Achieved Minimal Residual Disease Negativity Research Articles

Acalabrutinib plus venetoclax and rituximab in treatment-naive mantle cell lymphoma: 2-year safety and efficacy analysis

This phase 1b study (NCT02717624) evaluated the safety and efficacy of acalabrutinib, venetoclax, and rituximab (AVR) in treatment-naive mantle cell lymphoma (TN MCL). Patients received acalabrutinib from cycle 1 until progressive disease or undue toxicity, rituximab for 6 cycles with maintenance every other cycle through cycle 24 or until progressive disease, and venetoclax, beginning at cycle 2, for 24 cycles. Twenty-one patients were enrolled, 95.2% completed induction (6 AVR cycles), and 47.6% continued maintenance with acalabrutinib. Thirteen (61.9%) patients had grade 3-4 adverse events (AEs), most commonly neutropenia (33.3%). Seven (33.3%) patients had COVID-19 infection (6 [28.6%] serious AEs; 5 [23.8%] deaths, all among unvaccinated patients). There were no grade ≥ 3 events of atrial fibrillation, ventricular tachyarrhythmias, major hemorrhages, or tumor lysis syndrome. Overall response rate (ORR) by Lugano criteria was 100% (95% confidence interval [CI]: 83.9, 100.0) with 71.4% complete response (CR). With median follow-up of 27.8 months, median progression-free survival (PFS) and overall survival (OS) were not reached. PFS rates at 1 and 2 years were 90.5% (95% CI: 67.0, 97.5) and 63.2% (34.7, 82.0), respectively; both were 95% after censoring COVID-19 deaths. OS rates at 1 and 2 years were 95.2% (95% CI: 70.7, 99.3) and 75.2% (50.3, 88.9), respectively; both were 100% after censoring COVID-19 deaths. Overall, 87.5% of patients with available minimal residual disease (MRD) data achieved MRD negativity (10-6; next-generation sequencing) during treatment. AVR represents a chemotherapy-free regimen for TN MCL and resulted in high ORR and high rates of MRD negativity.

Real-world evidence on treatment pattern, effectiveness, and safety of blinatumomab in Chinese patients with B-cell acute lymphoblastic leukemia.

Blinatumomab is efficacious in patients with B-cell acute lymphoblastic leukemia (B-ALL), yet limited real-world data exists in this context. This retrospective study provided real-world data on the treatment pattern, effectiveness, and safety of blinatumomab in Chinese patients with newly diagnosed (ND) and relapsed/refractory (R/R) B-ALL. Patients with B-ALL who received at least one dose of blinatumomab in frontline or R/R settings between August 2021 and June 2023 were included. The primary outcome was the treatment pattern of blinatumomab. Key secondary outcomes included complete remission (CR)/CR with incomplete blood cell recovery (CRi) rate, minimal residual disease (MRD) negativity, median event-free survival (EFS), and safety. The study included 96 patients with B-ALL; 53 (55.2%) patients were in the ND group and 43 (44.8%) patients were in the R/R group. The median treatment duration was one cycle (range: 1-5). Most patients underwent chemotherapies, allo-HSCT, or experimental CAR-T following blinatumomab. The ND patients using blinatumomab induction therapy achieved 100% CR/CRi rate; 87.2% achieved MRD negativity within two cycles of blinatumomab. In R/R re-induction patients, the CR/CRi rate was 50%; MRD negativity rate was 64.2%. In R/R patients using blinatumomab for consolidation, MRD negativity rate was 90.9%. The median EFS was not reached in both ND and R/R patients; 1-year EFS rate was 90.8% (95% CI: 67%, 97%) and 55.1% (95% CI: 30%, 74%), respectively. Grade ≥ 3 adverse events were observed in 12.5% patients. Blinatumomab was found to be effective with a tolerable safety profile in real world setting.

Real-world advantage and challenge of post-autologous stem cell transplantation MRD negativity in high-risk patients with double-hit multiple myeloma

BackgroundAutologous stem-cell transplantation (ASCT) remains a beneficial approach for patients with newly diagnosed multiple myeloma (NDMM) in the age of novel therapeutic agents. Nevertheless, limited real-world data is available to establish criteria for identifying high-risk ASCT patients.MethodsWe analyzed outcomes for 168 NDMM patients who underwent ASCT at our center from December 2015 to December 2022. We investigated the impact of the number of high-risk cytogenetics (HRCA), defined as t(4;14), t(14;16), 1q21 gain/amplification, and del(17p), as well as the post-ASCT minimal residual disease (MRD) status as prognostic indicators. We assessed progression-free survival (PFS) and overall survival (OS), and focused on identifying risk factors.ResultsThe cohort included 42% of patients (n = 71) with 0 HRCA, 42% (n = 71) with 1 HRCA, and 16% (n = 26) with ≥ 2 HRCA. After a median follow-up of 31 months, the median PFS was 53 months (95% CI, 37–69), and OS was not reached for the entire cohort. Despite similar rates of MRD-negativity post-ASCT, patients with ≥ 2 HRCA, termed “double hit” (DH), had a significantly higher risk of progression/mortality than those with 0 or 1 HRCA. Multivariate analysis highlighted DH (HR 4.103, 95% CI, 2.046–8.231) and MRD positivity post-ASCT (HR 6.557, 95% CI, 3.217–13.366) as adverse prognostic factors for PFS, with DH also linked to inferior OS. As anticipated, DH patients with post-ASCT MRD positivity displayed the poorest prognosis, with a median PFS of 7 months post-ASCT. Meanwhile, DH patients with MRD negativity post-ASCT showed improved prognosis, akin to MRD-negative non-DH patients. It is noteworthy to exercise caution, as DH patients who initially achieved MRD negativity experienced a 41% cumulative loss of that status within one year.ConclusionsThis study strongly advocates integrating DH genetic assessments for eligible ASCT patients and emphasizes the importance of ongoing MRD monitoring, as well as considering MRD-based treatment adaptation for those patients in real-world settings.

Abstract 5071: Minimal residual disease (MRD) status by peripheral blood mononuclear cells (PBMCs) and circulating tumor DNA (ctDNA) demonstrates rapid, deep, and sustained response in patients (Pts) with relapsed/refractory follicular lymphoma (R/R FL) treated with subcutaneous (SC) epcoritamab monotherapy in the pivotal phase 1/2 EPCORE™ NHL-1 trial

Abstract Introduction: Outcomes in high-risk R/R FL are poor. Epcoritamab SC, a CD3xCD20 bispecific antibody, demonstrated promising efficacy with a manageable safety profile in pts with R/R FL after ≥2 prior lines of therapy (phase 1/2 EPCORE NHL-1; NCT03625037). Here we evaluated MRD with PBMCs and ctDNA in pts with R/R FL and correlated the results with clinical findings. Methods: Adults with R/R FL 1-3A enrolled in EPCORE NHL-1 received epcoritamab SC in 28-day cycles. MRD analysis was performed on longitudinal plasma and PBMC samples collected at prespecified timepoints (clonoSEQ assay, Adaptive Biotechnologies). Screening tumor biopsies were used to identify trackable tumor clones; samples were quantified as tumor clones detected per mL plasma for ctDNA and per one million nucleated cells for PBMC. Overall response and progression-free survival (PFS) were assessed using Lugano criteria by independent review committee. Results: Of 128 pts in the R/R FL 1-3A cohort, 91 with PBMC data and 100 with ctDNA data were MRD evaluable. Overall MRD negativity was achieved in 67.0% [95% CI: 56.4-76.5] of pts per PBMC and 68.0% [95% CI: 57.9-77.0] of pts per ctDNA. Concordance of subject-level MRD status was high (79 of 89 with PBMC and ctDNA data; 88.8%). In most pts, MRD negativity was reached prior to radiographic complete response (PBMC, 76.4%; ctDNA 58.5%). MRD negativity by PBMC preceded ctDNA (median days to MRD negativity, 28 [PBMC] vs 57 [ctDNA]), suggesting a difference in methodology in detecting tumor DNA. Pts who became MRD negative had prolonged PFS (median not reached). Baseline MRD levels were not associated with clinical outcomes (PBMC; Wilcoxon P=0.59, ctDNA P=0.39). PFS was similar in pts achieving MRD negative status (median not reached, PBMC and ctDNA), independent of high-risk/difficult-to-treat disease (≥4 prior lines, Ann Arbor stage III-IV, bulky disease, double refractory, FLIPI 3-5, and POD24). The overall MRD negativity rate was also similar in high-risk pts, except those with ≥4 prior lines of therapy. Conclusions: Based on the EPCORE-NHL-1 study, one of the first pivotal studies to report MRD in pts with R/R FL, epcoritamab drives rapid, deep, and sustained responses as supported by MRD assessment by both PBMC and ctDNA. MRD results correlate with clinical outcome, and achieving MRD negativity is associated with longer PFS. PFS was similar among all pts who achieved MRD negativity, including those with high-risk disease. Citation Format: David Soong, Işıl Altıntaş, John Karavitis, Kim M. Linton, Wojciech Jurczak, Catherine Thieblemont, Kevin Zhao, Edith Szafer-Glusman, Daniela Hoehn, Elena Favaro, Mariana Sacchi, Maria Jure-Kunkel. Minimal residual disease (MRD) status by peripheral blood mononuclear cells (PBMCs) and circulating tumor DNA (ctDNA) demonstrates rapid, deep, and sustained response in patients (Pts) with relapsed/refractory follicular lymphoma (R/R FL) treated with subcutaneous (SC) epcoritamab monotherapy in the pivotal phase 1/2 EPCORE™ NHL-1 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5071.

