Evaluating early intervention in smoldering myeloma clinical trials: a systematic review.

BACKGROUND: Smoldering multiple myeloma (SMM), an asymptomatic precursor of multiple myeloma (MM), carries a variable risk of progression to MM. There is little consensus on the efficacy or optimal timing of treatment in SMM. We systematically reviewed the landscape of all clinical trials in SMM. We compared the efficacy of treatment regimens studied in SMM to results from these regimens when used in newly diagnosed multiple myeloma (NDMM), to determine whether the data suggest deeper responses in SMM versus NDMM. METHODS: All prospective interventional clinical trials for SMM, including published studies, meeting abstracts, and unpublished trials listed on ClinicalTrials.gov up to April 1, 2023, were identified. Trial-related variables were captured, including treatment strategy and efficacy results. Relevant clinical endpoints were defined as overall survival (OS) and quality of life. RESULTS: Among 45 SMM trials identified, 38 (84.4%) assessed active myeloma drugs, while 7 (15.6%) studied bone-modifying agents alone. Of 18 randomized trials in SMM, only one (5.6%) had a primary endpoint of OS; the most common primary endpoint was progression-free survival (n = 7, 38.9%). Among 32 SMM trials with available results, 9 (28.1%) met their prespecified primary endpoint, of which 5 were single-arm studies. Six treatment regimens were tested in both SMM and NDMM; 5 regimens yielded a lower rate of very good partial response rate or better (≥VGPR) in SMM compared to the corresponding NDMM trial (32% vs 63%, 43% vs 53%, 40% vs 63%, 86% vs 89%, 92% vs 95%, and 94% vs 87%, respectively). CONCLUSION: In this systematic review of all prospective interventional clinical trials in SMM, we found significant variability in trial design, including randomization status, primary endpoints, and types of intervention used. Despite the statistical limitations, comparison of treatment regimens revealed no compelling evidence that the treatment is more effective when introduced early in SMM compared to NDMM.

Survivorship After Neurocritical Care: A Scoping Review of Outcomes Beyond Physical Status.

Following intensive care unit hospitalization, survivors of acute neurological injury often experience debilitating short-term and long-term impairments. Although the physical/motor impairments experienced by survivors of acute neurological injury have been described extensively, fewer studies have examined cognitive, mental health, health-related quality of life (HRQoL), and employment outcomes. This scoping review describes the publication landscape beyond physical and/or motor sequelae in neurocritical care survivors. Databases were searched for terms related to critical illness, intensive care, and outcomes from January 1970 to March 2022. English-language studies of critically ill adults with a primary neurological diagnosis were included if they reported on at least one outcome of interest: cognition, mental health, HRQoL or employment. Data extraction was performed in duplicate for prespecified variables related to study outcomes. Of 16,036 abstracts screened, 74 citations were identified for inclusion. The studies encompassed seven worldwide regions and eight neurocritical diagnosis categories. Publications reporting outcomes of interest increased from 3 before the year 2000 to 71 after. Follow-up time points included ≤ 1 (n = 15 [20%] citations), 3 (n = 28 [38%]), 6 (n = 28 [38%]), and 12 (n = 21 [28%]) months and 1 to 5 (n = 19 [26%]) and > 5 years (n = 8 [11%]), with 28 (38%) citations evaluating outcomes at multiple time points. Sixty-six assessment tools were used to evaluate the four outcomes of interest: 22 evaluating HRQoL (56 [76%] citations), 21 evaluating cognition (20 [27%] citations), 21 evaluating mental health (18 [24%] citations), and 2 evaluating employment (9 [12%] citations). This scoping review aimed to better understand the literature landscape regarding nonphysical outcomes in survivors of neurocritical care. Although a rising number of publications highlight growing awareness, future efforts are needed to improve study consistency and comparability and characterize outcomes in a disease-specific manner, including outlining of a minimum core outcomes set and associated assessment tools.

Higher tumor mutational burden and PD-L1 expression correlate with shorter survival in hematologic malignancies.

