%), circulating plasma cells at pre-lymphodepletion (LD), and grade ≥ 3 anemia at pre-LD were associated with grade ≥ 3 cytopenia at both days 30 and 90. Longer time from last bridging treatment to LD was the only significant risk factor for infection.

PURPOSE: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), two B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable efficacy in relapsed/refractory multiple myeloma (RRMM). We compare safety, efficacy, and survival among patients with RRMM treated with standard-of-care (SOC) ide-cel or cilta-cel. METHODS: Data were from a retrospective chart review of patients with RRMM leukapheresed by December 31, 2022, with the intent to receive SOC ide-cel or cilta-cel at 19 institutions. An inverse probability of treatment weighting (IPTW) approach was used to compare outcomes by therapy type. RESULTS: A total of 641 patients were leukapheresed by December 31, 2022, with ide-cel (n = 386) and cilta-cel (n = 255). Five hundred eighty-six patients were infused (n = 350 for ide-cel; n = 236 for cilta-cel) with a median follow-up of 12.6 and 13.0 months for ide-cel and cilta-cel, respectively. After IPTW, patient characteristics were well balanced. Cilta-cel was associated with higher likelihood of grade ≥3 cytokine release syndrome (CRS; odds ratio [OR], 6.80 [95% CI, 2.28 to 20.33]), infections (OR, 2.03 [95% CI, 1.41 to 2.92]), second primary malignancies (OR, 1.77 [95% CI, 0.89 to 3.56]), and delayed neurotoxicity (OR, 20.07 [95% CI, 4.46 to 90.20]). Cilta-cel was also associated with better treatment responses (≥complete response: OR, 2.42 [95% CI, 1.63 to 3.60]), longer progression-free survival (hazard ratio [HR], 0.48 [95% CI, 0.36 to 0.63]), and longer overall survival (HR, 0.67 [95% CI, 0.46 to 0.97]). No associations were observed between therapy type and immune effector cell–associated neurotoxicity syndrome, any CRS, severe cytopenia at days 30 and 90, or nonrelapse mortality. We observed consistent findings when repeating the analyses restricting the ide-cel cohort to patients infused during the same time period as Food and Drug Administration approval for cilta-cel (≥March 2022). CONCLUSION: Cilta-cel demonstrated superior efficacy and survival, with higher incidence of certain toxicities, compared with ide-cel.

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.

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