A Meta-Analysis of the Efficacy of Pomalidomide-Based Regimens for the Treatment of Relapsed/Refractory Multiple Myeloma After Lenalidomide Exposure.

INTRODUCTION: The objective was to assess the benefit of pomalidomide-based combination regimens in patients with relapsed/refractory multiple myeloma (RRMM) previously treated with lenalidomide. A pooled estimate was obtained for efficacy outcomes including overall response rate (ORR), complete response (CR) rate, and progression-free survival (PFS) based on multiple trials conducted in this patient population. PATIENTS AND METHODS: A literature search was conducted on March 22, 2022 for relevant trials published between January 1, 2016 and the search date. The search identified 12 eligible trials with publications dated between 2016 and 2021. The meta-analyses were conducted among the intention-to-treat (ITT) population (patients treated in all lines of therapy) and 2 subpopulations: 2L (only patients treated in the second line [2L]) and ≥2L (patients treated in the 2L and beyond). RESULTS: From the meta-analyses, ORR was 69.9% for ITT, 74.4% for ≥2L, and 87.2% for 2L. CR rate was 12.1% for ITT, 17.6% for ≥2L, and 29.7% for 2L. One-year PFS rates were 55.1% for ITT, 59.1% for ≥2L, and 74.0% for 2L. Two-year PFS rates were 29.3% for ITT, 36.0% for ≥2L, and 41.9% for 2L. CONCLUSION: Pomalidomide-based combination regimens were effective in patients with RRMM previously treated with lenalidomide and tended to be associated with better outcomes when used earlier in the treatment pathway. A drug class switch may not always be necessary when making treatment decisions for patients with RRMM for whom the benefits of lenalidomide have been exhausted, although this must be supported by comparative studies.

Impact of prenatal immune system disturbances on brain development.

As research into various aging-associated neurodegenerative disorders reveals their immense pathophysiological complexity, the focus is currently shifting from studying changes in an advanced disease state to investigations involving pre-symptomatic periods, possible aberrations in early life, and even abnormalities in brain development. Recent studies on the etiology of schizophrenia and autism spectrum disorders revealed a profound impact of neurodevelopmental disturbances on disease predisposition, onset and progression. Here, we discuss how a prenatal immune challenge can affect the developing brain-with a selective focus on the impact on microglia, the brain's immune cells-and the implications for brain aging and its associated risk of developing Alzheimer's disease.

Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that neuroinflammation, mediated by the brain's innate immune system, contributes to AD neuropathology and exacerbates the course of the disease. However, there is no experimental evidence for a causal link between systemic inflammation or neuroinflammation and the onset of the disease. METHODS: The viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C) was used to stimulate the immune system of experimental animals. Wild-type (WT) and transgenic mice were exposed to this cytokine inducer prenatally (gestation day (GD)17) and/or in adulthood. Behavioral, immunological, immunohistochemical, and biochemical analyses of AD-associated neuropathologic changes were performed during aging. RESULTS: We found that a systemic immune challenge during late gestation predisposes WT mice to develop AD-like neuropathology during the course of aging. They display chronic elevation of inflammatory cytokines, an increase in the levels of hippocampal amyloid precursor protein (APP) and its proteolytic fragments, altered Tau phosphorylation, and mis-sorting to somatodendritic compartments, and significant impairments in working memory in old age. If this prenatal infection is followed by a second immune challenge in adulthood, the phenotype is strongly exacerbated, and mimics AD-like neuropathologic changes. These include deposition of APP and its proteolytic fragments, along with Tau aggregation, microglia activation and reactive gliosis. Whereas Aß peptides were not significantly enriched in extracellular deposits of double immune-challenged WT mice at 15 months, they dramatically increased in age-matched immune-challenged transgenic AD mice, precisely around the inflammation-induced accumulations of APP and its proteolytic fragments, in striking similarity to the post-mortem findings in human patients with AD. CONCLUSION: Chronic inflammatory conditions induce age-associated development of an AD-like phenotype in WT mice, including the induction of APP accumulations, which represent a seed for deposition of aggregation-prone peptides. The PolyI:C mouse model therefore provides a unique tool to investigate the molecular mechanisms underlying the earliest pathophysiological changes preceding fibrillary Aß plaque deposition and neurofibrillary tangle formations in a physiological context of aging. Based on the similarity between the changes in immune-challenged mice and the development of AD in humans, we suggest that systemic infections represent a major risk factor for the development of AD.