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

Background: Tec is a BCMA-directed bispecific antibody (BsAb) approved for RRMM after ≥4 prior lines of therapy (LOT) based on the MajesTEC-1 trial. However, patients who had previously received a BCMA-DT were excluded from MajesTEC-1. Herein, we evaluated outcomes of RRMM patients with prior exposure to BCMA-DT treated with standard-of-care Tec. Methods: This was a multicenter retrospective cohort study. We compared variables between different groups using Chi-squared and Kruskal-Wallis tests, and assessed progression free survival (PFS) and overall survival (OS) using Kaplan Meier and Cox proportional hazards model. We used the maximally selected rank statistics method to determine the optimal cut-off point for continuous variables to find the most significant difference in PFS among different groups. Results: A total of 385 patients were included in this study. 193 patients had received a prior BCMA-DT, of whom 77%, 22%, and 1% had received 1, 2, and 3 prior anti-BCMA agents, respectively. In patients who had received a prior BCMA-DT, 35% were aged ≥70 years, 24% had ECOG performance status (PS) ≥2, 61% had high-risk FISH, 32% had extramedullary disease (EMD) at Tec initiation, and 42% were penta-refractory. Compared to the cohort without prior BCMA-DT (n=192), patients who were treated with prior BCMA-DT were more likely to have high risk FISH (61% vs 49%, p=0.02), and higher median number of prior LOT (7 vs 5, p <0.001). The specific types of prior BCMA-DTs with the respective overall response rate (ORR) to the most recent prior BCMA-DT were: antibody drug conjugate only (ADC, n=47, ORR 43%), chimeric antigen receptor T-cell therapy only (CAR T, n=99, ORR 86%), BsAb only (n=6, ORR 100%), ADC + CAR T (n=36, ORR 56%), and other ADC/CAR T/BsAb combinations (n=5, ORR 60%). Median follow up was 9.9 (95% CI:9.5-10.6) months. Patients with prior receipt of BCMA-DT had a lower ORR (51.4% vs 61.5%; p=0.012) and ≥very good partial response rate (39.4% vs 52.6%, p=0.009), but similar ≥complete response rate (22.3% vs 24%; p=0.78) to Tec compared to those without prior BCMA-DT. Moreover, patients with prior BCMA-DT had worse median PFS compared to patients without prior BCMA-DT (prior BCMA-DT: 4.6 months, 95% CI: 2.7-7.5; without prior BCMA-DT: 8.2 months, 95% CI: 5.7-12.2; p=0.017). On multivariable analysis incorporating prior BCMA-DT, age, cytogenetics, EMD, and ECOG PS, receipt of prior BCMA-DT was not independently associated with PFS (HR 1.25, 95% CI 0.95-1.64, p=0.1). The estimated 1-year OS rate was 58.9% (95% CI: 51.64-67.2) for the prior BCMA-DT group vs 65.1% (95% CI: 58.1-73.1) for the group without prior BCMA-DT, p=0.16. For the prior BCMA-DT cohort, response rates to Tec were numerically higher in patients who received CAR T (ORR 51.2%) followed by ADC (ORR 45.5%), and bispecific (ORR 30%) as their most recent prior BCMA-DT (p=0.39). No significant difference in PFS was noted when stratifying patients by number of prior BCMA-DTs, types of all prior BCMA-DTs received, type of most recent prior BCMA-DT, or depth of response to most recent BCMA-DT. Patients who responded to Tec had a numerically longer median time from most recent BCMA-DT exposure to Tec initiation compared to non-responders: 10.5 vs 7.5 months, p=0.48. We found that the optimal cut-off for time from last BCMA-DT exposure to Tec initiation was 8.7 months. Patients with > 8.7 months between last exposure to prior BCMA-DT and Tec initiation had a superior median PFS with Tec (8.1 months, 95% CI: 4.6-11.7) compared to patients with < 8.7 months from last exposure to prior BCMA-DT (2.5 months, 95% CI: 1.1-5.7), p=0.001. The toxicity profile for patients with prior BCMA-DT was similar to those who had not received a prior BCMA-DT. Grade ≥2 CRS occurred in 8.7% vs 13% (p=0.18), and grade ≥2 ICANS in 7.7% vs 6.7%, (p=0.85) of patients with and without prior BCMA-DT, respectively. Patients in the prior BCMA-DT cohort were more likely to have grade 3 thrombocytopenia in the first 30 days after Tec initiation (10.7% vs 6.6%; p=0.08). Conclusion: This is the largest study to date of any BCMA-directed BsAb among BCMA-exposed patients. Receipt of prior BCMA-DT was associated with a trend toward worse PFS, although not statistically significant, and lower likelihood of attaining an overall response. Waiting >9 months between sequencing BCMA therapies may be associated with improved PFS. D.D., M.A.V.M., J.A.D: co first authors; F.A., C.F., L.S.: co senior authors

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.

