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75 Background: The Rx landscape of pts with mCRPC has recently evolved with the approval of lutetium-177-PSMA-617 (Lu-177) and poly(ADP) ribose polymerase inhibitors (PARPi) either as single agents or as combinations with an androgen receptor pathway inhibitor (ARPI) [PMID: 37442702]. However, real-world data on the uptake of these agents are lacking. Herein, we sought to assess the Rx patterns and attrition rates of pts with mCRPC in the era of newly approved therapies. Methods: The de-identified nationwide Flatiron Health Electronic-Health Record (EHR)-derived database was used to extract pt-level data. Eligibility criteria: diagnosis of mCRPC and Rx line (L) information. The data cut-off date was 5/31/2024. Rx patterns in each line of therapies were summarized using frequency and percentages. All analysis was done using R version 4.2.3. Results: Of the overall cohort of 24,105 pts with metastatic prostate cancer, 12,333 pts diagnosed with mCRPC between 1/1/2013 and 5/9/2024 met the eligibility criteria and were included. Rx trends are summarized (Table). Of pts receiving 1L Rx, 61% of pts received 2L therapy, and 35% received 3L therapy. Androgen receptor pathway inhibitor (ARPI) was the most common Rx in the 1L setting (73.7%), followed by taxane (10%) and sipuleucel-T (3.8%). In 2L, ARPI was again the most frequent Rx (46.8%), followed by taxane (23.6%). In 3L, taxane became the most frequent Rx (35.4%), followed by ARPI (26.2%) and radium-223 (4.9%). Rx trends per year will be presented in the meeting. Conclusions: In the current era,a high proportion of pts with mCRPC receiving 1L Rx do not receive a subsequent line of Rx (39% of pts do not receive 2L, and 65% do not receive 3L Rx). ARPIs and taxanes remain the most frequently used Rx options in most L of therapy. These findings highlight the need for better tolerated Rx, therapies with a novel mechanism of action, and improved access to care for our pts. Rx trends per year will be presented in the meeting. Rx patterns in pts with mCRPC. Rx 1L, n (%)N = 12,333 2L, n (%)N = 7475 3L, n (%)N = 4316 4L, n (%)N = 2339 5L, n (%)N = 1225 ARPI 9085 (73.7) 3503 (46.8) 1130 (26.2) 356 (15.2) 157 (12.8) PARPi-based therapies 93 (0.8) 185 (2.5) 142 (3.3) 98 (4.2) 47 (3.9) Platinum-based therapy 127 (1) 216 (2.9) 198 (4.6) 148 (6.3) 130 (10.6) Lu-177-based therapies 50 (0.4) 109 (1.5) 169 (3.9) 143 (6.3) 103 (8.4) Radium-223 183 (1.5) 241 (3.2) 213 (4.9) 125 (5.3) 79 (6.4) Sipuleucel-T 474 (3.8) 94 (1.3) 53 (1.2) 18 (0.8) 8 (0.7) Taxane 1240 (10) 1763 (23.6) 1526 (35.4) 935 (40) 393 (32) Pembrolizumab 24 (0.2) 41 (0.5) 36 (0.8) 27 (1.2) 29 (2.4) Other*/not-applicable** 665 (5.4)/392 (3.2) 1000 (13.4)/323 (4.3) 602 (14)/247 (5.7) 320 (13.7)/169 (7.2) 162 (13.3)/117 (9.5) *Includes drugs approved for mCRPC in combination with unapproved agents or clinical trial drugs. **Includes agents not approved for prostate cancer.