Real-world prognostic significance of attaining minimal residual disease negativity in newly diagnosed multiple myeloma

The aim of the study was to evaluate the prognostic impact of minimal residual disease (MRD) in the real-world setting and the interaction between MRD and molecular risk, clinical response and autologous stem-cell transplant (ASCT). A retrospective analysis of 275 newly diagnosed multiple myeloma (NDMM) patients who achieved very good partial remission (VGPR) or better before maintenance were involved. We examined MRD status by multiparameter flow cytometry (MFC). At a median follow-up of 37 months (4–88 months), In patients who achieved ≥ VGPR, those with MRD negativity had significantly longer PFS (51 vs. 26 months; P < 0.001) and OS (Not reached: NR vs. 62 months, P < 0.001) than those with MRD positivity. MRD positivity was the independent prognostic factor for PFS with hazard ratios of 2.650 (95% CI 1.755–4.033, P < 0.001) and OS with hazard ratios of 2.122 (95% CI 1.155–3.899, P = 0.015). Achieving MRD negativity was able to ameliorate a poor prognosis associated with genetic high risk. MRD negativity was associated with better PFS regardless of ASCT treatment. MRD status was more predictable for clinical outcome than conventional clinical responses. Moreover, Sustained MRD negativity ≥ 12 or ≥ 24 months improved both PFS and OS. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes regardless of high-risk cytogenetics, ASCT and clinical responses in a real-world setting.

Role of minimal residual disease assessment in multiple myeloma.

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells. MM is a heterogeneous disease, featured by various molecular subtypes with different outcomes. With the advent of very efficient therapies including monoclonal antibodies, bispecific T cell engagers and chimeric antigen receptor T cells (CAR T cells), most of MM patients have now a prolonged survival. However, the disease remains incurable, and a subgroup of high-risk patients continue to have early relapse and short survival. Novel and highly sensitive methods have been developed allowing to detect minimal residual disease (MRD) during or after treatment. Achievement of MRD negativity is a strong and independent prognosis factor in both prospective randomized clinical trials and in real-world setting. While MRD assessment is now a validated endpoint in clinical trials, its incorporation in clinical practice is not yet established and its potential impact on guiding therapy remains under deep evaluation. We discuss in this chapter, the different available methods allowing MRD assessment and the role of MRD evaluation in multiple myeloma management.

Efficacy Outcomes and Characteristics of Patients with Multiple Myeloma (MM) Who Achieved Sustained Minimal Residual Disease Negativity after Treatment with Equecabtagene Autoleucel (Eque-cel, CT103A) in Fumanba-1

Background: Equecabtagene autoleucel (eque-cel, CT103A), which is designed with a fully human BCMA-specific CAR structure, was recently granted NMPA approval for the treatment of adult patients (pts) with relapsed/refractory multiple myeloma (RRMM) after ≥3 prior lines of therapy (LOT). The pivotal phase 2 FUMANBA-1 study (NCT05066646) demonstrated deep and durable responses with eque-cel in heavily pretreated patients with RRMM. Recent studies have demonstrated the utility of minimal residual disease (MRD) as a prognostic biomarker for long-term outcomes of RRMM, wherein achievement of sustained MRD-negative status was associated with an improvement in PFS of pts treated by eque-cel in FUMANBA-1 study. We sought to characterize the baseline and disease characteristics of pts with sustained MRD negativity (pts who continued to remain MRD negative ≥6 mo and ≥12 mo). Methods: FUMANBA-1 study enrolled RRMM pts who received ≥ 3 lines of prior therapies containing at least a proteasome inhibitor and an immunomodulatory agent and were refractory to their last line of treatment. All pts received a single infusion of eque-cel at the dose of 1.0 x 10 6 CAR-T cells/Kg. Pts who had progressed on previous BCMA CAR-T cell therapy were not included in this analysis. The primary endpoint was ORR. Additional endpoints included ≥CR rate (key secondary), DOR, PFS, and safety. ORR and CR were assessed per IMWG criteria; DOR and PFS were analyzed via Kaplan-Meier methods. MRD negativity was a secondary objective and was assessed on bone marrow samples at baseline; day 14, 28; and 2, 3, 6, 9, 12, 15, 18, 21 and 24 mo using EuroFlow next-generation flow, regardless of disease status. Evaluable samples passed calibration and quality control and included sufficient cells for evaluation at 10 -5 testing threshold. Characteristics were analyzed in pts who had MRD negativity &amp;lt;6 mo, or sustained ≥6 mo and ≥12 mo. Pts who did not achieve MRD negativity at any time point were considered to be MRD positive. Results: Of the 88 pts who achieved MRD negativity in FUMANBA-1, 74 had at least 6 mo follow up without progression after initial MRD-negativity and 43 had at least 12 mo follow up without progression after initial MRD-negativity. MRD negativity was sustained for ≥6 mo in 78.4% (58 of 74 with at least 6 mo follow-up without progression after initial MRD-negativity) and ≥12 mo in 74.4% (32 of 43 with at least 12 mo follow-up without progression after initial MRD-negativity; 7 pts evaluable for sustained MRD at ≥6 mo but not ≥12 mo had PD). Pts with sustained MRD negativity (≥6 mo, and ≥12 mo) had longer progression free survival (PFS; Figure 1A) compared with pts who did not (MRD negative &amp;lt;6 mo). Key pt and disease characteristics in these different groups (Figure 1B), and potential associations with sustained MRD negativity were analyzed descriptively. Baseline R-ISS disease stage III was more common in pts with MRD sustained for ≥6 mo (8.6%) and ≥12 mo (9.4%) compared with pts who had MRD negativity &amp;lt;6 mo (3.3%). Baseline high tumor burden diseases were less common in pts with MRD sustained for ≥6 mo (70.7%) and ≥12 mo (65.6%) compared with pts who had MRD negativity &amp;lt;6 mo (90%). Triple-class exposure was also less common in pts with MRD sustained for ≥6 mo (12.1%) and ≥12 mo (12.5%) compared with pts who had MRD negativity &amp;lt;6 mo (30%). Pts with sustained MRD negativity had trends toward shorter median time since diagnosis (38.6 mo and 40.2 mo for pts with MRD negativity sustained ≥6 and ≥12 mo, respectively versus 43.5 mo for those with MRD negativity &amp;lt;6 mo). Other baseline characteristics, including presence of high-risk cytogenetics, ECOG performance status, extramedullary disease and number of prior LOT did not differ across MRD subgroups, and were similar to the overall FUMANBA-1 population. Conclusions: Based on our descriptive analysis, pts receiving eque-cel achieved MRD negativity irrespective of their high-risk cytogenetics, extramedullary disease, number of prior LOT and performance status. Presence of high tumor burden at baseline, and prior triple-class exposure might be factors that impact achievement of sustained MRD negativity. These data suggest that while eque-cel is effective for a broad range of pts, specific pt and disease characteristics may be associated with sustained MRD negativity and better long-term outcomes. Sustained MRD negativity might be a promising prognostic indicator for RRMM pts treated by eque-cel.