Introduction: Waldenström macroglobulinemia (WM)remains incurable with current therapies. Treatment options for patients beyond initial therapy are limited, underscoring the need for new agents with novel mechanisms of action. Iopofosine I 131 is a novel radiopharmaceutical composed of a lipid raft-targeting phospholipid ether covalently bound to 131I, a beta-emitting radioisotope. Herein, we report the results of the CLOVER-WaM study [NCT02952508] in patients with previously treated WM. Methods: Eligible WM patients had received >2 prior therapies and had symptomatic disease requiring therapy according to consensus recommendations for WM. Treatment consisted of 2 cycles of iopofosine I 131 administered at 15 mCi/m2 on days 1 and 15 of each 57-day cycle. Dose reduction to 10 mCi/m2 was allowed in the second cycle in patients with incomplete hematologic recovery or if the expected total dose exceeded 132 mCi. Supportive care with growth factors and transfusions was permitted per treating physician discretion. The primary endpoint was major response rate (MRR, defined as partial response or better) as determined by the modified VIth International Workshop on Waldenström Macroglobulinemia Response Criteria. Secondary endpoints included overall response rate (ORR), treatment-free survival (TFS), duration of response (DOR), and clinical benefit rate (CBR, defined as stable disease or better). Efficacy endpoints were assessed in the modified intent-to-treat (mITT) population, defined as all patients who received ≥60 mCi total administered dose of iopofosine I 131. MRR was analyzed with a 95% 2-sided confidence interval (CI) using the Clopper-Pearson interval method. In this population, MRR >20% was considered statistically significant. Time-dependent efficacy endpoints were analyzed using the Kaplan-Meier method. Safety was evaluated using CTCAE v4.03 in patients who received >1 dose of iopofosine I 131. The data cut-off for this analysis was May 31, 2024. Results: In 65 patients enrolled (safety population), the median age was 70 (range, 50-88) years; 48 (73.8%) were male, and 17 (26.2%) were female. Sixty-one (93.8%) were White, 1 (1.5%) was Black/African American, and 3 (4.6%) were other or unknown. Fifty-five patients met mITT criteria and were evaluable for efficacy. The median number of prior therapies was 4 (range, 2-15). Bruton's tyrosine kinase inhibitor (BTKi) exposure was noted in 39 (71%) patients, of whom 31 (56%) were BTKi-refractory. Sixteen (29%) patients had MYD88-wild type, and 5 (9%) had CXCR4-mutated disease. The MRR was 56.4% (95% CI, 42.3-69.7). ORR was 80%; among MYD88-wild type patients, ORR was 81%, and among post-BTKi patients, ORR was 72%. CBR was 98%. The median DOR and TFS were not reached at a median follow-up of 8.8 months, with an estimated 72% of responding patients remaining progression-free at 18 months. In the safety population, any-grade adverse events, regardless of causality, were reported in 57 (87%) patients. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurring in >10% of patients included thrombocytopenia (80%), neutropenia (69.2%), anemia (44.6%), lymphopenia (13.8%), infections (12.3%), and febrile neutropenia (10.8%). Adverse event-related death occurred in 1 patient due to bacterial sepsis. Conclusion: Iopofosine I 131 demonstrated durable efficacy in previously treated WM patients, with no current standard of care therapy. The treatment was well-tolerated with a manageable toxicity profile across broad biologic and clinical subgroups, irrespective of risk stratification. Based on the results of this trial, iopofosine I 131 shows promise as a novel treatment for WM patients.

