Search

Bone marrow microenvironment plays an important role in promoting growth and survival of multiple myeloma (MM) cells. The tumor-promoting immune microenvironment is augmented while anti-tumor immune responses are inhibited. Although clinical and genomic markers of high-risk MM have been described, the immune status is just being recognized as a potential mediator of disease behavior. This is even more important with the development of a number of immune-based therapies. Based on these considerations, we evaluated peripheral blood absolute lymphocyte count (ALC) as an easily accessible marker representing immune microenvironment at diagnosis and following treatment of MM. We retrospectively evaluated 11,427 patients diagnosed with MM between 2000 and 2019 at Veteran's Administration hospitals using ALC obtained closest to diagnosis and up to 2.5 years thereafter. Patients were stratified into 3 ALC categories: severely low, low, and normal (<1, 1-1.5, and >1.5 x 103/mm3, respectively). Lymphopenia (including severely low and low ALC) was present in 53% of patients at MM diagnosis and was associated with inferior overall survival (OS). Median OS of patients with severely low, low, and normal ALC at diagnosis was 2.7, 3.3, and 4.2 years (P < .001), respectively. Moreover, persistent or new development of lymphopenia during treatment and follow-up was also associated with inferior OS. Our findings support the use of ALC as a biomarker for risk stratification in MM., (Copyright © 2024 American Society of Hematology.)

Background: In ATTR amyloidosis, transthyretin (TTR) protein is secreted from the liver and deposited as toxic aggregates at downstream target tissues. Despite recent advancements in treatments for ATTR amyloidosis, the mechanisms underlying misfolded TTR-mediated cellular damage remain elusive., Methods: In an effort to define early events of TTR-associated stress, we exposed neuronal (SH-SY5Y) and cardiac (AC16) cells to wild-type and destabilized TTR variants (TTR V122I (p.V142I) and TTR L55P (p.L70P)) and performed transcriptional (RNAseq) and epigenetic (ATACseq) profiling. We subsequently compared TTR-responsive signatures to cells exposed to destabilized antibody light chain protein associated with AL amyloidosis as well as ER stressors (thapsigargin, heat shock)., Results: In doing so, we observed overlapping, yet distinct cell type- and amyloidogenic protein-specific signatures, suggesting unique responses to each amyloidogenic variant. Moreover, we identified chromatin level changes in AC16 cells exposed to mutant TTR that resolved upon pre-incubation with kinetic stabilizer tafamidis., Conclusions: Collectively, these data provide insight into the mechanisms underlying destabilized protein-mediated cellular damage and provide a robust resource representing cellular responses to aggregation-prone proteins and ER stress.