Blinatumomab Therapy for Low Level Minimal Residual Disease Detected By Next-Generation Sequencing in Adult B-Cell Acute Lymphoblastic Leukemia

Introduction: Blinatumomab, a bi-specific T-cell engager, has shown clinical benefit in patients with relapsed-refractory and hematologic complete remission with minimal residual disease (MRD)-positive Acute Lymphoblastic Leukemia (ALL). The BLAST trial (Gökbuget N et al., Blood. 2018) demonstrated improved overall survival (OS) and disease-free survival (DFS) in patients with MRD-positive disease (≥0.1%) who achieved MRD response with Blinatumomab. We sought to evaluate the utility of Blinatumomab in low levels of MRD (&amp;lt;0.1%) using clonoSEQ with a sensitivity of (0.0001%). Methods: Adult (18+) B- ALL patients that underwent treatment for B-cell ALL at Norris Comprehensive Cancer Center (NCCC) between 2016 and 2022 who had residual disease tracked using the Next Generation Sequencing (NGS)-based clonoSEQ assay (Adaptive Biotechnologies, Seattle, WA) were included. Patients who received Blinatumomab for MRD positivity were included only if they had a tracked clonoSEQ sequence within one month before starting treatment. Patients who didn't receive Blinatumomab were included if they had an MRD-positive clonoSEQ report. Those who were relapse/refractory when found to be MRD positive were excluded. Cumulative incidence of relapse (CIR) was evaluated using competing risk regression (Fine-Gray method), with death as a competing outcome. At the same time, OS and DFS were analyzed using Cox proportional hazards model. The start time was set to the date of the MRD report, and patients were censored until the last follow-up. Confounder-adjusted KM curves were calculated using direct standardization. Results: 47 patients were included with a median age at diagnosis of 45 years (range: 21-70). Most were Hispanic (N = 33, 70.2%), and the median follow-up time was 12 months. The 3-year OS, DFS, and CIR were 95.4% (95% CI 89.3-100%), 75.1% (95% CI 60.4-93.5%), and 20.3% (95% CI 7.2-38.0%). Twenty-six patients were treated with Blinatumomab (median two cycles, range 1-9), with most (N= 14, 53.8%) having low levels of MRD (&amp;lt;0.1%). Fourteen patients (53.8%) achieved MRD negativity with a median time to MRD negativity of 3.1 months. There were no relapses or death in patients who achieved MRD negativity in the treated group. However, non-responders with Blinatumomab had one death and two relapses. All patients continued Maintenance therapy after receiving Blinatumomab and did not proceed with the transplant. The patients who received Blinatumomab were more likely to be MRD positive on multiparameter flow cytometry (MFC) (60.0% vs. 28.6%, P = 0.042) but had a similar distribution of patient age, treatment type, and receipt of transplant. Additionally, there was a trend toward increased median percent residual cells on clonoSEQ (0.018% vs. 0.003% P =0.244) and flow (0.02% vs 0% P =0.066) in the Blinatumomab treatment group. On univariate analysis, significant predictors of CIR and DFS were flow percent (DFS: HR = 1.54; 95% CI 1.07-2.23; P = 0.019; CIR: HR = 1.83; 95% CI 1.38-2.41; P&amp;lt;0.001) and clonoSEQ residual cell count(DFS: HR = 1.58; 95% CI 1.04-2.41; P = 0.031, CIR: HR = 1.88; 95% CI 1.18-2.97 P=0.008). When controlling for the number of residual cells on close, patients who received Blinatumomab had significantly better CIR(HR = 0.11; 95% CI 0.02-0.69; P = 0.019) and a trend towards improved DFS(HR = 0.21; 95% CI 0.04-1.28; P = 0.092), but no difference in OS. On subgroup analysis of the 31 patients with low levels of MRD (&amp;lt;0.1%), there was no improvement in DFS for patients who were treated with Blinatumomab (HR = 0.41; 95% CI 0.04-3.91; P = 0.44). Of those with low levels of MRD, only two relapsed, and both did not receive Blinatumomab. Conclusions: In B cell ALL, Blinatumomab may offer a CIR benefit to patients with low levels of MRD as detected on clonoSEQ.

Minimal Residual Disease (MRD) Testing By Next Generation Sequencing (NGS) after Two Cycles (CY) of Non-Intensive Chemoimmunotherapy Is Predictive of Remission Duration and Need for Maintenance Therapy (MT) in Previously Untreated Mantle Cell Lymphoma (MCL): A Wisconsin Oncology Network Study

Introduction: Despite the variable course of MCL, limited prospective markers exist to identify more indolent disease. MCL is often diagnosed in older patients (pts) less able to tolerate intensive approaches. Bendamustine/rituximab (BR) is a standard non-intensive regimen for MCL, and use of MT remains controversial. Emerging data in MCL suggest a correlation between achieving MRD negativity (MRD-) and progression-free survival (PFS). The GALLIUM study (Marcus R, et al, N Engl J Med 2017) previously showed improved PFS with a bendamustine/obinutuzumab (BO) induction compared with BR in follicular lymphoma, and we postulated this benefit may be observed in MCL. Using MRD testing, we predicted that MT may be omitted in pts achieving MRD- status after induction BO chemoimmunotherapy for MCL. Methods: Adult pts ≥18 years (yrs) with previously untreated MCL who were ineligible for more intensive therapies (including transplant) were enrolled. Pts received 4-6 CY of BO induction intravenously (IV) every 28 days (D) with B 90 mg/m2 IV D1 &amp; 2 every 28D for 6 CY concurrent with O IV (cycle 1 = 100 mg D1, 900 mg D2, and 1000 mg D8 &amp; 15; then 1000 mg D1, CY 2-6). Peripheral blood (PB) MRD was obtained using NGS (ClonoSEQ®) after cycle 2 BO as an exploratory endpoint. Consolidation O (CO) 1000 mg IV weekly for 4 doses was initiated ≤12 weeks after the final dose of BO. Restaging and MRD testing of PB and bone marrow aspirate (BMA) was done ≤30 days after CO completion. For pts with complete response (CR) radiographically and MRD- in PB/BMA, maintenance O (MO) was omitted. For pts without CR or persistent MRD positivity (MRD+) in the PB or BMA, MO was given with 1000 mg IV D1 of a 56-day cycle for 8 CY. Pts were followed for ≥2 years from therapy completion. The primary endpoint is PFS from D1 of BO induction. Secondary endpoints are MRD status, concordance rate of PB/BMA in predicting MRD status, response rates and overall survival (OS). Results: Twenty-one pts (of planned 32) enrolled beginning 2/2018, with follow-up through 6/1/2023. The study closed prematurely due to slow enrollment. Median age is 70 yrs with 3 pts &amp;gt;80 yrs; majority were men (76%). Median MIPI score is 6.11 and median ECOG performance status 0. Twenty pts (95%) have stage IV disease. Twenty pts completed 4 (n=1) or 6 CY BO. Ten pts received MO; 10 did not receive MO per protocol due to radiographic CR and MRD- PB/BMA post-CO. Six pts did not complete MO for reasons of progressive disease (n=4), infection (n=1) and new carcinoma (n=1). After cycle 2 BO, PB analysis was MRD+ in 7 pts and MRD- in 13. Concordance rates between post-CO MRD testing in PB and BMA was 70% (14/20). Of non-concordant values, all had PB MRD- but BMA MRD+. Best responses in 20 assessable pts are: CR 75% (15/20), partial response 20% (4/20), and stable disease 5% (1/20). Most common grade 3/4 toxicities were: neutropenia (10/21), leukopenia (6/21), infections (5/21) and infusion reactions (2/21). One pt had grade 5 cardiac arrest with sepsis during BO. Most common grade 3 infections were abdominal/colitis (n=3) and pneumonia (n=2). Most common grade 1/2 toxicities were nausea (14/21), diarrhea (10/21), constipation (8/21), dysgeusia (6/21), fatigue (8/21) and dry skin/rash (12/21). After a median duration of follow-up of 43.9 months (mos) (95% confidence interval [CI] 28.3-60.1), PFS at 2-yrs and 3-yrs is 66.0% (95% CI 41.6-82.2) and 58.7% (95% CI 33.2-77.3), respectively; and median PFS is 46.5 mos (95% CI 16.4-∞). MRD- status after the exploratory endpoint post-C2 BO was predictive of 2-year PFS (Figure 1a), 83.3% (95% CI 48.2-95.6) for MRD- vs. 42.9% (95% CI 9.78-73.4) for MRD+, with hazard ratio [HR] 0.34 (95% CI 0.09-1.39), p value 0.133. Evaluation of PFS by MRD status post-CO showed similar outcomes regardless of receiving MO (Figure 1b): 2-year PFS is 77.8% (95% CI 36.5-93.9) in MRD- pts post-CO vs 60.0% (95% CI 25.3-82.7) in MRD+ pts; HR 0.45 (95% CI 0.10-1.91, p value 0.278. Median OS is 46.5 mos (95% CI 35.1-∞). Conclusion: Omission of MO in pts achieving MRD- status after induction/CO did not result in worsening PFS. Observed PFS and toxicities with BO induction and CO appears comparable with other data sets utilizing a BR-based induction +/- MT in older, less fit MCL pts. Correlation between PFS and PB MRD testing after C2 induction therapy represents a potential new prognostic marker of MCL behavior, and may be an important early disease indicator in development of risk-adapted therapies.