104 Background: Androgen deprivation therapy (ADT) intensification [ADT + androgen receptor-pathway inhibitor (ARPIs) +/- docetaxel] has been shown to improve survival outcomes in pts with mHSPC and is recommended as standard of care by all major guidelines. However, prior studies have shown underutilization of ADT intensification [PMID: 39191549]. There are limited updated and large-scale studies on the use of ADT intensification, beyond January 2023. In this study, we aimed to assess the treatment patterns of ADT intensification in real-world pts with mHSPC in the US, including data on those treated since January 2023. Methods: This retrospective study utilized the nationwide Flatiron Health Electronic Health Record (EHR) derived de-identified database. Eligibility: Pts diagnosed with mHSPC and availability of treatment information (ADT and/or line of therapy in mHSPC). The data cut-off date was 5/31/2024. Treatment patterns were summarized using frequency and percentages. All analysis was done using R version 4.2.3. Results: Among 24,105 pts with metastatic prostate cancer in the database, a total of 14,084 were eligible and included. The median age at metastatic diagnosis was 72 years (IQR 65 – 79), and 60% were White non-Hispanic. In the overall cohort (1/1/2013–5/15/2024), 56.8% received ADT monotherapy, and 37.7% received ADT intensification. Table summarizes the treatment patterns by year, highlightinga consistent increase in adoption of intensified ADT regimens, and a decline in use of ADT monotherapy. Notably, since January 2023, 76.8% pts with mHSPC received ADT intensification while only 17.3% of pts received ADT monotherapy. Conclusions: To our knowledge, this is the first and largest study to evaluate the current use of ADT intensification. These data indicate a notable improvement in the adoption of level 1 evidence (ADT intensification) in the treatment of pts with mHSPC. These encouraging data emphasize the benefits of continued efforts to promote guideline-concordant care and provide the current treatment landscape to design clinical trials. Treatment patterns by year in pts with mHSPC. Treatment 2013–2017n = 5,263(%) 2018n = 1,313 (%) 2019n = 1,407(%) 2020n = 1,353(%) 2021n = 1,483(%) 2022n = 1,556(%) 2023n = 1,459(%) 2024n = 250(%) ADT monotherapy 4,095 (77.8) 856 (65.2) 819 (58.2) 664 (49) 698 (47.1) 569 (36.6) 291 (20) 5 (2) ADT + ARPI 155 (2.9) 238 (18) 354 (25.1) 452 (33) 555 (37.4) 695 (44.7) 842 (58) 154 (61.6) ADT + Docetaxel 709 (13.5) 156 (12) 175 (12.4) 156 (12) 134 (9.0) 117 (7.5) 78 (5.3) 19 (7.6) Triplet(ADT + ARPI + Docetaxel) 6 (0.1) 2 (0.2) 1 (0.1) 2 (0.1) 9 (0.6) 82 (5.2) 166 (11.1) 53 (21.2) Other therapies 298 (5.7) 61 (4.6) 58 (4.1) 79 (5.8) 87 (5.9) 93 (6) 82 (5.6) 19 (7.6)

AbstractBackgroundExternal‐beam radiation (EBRT) is a noninvasive therapeutic alternative to transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). The objective of this study was to conduct a systematic review and meta‐analysis of prospective randomized clinical trials to assess the clinical efficacy of EBRT versus TACE for HCC as either a definitive monotherapy or as a bridge to transplantation/surgery.MethodsA systematic review and meta‐analysis were performed to include prospective randomized trials comparing EBRT versus TACE. Data was analyzed with random and fixed‐effects models. The inconsistency index (I2) was chosen to assess heterogeneity. Three publications were included with a total of 142 patients. Outcomes included local control (LC), overall survival (OS), progression‐free survival (PFS), and occurrences of grade ≥3 toxicity. Comparisons are reported as hazard ratios (HRs) or risk ratios (RRs) with 95% confidence intervals (CIs).ResultsThere were three randomized trials that met inclusion criteria. The EBRT was delivered in three to 15 fractions with a total dose between 30 and 75 gray(Gy). EBRT was associated with significantly improved LC (HR, 0.16; 95% CI, 0.08–0.34; I2 = 0%) and PFS (HR, 0.37; 95% CI, 0.23–0.60; I2, 0%) compared with TACE. There was no significant difference between EBRT and TACE in OS (RR, 0.79; 95% CI, 0.51–1.22; I2 = 0%) or grade ≥3 toxicity (RR, 0.86; 95% CI, 0.31–2.37; I2 = 57%). None of the analyses had statistically significant heterogeneity.ConclusionsCompared with TACE, EBRT yields superior LC and PFS without providing a survival benefit in early and intermediate stage HCC. Additional larger prospective randomized controlled trials should be conducted to further investigate differences in clinical outcomes amongst patients with more advanced disease.