Patients with systemic light chain (AL) amyloidosis undergoing treatment with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) may develop renal and cardiac toxicities potentially exacerbated by the co-solvent propylene glycol in conventional melphalan formulations. We investigated the safety and efficacy of propylene glycol-free melphalan (PGF-Mel) during HDM/SCT in patients with AL amyloidosis (ClinicalTrials.gov identifier NCT02994784). The primary objective of this phase II, open-label study was evaluation for renal dysfunction, new cardiac arrhythmias, and postural hypotension related to autonomic dysfunction. Secondary objectives included time to neutrophil and platelet engraftment, treatment-related mortality (TRM), overall hematologic response, organ response, and number of peritransplantation hospitalizations. Twenty-eight patients with AL amyloidosis enrolled, of whom 27 underwent HDM/SCT. PGF-Mel at 140 to 200 mg/m 2 was administered i.v. in 2 equally divided doses. Patients were monitored for up to 30 days after the last administration of PGF-Mel to assess for treatment-related toxicity. Patients were followed for 12 months from the time of treatment with HDM/SCT for evaluation of hematologic and organ responses. Kaplan-Meier analysis was used to estimate progression-free survival. Two patients (7%) developed renal dysfunction, 5 (19%) experienced new cardiac arrhythmias, and 3 (11%) developed orthostatic hypotension. All patients achieved neutrophil and platelet engraftment, at a median of 10 days and 17 days post-HDM/SCT, respectively. TRM on day +100 was 0%. Peritransplantation hospitalization was required for 23 patients (85%). The most common nonhematologic adverse events were diarrhea (93%), fatigue (82%), and nausea (74%). At 6 months post-HDM/SCT, hematologic complete response or very good partial response occurred in 66% of the patients. At 12 months post-HDM/SCT, renal response occurred in 12 of 23 (52%) patients with renal involvement, and cardiac response occurred in 3 of 11 (27%) patients with evaluable cardiac involvement. Our data indicate that PGF-Mel is safe and efficacious as a high-dose conditioning regimen for autologous SCT in patients with AL amyloidosis., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: Gestational diabetes and overweight during pregnancy are associated with future type 2 diabetes. Postpartum weight loss can reduce diabetes risk. However, effective interventions for postpartum weight loss are lacking, in particular for Latina populations, despite their disproportionate burdens of gestational diabetes, overweight, and diabetes., Study Design: This was a community-based RCT., Setting/participants: Researchers recruited pregnant individuals with gestational diabetes or BMI>25 kg/m 2 from safety-net health care settings and Women, Infants, and Children offices in Northern California in 2014-2018. Of 180 individuals randomized to intervention (n=89) or control (n=91), 78% identified as Latina, 61% were primarily Spanish speaking, and 76% perceived their diabetes risk to be low., Intervention: The intervention consisted of a 5-month postpartum telephone-based health coaching intervention delivered in English or Spanish., Main Outcome Measures: Data were collected through surveys at enrollment and 9-12 months after delivery and chart review up to 12 months after delivery. The primary outcome, weight change from prepregnancy to 9-12 months after delivery, was compared between the groups, overall and within strata defined a priori according to language (Spanish or English) and diabetes risk perception (none/slight or moderate/high)., Results: The intent-to-treat estimated intervention effect was +0.7 kg (95% CI= -2.4 kg, +3.8 kg; p=0.67). In stratified analyses, intervention effects remained nonsignificant but varied in direction: effects were favorable among English speakers and those with higher perceived diabetes risk, and unfavorable among Spanish speakers and those with lower perceived risk. Analyses were conducted in 2021-2022., Conclusions: A postpartum health coaching intervention, designed for low-income Latina women at increased risk for diabetes, did not reduce postpartum weight gain. Intervention effects were nonsignificantly more favorable among English speakers versus Spanish speakers, and among those who perceived their diabetes risk to be high versus low., Trial Registration: This study is registered at www., Clinicaltrials: gov NCT02240420., (Copyright © 2023. Published by Elsevier Inc.)

Postpartum lifestyle modification is recommended to hypertension risk. We conducted a systematic literature review to assess the evidence for postpartum lifestyle interventions to reduce blood pressure. We searched for relevant publications from 2010 through November 2022. Two authors independently conducted article screening and data extraction; a third resolved discrepancies. Ultimately, nine studies met inclusion criteria. Most were randomized controlled trials and had sample sizes <100. In all but one of the eight studies reporting race data, nearly all participants identified as White. None of the studies reported a significant intervention effect on blood pressure. However, most interventions were associated with improvements in other outcomes, such as physical activity. Overall, the evidence for postpartum lifestyle interventions to reduce blood pressure is limited to a handful of studies characterized by small sample sizes and a lack of racial diversity. Additional research with larger samples, more diverse populations, and intermediate outcomes is warranted., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

