IMPORTANCE: Multiple myeloma is a hematologic malignancy characterized by presence of abnormal clonal plasma cells in the bone marrow, with potential for uncontrolled growth causing destructive bone ...lesions, kidney injury, anemia, and hypercalcemia. Multiple myeloma is diagnosed in an estimated 34 920 people in the US and in approximately 588 161 people worldwide each year. OBSERVATIONS: Among patients with multiple myeloma, approximately 73% have anemia, 79% have osteolytic bone disease, and 19% have acute kidney injury at the time of presentation. Evaluation of patients with possible multiple myeloma includes measurement of hemoglobin, serum creatinine, serum calcium, and serum free light chain levels; serum protein electrophoresis with immunofixation; 24-hour urine protein electrophoresis; and full-body skeletal imaging with computed tomography, positron emission tomography, or magnetic resonance imaging. The Revised International Staging System combines data from the serum biomarkers β2 microglobulin, albumin, and lactate dehydrogenase in conjunction with malignant plasma cell genomic features found on fluorescence in situ hybridization—t(4;14), del(17p), and t(14;16)—to assess estimated progression-free survival and overall survival. At diagnosis, 28% of patients are classified as having Revised International Staging stage I multiple myeloma, and these patients have a median 5-year survival of 82%. Among all patients with multiple myeloma, standard first-line (induction) therapy consists of a combination of an injectable proteasome inhibitor (ie, bortezomib), an oral immunomodulatory agent (ie, lenalidomide), and dexamethasone and is associated with median progression-free survival of 41 months, compared with historical reports of 8.5 months without therapy. This induction therapy combined with autologous hematopoietic stem cell transplantation followed by maintenance lenalidomide is standard of care for eligible patients. CONCLUSIONS AND RELEVANCE: Approximately 34 920 people in the US and 155 688 people worldwide are diagnosed with multiple myeloma each year. Induction therapy with an injectable proteasome inhibitor, an oral immunomodulatory agent and dexamethasone followed by treatment with autologous hematopoietic stem cell transplantation, and maintenance therapy with lenalidomide are among the treatments considered standard care for eligible patients.
CONTEXT Whether epidural analgesia is a better method than parenteral opioids
for postoperative pain control remains controversial. OBJECTIVE To systematically review the efficacy of postoperative ...epidural analgesia
vs parenteral opioids, the primary alternative technique. DATA SOURCES Studies were identified primarily by searching the National Library
of Medicine's PubMed database (1966 to April 25, 2002) and other sources for
studies related to postoperative epidural analgesia. STUDY SELECTION Inclusion criteria were a comparison of epidural therapy vs parenteral
opioids for postoperative analgesia, measurement of pain using a visual analog
scale (VAS) or numeric rating scale, randomization of patients to either therapy,
and adult patients (≥18 years). A total of 1404 abstracts were identified,
100 of which met all inclusion criteria. DATA EXTRACTION Each article was reviewed and data extracted from tables, text, or extrapolated
from figures as needed. Weighted mean pain scores, weighted mean differences
in pain score, and weighted incidences of complications were determined by
using a fixed-effect model. DATA SYNTHESIS Epidural analgesia provided better postoperative analgesia compared
with parenteral opioids (mean SE, 19.40 mm 0.17 vs 29.40 mm 0.20 on
the VAS; P<.001). When analyzed by postoperative
day, epidural analgesia was better than parenteral opioids on each postoperative
day (P<.001 for each day after surgery). For all
types of surgery and pain assessments, all forms of epidural analgesia provided
significantly better postoperative analgesia compared with parenteral opioid
analgesia (P<.001 for all), with the exception
of thoracic epidural analgesia vs opioids for rest pain after thoracic surgery
(weighted mean difference, 0.6 mm; 95% confidence interval, –0.3 to
1.5 mm; P = .12). The complication rates were lower
than expected for nausea or vomiting and pruritus but comparable with existing
data for lower extremity motor block. CONCLUSION Epidural analgesia, regardless of analgesic agent, location of catheter
placement, and type and time of pain assessment, provided better postoperative
analgesia compared with parenteral opioids.
The human gut microbiota produces dozens of metabolites that accumulate in the bloodstream, where they can have systemic effects on the host. Although these small molecules commonly reach ...concentrations similar to those achieved by pharmaceutical agents, remarkably little is known about the microbial metabolic pathways that produce them. Here we use a combination of genetics and metabolic profiling to characterize a pathway from the gut symbiont Clostridium sporogenes that generates aromatic amino acid metabolites. Our results reveal that this pathway produces twelve compounds, nine of which are known to accumulate in host serum. All three aromatic amino acids (tryptophan, phenylalanine and tyrosine) serve as substrates for the pathway, and it involves branching and alternative reductases for specific intermediates. By genetically manipulating C. sporogenes, we modulate serum levels of these metabolites in gnotobiotic mice, and show that in turn this affects intestinal permeability and systemic immunity. This work has the potential to provide the basis of a systematic effort to engineer the molecular output of the gut bacterial community.