Background: Zamto-cel is an investigational autologous tandem CD20-CD19-directed non-cryopreserved CAR-T cell product administered as a fresh formulation to patients (pts) with relapsed/refractory Diffuse Large B Cell Lymphoma (r/r DLBCL) in the DALY II USA clinical trial (NCT04792489), a multicenter, open label, single-arm Phase 2 study. Here, we report efficacy and safety outcomes as part of a pre-planned interim analysis of 59 evaluable patients and 69 patients in the safety population. Methods: Eligible adults had r/r DLBCL after at least 2 prior lines of treatment including anti-CD20 monoclonal antibody and anthracycline-containing regimen and measurable disease per Lugano 2014 classification. Zamto-cel was manufactured utilizing CliniMACS Prodigy® (Miltenyi Biotec), a closed, automated system with a 14-day vein-to-vein time and administered as a fresh formulation. Lymphodepletion chemotherapy was initiated during the manufacturing process (either cyclophosphamide/ fludarabine or bendamustine) prior to receiving a single dose of zamto-cel at a dose of 2.5x106 CAR T cells/kg on Day 0. The primary endpoint was overall response rate (ORR) defined as best overall response (BOR) of either complete response (CR) or partial response (PR). Secondary endpoints included complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and CD19 and CD20 antigen expression at relapse. Results: As of March 29th, 2024, 69 pts received zamto-cel of which 59 were evaluable having received a fresh, conforming product and completed a minimum of 3 months follow-up. Median age was 63 years (range 25-85), 39 (66%) were male. Sixteen pts (27%) received 3 or more lines of prior treatment. The majority of pts (53%) had elevated LDH at study entry, and 49% had ≥ 2 extranodal lesions, indicative of a study population with advanced disease. No pts received any bridging therapy, in the week after apheresis and before lymphodepletion. Only 7 pts (12%) received bendamustine as lymphodepleting regimen. Successful manufacturing of a fresh, in specification product occurred in 91.3% out of 69 treated pts. Four patients received a cryopreserved formulation to permit time for comorbid condition management. The mean viability of the final product was 96.0% with 29.4 % transduction efficacy. No patient died or withdrew during the manufacturing process. The ORR in the evaluable patient population (n=59) as assessed by an Independent Radiology Committee (IRC) was 72.9% (95% CI, 59.7-83.6), with a CRR of 49.2% (95% CI,35.9-62.5). The 6 month and 12 month-PFS was 55% (95%CI, 41-67) and 42% (95%CI, 28-56), respectively; 12 month-OS was 72% (95%CI, 57-83). The median DOR was 11.4 months. All 69 treated pts were assessed for safety outcomes. Treatment-emergent adverse events (TEAEs) were mostly of grade 1-2, the majority of grade ≥ 3 were hematological. Thirty-two pts (46.4%) experienced cytokine release syndrome (CRS), all grade 1-2. Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 12 pts (17.4%), grade 1-2 (9 pts; 13.1%); grade 3 (3 pts; 4.3%). One patient experienced immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), which resolved after 2 days. Biopsies at progression were available in 24 pts. CD19-negative relapse (defined as H Score <100) was seen in 2 pts, CD20-negative relapse was observed in 3 pts. Only one patient experienced loss of both antigens compared to pre-treatment status, demonstrating that most lymphomas maintain target antigen expression at relapse after treatment with zamto-cel. Conclusion: This pre-planned interim analysis represents the first pivotal trial of a tandem CD20-CD19 directed non-cryopreserved CAR-T cell product for patients with third-line r/r DLBCL. The trial plans to enroll 100 evaluable patients and the final data will be presented upon study completion. Among the 59 evaluable patients at the interim analysis, there is encouraging activity and a favorable safety profile in DLBCL patients treated with zamto-cel. Unlike currently registered CAR-T cell products, zamto-cel is administered as a fresh product with a short vein-to-vein time of 14 days with lymphodepletion initiated during the manufacturing process. With a manufacturing success rate of 91% we have demonstrated the feasibility of this process among high-risk patients with r/r DLBCL.