ABSTRACTBackgroundThe carbon‐13 spirulina gastric emptying breath test (GEBT) is approved to identify delayed, but not accelerated, gastric emptying (GE). We compared the utility of the GEBT to scintigraphy for diagnosing abnormal GE in patients with diabetes mellitus.MethodsTwenty‐eight patients with diabetes ate a 230‐kcal test meal labeled with technetium 99 m and 13C‐spirulina, after which 10 scintigraphic images and breath samples (baseline, 15, 30, 45, 60, 90, 120, 150, 180, 210, and 240 min) were collected on 2 occasions 1 week apart. We assessed the accuracy of 13C‐spirulina GEBT excretion rate (percent dose multiplied by 1000 [kPCD] min−1) values to predict scintigraphic half‐life and distinguish between normal, delayed, and accelerated GE and the intraindividual reproducibility of the GEBT.Key ResultsScintigraphy revealed normal, delayed, and accelerated GE, respectively, in 17 (30%), 29 (52%), and 10 (18%) test results. GE T½ values measured with scintigraphy and GEBT were highly concordant within individuals; the intraindividual reproducibility was 34% (scintigraphy) and 15% (GEBT). Compared to current criteria, the kPCD150 (150 min) and kPCD180 values provided equally sensitive (90%) and more specific (81% vs. 67%) approach for distinguishing between delayed versus normal/accelerated GE. A new metric (kPCD60–kPCD15 min) was 90% sensitive and 83% specific for distinguishing between accelerated versus normal/delayed GE. These findings were used to create nomograms and an algorithm for interpreting GEBT results.Conclusions and InferencesAmong patients with poorly controlled diabetes, the 13C‐spirulina GEBT can accurately and precisely assess GE and effectively distinguish between normal, delayed, and accelerated GE.

Introduction Induction therapy (Tx) followed by ASCT and lenalidomide (LEN) maintenance is the standard of care in transplant-eligible pts with NDMM. Pts who have suboptimal response after front-line ASCT, however, have an increased risk of progression or death. Ide-cel demonstrated significantly improved median progression-free survival (PFS) and overall response rate (ORR) vs standard regimens in KarMMa-3 in pts with early-line triple-class-exposed relapsed and refractory multiple myeloma (MM). KarMMa-2 (NCT03601078) is a multicohort, phase 2, multicenter trial evaluating the efficacy and safety of ide-cel in several MM disease settings; cohort 2c includes pts with NDMM who achieved < very good partial response (VGPR) after front-line ASCT. An extended follow-up analysis (median follow-up of 39.4 months) of cohort 2c was presented at ASH 2023 (Dhodapkar M, et al. ASH 2023; P2101). Here, we report results with 55.4 months of median follow-up and additional data on pts who received LEN maintenance at the investigator's discretion. Methods Adult pts with NDMM who received ≥ 3 cycles of induction Tx (proteasome inhibitor, immunomodulatory agent, dexamethasone), and had < VGPR 70-110 days after ASCT (single/tandem) were eligible. Pts received a single ide-cel infusion (150-450 × 106 chimeric antigen receptor-positive T cells) and could receive maintenance Tx post-infusion at investigator discretion. The primary endpoint was complete response rate (CRR); secondary endpoints included ORR, duration of response (DOR), PFS, overall survival (OS), safety, cellular kinetics, and patient-reported outcomes on health-related quality of life (HRQoL). Minimal residual disease (MRD) negativity (sensitivity, 10-5), an exploratory endpoint, is also reported. Results At data cutoff (June 28, 2024), with a median follow-up of 55.4 (range, 51.4-59.5) months, all 31 pts treated with ide-cel were alive; 28 (90.3%) remained in follow-up and 3 (9.7%) discontinued due to disease progression or withdrawal by pt. Eight pts received LEN maintenance after ide-cel at the investigator's discretion. Among all 31 ide-cel-treated pts, CRR and ORR were 80.6% and 87.1%, respectively. Among the 8 pts who received LEN maintenance, CRR and ORR were 75.0% and 100.0%, respectively. Median DOR, PFS, and OS were not reached; 36-month event-free rates were 81.5%, 76.8%, and 100.0%, respectively. Of the 8 pts who received LEN maintenance after ide-cel infusion, none experienced disease progression. At 36 months, MRD negativity was confirmed in 12/18 (66.7%) evaluable pts; all 12 achieved ≥ CR. Since last data cutoff, 1 pt with MRD-negative MM changed to MRD-positive