We report a case of a 23-year-old man who presented with progressive asymmetric weakness and numbness in his distal extremities over 4 months, with initial symptoms starting days after a coronavirus 2019 (COVID-19) vaccine booster. Initial neurologic examination was notable for distal weakness of both upper and lower extremities that was more pronounced on the left, complete areflexia, and decreased distal sensation to pinprick and vibration without loss of proprioception. Nerve conduction studies demonstrated a generalized, non-length-dependent, sensorimotor, demyelinating polyneuropathy, with conduction block seen in multiple compound muscle action potentials. Sensory nerve action potentials were normal in absolute terms but had asymmetric amplitudes.Based on the patient's nerve conduction studies, he was diagnosed with a specific immune-mediated neuromuscular disorder. He was started on intravenous immunoglobulin, but within days of the first infusions experienced a rare and potentially life-threatening complication. He received appropriate treatment and was started on alternative immunotherapy, after which his symptoms improved.Our case exemplifies the features of a specific subtype of a more common immune-mediated neuromuscular diagnosis with unique elements of history, examination, and nerve conduction studies that required interpretation in the clinical context. We also discuss a rare side effect of a commonly used immunotherapy and its risk factors and comment on the likelihood that this diagnosis may be related to a preceding COVID-19 vaccine booster., (© 2022 American Academy of Neurology.)

Background: Many adverse pregnancy outcomes (APOs) are associated with elevated cardiovascular disease (CVD) risk. However, APO data in the context of pre-existing CVD risk factors, and from diverse populations, are limited. We assessed the occurrence of APOs among individuals with and without prepregnancy CVD risk factors, overall and by race/ethnicity. Methods: We conducted a retrospective study using electronic medical record data from a large urban safety-net hospital. Individuals with prenatal care and delivery between 2016 and 2018 at the hospital were included, and data from prenatal intake through the delivery hospitalization were captured. The exposure, prepregnancy CVD risk factors (hypertension, diabetes, tobacco use, and obesity), and the outcome, APOs (hypertensive disorders of pregnancy, gestational diabetes, preterm delivery, low birth weight, and stillbirth), were identified from electronic medical records. Results: We identified 3760 unique delivering individuals, of whom 55.1% self-identified as Black non-Hispanic and 17% as Hispanic. Prepregnancy CVD risk factor prevalence was 45.6%, most commonly obesity (26.6%). APO prevalence was 35.6%, most commonly a hypertensive disorder of pregnancy (20.1%). Overall, 45.7% of APOs occurred in the absence of recognized prepregnancy CVD risk factors, representing 16.3% of the total sample. Among individuals without prepregnancy CVD risk factors, APO prevalence was 30.0% and did not vary by race/ethnicity. Conclusions: In this racially and ethnically diverse hospital-based sample, APOs were present in one in three parous individuals without prepregnancy CVD risk factors-a group with potentially elevated CVD risk who might otherwise be missed by traditional CVD risk factor screening.