MRD Monitoring By Euroclonality IGH Based NGS Approach Predicts Outcome in Follicular Lymphoma Patients Lacking a Conventional BCL2::IGH Marker: A Substudy from the Fondazione Italiana Linfomi (FIL) FOLL12 Trial

Background. Despite durable clinical responses achieved by chemo-immunotherapy in follicular lymphoma (FL) patients, most of them eventually relapse. Actually, minimal residual disease (MRD) analysis based on the detection of BCL2::IGH rearrangement by PCR is the most widely used and standardized approach, able to early identify patients at high risk of disease reappearance. Nevertheless, this tool fails the molecular marker definition in up to 45% of cases, hampering the disease monitoring in a large group of patients. In the last decade, the continuous improvement of next-generation sequencing (NGS) techniques allowed to introduce these novel tools for MRD monitoring in some hematologic diseases, as acute lymphoblastic leukemia and multiple myeloma, thus reducing PCR limitations and increasing the number of patients eligible for MRD. Nonetheless, applications of NGS tools for MRD detection in FL are still scant. Aims. Therefore, we tested the feasibility of the EuroClonality (EC) IGH-based NGS approach [Brüggeman, Leukemia 2019] to identify novel molecular markers suitable for MRD monitoring in the context of the large prospective trial “FOLL12” (EudraCT: 2012-003170-60) by the Fondazione Italiana Linfomi (FIL), where 57% of patients were already studied for MRD by classic PCR methods targeting the BCL2::IGH rearrangement.[Luminari, JCO2022] Methods. Advanced FL patients received upfront treatment with either R-CHOP or BR, followed by a combined PET/MRD response-based maintenance with rituximab. Bone marrow (BM) samples were centralized to the FIL MRD Network for standardized MRD analysis. Baseline gDNA of “no marker” patients was screened by IGH-based NGS using EC-IGH two-steps PCR approach in the EuroMRD certified lab of Torino university; then MRD was monitored in those patients harboring a IGH clonal marker at baseline by one step EC-IGH method. The identification of baseline clonotypes and MRD clones was performed by ARRest/Interrogate tool. Results. 343/786 enrolled patients (43%) lacked a conventional BCL2::IGH marker and 161/343 (47%) showed morphologic BM lymphoma infiltration: of these, 124 (77%) had an available BM baseline sample for IGH screening and were thus included in the analysis. Overall, IGH clonotypes suitable as novel molecular markers were identified in 75/124 patients (60%), of which 73 monoclonal and 2 biclonal. Of this series, 47 patients had centralized a BM sample for MRD analysis at end of induction. Median age of this subset was 59 years (33-81), 53% were female, all were Ann Arbor stage IV, 34% were FLIPI intermediate and 43% high risk, respectively. Moreover, 56% received R-CHOP and 44% BR as induction treatment, resulting in a 79% CR rate and 89% MRD negativity rate (in line with the results of the general trial population). PFS at 3 years for this series was 69%: however, the 5 patients who scored MRD positive (MRD+) showed statistically significant worse PFS at 3 years than MRD negative cases (22% vs 73%, respectively, p=0.0069, Figure 1). Notably, 4 out of 5 MRD+ patients experienced POD24. Focusing on biclonal cases, one presented superimposable MRD trends between clones (both achieving MRD negativity), while in the other both clones remained MRD positive but showing one Log difference between them. Interestingly, only one of the two clones showed a MRD increase in the following timepoint (6 months after end of induction), heralding the clinical relapse subsequently occurred at month 12 (Figure 2). On the other hand, no IGH clonotype was identified in the first 17 patients who were screened for a novel MRD marker despite the absence of BM infiltration. Conclusions. The first data on the large-scale application of NGS-based marker screening tools in FL patients lacking a conventional BCL2::IGH marker for MRD enrolled in a prospective clinical trial showed that the EC IGH-based NGS approach was able to provide a new molecular marker in 60% of patients with evidence of BM infiltration (that means about the 28% of “no marker” FL patients); importantly, this approach was predictive of worse PFS for MRD+ cases. Overall, these data are promising for the wide employment of novel, effective MRD monitoring tools, able to recover more than one fourth of FL patients lacking a conventional molecular marker and so, by combining conventional and NGS-based techniques, potentially rising the percentage of MRD evaluable cases up to at least 70% cases.

How Induction Cycles before Remission Influence Long-Term Survival in Acute Myeloid Leukemia

Background ： Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by accumulation and expansion of immature myeloid cells in the bone marrow, peripheral blood and other tissues. Despite the progress made in mechanisms and approval of new therapeutics, the clinical outcome of AML remains suboptimal. The achievement of complete remission (CR) after induction chemotherapy is critical because the prognosis of refractory AML was especially unfavorable. However, little is known about the association between remission after first induction therapy and the overall survival (OS) in different subgroups of AML. Study Design and Methods: We retrospectively analyzed patients with newly diagnosed AML from January 2019 to August 2022. The diagnosis and treatment strategies were based on European Leukemia Net (ELN) criteria and National Comprehensive Cancer Network (NCCN) guideline. Composite complete remission (CRc) rate (CR+CR with incomplete recovery [CRi]) were assessed at the completion of induction or re-induction therapy. Minimal residual disease (MRD) was assessed using multiparameter flow cytometry with a minimum sensitivity of 0.1%. OS was measured from the day of diagnosis until death or the last follow-up date. Results : In total, 679 patients were included and the median age was 59.0 (range, 14.0-93.0) years old. There were 56.8% (386/679) of patients who achieved CRc after the induction therapy (group A), 18.1% (123/679) achieved CRc after the re-induction therapy (group B). The median follow-up period was 24.2 months. Even though there was no significant difference between group A and group B on OS, group A exhibited improved OS when censored at allogenic hematopoietic stem cell transplantation (HSCT) compared to that in group B (group A vs group B:3-year OS rates 65.7% vs 51.1%，p=0.004，Figure A). We further explored the effects of remission depth on survival. The results showed that, after induction therapy, patients achieved CR exhibited superior OS compared with that in CRi (CR vs. CRi, 3-year OS rates 69.4% vs 51.6%, p=0.006). Also, compared with these patients who failed to achieved MRD negativity within re-induction therapy, patients achieved MRD negativity within re-induction therapy showed superior OS when censored at HSCT (MRD- vs. MRD+, 3-year OS rates 64.7% vs 34.9%, p=0.040). After the first reduction therapy, patients achieved CRc but MRD positive benefit from HSCT (HSCT vs Non-HSCT, 3-year rates 83.0% vs 57.9%, p=0.017), but in patients with MRD negativity, HSCT did not improve the survival outcomes (HSCT vs Non-HSCT, 3-year rates 76.8% vs 65.7%, p=0.078). The next-generation sequencing (NGS) results were available in 520 patients. Based on the 2022 ELN risk stratification, the 3-year OS rates were 60.3%, 44.2% and 35.0% in favorable, intermediate and adverse group, respectively. Moreover, there were 43, 47, 60 patients in favorable, intermediate, and adverse subgroups underwent HSCT subsequently. In intermediate risk subgroup, patients who failed to achieve CRc after the first induction therapy, HSCT may serve as an effective intervention to prolong survival (3-year rates 100% vs 12.1%, P&amp;lt;0.001,). On the contrary, patients who achieved CRc in induction therapy, the overall survival were not influenced by HSCT status (3-year rates 81.5% vs 31.7%, p=0.153, Figure B). Conclusion: Our finding indicated that remission after the first cycle of induction therapy may be a prognostic factor for OS. Moreover, earlier and deeper remission may lead to improved survival. For those patients in intermediate risk group, who achieved CRc in induction therapy or achieved CRc with MRD negativity within re-induction therapy, HSCT may not influence the survival outcome.