at 36 months, and 1 pt who had previously achieved MRD negativity was indeterminate at 36 months. Among the 6 evaluable pts who received LEN maintenance, 3/6 (50.0%) achieved MRD negativity at 36 months. There were no new safety signals nor reports of parkinsonism or Guillain-Barré syndrome since the previous data cutoff. In the 8 pts who received LEN maintenance, 6 (75.0%) experienced grade 3/4 AE, most commonly neutropenia, and 1 (12.5%) experienced grade 3/4 infection on or after LEN maintenance. All 8 pts were still receiving LEN at data cutoff. Robust CAR+ T cell expansion was observed in 31 pts, with higher expansion in pts with ≥ CR vs < CR. Following ide-cel treatment, HRQoL improved and disease symptoms were stable over time (assessed by European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Core Questionnaire and EORTC Quality of Life Multiple Myeloma Module 20 Questionnaire). More than 75% of pts had improved or stable global health status/QoL by month 3. Conclusions With extended follow-up, ide-cel continued to demonstrate deep, durable responses in pts with < VGPR to front-line ASCT. No new safety signals were observed and no deaths were reported. Data in a small group of pts in cohort 2c showed that ide-cel followed by LEN maintenance extended disease control. Pts who received LEN maintenance did not experience disease progression regardless of MRD status. Stable or improved HRQoL was observed after ide-cel treatment. Overall, ide-cel continued to show a favorable clinical benefit-risk profile in NDMM after ASCT. The phase 3 KarMMa-9 study (NCT06045806), currently recruiting, will compare ide-cel followed by LEN maintenance vs LEN maintenance alone in pts with NDMM after suboptimal response to ASCT.

Introduction Despite improvements in outcomes with triplet and quadruplet combination regimens in front-line (1L) multiple myeloma (MM) treatment (Tx), pts with disease that relapses early after 1L Tx or responds inadequately to 1L autologous stem cell transplantation (ASCT) have poor prognosis. Therefore, Txs with novel mechanisms of action are needed. Ide-cel, a BCMA-directed CAR T cell therapy, resulted in deep and durable responses in pts with functional high-risk MM. KarMMa-2 (NCT03601078) is a phase 2, multicenter, multicohort trial of ide-cel: cohort 2a includes pts who progressed ≤ 18 mo of starting 1L therapy with ASCT, cohort 2b includes pts who progressed ≤ 18 mo of starting 1L therapy without ASCT, and cohort 2c includes pts who achieved less than very good partial response ~100 d after 1L ASCT. With a median follow-up of 21.5, 30.1, and 39.4 mo, respectively, median PFS (95% CI) for cohorts 2a, 2b, and 2c was 11.4 mo (5.6-19.6), not reached (NR; 12.2-NR), and NR (38.0-NR). Previous correlative analyses of ide-cel in relapsed and refractory MM have shown that pts with lower pre-Tx tumor burden and lower pre-Tx indicators of basal inflammation had better responses. This cross-cohort analysis evaluated tumor burden, baseline inflammatory status, and T-cell quality differences to develop hypotheses for biologic features underpinning robust PFS previously observed with ide-cel. Methods Levels of soluble BCMA (sBCMA) and 25 exploratory cytokines at infusion and post-Tx were measured by immunoassay. Apheresis and drug product material were characterized by high-parameter flow cytometry and immunoassay. Pharmacokinetics (PK) were evaluated by droplet digital polymerase chain reaction. These analyses were exploratory and post hoc in nature; statistical tests were utilized to identify relationships of interest to develop working hypotheses of the underlying biology. Results Baseline tumor burden, evaluated by median sBCMA (interquartile range [IQR]), was highest in cohort 2b at 156 ng/mL (83-300) compared with 2a at 91 ng/mL (41-169) and 2c at 27 ng/mL (19-48). Pts in cohort 2b had the lowest baseline levels of a subset of inflammatory cytokines, including interferon [IFN]-γ and interleukin-4. Phenotypic data from apheresis material showed that, among the 3 cohorts, pts in cohort 2b also had the lowest amount of effector memory T cells positive for CD45RA (TEMRA; terminally differentiated T cells) and CD57+ T cells (senescent T cells), and the highest amount of CCR7+CD27+ T cells (early memory T cells). Cohorts 2a and 2c had similar phenotypic profiles in the apheresis material. Median time from ASCT to infusion (IQR) was 12.1 