Hansen, Doris K.

ABSTRACT Chimeric antigen receptor T-cell (CART) and T-cell engager (TCE) therapies targeting B-cell maturation antigen (BCMA) are transforming the treatment landscape for relapsed multiple myeloma (MM). However, despite impressive initial response rates, most patients eventually relapse. To investigate this unmet medical need, we applied whole-genome sequencing (WGS) to MM cells from cohorts of 102 relapsed patients treated with anti-BCMA CART and TCE therapies. Several genomic alterations were associated with clinical outcomes, particularly primary refractoriness, including high genomic complexity and mutations in genes regulating plasma cell identity, which predicted resistance to therapy. Single-cell RNA sequencing further revealed that MM cells from refractory patients exhibited high proliferation signatures and reduced expression of TNFRSF17 (encoding BCMA), while were less enriched for plasma cell–associated transcriptional programs, a phenomenon we term “plasma cell identity escape.” This profile was strongly associated with immune dysregulation of CD8 T cells including increased activation and exhaustion. This evolution of MM toward a more proliferative and lineage-divergent state, refractory to the anti-BCMA T-cell redirecting therapies, was functionally validated in preclinical MM mouse models. Collectively, our results comprehensively define the cellular and molecular mechanisms underlying primary resistance to anti-BCMA therapies.

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.

*Authors contributed equally. Introduction. Two chimeric antigen receptor (CAR) T-cell therapies have been FDA approved for patients with relapsed/refractory multiple myeloma (RRMM): idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). Prior work from our consortium identified racial and ethnic differences in safety and response to ide-cel among patients treated in the standard of care (SOC) setting; despite these differences, survival was similar across race and ethnicity. Here, we extend this work to investigate racial and ethnic differences in safety, efficacy, and outcomes in a larger cohort of patients treated with SOC ide-cel with longer follow-up and patients treated with SOC cilta-cel. Methods. Data for RRMM patients who underwent leukapheresis by 12/31/2022 and were treated with SOC ide-cel or cilta-cel were pooled across 19 institutions in the U.S. Multiple Myeloma Immunotherapy Consortium. We compared Non-Hispanic White, Non-Hispanic Black, and Hispanic (any race) patients, excluding other racial and ethnic groups due to small sample sizes that precluded sub-group investigations. Separately for each CAR T-cell therapy, racial and ethnic differences in baseline patient characteristics, safety, and treatment responses were examined using chi-square and Kruskal-Wallis rank sum tests. Kaplan-Meier survival curves and log-rank tests were used to examine progression-free survival (PFS) and overall survival (OS) by race and ethnicity. Results. Among 332 RRMM patients treated with ide-cel, Non-Hispanic Black and Hispanic patients comprised 17% and 10% of the cohort, respectively. Hispanic patients were younger at infusion compared to Non-Hispanic Black and Non-Hispanic White patients (55.5 vs. 63 vs. 66 years, p<0.001). Non-Hispanic Black patients had a higher disease burden (≥ 50% bone marrow plasma cell percentage) compared to Non-Hispanic White and Hispanic patients (35% vs. 20% vs. 19%, p=0.05), while a higher proportion of Non-Hispanic White patients had high-risk cytogenetics compared to Non-Hispanic Black and Hispanic patients (37% vs. 23% vs. 10%, p=0.003). Non-Hispanic Black patients were more likely to develop severe (≥ grade 3) cytopenia at day 30 (p<0.001) and day 90 (p=0.01) post-infusion, and these differences were particularly driven by higher rates of severe neutropenia among Non-Hispanic Black patients at these time points. Non-Hispanic White patients were more likely to achieve a best response of partial response (PR) or better (82%) compared to Non-Hispanic Black (75%) and Hispanic patients (63%, p=0.02). No other racial and ethnic differences in baseline patient characteristics (including cytopenias), safety, PFS, and OS were observed (p>0.05). Among 222 RRMM patients treated with cilta-cel, Non-Hispanic Black and Hispanic patients comprised 12% and 9% of the cohort, respectively. At baseline, Non-Hispanic Black and Hispanic patients were more likely to have anemia (p=0.01), and Non-Hispanic Black patients were more likely to have thrombocytopenia (p=0.02) and neutropenia (p=0.06) compared to Non-Hispanic White patients. No other differences in baseline patient characteristics were observed by race and ethnicity. While not statistically significant, a higher rate of severe (≥ grade 3) cytopenia at day 90 post-infusion was observed among Non-Hispanic Black and Hispanic patients compared to Non-Hispanic White patients (33% vs. 44% vs. 21%, p=0.07), similar to the ide-cel cohort. This finding was primarily driven by higher rates of severe neutropenia among Non-Hispanic Black patients and higher rates of anemia among Hispanic patients. No other racial and ethnic differences in safety, responses to cilta-cel, PFS, or OS were not observed in the cilta-cel cohort (p>0.05). Conclusion. In a large cohort of RRMM patients treated with SOC ide-cel or cilta-cel, we observed a higher rate of cytopenias post-infusion and inferior ide-cel responses among racial and ethnic minority patients compared to Non-Hispanic White patients. Despite these differences, survival was similar across race and ethnicity, suggesting that both available CAR T-cell therapies for RRMM patients can be utilized across all populations. Future studies that include larger patient cohorts of racially and ethnically diverse patients should be conducted to confirm these findings and additionally evaluate long-term outcomes.