Efficacy and Safety in Patients with Lenalidomide-Refractory Multiple Myeloma after 1-3 Prior Lines Who Received a Single Infusion of Ciltacabtagene Autoleucel As Study Treatment in the Phase 3 CARTITUDE-4 Trial

Introduction: CARTITUDE-4 (NCT04181827) is a randomized, phase 3 trial comparing ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, with standard of care (SOC; pomalidomide, bortezomib, and dexamethasone [PVd] or daratumumab, pomalidomide, and dexamethasone [DPd]) in patients (pts) with lenalidomide (len)-refractory multiple myeloma (MM). The trial recently showed that pts in the cilta-cel arm experienced significantly improved progression-free survival (PFS) vs SOC (HR, 0.26; P&amp;lt;0.0001) and a significantly higher rate of complete response (CR) or better and overall response rate (ORR) in the intent-to-treat (ITT) set (San-Miguel et al, New Engl J Med 2023). We report efficacy and safety in pts who received cilta-cel as study treatment (‘as-treated’ set) in the experimental (cilta-cel) arm of the study. Methods: Pts had 1-3 prior lines of therapy (LOT), including a proteasome inhibitor and immunomodulatory drug. A single cilta-cel infusion (target dose, 0.75×10 6 CAR+ viable T cells/kg) was administered after apheresis, bridging therapy (DPd [28-day cycles] or PVd [21-day cycles]), and lymphodepletion. Treatment responses and disease progression were assessed per IMWG criteria; minimal residual disease (MRD) negativity at 10 -5 was assessed by next-generation sequencing starting at day 56 post infusion; time-to-event endpoints were analyzed using the Kaplan-Meier method. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) were graded per ASTCT criteria; other adverse events (AEs) were graded per NCI-CTCAE criteria. Results: As of Nov 1, 2022, 176 of 208 pts randomized to the cilta-cel arm had received cilta-cel as study treatment (median age, 61 years; 34% with 1 prior LOT; 6% ISS stage III; 60% with high-risk cytogenetic profile; 17% with soft tissue plasmacytoma; 13% with high tumor burden; 11% triple-class refractory). Baseline characteristics were consistent with those of the ITT set. In the as-treated set, median follow-up from randomization was 16 months (mo), and 22% of pts had received 1 bridging therapy cycle, 59% 2 cycles, and 18% 3 cycles. Disease burden was effectively controlled in the as-treated set during bridging therapy. Median PFS was not reached and the 12-mo PFS rate from infusion was 85%; 12-mo overall survival rate from infusion was 92%. 175 of 176 pts who received cilta-cel as study treatment responded (99% ORR), including 86% who achieved ≥CR. Median time from randomization to first response was 2.1 mo and responses deepened over time; 2% of pts achieved ≥CR by 2 mo post randomization, and rates increased to 40% by 6 mo and 80% by 12 mo (Figure A). Median duration of response was not reached. 72% of the as-treated set (88% of 144 MRD evaluable) achieved MRD negativity at any time. 111 of 144 MRD-evaluable pts (77%) achieved both MRD negativity and ≥CR. These pts had improved PFS vs pts who remained MRD positive and/or had &amp;lt;CR (HR, 0.36; 95% CI, 0.15-0.88; P=0.0196); respective 12-mo PFS rates were 89% and 71% (Figure B). The most common CAR-T cell-related toxicity was CRS (76% any grade [gr]; 1% gr 3). The overall CAR-T cell neurotoxicity rate was 21% (3% gr 3/4). ICANS occurred in 5% of pts (no gr 3/4). Other neurotoxicities occurred in 17% of pts (2% gr 3/4); these included cranial nerve palsy (CNP) in 9% (1% gr 3/4), peripheral neuropathy in 3% (1% gr 3/4), and 1 pt with gr 1 movement/neurocognitive treatment-emergent AEs (MNT). By clinical cut-off, CRS and ICANS had resolved in all pts; CNP and peripheral neuropathy had resolved in all but 2 pts; and the 1 MNT case had not yet resolved. Conclusions: This analysis of the as-treated set in CARTITUDE-4 shows potent effects of cilta-cel in pts with len-refractory MM after 1-3 LOT. The PFS rate of 85% at 12 mo post infusion (89% in pts with MRD-negative ≥CR) compares favorably with real-world data in similar populations (12-mo PFS rate &amp;lt;50%; Lecat et al, Front Oncol 2021). Effective bridging therapy during the CAR-T manufacturing period may help ensure that pts can receive cilta-cel. In the context of longer-term data from cohort A of the CARTITUDE-2 study (Hillengass et al, ASH 2023, submitted) in a similar pt population, these results support the potential for prolonged disease control and the benefit of cilta-cel for pts with MM as early as after first relapse.

Venetoclax in Combination with Daratumumab and Dexamethasone Elicits Deep, Durable Responses in Patients with t(11;14) Relapsed/Refractory Multiple Myeloma: Updated Analyses of Minimal Residual Disease Negativity in Phase 1/2 Study

Introduction: Venetoclax (Ven) is a potent and selective oral BCL-2 inhibitor with demonstrated anti-myeloma activity in patients with t(11;14)-positive relapsed/refractory multiple myeloma (RRMM). The combination of Ven with daratumumab (D) and dexamethasone (d) has shown a high overall response rate (ORR) and tolerable safety profile in the Phase 1/2 study ( Blood [2021] 138 [Supplement 1]: 817). Here, we report updated analyses of minimal residual disease (MRD) negativity from the Phase 1/2 trial of VenDd at 400 and 800 mg Ven dose levels, versus bortezomib plus Dd (DVd) in patients with t(11;14)-positive RRMM. Methods: Parts 1 (nonrandomized) and 3 (randomized among Ven [400 mg] Dd, Ven [800 mg] Dd and DVd arms) in this Phase 1/2 multicenter study evaluated VenDd versus DVd in patients with t(11;14)-positive RRMM (as determined by central lab plasma-cell enriched fluorescence in situ hybridization), who had ≥1 prior line of therapy (LOT), including proteasome inhibitor and immunomodulatory drug exposure (NCT03314181). Patients in the investigational arm (VenDd, 28 day cycles [C]) received oral Ven once daily (400 mg or 800 mg) with D (either 16 mg/kg intravenous [IV] or 1800 mg subcutaneous [C1-2: Days 1, 8, 15, 22; C3-6: Days 1 and 15; C7+: Day 1]) and d (40 mg weekly; oral/IV); patients in the DVd arm were dosed per label. MRD negativity (&amp;lt;10 −5) was assessed in bone marrow aspirates by next-generation sequencing (clonoSEQ®, Adaptive, Seattle, WA) at the time of suspected complete response (CR) / stringent CR (sCR), and 6- and 12-months post confirmation of CR/sCR. Patients with a missing or indeterminate assessment were considered MRD positive. Results: As of March 10, 2023, Part 1 enrolled 5 patients (Ven [400 mg] Dd) and 19 patients (Ven [800 mg] Dd). Part 3 enrolled 21 patients (Ven [400 mg] Dd), 10 patients (Ven [800 mg] Dd), and 26 patients (DVd). A total of 80 patients were enrolled (Parts 1 and 3 combined); 55 patients received VenDd (24% high-risk cytogenetics, 53% 1 prior LOT, 2% prior anti-CD38 monoclonal antibody [mAb], 76% lenalidomide-refractory); and 26 received DVd (23% high-risk cytogenetics, 38% 1 prior LOT, 4% anti-CD38 mAb, 92% lenalidomide-refractory). Median (range) follow-up for survivors was longer with VenDd than DVd (28.2 months [1.0-55.7 months] with VenDd vs 16.9 months [0.0-34.1 months] with DVd). VenDd achieved 96% ORR, 93% ≥ very good partial response (VGPR), 67% ≥ CR, and median progression-free survival (PFS) not reached (95% confidence interval [CI]: 35.0- not estimable [NE]). DVd achieved 65% ORR, 39% ≥ VGPR, 19% ≥ CR, and median PFS 15.5 months (7.5-NE). The 33-month PFS rate was 73.4% (95% CI: 56.4-84.6) versus 38.8% (16.3-61.1) for VenDd versus DVd. MRD negativity rates were 38% with VenDd and 8% with DVd. MRD negativity rates in key subgroups, including number of prior LOTs, lenalidomide refractory status, and high-risk cytogenetics, were higher with VenDd compared to DVd (Table). Of 8 VenDd-treated patients assessed for duration of MRD negativity, 6 were MRD negative &amp;gt;6 months, of whom 2 achieved MRD negativity &amp;gt;12 months. No DVd-treated patients had durable MRD negativity &amp;gt;6 months (Figure). No new safety signals were observed. Conclusions: VenDd treatment showed higher rates of MRD-negativity and sustained MRD-negativity compared to DVd in patients with t(11;14)-positive RRMM, which was associated with longer PFS with VenDd.