With the growing knowledge of multiple myeloma (MM) pathobiology and the introduction of novel therapies, risk stratification continues to evolve. Myeloid-derived suppressor cells and tumor-associated macrophages, derived from peripheral blood monocytes, support malignant plasma cell proliferation in the bone marrow. Because peripheral blood absolute monocyte count (AMC) is thought to reflect the bone marrow microenvironment, we sought to evaluate the prognostic significance of AMC in MM. We retrospectively analyzed 10 822 patients newly diagnosed with MM between 2000 and 2019 at Veteran's Administration hospitals. We obtained AMC closest to diagnosis and every 3 months thereafter up to 2.5 years. Patients were stratified into 4 groups: low, normal, elevated, and severely elevated AMC (<0.2, 0.2-<0.8, 0.8-<1.25, and ≥1.25 × 103/mm3, respectively). Abnormal AMC at diagnosis was observed in 25.3% of the patients and was associated with an inferior overall survival (OS). In patients with low, severely elevated, elevated, and normal AMC, respectively, median OS at diagnosis was 2.3, 2.7, 3.1, and 3.6 years (P < .001) and at 2.5 years was 2.0, 2.6, 3.4, and 3.9 years (P < .001). Patients with normal AMC at diagnosis who developed an abnormal AMC >1 year after diagnosis also had an inferior OS relative to patients who maintained a normal AMC. Abnormal AMC was also associated with inferior OS independent of validated prognostic markers, including the international staging system and lactate dehydrogenase. Our findings provide novel clues for future prospective studies on the functional role of monocytes in MM, which could be a readily available metric for risk stratification., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) induces deep hematologic responses (HR) in patients with newly diagnosed systemic immunoglobulin light-chain (AL) amyloidosis. Modifying melphalan conditioning dose (mHDM <140 mg/m 2 ) is considered in older patients because of concerns regarding tolerability. Age does not predict frailty, and dose modification could compromise responses in an era where effective non-transplant regimens are available. We analyzed 43 patients ≥ 65 years with AL amyloidosis who underwent SCT at Boston University Amyloidosis Center between 2011 and 2020. Median age was 66 years (range 65-68) versus 69 years (range 65-76) in the HDM and mHDM groups, respectively. HR of ≥ very good partial response at 12 months was 66.7% versus 42.3% for patients treated with HDM versus mHDM. Median progression-free survival (PFS) from day 0 of SCT was not reached versus 12.0 months (P =.13); grade ≥ 3 non-hematologic transplant-related toxicities occurred in 87.5% versus 76.9%; and transplant-related mortality was 0% versus 2.3% in the HDM versus mHDM group, respectively. In carefully selected older patients with AL amyloidosis, HDM is well tolerated. Use of mHDM results in reduced HR and PFS; an important consideration with the advent of highly effective non-transplant therapies., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Mortality from non-small cell lung cancer (NSCLC) has improved with screening and novel treatments. The substance use epidemic has threatened health outcomes in a variety of diseases, but little is known about how it is associated with NSCLC outcomes., Methods: We performed a retrospective cohort study of 211 patients with NSCLC treated at a safety-net hospital. Sociodemographic data and clinical outcomes were extracted via review of electronic medical records. Patients were stratified based on substance use status. Comparative and multivariable analyses were performed to evaluate baseline characteristics and lung cancer outcomes including survival., Results: Among 193 patients (91.5%) with information available on substance use, 24.9% reported substance use; specifically, alcohol, marijuana, and illicit substances. Patients with substance use were more likely to have increased health care utilization and poor social determinants of health, including safe housing, stable employment, and social support. There were no significant differences in treatment adherence. Only 6.3% of patients with substance use did not receive guideline concordant care (GCC) compared to 24.8% of patients without substance use; due to poor performance status, increased comorbidities, or loss to follow up. On univariable analysis, patients with substance use experienced inferior median overall survival (OS) if they had metastatic disease (0.40 vs. 1.03 years, P=0.01). However, in the multivariable analysis, substance use did not predict for survival. Independent predictors of mortality were sex (male HR, 1.67; 95% CI: 1.04-2.68; P=0.04), smoking status (current smoking HR, 2.63; 95% CI: 1.14-6.08; P=0.02), and stage (stage IV HR, 14.96; 95% CI: 6.28-35.63; P=0.008)., Conclusions: Substance use is associated with poor social determinants of health and increased health care utilization. On multivariable analysis, substance use was not independently associated with OS once guideline-concordant care was used. Future studies should focus on improving our understanding of these associations, delineating potential mechanisms, and developing evidence-based strategies to reduce health care utilization and overcome challenges related to poor social determinants of health., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-21-1992/coif). HJC reports receiving grants and support from NIH-NCATS-1UL1-TR001430 through the Boston University CTSA Award. UT reports receiving a grant from Pfizer Inc., consulting fees from Glaxo-Smith-Kline, honoraria from Astra Zeneca, and serving on the advisory board of Sanofi/Genzyme/Regeneron. The other authors have no conflicts of interest to declare., (2022 Journal of Thoracic Disease. All rights reserved.)