Background: The prognostic implications of tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are poorly studied in hematologic malignancies. Objectives: This study aimed to better understand the characteristics and prognostic value of TMB and PD-1/PD-L1 in hematologic malignancies. Design: This real-world study was conducted among patients with hematologic malignancies who had next-generation sequencing (NGS) (Foundation Medicine) at the University of California San Diego Moores Cancer Center (2014-2018). Methods: TMB was measured by NGS. PD-L1 expression (tumor proportion score, TPS) was measured by immunohistochemistry (classified as high (⩾50%), low (1-49%), and negative (<1%)). Data was curated from the electronic medical records. Results: In 388 evaluable patients, the most common diagnoses were B-cell non-Hodgkin lymphoma (NHL) (35%) and Philadelphia chromosome-negative myeloproliferative disorders (16%). Median TMB was 1.6 mutations/Mb (range, 0-46.83). Forty-eight patients (12%) had TMB ⩾10 mutations/Mb, 90% of which were B-cell or T-cell NHL. In 85 samples with available PD-L1 scores, 11 were high; 26, low; and 48, no tumor cell expression. PD-L1 TPS positive (⩾1%) was most common in T-cell NHL (7/9 (77%) cases) followed by B-cell NHL (21/51 (41%) cases). TMB ⩾4 mutations/Mb and PD-L1 score ⩾1% were significantly associated with shorter overall survival (OS) from diagnosis, with hazard ratio (HR) = 1.46 (p = 0.02, 95% confidence interval (CI) 1.05-2.03) and HR = 2.11 (p = 0.04, 95% CI 1.04-4.30), respectively; the relationship was more pronounced when PD-L1 ⩾50% versus <50% was used (HR = 2.80, p = 0.02, 95% CI 1.19-6.59). Higher TMB and higher PD-L1 positivity correlation were significant but weak (Pearson correlation coefficient R 2 = 0.04, p = 0.04). Conclusion: TMB ⩾4 mutations/Mb and positive PD-L1 TPS are poor prognostic factors, correlating with shorter OS across hematologic malignancies. Trial registration: ClinicalTrials.gov NCT02478931.

Outcomes of Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with Large B-Cell Lymphoma (LBCL): A Single-Institution Experience.

Chimeric antigen receptor T-cell (CAR T-cell) therapy has revolutionized the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We describe the real-world baseline characteristics, efficacy, safety, and post-relapse outcomes of adult patients with R/R LBCL who received CAR T-cell therapy at the University of California San Diego. A total of 66 patients with LBCL were treated with tisagenlecleucel or axicabtagene ciloleucel. The median age was 59.5, and 21% were over 70 years old. Additionally, 20% of the patients had an Eastern Cooperative Oncology Group (ECOG) performance score of ≥2. Cytokine release syndrome incidence was 88%; immune effector cell-associated neurotoxicity syndrome incidence was 56%. All-grade infection occurred in 48% of patients and in 79% of patients > 70 years old. Complete response (CR) was achieved in 53% and partial response in 14%. Median progression-free survival (PFS) was 10.3 months; median overall survival (OS) was 28.4 months. Patients who relapsed post-CAR T-cell therapy had poor outcomes, with a median OS2 of 4.8 months. Upon multivariate analysis, both ECOG (HR 2.65, 95% CI: 1.30-5.41; p = 0.007) and ≥2 sites of extranodal involvement (HR 2.22, 95% CI: 1.15-4.31; p = 0.018) were significant predictors of PFS. Twenty-six patients were R/R to CAR T-cell therapy; six patients were in remission at the time of data cut off, one of whom received allogeneic transplant. Overall, older patients can safely undergo CAR T-cell therapy, despite the increased risk of all-grade infection. In our cohort, ECOG performance score and ≥2 sites of extranodal disease are significant predictors of PFS.

Simulation-Based Training Improves Fellows' Competence in Brain Death Discussion and Declaration.

BACKGROUND: Despite well-defined American Academy of Neurology guidelines for death by whole brain criteria (brain death), there is marked variability in national practice, which some have attributed to lack of formal education. Further, communication with surrogates and families about brain death is integral to brain death declaration. As such, we developed a targeted brain death curriculum combining didactics and simulation-based education to improve examination and subsequent communication skills with families. METHODS: Multidisciplinary critical care fellows participated in (1) didactic and case-based curriculum, (2) brain death simulated examination (SimMan3G mannequin), and (3) a standardized family scenario with delivery of a brain death diagnosis to a surrogate "family member". Fellows completed a precurriculum and postcurriculum multiple choice knowledge test and survey (Likert 1 to 10 scale) evaluating measures regarding diagnosis and communication of brain death. t Test and 2-tailed Wilcoxon signed rank test were used for statistical analysis (P<0.05). RESULTS: Thirteen critical care fellows participated in the curriculum. Most fellows [80% (N=12)] had only participated in 0 to 5 brain death declarations before this intervention. There was significant improvement across all measures: self-rated knowledge (P=0.004), perceived knowledge relative to peers (P=0.002), confidence (P=0.001), and comfort (P=0.001) with performing a brain death exam, and comfort with family discussion (P=0.01). Objective test scores improved from 56 to 73% after simulation (P=0.004). All fellows found the curriculum beneficial. CONCLUSION: Trainees may lack sufficient exposure to brain death education. Didactics with simulation-based education can improve objective knowledge and subjective measures of comfort with brain death declaration and surrogate communication.