Andriy Derkach

B-cell maturation antigen (BCMA)– and G protein–coupled receptor class C group 5 member D (GPRC5D)–directed therapies have shown high efficacy in the treatment of relapsed or refractory multiple myeloma, with multiple new immune therapies now approved. Preclinical studies have shown that the expression of BCMA and GPRC5D is heterogeneous in malignant plasma cells. We conducted a phase 1 dose-escalation trial of the BCMA chimeric antigen receptor (CAR) T-cell therapy MCARH125 alone or in combination with the GPRC5D CAR T-cell therapy MCARH109 in patients with relapsed or refractory multiple myeloma. Patients were treated across 3 dose levels, with the primary objective of establishing the safety of concurrent infusion. We treated 15 patients across 3 dose levels, including 6 patients who received MCARH125 alone and 9 patients treated with the concurrent infusion of MCARH125 and MCARH109. One patient each with MCARH 125 alone and the coinfusion of MCARH125 and MCARH109 developed immune effector cell–associated hemophagocytic syndrome. There were no instances of grade ≥3 cytokine release syndrome or immune effector cell–associated neurologic syndrome. The overall response for coinfusion was 78%, with a median progression-free survival of 18.2 months. Correlative analysis suggests that antigen loss may be an important mechanism of resistance even with dual-antigen targeting, and we show, to our knowledge for the first time that expansion of 1 CAR population may limit expansion of the second population because patients treated with dual CARs had significantly less BCMA CAR expansion compared with patients treated with BCMA CAR alone, despite equivalent BCMA CAR T-cell doses at infusion. This trial was registered at www.clinicaltrials.gov as NCT05431608.

Although adults with Philadelphia chromosome-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL) may achieve a measurable residual disease-negative (MRD-) complete response (CR) after frontline treatment and blinatumomab (blina) consolidation, survival outcomes are heterogeneous, and known prognostic factors are limited. We conducted a retrospective, multicenter study of 81 adults with Ph+ B-ALL in MRD- (<10-4) CR1 after blina consolidation and stratified them by pre-blina MRD status as determined by multiparametric flow cytometry (flow). Patients who were pre-blina flow MRD- (n = 56) and flow MRD+ (n = 25) had similar baseline characteristics. With a median follow-up of 31.0 months, pre-blina flow MRD- patients had superior disease-free (DFS) and overall survival (OS) on univariate (p = 0.049 and p = 0.045, respectively) and multivariable analyses (HR 0.27, 95% CI 0.08-0.87 and HR 0.17, 95% CI 0.03-0.90, respectively) relative to pre-blina flow MRD+ patients. Inferior DFS was seen with the IKZF1-plus genotype (HR 3.51, 95% CI 1.08-11.44) and extramedullary disease at diagnosis (HR 3.90, 95% CI 1.19-12.73). In exploratory analyses, pre-blina flow MRD+ status remained associated with inferior DFS (p = 0.0005) and OS (p < 0.0001) for patients who did not receive a subsequent hematopoietic cell transplant (HCT) in CR1, but not in patients who did (p = 0.55 and p = 0.99, respectively). In summary, flow MRD+ status before blina consolidation was associated with inferior survival in patients with Ph+ B-ALL in CR1 despite subsequent clearance, and consolidative HCT may reduce this prognostic effect.

Thrombopoietin receptor agonists (TPO‐RAs), such as romiplostim, are commonly utilized to facilitate timely platelet recovery and administration of chemotherapy in patients with cancer and chemotherapy‐induced thrombocytopenia (CIT). However, there are limited data on the effect of TPO‐RAs on clinically important outcomes. A target trial emulation study was implemented to assess the effects of romiplostim in patients with solid tumors and persistent CIT, compared to controls. Patients were exact‐matched on chemotherapy, cancer type, degree of thrombocytopenia, and 1:1 propensity‐score‐matched on clinical/laboratory variables on Day 1 of romiplostim treatment or quasi‐index date for controls. Study outcomes included overall survival over 24 months and venous thromboembolism (VTE) at 6 months. This study included 165 romiplostim‐treated patients and 165 controls. Baseline characteristics were well‐balanced. The median age was 61 years and 52% were female. The median romiplostim duration was 1.38 months. Median overall survival was 13 months (95% CI: 9.9–23) in the romiplostim group and 9.5 months (95% CI: 7.1–14.0) in controls (hazard ratio [HR] 0.86 [95% CI: 0.65–1.13]). There was a numerical improvement in survival with romiplostim (0.80 [95% CI: 0.60–1.06]) which was statistically significant in the subgroup of patients with metastatic disease (HR 0.70 [95% CI: 0.52–0.95]). The 6‐month cumulative incidence of VTE was 10.0% (95% CI: 6.3%–16.0%) in the romiplostim group and 8.0% (95% CI: 4.5%–13.0%) in controls (HR 1.31 [95% CI: 0.64–2.70]), with death as a competing risk. In conclusion, these results support the safety of romiplostim in CIT with observed numerical improvement in overall survival at 2 years.