mo (9.7-14.3) in cohort 2a and 5.8 mo (5.2-6.2) in cohort 2c. Pts in cohort 2b also had a higher CD4:CD8 ratio in the apheresis material vs the other 2 cohorts. Profiling the drug products from pts in cohort 2b showed higher CAR+ T cell frequency and CAR-specific IFN-γ, and tumor necrosis factor-α and granzyme secretion upon stimulation vs 2a and 2c, with a consistent and comparable potency profile among all cohorts. While sBCMA level at infusion was lower in cohort 2c vs 2a, the similarity in inflammatory state and T-cell quality may reflect impacts from recent melphalan use before ASCT and bone marrow recovery after ASCT, as most pts in both cohorts were < 18 mo from ASCT. Robust cell expansion was observed across cohorts. Conclusions The encouraging median PFS outcome previously observed in cohort 2b relative to existing therapies in this high-risk pt population may be driven by the higher T-cell quality and better inflammatory state pre-Tx despite high baseline tumor burden (sBCMA). Pts in cohorts 2c and 2a had comparatively less optimal baseline immune status vs cohort 2b. The promising PFS observed in cohort 2c may be reflective of sufficient T-cell quality to drive optimal responses in the context of relatively low tumor burden at study entry. The median PFS in cohort 2a may reflect the combination of high tumor burden and less optimal baseline inflammatory status. These observations suggest a working model in which ide-cel may demonstrate robust PFS in pts with early-line, high-risk MM and high tumor burden with good baseline immune status and T-cell quality, and in pts with less favorable baseline immune status and T-cell quality when tumor burden is relatively low and stable.

Introduction: TP53 mutations are found in 18% of adult patients (pts) with acute lymphoblastic leukemias (ALL), and portends poor prognosis (Saygin, Blood Cancer Discov 2024). TP53 mutations are often associated with low hypodiploidy and Li Fraumeni syndrome (germline) in children. However, we and others have shown that TP53-mutant (TP53-m) ALL arises from pre-existing TP53-m clonal hematopoiesis in adults as opposed to germline origin. The impact of co-occurring mutations, TP53 allelic frequency (AF) and different types of treatment on outcomes of TP53-m ALL are not fully characterized. We set out to investigate the clinical and molecular predictors of outcomes in adults with TP53-mutant ALL. Methods: We retrospectively studied 107 patients with TP53-m ALL treated at seven different academic centers in North America. Genetic profiling of pre-treatment bone marrow samples was performed with a comprehensive panel covering 147 myeloid and lymphoid genes. We also performed RNA-sequencing to identify fusions that define ALL subtypes. Single nucleotide polymorphism (SNP) array was used to define low hypodiploidy. Results: The median age at diagnosis was 59 years (range, 10-80), 42% were female, 70% White. 89% of pts had B-ALL while 11% had T-lineage ALL. 24% of pts were classified to have therapy-related ALL based on their history of exposure to genotoxic therapy for another cancer. 45% of pts had hypodiploid karyotype, 79% of whom were low-hypodiploid. 7% had hyperdiploid karyotype and 5% had BCR::ABL1. 11 pts had two different TP53 variants. 90% of TP53 variants involved the DNA binding domain. Most frequently observed co-occurring mutations involved CDKN2A (20%), NOTCH1 (12%) and RB1 (10%) genes. 71% of pts were treated with standard cytotoxic chemotherapy, while the remaining pts received newer antibody-based therapies (i.e., inotuzumab, blinatumomab) or venetoclax in first-line setting. 11% of pts received allogeneic hematopoietic cell transplant (HCT) in first complete remission (CR1) while 3% received HCT after relapse (CR2 or CR3). When patients with vs without low hypodiploidy were compared, we did not observe a significant difference in overall survival (OS) as outcomes were poor in both groups (median, 17 vs 19 months, p= 0.89). However, pts who had TP53 AF >0.5 had significantly worse OS when compared to pts with TP53 VAF <0.5 (13 vs 25 months, p= 0.03). Conclusions: TP53-m ALL is a very high-risk disease subtype and its dismal outcome is independent from presence of co-existing low hypodiploidy. Loss of heterozygosity, characterized by TP53 AF >0.5 is associated with even worse survival. New therapies are urgently needed to improve outcomes in this subset.