Introduction: Scant data exist on prognostic factors, survival and treatment (Tx)-related outcomes in SCNSL. We conducted a multicenter international analysis to identify prognostic factors and outcomes in SCNSL at diagnosis (de novo), or after frontline Tx (1L) either with (concomitant) or without (isolated) systemic (syst) relapse. Methods: This study collected data from patients (pts) treated between 2001-2023 at 35 centers. Overall (OS) and progression-free survival (PFS) were calculated from SCNSL diagnosis to first event (death for OS, relapse/death for PFS) or last follow-up. Uni- (UVA) and multivariable (MVA) Cox analyses were performed to assess prognostic factors; Kaplan-Meier method was used to estimate survival. Results: 1173 (US: 863, UK: 273, Canada: 37) pts with SCNSL were included. Baseline characteristics were median age: 62 years (interquartile range 52.5-69), male sex: 58.7%, elevated LDH: 71.1%, stage III/IV: 88.6%, HIV: 3%, transformed LBCL (tLBCL): 13.8%, non-germinal center B-cell like (non-GCB) subtype: 52.3%, double expressor (DE): 40%, MYC rearrangement (MYC-R): 28.3%, MYC/BCL2 double hit: 16.6%, MYC/BCL2/BCL6 triple hit (TH): 6.1%. Among 522 pts with de novo SCNSL, 84.2% had involvement of a single CNS compartment (44.7% brain parenchyma; 40.4% leptomeningeal [lepto]). 1L regimens included 36.2% R-CHOP with high-dose methotrexate (HD-MTX), 12.5% MARIETTA-type, and 9.8% R-CODOX-M/IVAC; 54.6% received intrathecal chemotherapy. Consolidation Thiotepa-based autologous stem cell transplant (TT-ASCT) occurred in 15.3%. The majority of pts who underwent TT-ASCT had previously achieved CR or PR in syst (92.5%) and CNS (72.5%) compartments. At median follow-up 25.7 months (mos), subsequent relapse was observed in 27.5% TT-ASCT recipients: 36.3% had isolated CNS, 27.4% syst, and 36.3% concomitant. 588 pts presented with SCNS after 1L (66.2% isolated, 33.8% concomitant). Brain parenchyma involvement was observed in 56.8%, lepto in 22.6%. Tx included 31.6% HD-MTX combination (eg, R-MPV, MTR); 18.4% HD-MTX +/- rituximab; 16.2% MARIETTA-type; and 9.4% platinum-based regimen. Consolidation TT-ASCT occurred in 22.4% (n=132), and 13.8% (n=81) received CAR-T cell therapy (excluding subsequent relapses in de novo group). Syst (65.1%) & CNS (69.1%) responses (CR/PR) were higher before TT-ASCT compared to CAR-T cell (49.5% & 54.5%, respectively). After TT-ASCT, 52 pts (39.3%) relapsed, mainly in the CNS (n=30, 57.7%), with only 4 (7.7%) concomitant. After CAR-T, 48 pts (59.3%) relapsed: 15 (31.2%) isolated in CNS and 15 (31.2%) concomitant. 12-month cumulative incidence of relapse (with death as competing risk) was 21.1% after TT-ASCT and 55.8% after CAR-T. In 63 pts (5.4%), the first CNS event occurred >2 lines of Tx. With median follow-up of the entire cohort of 24.6 mos, median PFS and OS were 11 and 21 mos, respectively. mPFS and mOS were significantly better in pts with de novo SCNSL (13.4 & 47.4 mos) compared to SCNSL after 1L (10.4 & 14.2 mos) and >2 lines of Tx (6.5 & 9.7 mos); P<0.0001. Factors associated with significantly shorter OS in UVA across all presentations were age >60, male sex, GCB subtype, MYC-R, tLBCL, DE, TH, elevated LDH, ECOG PS ≥2, SCNSL after 1L (vs. de novo), and failure to achieve syst/CNS response to 1L. Of these, age >60, male sex, MYC-R, ECOG PS ≥2, and failure to achieve response to 1L remained significant in MVA. In de novo cases, age >60, DE, ECOG PS≥2, and failure to achieve syst/CNS response to 1L were associated with poorer OS; for pts with SCNSL after 1L, age >60, GCB subtype, and ECOG PS ≥2 were significant. Pts treated with HD-MTX-based regimens after 1L experienced longer OS than those treated with platinum regimens or high-dose cytarabine. In de novo cases, TT-ASCT was significantly associated with longer OS (HR=0.58; P=0.025) in MVA after adjusting for significant factors, 1L type, and response. For SCNSL at relapse, TT-ASCT (HR=0.34; P<.0001) and isolated SCNSL presentation (vs. concomitant HR=0.70, P=0.007) were associated with longer OS, adjusting for significant factors, type of second-line Tx, & site of CNS relapse. Conclusions: This study represents the largest analysis of SCNSL inclusive of all modes of presentation. Concomitant SCNSL at relapse was associated with poor outcomes, while TT-ASCT consolidation was associated with improved OS in de novo & relapsed disease. Despite advances in LBCL SCNSL remains an unmet therapeutic need.