High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was achieved by 39% of patients. The median duration of hematologic CR was 12.3 years, and 45% of patients with a hematologic CR had no evidence of a recurrent plasma cell dyscrasia at 15 years after HDM/SCT. With a median follow-up interval of 8 years, the median event-free survival (EFS) and overall survival (OS) were 3.3 and 7.6 years, respectively. Patients with a hematologic CR had a median OS of 15 years, and 30% of these patients survived >20 years. On multivariable analysis, dFLC >180 mg/L and BM plasma cells >10% were independently associated with shorter EFS, whereas BNP >81 pg/mL, troponin I > 0.1 ng/mL, and serum creatinine >2.0 mg/dL were independently associated with shorter OS. We developed a prognostic score for EFS, which incorporated dFLC >180 mg/L and BMPC% >10% as adverse risk factors. Patients with low-risk (0 factors), intermediate-risk (1 factor), and high-risk (2 factors) disease had median EFS estimates of 5.3, 2.8, and 1.0 years, respectively (p < .001). The 100-day treatment-related mortality rate was 3% in the latest treatment period (2012-2021), and the 25-year risk of t-MDS/AML was 3%. We conclude that HDM/SCT induces durable hematologic responses and prolonged survival with improved safety in selected patients with AL amyloidosis., (© 2022 Wiley Periodicals LLC.)

Daratumumab as a single agent (sDARA) or in combination with chemotherapies (cDARA) leads to impressive hematologic and organ responses in AL amyloidosis. However, predictive factors associated with outcomes, and optimal duration of therapy remain unclear. We analyzed 107 patients with AL amyloidosis treated with daratumumab between 2017 and 2020. The median overall survival (OS) was not reached while the median major organ deterioration progression free survival (MOD-PFS) was 36 months in the sDARA cohort and not reached in the cDARA cohort, respectively. Hematologic response > VGPR was achieved in 81% of patients receiving sDARA and 86% of patients treated with cDARA. Several predictive factors were identified on a univariate analysis, including NTproBNP >8500 pg/mL but only achievement of at least VGPR and presence of 1q21 gain were independently associated with MOD-PFS and OS on a multivariate analysis. Finally, patients receiving > 12 cycles had significantly longer MOD-PFS (30 vs.13 months; (p = .0018) and OS (NR vs. 15 months; p < .0001). NTproBNP > 8500 pg/mL, presence of 1q21 gain and shorter duration of therapy (≤ 12 cycles) are strong negative predictive factors for outcomes with daratumumab therapy in AL amyloidosis., (© 2021 Wiley Periodicals LLC.)

Systemic immunoglobulin light-chain amyloidosis is characterized by pathologic deposition of immunoglobulin light chains as amyloid fibrils in vital organs, leading to organ impairment and eventual death. That the process is reversible was evidenced in an in vivo experimental model in which fibril-reactive chimeric monoclonal antibody (mAb) 11-1F4 directly targeted human light-chain amyloid deposits and affected their removal via a phagocyte-mediated response. To determine the tolerability and potential amyloidolytic effect of this agent (now designated mAb CAEL-101), we conducted a phase 1a/b study involving 27 patients, most of whom had manifestations of organ involvement. This was an open-label study in which phase 1a patients received mAb CAEL-101 as a single intravenous infusion with escalating dose levels from 0.5 mg/m2 to 500 mg/m2 to establish the maximum tolerated dose (MTD). In phase 1b, the antibody was administered as a graded series of 4 weekly infusions. For both phases, there were no drug-related serious adverse events or dose-limiting toxicities among recipients, and the MTD was not reached. The majority of patients had deep hematologic responses but persistent organ disease prior to treatment. Fifteen of 24 patients (63%) who manifested cardiac, renal, hepatic, gastrointestinal, or soft tissue involvement had a therapeutic response to mAb CAEL-101 as evidenced by serum biomarkers or objective imaging modalities with a median time to response of 3 weeks. Infusions of mAb CAEL-101 were well tolerated and, for the majority, resulted in improved organ function, notably for those with cardiac impairment. This trial was registered at www.clinicaltrials.gov as #NCT02245867., (© 2021 by The American Society of Hematology.)