Introduction: Phase I trials are designed to evaluate the safety and tolerability of new treatments. Review of adverse events (AEs) experienced by trial participants is a critical aspect of these early phase trials. Current practice for safety and tolerability data collection is for clinicians to evaluate AEs using the Common Terminology Criteria for Adverse Events (CTCAE). Past work has demonstrated that clinicians may miss or underreport symptomatic AEs. The Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE) is an item library of questions for patients to self-report symptomatic AEs in clinical trials that is complementary to the CTCAE. PRO-CTCAE offers a patient-centric method for capturing symptomatic AEs, which may be missed or underreported by clinicians. The PRO-CTCAE library includes questions using patient friendly terms to assess frequency, severity, and interference of symptomatic AEs on 0-4 verbal descriptor scales (e.g., severity is rated by patients as none, mild, moderate, severe, or very severe). The goal of the current work was to demonstrate how to incorporate AE information from PRO-CTCAE and CTCAE into a Phase I dose review report. Methods: We used data from a Phase I clinical trial of patients with relapsed or refractory acute myeloid leukemia. Therapy was administered on 28-day cycles. Patients completed questionnaires on an electronic device on days 1, 8, 15, and 22 of the first cycle of treatment. Through iterative feedback from clinicians and statisticians, we developed an example dose review report. The report summarized data for one dose level in which 4 patients were treated. These 4 patients comprised the first patient cohort enrolled in the available Phase I clinical trial. The report was intended to be representative of the type of report that would be reviewed to make a decision about the next dose level for a new cohort of patients. Results: The final dose review report included narratives for each patient generated by the statistical team based on patient-reported and physician-graded AEs in cycle 1, tabular summaries integrating CTCAE and PRO-CTCAE, and novel graphical presentation of PRO-CTCAE and CTCAE, including swimmer plots and butterfly plots for symptoms listed as dose limiting toxicity criteria. In this cohort, 3/4 (75%) patients had at least one grade 3+ AE, as assessed by CTCAE, and 4/4 (100%) patients had at least one score 3 symptomatic AE, as assessed by PRO-CTCAE. All 4/4 (100%) patients had at least one reported symptom on the PRO-CTCAE that was not captured by CTCAE or was reported at a lower grade by CTCAE. Multiple versions of the example dose review report were presented to the study team and iterative feedback was solicited from clinicians and statisticians. Feedback highlighted the usefulness of narratives and patient-level graphical displays. Narratives within the dose review report were refined to focus on treatment emergent AEs, minimizing text and succinctly presenting baseline symptoms where relevant. Symptom-level graphics of combined PRO-CTCAE scores and CTCAE grades were preferred over graphics consolidating data for multiple symptoms. Final graphics and report will be presented. Conclusions: We demonstrated that PRO-CTCAE, which captures patient-reported symptoms, complements traditional AE reporting and that reporting PRO-CTCAE and CTCAE jointly in a Phase I dose level report can provide a more complete picture of safety and tolerability in the Phase I setting.