Introduction. Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), two anti-B-cell maturation antigen (BCMA) CAR T therapies, have demonstrated remarkable responses and improved survival among patients with relapsed/refractory multiple myeloma (RRMM) in the clinical trials and standard of care (SOC) setting. Here, we compare safety, efficacy, and survival for patients treated with SOC ide-cel and cilta-cel. Methods. Data were from a retrospective chart review of RRMM patients leukapheresed by 12/31/2022 with the intent to receive SOC ide- or cilta-cel at 19 institutions in the US Multiple Myeloma Immunotherapy Consortium. An inverse probability of treatment weighting (IPTW) approach was used to compare outcomes by therapy type (cilta- vs. ide-cel), balancing on age, sex, race and ethnicity, performance status, extramedullary disease, high-risk cytogenetics, prior BCMA therapy, bone marrow plasma cells, penta-refractory status, lymphodepleting chemotherapy, baseline ferritin, low cell dose, and bridging therapy response. Logistic regression and Cox proportional hazard models were used to examine the association of treatment type with safety, efficacy, and survival accordingly, while adjusting for IPTW weights. We employed propensity score matching utilizing the same covariates to identify the association of treatment type with progression-free survival (PFS) within relevant patient sub-groups. Results. A total of 641 patients were leukapheresed by 12/31/2022 with ide-cel (n=386) and cilta-cel (n=255). 586 patients were infused (n=350 for ide-cel; n=236 for cilta-cel) with a median follow-up of 13.0 and 12.6 months, respectively. After IPTW, patient characteristics were well-balanced. Patients treated with cilta-cel were more likely to have grade ≥ 3 cytokine release syndrome (CRS) (OR=5.52, 95% CI=1.76-17.30, p=0.004), infections (OR=2.07, 95% CI=1.44-2.97, p<0.001), and delayed neurotoxicity (NT) (OR=20.97, 95% CI=4.75-92.42, p<0.001) compared to patients treated with ide-cel. In the cilta-cel cohort, 24 patients (10%) experienced delayed NT compared to 2 patients (1%) in the ide-cel cohort. Although not statistically significant, patients treated with cilta-cel were more likely to have any second primary malignancies (SPMs) (OR=1.87, 95% CI=0.94-3.71, p=0.08) and any SPMs excluding non-melanoma skin cancers (OR=1.78, 95% CI=0.78-4.10, p=0.2) but no association was observed for odds of hematologic SPMs (OR=0.98, 95% CI=0.26-3.61). No association was observed for therapy type with any or severe immune effector cell-associated neurotoxicity syndrome, any CRS, severe cytopenias, and non-relapse mortality. Compared to ide-cel, cilta-cel was associated with better treatment responses of ≥ complete response (OR=2.38, 95% CI=1.61-3.51, p<0.001) and ≥ partial response (OR=1.74, 95% CI=0.99-3.05, p=0.06). Patients treated with cilta-cel had a longer PFS and overall survival (OS) than ide-cel (HR=0.47, 95% CI=0.35-0.62, p<0.001 and HR=0.63, 95% CI=0.42-0.93, p=0.02, respectively), and these findings were similar in the intention to treat cohort (PFS: HR=0.44, 95% CI=0.34-0.55, p<0.001; OS: HR=0.55, 95% CI=0.41-0.73, p<0.001, respectively). We observed consistent findings when repeating the analyses restricting the ide-cel cohort to patients infused during the same time-period as FDA approval for cilta-cel (≥ March 2022), restricting to patients with data on all covariates, and restricting to sites that contributed data for both products. In a propensity matched population, (n=380; n=190 for cilta-cel and n=190 for ide-cel), patients treated with cilta-cel had superior PFS compared to those treated with ide-cel in most subgroups with respect to age and disease characteristics including extramedullary disease, high-risk cytogenetics, and elevated baseline ferritin (p<0.05). Conclusion. Our results suggest superior efficacy of cilta-cel with a higher incidence of certain toxicities compared to ide-cel in the SOC setting. This study provides valuable information for patient counseling and guiding the selection of CAR T-cell therapy for specific patient populations. Further validation through similar large-scale real-world experiences or prospective studies is needed to confirm our results and enhance applicability in the clinical setting. *DH, LP, & DD are co-first authors * YL, KP, & SS are co-last authors