AbstractCurrent US clinical practice guidelines for advanced prostate cancer management contain recommendations based on high‐level evidence from randomized controlled trials; however, these guidelines do not address the nuanced clinical questions that are unanswered by prospective trials but nonetheless encountered in day‐to‐day practice. To address these practical questions, the 2024 US Prostate Cancer Conference (USPCC 2024) was created to generate US‐focused expert clinical decision‐making guidance for circumstances in which level 1 evidence is lacking. At the second annual USPCC meeting (USPCC 2024), a multidisciplinary panel of experts convened to discuss ongoing clinical challenges related to 5 topic areas: biochemical recurrence; metastatic, castration‐sensitive prostate cancer; poly [ADP‐ribose] polymerase inhibitors; prostate‐specific membrane antigen radioligand therapy; and metastatic, castration‐resistant prostate cancer. Through a modified Delphi process, 34 consensus recommendations were developed and are intended to provide clinicians who manage prostate cancer with guidance related to the implementation of novel treatments and technologies. In this report, the authors review the areas of consensus identified by the USPCC 2024 experts and evaluate ongoing unmet needs regarding translational application of the current clinical evidence.

Background: Tibiotalar arthrodesis (TTA) is a common operation for end-stage ankle arthritis. Elevated body mass index (BMI) is believed to contribute to complications following TTA. Previous studies involved national registries or small, underpowered cohorts. This study aimed to determine the effects of elevated BMI on nonunion and complication rates following TTA with a large cohort from a single academic institution. Methods: A retrospective study identified 514 patients (527 ankles) who underwent primary TTA from 2005-2017. Mean age was 60 years. Patients were stratified by BMI according to the World Health Organization classification. A reference group of 203 patients (208 ankles) included normal weight or mildly overweight patients (BMI 18.5 to <30). Ankle radiographs were evaluated to determine union or nonunion. Other outcomes included revision TTA, reoperations, subsequent adjacent joint arthrodesis, infection, and readmission. Data were analyzed using Pearson χ 2 and odds ratios for categorical variables. Analysis of variance and Kaplan-Meier estimation assessed continuous variables and time-to-event outcomes, respectively. Mean follow-up was 34.3 months. Results: Obesity class III patients had elevated risk of complications compared with normal weight patients including nonunion (odds ratio [OR] 3.96, P = .002), revision (OR 3.69, P = .03), superficial infection (OR 9.36, P = .002), and readmission (OR 10.90, P = .01). Superficial infection rates were elevated in class I (OR 6.36, P = .007) and readmissions in class II (OR 9.98, P = .01). No differences were found in reoperation ( P = .448), symptomatic implant removal ( P = .805), adjacent joint arthrodesis ( P = .353), or deep infection ( P = .507) rates. Discussion: In this retrospective review after TTA, increased rates of nonunion, revision, superficial infection, and readmission were found in obesity class III patients, compared with the reference group of normal weight or mildly overweight patients. Superficial infection rates were likewise relatively elevated in class I and readmission rates in class II patients.

Background: Second-generation highly cross-linked polyethylene (HXLPE) has revolutionized total hip arthroplasty. However, the long-term risks and benefits of HXLPE in primary total knee arthroplasty (TKA) remain unknown. This randomized clinical trial evaluated implant survivorship, complications, radiographic results, and clinical outcomes of HXLPE and conventional ultra-high molecular weight polyethylene (UHMWPE) inserts in primary TKAs. Methods: We enrolled 518 patients (518 knees) who underwent primary TKA in 3 centers within 1 tertiary referral network. The mean age was 67 years, the mean body mass index was 32 kg/m 2 , and 58% of the patients were women. All of the patients underwent primary TKA with a cemented posterior-stabilized tibial insert and patellar resurfacing. Randomization proceeded via stratified dynamic allocation. The patients were blinded to their study group allocation: those in the control group (254 knees) underwent TKA with an UHMWPE insert (N2Vac; Stryker); those in the treatment group (264 knees) received an HXLPE insert (X3; Stryker). Kaplan-Meier survivorship, radiographic results, and clinical outcomes were assessed. This trial was registered with ClinicalTrials.gov. The mean follow-up was 11 years. Results: The 10-year overall survivorship free from any revision and from any reoperation was 96% and 94%, respectively. There were no differences in the risk of revision or reoperation between the groups (p > 0.05). There were a total of 19 revisions. Revision indications included periprosthetic joint infection (14 knees), instability (4 knees), and open reduction and internal fixation (ORIF) for a patellar fracture due to osteolysis around a UHMWPE insert (1 knee). There were no revisions due to polyethylene wear, osteolysis, or fracture of the post in the HXLPE group. The radiographic results and clinical outcomes were otherwise similar. Conclusions: Notably, no wear-related failures were identified in the HXLPE group, but there was 1 case of osteolysis in the UHMWPE group. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.