Background: Anti-BCMA CAR T cells are a new standard of care for the treatment of RRMM patients. Hence, it is paramount to identify determinants of response and resistance for individualized approaches. There is emerging data about the importance of depth of response in prolonged progression-free survival (PFS) and of genetic antigen escape in treatment resistance. By contrast, there is limited understanding of how patient' outcomes are shaped by immune fitness prior aphaeresis, and virtually no data about CAR T and endogenous profiles post infusion. Aim: Characterize immune dynamics and investigate its prognostic value in RRMM patients treated with CAR T cells. Methods: Immune profiling was performed using multidimensional and computational flow cytometry in 285 bone marrow aspirates from 120 RRMM patients enrolled in the KarMMa phase 2 trial. In total, 170 immune clusters were identified and systematically quantified in a pileup analysis of samples collected before and at months 1, 3, 6 and 12 after CAR T infusion. Immune scores were developed using cox regression with 10-fold cross-validation. Results: At baseline (n = 63), there were significant associations between the bone marrow immune composition and the number of prior lines of treatment, prior autologous transplant and staging. Namely, there were higher proportions of ICOS, PD1, TIGIT and TIM3 positive cells within the CD4+ and CD8+ T cell compartments from heavily pretreated patients and those with R-ISS 3. A baseline immune score defined by the percentages of GrzmB+HLADR+ cytotoxic NK cells, TIGIT+ Tregs, CD4+CD127+ICOS+ and CD4+CD25+CD127+TIGIT+, CD8+TIGIT+, CD8+GrzmB+HLADR+ and CD8+CD27+CD95+CD45RAloCD197lo T cells was associated with PFS. Patients with low vs high risk immune score at baseline had median PFS of 25 vs 6 months, respectively (p < .001). Interestingly, there were no significant associations between the baseline risk score and treatment or staging, suggesting potential complementarity of immune profiling with other prognostic factors. At month 1 after infusion (n = 55), the presence of >1% vs <1% CAR T cells was associated with longer PFS (medians of 20 vs 8 months, p = .002). In addition to the magnitude of CAR T persistence, it was interesting to observe increased percentages of CD8+ CAR T cells in patients with <5 prior lines of therapy, of CD4+HLADR+ and CD8+TEMRA CAR T cells in patients with R-ISS 1/2, as well as of PD1+TIM3+ CD4+ and CD8+ CAR T cells in patients with R-ISS 3. Moreover, the phenotype of CAR T cells was associated with PFS. Patients with low vs high risk immune score (ie, based on the percentages of CD4+CD57+, CD8+CD27-EM, CD8+PD1+TIM3+ and CD4+CD8+ CAR T cells) had median PFS not reached vs 11 months, respectively (p < .0001). Similarly to the above, there were no significant associations between the CAR T immune risk score and treatment or staging, suggesting potential complementarity of CAR T quantification and phenotyping post-infusion with other patient' characteristics. Next, we investigated endogenous T cell dynamics in 51 RRMM patients with paired samples prior and after CAR T infusion. There were significant differences in the frequencies of 30 immune clusters, including CD27+ naïve and EM CD4+ and CD8+ T cells, ICOS+ and TIGIT+ Tregs, CD4+ and CD8+ T cells, as well as of CD25+CD127+ CD4+ and CD8+ T cells. Furthermore, an immune risk score defined at the latest available time point (n = 95) was associated with PFS (p < .0001). Patients with lower levels of GrzmB+ cytotoxic NK cells and of immunoregulatory HLADR- NK cells, as well as of CD4+CD27+CD95+CM, CD4+HLADR+, CD8+PD1+ and CD8+CD27-CD95+EM T cells showed a high risk score and a median PFS of 6 vs 20 months in patients with low risk immune score. Conclusions: This is one of the largest dynamic studies of immune profiling in a clinical trial investigating anti-BCMA CAR T cells in RRMM. Our results uncovered that patient' immune status is shaped by prior treatment and staging, and that the distribution of different NK, Treg, CD4+ and CD8+ T cells prior aphaeresis is associated with PFS. Furthermore, the phenotype of CAR T cells at month 1 after infusion may be as prognostic as its percentage. We also showed how treatment with CAR T cells modulates the bone marrow immune composition and how it may contribute to immune escape vs surveillance. Altogether, this study supports immune profiling for improved understanding of response and resistance to CAR T cells in RRMM.