Phase II Trial of Daratumumab, Bortezomib, Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Background: Daratumumab, bortezomib, lenalidomide and dexamethasone (D-RVD) has shown high rates of minimal residual disease (MRD) negativity in newly-diagnosed multiple myeloma (MM) and is now a standard regimen in transplant-eligible patients. Lenalidomide has shown to delay progression in patients with high-risk smoldering multiple myeloma (HR-SMM) and curative intent trials with carfilzomib-based therapy and stem cell transplantation have been recently reported in HR-SMM leading to deep responses but with concern for treatment-related toxicities. Thus, we proposed to examine the activity and safety of fixed duration D-RVD in patients with HR-SMM, with MRD-adaptive duration of therapy. Methods: This is a phase II, open-label study evaluating D-RVD in HR-SMM. Eligibility criteria includes HR-SMM per Mayo 2018 “20-2-20” model and other previously established criteria including Mayo 2008 criteria, PETHEMA criteria, evolving type of SMM, and high-risk FISH. Treatment with D-RVD is 2 years (24 cycles) with daratumumab subcutaneous (SQ) per standard dose and schedule, bortezomib 1.3mg/m2 SQ on days 1, 8, 15 for cycles 1-6 then biweekly until completion of cycle 24, lenalidomide 25mg on days 1-21 for cycles 1-6 followed by 15mg d1-21 from cycles 7-24 with weekly low dose dexamethasone. All eligible patients undergo stem cell collection after 6 cycles of therapy. The primary objective is rate of MRD-negativity at 2 years. Secondary objectives include PFS, ORR, and safety. In part 2 of the study, patients that are MRD-positive after 2 years of treatment will be randomized to observation vs continued therapy with daratumumab and lenalidomide for an additional 24 months. The primary objective of part 2 is rate of MRD conversion from positive to negative. Results: At the time of data cut off in May 2023, 38 patients have been enrolled to part 1 with a median follow up of 18 months. The median age is 62 years old (range 36-77) with 23 females (61%) and 15 males (39%). The median plasmacytosis of enrolled patients was 20%, with median M-protein of 2.17 g/dL and median FLC ratio of 8.1. Twenty-four patients (62%) had at least one high-risk FISH abnormality (fifteen with 1q gain, four with t(4;14), one with t(14;16) and one with del 17p). Eight patients (21%) had more than one high-risk FISH abnormality. Most common grade 3 toxicities included neutropenia (13%), ALT increased (8%), and diarrhea (8%). Upper respiratory infections occurred in 61% of patients but were mostly low-grade (COVID-19 infection in 11 patients, 1 with grade 3). No patients discontinued therapy due to toxicity. Of the 35 patients that completed at least 2 cycles of therapy, the ORR is 100% with 43% CR, 34% VGPR and 17% PR with responses deepening over time. Seventy-seven percent of patients achieved VGPR or greater. MRD was evaluable in 22 patients at 6 months with MRD negativity rate of 59% and 14% at thresholds of 10 -5 and 10 -6, respectively. At 12 months, 20 patients were MRD-evaluable with 65% and 20% achieving MRD negativity at 10 -5and 10 -6, respectively. Of the 10 MRD-evaluable patients at 24 months, 60% were MRD negative at 10 -5 and 40% at 10 -6. No patients have progressed on treatment. Stem cell collection was successful in all eligible patients with average stem cell yield of 5.53 x 10 6 CD34+ cells/kg. Conclusions: D-RVD in HR-SMM demonstrates significant activity, including a 100% ORR and high rates of MRD-negative disease, preventing progression to overt myeloma.

Updated Results of a Phase I Open-Label Single-Arm Study of Dual Targeting BCMA and CD19 Fastcar-T Cells (GC012F) As First-Line Therapy for Transplant-Eligible Newly Diagnosed High-Risk Multiple Myeloma

Background High-risk (HR) newly-diagnosed multiple myeloma (NDMM) has poor outcomes with standard first-line therapies, even in transplant-eligible (TE) patients (pts). A CAR-T therapy with high efficacy and manageable safety profile would be a potential solution to this significant unmet need. GC012F is an autologous B cell maturation antigen (BCMA) and CD19 dual-targeting CAR-T cells therapy developed on the novel FasTCAR-T enabling next-day manufacturing platform [J Clin Oncol 41, 2023 (suppl; abstr 8005)]. The phase I single-arm study has been conducted in frontline setting for TE high-risk NDMM pts to characterize the safety and feasibility of GC012F CAR-T cell therapy (NCT04935580). The data was presented at ASH 2022 for initial 13 pts (Blood (2022) 140 (Supplement 1): 889-890.). Here we present updated data with longer follow up and 9 additional pts treated (total N=22) in this study. Methods This is a single arm, open-label phase I investigator-initiated study (NCT04935580). TE NDMM pts, aged between 18-70, and with one or more of the following features were considered eligible for the study: R-ISS-II or-III; del17p, t (4;14), t (14;16), or 1q21amp ≥ 4 copies; extramedullary disease (EM); IgD or IgE subtype; LDH &amp;gt; the upper limit of normal; or any of the high-risk definition of mSMART3.0. As of the data cutoff date, 22 evaluable pts (median age 59, range 43-69) are reported here. The median time from diagnosis to infusion was 100 days (range 63-152). All patients had one or more high-risk features including 91% R-ISS stage II or III, 55% with EM, 32% 1q21≥4 copies, and 9% IgD type. Of the 22 pts, 21 pts received 2 cycles induction therapy of bortezomib, lenalidomide and dexamethasone (VRd), and one patient received 1 cycle bortezomib, epirubicin, and dexamethasone (PAD) and 1 cycle VRd prior to the infusion. GC012F was administered as a single infusion at 3 doses levels (DL) of 1x10 5/kg (n=1), 2x10 5/kg (n=4), or 3x10 5/kg (n=17), after a standard 3-day lymphodepletion consisting of cyclophosphamide and fludarabine . Results As of June 9 th, 2023 data cutoff, 22 patients were enrolled and evaluable for safety and efficacy. Median follow-up was 13.6 months (range 2.1-23.9 months). Overall response rate (ORR) was 100% and stringent complete response (sCR) rate was 95.5%. All treated pts (100%) across all dose levels achieved minimal residual disease (MRD) negativity assessed by Euroflow (sensitivity of 10 -6). All evaluable pts achieved MRD negativity at Month 1, and maintained MRD- at landmark analysis of Month 6 and Month 12. Median duration of response (DOR) and progression-free survival (PFS) were not reached. Only 6 pts (27%) experience low-grade cytokine release syndrome (CRS), including 23% grade 1 (n=5) and 4% grade 2 (n=1). No treatment-related grade ≥3 CRS, nor ICANS of any grade, and nor deaths occurred in the study. Robust CAR T-cell expansion was observed in all pts; the median peak expansion (Cmax) was 62,131 (range: 8,754-331,159) copies /μg DNA with a median Tmax of 10 days (range 9-14 d). Conclusion Consistent with the previous RRMM cohort treated with GC012F, initial data from this phase I study demonstrated that BCMA-CD19 dual-targeting FasTCAR-T GC012F resulted in deep and durable response in transplant-eligible newly-diagnosed high-risk pts with a very favorable safety profile. All three dose groups achieved 100% MRD negativity and 100% ORR and sCR. The promising preliminary results achieved with GC012F demonstrate potential of CAR-T therapy in newly-diagnosed MM pts. Further research with larger patient population and longer follow-up shall bring the hope to this unmet medical need.

The Phase 2 CARTITUDE-2 Trial: Updated Efficacy and Safety of Ciltacabtagene Autoleucel in Patients with Multiple Myeloma and 1-3 Prior Lines of Therapy (Cohort A) and with Early Relapse after First Line Treatment (Cohort B)