Bispecific antibody (BsAb) treatment in multiple myeloma can be associated with adverse events including cytokine release syndrome (CRS), cytopenias, and infections. While granulocyte colony-stimulating factors (G-CSF) can be used to treat neutropenia, little is known about their safety during the BsAb initiation period and whether G-CSF can increase the risk of CRS. To assess the impact of G-CSF on risk of CRS, we included all patients with multiple myeloma who received at least one dose (step-up doses [SUD] and first treatment dose [FTD]), of commercial teclistamab, elranatamab, or talquetamab between November 2022 and April 2024 at Memorial Sloan Kettering Cancer Center (N = 186). Exposure to G-CSF was defined as administration of at least one dose of filgrastim from 48 h before up to 7 days after BsAb SUD or FTD, or one dose of peg-filgrastim between 7 days prior to up to 7 days after BsAb SUD or FTD. Of the 186 patients, 22 were classified as G-CSF exposed. CRS occurred in 16/22 (73%) patients with G-CSF exposure vs 76/164 (46%) of non-exposed. All CRS was grade 1 (56%) or grade 2 (44%) and the majority occurred prior to G-CSF was given (16/22 patients). The median absolute neutrophil count (ANC) at time of G-CSF exposure was 0.5 × 10⁹/L (0.4-0.7). There was a trend towards increased risk of CRS after G-CSF exposure, although not significant (hazard ratio [HR] 1.7, 95% confidence interval [CI] 0.6-4.7, p = 0.3). These results suggest that G-CSF administration can be considered for neutropenia during BsAb initiation.

Nonimmune effector cell–associated neurotoxicity syndrome neurotoxicities (NINTs) are serious, atypical toxicities associated with ciltacabtagene autoleucel (cilta-cel), a US Food and Drug Administration chimeric antigen receptor T cell (CAR T cell) therapy approved for relapsed/refractory multiple myeloma (RRMM). Risk factors contributing to the development of NINTs are poorly understood. In a cohort of 109 patients with RRMM treated with cilta-cel, we identify predisposing risk factors and propose strategies to mitigate NINTs. We show that high-peak absolute lymphocyte count is a strong NINT predictor, which directly correlates with flow cytometry–based peripheral blood CAR T cell quantitation. The observed CAR lymphocytosis was polyclonal with a bias toward CD4 ⁺ CAR T cells rich in memory marker expression. We then identified CAR lymphocytosis–associated CD4 ⁺ CAR T cell populations, which exhibited increased inflammatory pathway gene expression. Last, we characterize NINT-associated CD4 ⁺ CAR T cell populations, which are potential therapeutic targets for future exploration.

Adolescents and young adults (AYA) with acute myeloid leukemia (AML) represent a biologically and clinically distinct population managed across pediatric and adult oncology services, with no established optimal treatment paradigm. In this single-center retrospective study, we analyzed 81 AYA patients aged 14-29 years with newly diagnosed AML treated at Memorial Sloan Kettering Cancer Center between 2010 and 2025. Patients were stratified by treating service, European LeukemiaNet (ELN) 2022 risk category, and induction regimen. Pediatric patients received two cycles of cytarabine, daunorubicin, and etoposide (ADE)-based induction, while adult patients received one cycle of cytarabine plus daunorubicin (7+3) induction-three of whom required 7+3 reinduction-followed by risk-adapted consolidation including allogeneic hematopoietic stem cell transplantation. Composite complete response rates were similar between adult and pediatric cohorts (79% vs. 78%), as were rates of MRD negativity by multicolor flow cytometry among responders (63% vs. 55%). Despite comparable depth of response, five-year overall survival favored adult-service patients in both the full cohort (77.9% vs. 56.7%) and the ELN 2022 intermediate-adverse risk subgroup (62.7% vs. 47.9%), while relapse-free survival was nearly identical. On multivariable analysis, ELN 2022 risk retained independent prognostic significance, whereas treatment protocol did not. These findings demonstrate that pediatric-style and adult AML regimens achieve comparable remission depth in AYA patients. The survival advantage observed with adult protocols challenges the assumption that further cytotoxic intensification improves outcomes in this population.