Background: ctDNA clearance after frontline DLBCL tx has shown strong prognostic value for favorable outcomes, with the potential to improve MRD-driven therapeutic strategies and establish MRD as a surrogate endpoint in future studies (Roschewski M, et al. Blood 2022; Goldstein J, et al. Blood 2023). However, further study is needed to evaluate the association of this noninvasive approach with efficacy outcomes after 2L LBCL tx. We previously reported ctDNA analysis after liso-cel infusion in TRANSFORM (NCT03575351; Stepan L, et al. Blood 2023;142[suppl 1]). Here, we describe the predictive value of pre-tx and on-tx ctDNA levels for durable clinical benefit (CR and event-free survival [EFS]) in both liso-cel and SOC arms from TRANSFORM (Kamdar M, et al. J Clin Oncol 2024), evaluating ctDNA as an earlier surrogate for conventional clinical outcomes. Methods: Baseline (prerandomization) and longitudinal ctDNA levels were assessed in randomized pts treated with liso-cel or SOC in TRANSFORM using the phased variant enrichment and detection sequencing assay (PhasED-Seq; Foresight Diagnostics). Phased variants were identified from baseline plasma samples for longitudinal ctDNA monitoring at multiple on-tx time points, as previously described (Stepan L, et al. Blood 2023;142[suppl 1]). Randomization was defined as study Day 1. Association of ctDNA levels with response per independent review committee using Lugano 2014 criteria and EFS was investigated at various predefined time points, including Day 43 (after 2 cycles of salvage immunochemotherapy for SOC; Day 15 after liso-cel infusion), Day 64 (after 3 cycles of salvage immunochemotherapy for SOC; 1 month after liso-cel infusion), and Day 126 (within 2 months after ASCT; 3 months after liso-cel infusion). To assess the surrogacy value of ctDNA, ctDNA-MRD dynamics and ctDNA clearance were investigated within both arms. Results: In pooled analyses combining the liso-cel and SOC arms, higher baseline ctDNA levels (above the median) were associated with shorter EFS (P = 0.05). Pts achieving Day 126 CR had substantial reductions in ctDNA burden vs baseline, while pts with PD or stable disease had persistently high ctDNA levels vs baseline. Achieving undetectable ctDNA at different time points was associated with significantly longer EFS in pooled analyses, observed as early as study visit Day 43, with the strongest association at Day 126. HR (95% CI) for inferior EFS was 3.0 (1.6-5.7) at Day 43, 3.8 (2.1-7.0) at Day 64, and 4.2 (2.3-7.7) at Day 126 in pts with detectable vs undetectable ctDNA. In the analysis by tx arm, consistent with the pooled analyses, ctDNA clearance was associated with EFS benefit at all measured time points with either liso-cel or SOC. Significantly more pts achieved undetectable ctDNA with liso-cel vs SOC during the study (39/63 [62%] vs 25/65 [38%], respectively; P = 0.013), consistent with superior EFS (primary endpoint) with liso-cel in TRANSFORM. All pts in the SOC arm with evaluable ctDNA at Day 126 (n = 28) had received high-dose chemotherapy (HDCT)/ASCT. However, pts with undetectable ctDNA in the liso-cel vs SOC arm had longer EFS at all predefined time points and had statistically longer EFS at Day 126 (SOC vs liso-cel: HR, 3.9 [95% CI, 1.4-10.6]), indicating a deeper and more durable response with liso-cel vs SOC. In pts with CR, ctDNA showed significant predictive value beyond the response assessment at all time points in the liso-cel arm with a HR (95% CI) of 3.8 (1.3-11.0) at Day 64 and 7.0 (2.0-24.3) at Day 126 for EFS in pts with detectable ctDNA vs undetectable ctDNA. Among pts in the SOC arm who experienced subsequent PD despite achieving CR (all received HDCT/ASCT) and undetectable ctDNA at Day 126, serial ctDNA assessment showed consistent reversion to detectable ctDNA at later time points. Conclusions: ctDNA data from TRANSFORM confirm the value of ctDNA as a biomarker for disease burden monitoring and early prediction of durable clinical benefit after 2L LBCL treatment. Furthermore, longitudinal ctDNA molecular response results agree with previously reported clinical efficacy data and confirm the superiority of liso-cel with deeper responses over the historical SOC in 2L LBCL. ctDNA may have a key role as a surrogate endpoint in future LBCL studies, including after CAR T cell therapies.