Introduction: CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel), an anti-BCMA chimeric antigen receptor (CAR)-T cell therapy, in various populations of patients with multiple myeloma (MM). We previously reported 17-month median follow-up results from cohort A (1-3 prior lines of therapy [LOT] and lenalidomide [len]-refractory) and 18-month median follow-up results from cohort B (early relapse: ≤12 months after either autologous stem cell transplant [ASCT] or start of initial anti-myeloma treatment, if not transplanted). Cilta-cel is also under evaluation in patients with len-refractory MM after 1-3 LOT in the phase 3 CARTITUDE-4 study, which showed cilta-cel significantly prolonged progression-free survival (PFS) vs standard of care (HR, 0.26) at a median follow-up of 16 months. Here, we present updated efficacy and safety data from CARTITUDE-2 cohorts A and B, both with a median follow-up of ~29 months. Methods: Patients in cohorts A and B, all naive to CAR-T and/or anti-BCMA therapies, received a single cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg) 5-7 days after lymphodepletion. In both cohorts, the primary endpoint was minimal residual disease (MRD)-negativity (10 -5 threshold, by next-generation sequencing or next-generation flow cytometry). Management strategies were implemented after the phase 1b/2 CARTITUDE-1 study to reduce risk of movement and neurocognitive treatment-emergent adverse events (MNTs). Results: As of April 2023, 20 patients in cohort A had received cilta-cel (median follow-up, 29.9 months; 35% with high-risk cytogenetics; median 2 prior LOT; 95% refractory to last LOT; 40% triple-class refractory; 85% with prior ASCT). At the same data cut-off, 19 patients in cohort B hadreceived cilta-cel (median follow-up, 27.9 months; 16% with high-risk cytogenetics; 79% refractory to last LOT; 16% triple-class refractory; 79% with prior ASCT). All (100%) 17 MRD-evaluable patients in cohort A and 14 (93%) of 15 MRD-evaluable patients in cohort B achieved MRD negativity (10 -5 threshold). Eight (40%) of 20 patients in cohort A and 10 (53%) of 19 patients in cohort B sustained MRD negativity at 10 -5 for ≥6 months (Table 1). In the 20 patients in cohort A and 19 in cohort B, cilta-cel led to overall response rates of 95% (complete response or better [≥CR], 90%) and 100% (≥CR, 90%), respectively. Median PFS was not reached in either cohort, and 24-month PFS rates were 75% in cohort A and 73% in cohort B; respective 24-month overall survival rates were 75% and 84%. In cohort A, hematologic treatment-emergent adverse events (TEAEs) occurring between 17.1- and 29.9-month median follow-up included maximum grade (gr) 3/4 leukopenia in 1 patient (all gr,12 total; 60%), maximum gr 3/4 lymphopenia in 2 patients (all gr,16 total; 80%), and maximum gr 3/4 thrombocytopenia in 1 patient (all gr,16 total; 80%). In cohort B, no new patients reported hematologic TEAEs between 18.0- and 27.9-month median follow-up (Table 2). In cohort A, no new patients had CAR-T cell neurotoxicity, and no patients had a second primary malignancy (SPM). In cohort B, no new patients had MNTs, but other neurotoxicity (gr 2 sensory loss) occurred in 1 additional patient (all gr, 5 total; 26%) and resolved; and SPM (gr 4 choroid melanoma) occurred in 1 additional patient (all gr, 2 total; 11%). One new death (total 5) occurred in cohort A on day 666 due to progressive disease, and 1 new death (total 4) occurred in cohort B on day 749 due to cardiac arrest (not treatment related). Conclusions: These longer-term follow-up data show that patients treated with cilta-cel in earlier LOT, both those with len-refractory MM after 1-3 LOT (cohort A) and those with early relapse (cohort B), experienced deep and durable responses. No new CAR-T-related safety signals, except for 1 additional CAR-T cell neurotoxicity in cohort B, were reported. Cohort A provides insight into potential longer-term survival outcomes that may be expected in the phase 3 CARTITUDE-4 trial, which enrolled the same patient population but has shorter follow-up thus far. The long-term cohort B data highlight the durable efficacy of cilta-cel in patients who had early relapse; this is a functionally high-risk population for whom standard risk factors, including a high-risk cytogenetic profile, may not predict risk of relapse and for whom there is significant unmet need.

A Real-World Evidence on Effectiveness and Safety of Blinatumomab in Patients with B-Cell Acute Lymphoblastic Leukemia

Introduction Blinatumomab, a bispecific T-cell antibody, has emerged as a novel therapy with a promising efficacy and tolerable safety in patients with B-cell acute lymphoblastic leukemia (B-ALL). However, there is a paucity of data on blinatumomab for patients with newly diagnosed and relapsed/refractory (R/R) B-ALL in frontline and relapsed settings outside the clinical trials. This study aimed to describe the treatment patterns, effectiveness and safety of blinatumomab in Chinese patients with B-ALL. Methods In this retrospective observational study, data of patients with B-ALL who received at least one dose of blinatumomab in frontline or relapsed settings between August 2021 and June 2023 were collected from electronic medical data of the Department of Haematology of the First Affiliated Hospital of Soochow, China. The primary endpoint of the study was the treatment pattern of blinatumomab therapy, including median treatment cycles. Secondary endpoints included complete remission (CR)/CR with incomplete blood cell recovery (CRi) rate, minimal residual disease (MRD) negativity (i.e., complete MRD remission, defined as MRD &amp;lt;0.01%), median event-free survival (EFS) and 1-year EFS rate, median overall survival (OS) and 1-year OS rate, duration of response (DOR) and adverse events (AEs). Results In total, 96 patients with B-ALL (53 males and 43 females) were included. Of these, 53 received frontline treatment (blinatumomab used for first line remission induction: n=6; first line consolidation: n=39; first line induction or consolidation unknown: n=8), and 43 were R/R patients (blinatumomab for remission re-induction: n=28; R/R consolidation: n=14; R/R re-induction or consolidation unknown: n=1). The median age was 34 years (range: 11-67). Among R/R patients, 18 (18.8%), 12 (12.5%) and 13 (13.5%) had received 2, 3, and ≥3 previous lines of treatments, respectively. Sixteen patients were refractory to the last treatment. Among patients using blinatumomab for consolidation, MRD status at the start of therapy was positive in 29 (30.2%), and negative in 23 (24.0%) patients. Most of the patients (66.7%) received 1 cycle of blinatumomab followed by 2 (20.8%), 3 (7.3%), 4 (4.2%), and 5 (1.0%) cycles of the drug. The median treatment cycle was 1 (range: 1-5) with a median follow-up of 205 days (range: 15-652). In frontline treatment, all those using blinatumomab for remission induction and first line unknown status achieved CR with the CR/CRi rate of 100% (14/14) after blinatumomab. In patients with evaluable MRD (n=47) in the frontline setting, 87.2% (n=41) achieved MRD negativity within the 2 cycles of blinatumomab. In the following cycles, 3 more patients achieved MRD remission with overall complete MRD remission rate of 93.6% (44/47). In R/R re-induction patients, the CR/CRi rate was 50% (14/28) after blinatumomab treatment. Complete MRD remission rate in R/R patients who achieved CR within 2 cycles of blinatumomab was 73% (19/26). Median EFS was not reached (NR) in both frontline and R/R patients and the 1-year EFS rate was 90.8% (95% CI: 67% - 97%) and 55.1% (95% CI: 30% - 74%), respectively (Figure 1). Stratification of EFS by CR status at blinatumomab initiation showed 1-year EFS rate of 93.8% and 100% in first line consolidation and remission induction patients, respectively, whereas, R/R consolidation and re-induction patients showed 1-year EFS rate of 66.8% and 59.3%, respectively. None of the frontline treated patients died until the last follow-up time. In R/R patients the median OS was not reached and the 1-year OS rate was 70.9% (95% CI: 50% - 84%). OS stratified by CR status in R/R patients showed 1-year OS of 87.5% in consolidation and 69.9% in re-induction patients. Median DOR was NR in both frontline and relapsed settings. Seven (7.3%), and 3 (3.1%) patients reported any grade, and grade ≥3 cytokine release syndrome, respectively. Immune effector cell-associated neurotoxicity syndrome was reported by 1 patient (grade ≥3). Infection of any grade and grade ≥3 was reported by 6 (6.2%) and 4 (4.2%) patients, respectively. Increase in liver enzymes and neutropenia were observed in 1 patient (grade ≥3) each. Conclusion This study showed that using blinatumomab for remission induction and consolidation with one to five cycles was effective in the treatment of patients with B-ALL in the frontline as well as relapsed settings and had a tolerable safety profile.

Long-Term Efficacy and Safety of Elranatamab Monotherapy in the Phase 2 Magnetismm-3 Trial in Relapsed or Refractory Multiple Myeloma (RRMM)

BACKGROUND Elranatamab is a humanized, bispecific antibody that targets B-cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells, with the aim of inducing T-cell-mediated cytolysis of the myeloma cells. In the MagnetisMM-3 (NCT04649359) trial, an open-label, multicenter, non-randomized, phase 2 registrational study of elranatamab monotherapy, patients with RRMM who had not received prior BCMA-directed therapy (ie, BCMA-naïve patients; n=123) achieved objective responses with an overall response rate (ORR) of 61%. Here, we report the long-term efficacy and safety of elranatamab. METHODS Eligible patients had previously received at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Patients received step-up doses of 12 and 32 mg elranatamab subcutaneously on days 1 and 4 of cycle 1, respectively, followed by 76 mg elranatamab once-weekly (QW), starting on day 8 of the first 4-week cycle. Patients who received ≥6 months of QW dosing and achieved ≥ partial response lasting at least 2 months were transitioned to a once every 2 weeks (Q2W) dosing schedule and from Q2W to once every 4 weeks after at least 6 Q2W cycles. Treatment with elranatamab continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was ORR, assessed by blinded-central review per International Myeloma Working Group criteria. Minimal residual disease (MRD) status was assessed using next-generation sequencing, with MRD negativity defined as &amp;lt;1 myeloma cell in 10 5 nucleated cells. Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) severity were graded by American Society for Transplantation and Cellular Therapy criteria. RESULTS After a median follow-up of 15.9 months (data cutoff, April 16, 2023), 32.5% of patients remained on treatment. The confirmed ORR was 61.0% (n=123; 95% CI, 51.8-69.6), with 35.8% of patients achieving complete responses (CR) or better. Among evaluable patients (those with ≥CR and evaluable for MRD, n=29), 89.7% achieved MRD negativity. Median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) have not been reached, and the probabilities of maintaining a response, being progression-free, and being alive at 15 months were 70.8% (95% CI, 58.2-80.2), 50.2% (95% CI, 40.2-59.3), and 56.3% (95% CI, 47.0-64.6), respectively. All participants (100%) had ≥1 any grade treatment-emergent adverse events (TEAEs), and 70.7% of patients had grade 3/4 TEAEs. The most common any grade (≥25%) and grade 3/4 (≥10%) adverse events (any grade, grade 3/4) were infections (69.9%, 40.7%), CRS (57.7%, 0%), anemia (48.8%, 37.4%), neutropenia (48.8%, 48.8%), diarrhea (41.5%, 1.6%) thrombocytopenia (31.7%, 23.6%), lymphopenia (26.8%, 25.2%), fatigue (36.6%, 4.1%), nausea (26.8%, 0%), injection site reaction (26.8%, 0%), hypokalemia (26.0%, 10.6%), cough (26.0%, 0%) pyrexia (30.9%, 4.1%), decreased appetite (33.3%, 0.8%), leukopenia (15.4%, 13.0%) and COVID-19 pneumonia (14.6%, 11.4%). CONCLUSIONS Extended follow-up from the ongoing phase 2 MagnetisMM-3 trial of elranatamab in heavily pretreated participants with RRMM demonstrated sustained clinical efficacy, with median DOR, PFS, and OS not reached, and no new safety signals.

A Phase II Study of Isatuximab, Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, in Newly Diagnosed, Transplant-Eligible Multiple Myeloma (The SKylaRk Trial)

Background: Clinical data support the combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid for the treatment of newly diagnosed multiple myeloma (NDMM). Isatuximab (Isa) is approved in combination with carfilzomib and dexamethasone (dex) for relapsed, refractory MM based on the results of the IKEMA study, as well as with pomalidomide and dex based upon ICARIA and is now being explored in novel combinations in the newly diagnosed setting. Our study evaluated the addition of isa to weekly carfilzomib (K), lenalidomide (len), and dex in all-risk, transplant-eligible patients with NDMM and stratifies maintenance based on cytogenetic risk. Study Design and Methods: Phase II study of isa-KRd in 50 transplant-eligible NDMM patients (NCT04430894). All patients received 4 cycles of isa-KRd followed by stem cell collection with option of upfront versus deferred stem cell transplant (SCT). Upfront SCT patients received 2 additional cycles then maintenance. Deferred SCT patients received 4 additional cycles then maintenance. Each 28-day cycle consisted of isa 10 mg/kg iv weekly cycles 1-2, Q2 weeks cycles 3-6, then Q4 weeks; K (20 mg/m 2 cycle 1, day 1 only) 56 mg/m 2 iv days 1, 8, 15; len 25 mg po days 1-21; and dex 20 mg po days 1, 2, 8, 9, 15, and 16 (and days 22, 23 cycles 1-2). For maintenance, standard-risk received len 10 mg po days 1-21 and high-risk (del 17p, gain 1q, t(4:14), t(14;16), t(14;20)) isa 10 mg/kg iv day 1; K 56 mg/m 2 iv days 1, 15; len 10 mg po days 1-21. Main Outcomes and Measures: Primary end point was complete response (CR + stringent CR) rate after 4 cycles by the IMWG response criteria. Secondary endpoints included safety and tolerability; minimal residual disease (MRD), progression-free survival (PFS), and overall survival (OS) rates, quality of life, body composition, and T cell repertoire. Results: Fifty patients enrolled between August 2020 and February 2022. Median age was 59 years (range 39-70) and 54% were male. Forty-six percent of patients had high-risk cytogenetics. Median follow-up is 26 months. Of 45 patients evaluable for response after 4 cycles, ORR was 100% and 89% (39/45) achieved a very good partial response (VGPR) or better and 36% (16/45) a CR. Of those, 43% (12/28) were MRD negative at 10 -5. After the completion of C6/C8, ORR was 100% and 64% (29/45) achieved a CR and 96% (43/45) achieved a VGPR or better. After C6/C8, 41 patients, 66% (27/41) were MRD negative at 10 -5. The 24-month PFS was 91.3% (95% CI 83.4% -99.8%) and OS was 95.8% (95% CI 90.2%-100%). SCT was deferred in most patients (40/45, 89%). Grade 3 or 4 side effects (≥2 patients) included neutropenia (24%), elevated alanine aminotransferase (10%), acute kidney injury (6%), and thrombocytopenia (6%). Grade 1-2 infusion-related reactions in 20%, no grade 3. Hypertension in 49% grade 1-2 and one grade 3; one grade 3 myocardial infarction. There was one death assessed as unrelated. Two patients withdrew for acute kidney injury. Two patients were not evaluable at C4 and C6/C8 because measurable disease could only be assessed by PET CT. There were statistically significant within-patient improvements in global health status ( p&amp;lt;.01), physical ( p&amp;lt;.01), role ( p&amp;lt;.01), emotional ( p=.01), and social functioning ( p&amp;lt;.01), body image ( p&amp;lt;.01), future perspective ( p&amp;lt;.01), fatigue ( p&amp;lt;.01), pain ( p&amp;lt;.01), loss of appetite ( p&amp;lt;.01), and symptoms ( p&amp;lt;.01). There were no statistically significant changes in body composition measurements between baseline and the completion of 4 cycles or consolidation/induction. There was a significant improvement in total lean mass ( p=0.01) between baseline and end of induction adjusted for SCT status. In terms of correlatives to-date, there were no significant differences in total T cells, total templates, total productive templates; total and productive rearrangements; or clonality, maximum productive frequency and T cell fraction between those patients achieving MRD negativity and those not and no significant differences between clonality at baseline and post-induction/consolidation. Conclusions: Isa-KRd induces deep and durable responses, with an ORR of 100% (including 96% VGPR or better, 66% MRD negative) as well as improved quality of life in transplant-eligible patients with NDMM, with or without SCT. The overall safety profile was favorable and consistent with similar regimens in this setting, with toxicities proving generally manageable.

Functional Imaging As a Key Diagnostic Tool in the Follow-up of RRMM Patients after CAR-T-Cell Therapy

Introduction: Anti BCMA CAR T-cell therapy (CART) is establishing itself as a new standard of care for relapsed and refractory multiple myeloma (RRMM). However, the optimal follow-up strategy post CART has yet to be determined. Prior studies of our own and others have emphasized the role of functional imaging in monitoring RRMM patients post traditional chemotherapy, revealing residual disease in up to 50 % of otherwise minimal residual disease (MRD) negative patients (Rasche et al. Leukemia 2019). Whether a similar patchy disease pattern is relevant post CART remains unknown. To address this, we implemented a standardized follow-up program post CART, which includes 18F-FDG PET-CT, diffusion-weighted MRI, and bone marrow aspiration with MRD measurements at our center. Methods: We conducted monthly ambulatory visits and serological testing to monitor patients post CART infusion. Additionally, an extended follow-up visit at three months post CART infusion was performed, encompassing whole body PET-CT, whole body diffusion-weighted MRI, and bone marrow aspiration with MRD testing. Response assessments were based on IMWG criteria. MRI classified focal lesions as vital if they exhibited 1) significant diffusion-restriction, 2) a fat fraction less than 20 %, and 3) homogenous hypointensity on T2-weighted images. MRD measurements were performed with flow cytometry with a sensitivity of at least 10 -5 following the Euroflow recommendations. Results: From December 2021 to July 2023 we treated 37 heavily pretreated patients with idecabtagene vicleucel at our center. These patients had a median of 5 prior lines of therapy. High-risk cytogenetics, extra-medullary disease (EMD), and non-secretory disease were seen in 17, 14 and 6 patients, respectively. At data cut off, the ORR, VGPR and CR rates were 78 %, 27 % and 27 %, respectively. We observed primary refractory disease in 14 % of the patients. Among the 22 patients who underwent extended follow-up examinations at three months, the majority achieved MRD negativity, with only 7/22 (32 %) remaining MRD positive after CART. However, functional imaging revealed a higher number of patients with residual disease, with positive results on PET-CT and DW-MRI in 9/22 (41 %) and 10/22 (45 %) of patients, respectively. Notably, 6 of 22 (27 %) patients displayed active lesions on imaging despite MRD negativity at the iliac crest at this time point. Next, we focused on patients who experienced relapse from CART and sought to determine the necessary technology to detect relapse in this setting. Thirteen patients experienced relapse during the study period, and in 8 (61%) of them, functional imaging was the sole method to detect progressive disease. Only 1 patient transitioned from MRD negative to positive during the follow-up period, while the remaining 4 patients showed a significant M protein increase as defined by the IMWG criteria. Conclusion: In our heavily pretreated RRMM population, functional imaging emerged as a crucial diagnostic tool, detecting relapse alone in more than half of the patients. Our data supports inclusion of cross-sectional imaging in a comprehensive follow-plan after CART.