B-cell maturation antigen (BCMA) is a validated target for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). Despite promising objective response rates, most patients relapse, ...and low levels of BCMA on a subset of tumor cells has been suggested as a probable escape mechanism. BCMA is actively cleaved from the tumor cell surface by the ubiquitous multisubunit γ-secretase (GS) complex, which reduces ligand density on tumor cells for CAR T-cell recognition and releases a soluble BCMA (sBCMA) fragment capable of inhibiting CAR T-cell function. Sufficient sBCMA can accumulate in the bone marrow of MM patients to inhibit CAR T-cell recognition of tumor cells, and potentially limit efficacy of BCMA-directed adoptive T-cell therapy. We investigated whether blocking BCMA cleavage by small-molecule GS inhibitors (GSIs) could augment BCMA-targeted CAR T-cell therapy. We found that exposure of myeloma cell lines and patient tumor samples to GSIs markedly increased surface BCMA levels in a dose-dependent fashion, concurrently decreased sBCMA concentrations, and improved tumor recognition by CAR T cells in vitro. GSI treatment of MM tumor-bearing NOD/SCID/γc−/− mice increased BCMA expression on tumor cells, decreased sBCMA in peripheral blood, and improved antitumor efficacy of BCMA-targeted CAR T-cell therapy. Importantly, short-term GSI administration to MM patients markedly increases the percentage of BCMA+ tumor cells, and the levels of BCMA surface expression in vivo. Based on these data, a US Food and Drug Administration (FDA)-approved clinical trial has been initiated, combining GSI with concurrent BCMA CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT03502577.
•Small-molecule GSIs increase BCMA surface expression on myeloma cells, resulting in enhanced CAR T-cell efficacy.
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Cattaneo et al. report a unique case of a multiple myeloma patient with elevated B‐cell maturation antigen (BCMA) surface density, potentially due to genetic alterations in the gamma‐secretase ...protease complex—responsible for BCMA cleavage from plasma cells. No mutations in the BCMA gene were detected, but there was partial deletion of PSEN1 and amplification of PSEN2 (components of the gamma‐secretase complex), which may explain the lack of response to the gamma‐secretase inhibitor DAPT. This case, along with recent published literature, underscores the significance of gamma secretase in modulating BCMA density and the potential impact of its genetic alterations.
Commentary on: Cattaneo et al. Genetic defects of gamma‐secretase genes in a multiple myeloma patient with high and dysregulated BCMA surface density: A case report. Br J Haematol 2024;204:571‐575.
Amyloidosis of the gastrointestinal tract, with biopsy-proven disease, is rare. We reviewed a series of patients who presented with biopsy-proven gastrointestinal amyloidosis and report their ...clinical characteristics, treatments, and survival. This is a retrospective review of data prospectively collected from January 1998 to December 2011 in a tertiary referral center; 2,334 patients with all types of amyloidosis were evaluated during this period. Seventy-six patients (3.2%) had biopsy-proven amyloid involvement of the gastrointestinal tract. Their median age was 61 years (range, 34-79). Systemic amyloidosis with dominant gastrointestinal involvement was present in 60 (79%) patients, whereas the other 16 (21%) patients had amyloidosis localized to the gastrointestinal tract without evidence of an associated plasma cell dyscrasia or other organ involvement. Of the 60 systemic cases, 50 (83%) had immunoglobulin light-chain, five (8%) had familial lysozyme, three (5%) had wild-type transthyretin, and two (3%) had mutant transthyretin amyloidosis. The most frequent symptoms for all patients were weight loss in 33 (45%) and gastrointestinal bleeding in 27 (36%). Incidental identification of amyloidosis on routine endoscopic surveillance played a role in the diagnosis of seven patients with systemic immunoglobulin light-chain, and four patients with immunoglobulin light-chain localized to the gastrointestinal tract. Amyloid protein subtyping was performed in 12 of the cases of localized disease, and all had lambda light chain disease. Of the 50 patients with systemic immunoglobulin light-chain amyloidosis, 45 were treated with anti-plasma cell therapy. The median survival has not been reached for this group. For the 16 patients with localized gastrointestinal amyloidosis, supportive care was the mainstay of treatment; none received anti-plasma cell therapy. All 16 are alive at a median follow-up of 36 months (range, 1-143). Patients with biopsy-proven gastrointestinal amyloidosis often present with weight loss and bleeding. In localized cases, all that underwent typing were due to lambda light chain amyloidosis and none progressed to systemic disease during the period of follow-up. Most patients with systemic disease had immunoglobulin light-chain, and their tolerance of therapy and median survival were excellent. Although a rare manifestation of amyloidosis, staining for amyloid should be considered in patients undergoing gastrointestinal biopsy who have unexplained chronic gastrointestinal symptoms.
Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple ...myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10−5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P < .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.
•D-RVd improved sCR rates and MRD negativity vs RVd, both of which deepened over time.•No new safety concerns were observed with D-RVd, and no clinically significant impact on stem cell mobilization or engraftment was noted.
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For many years, the view that Gal 3:10-14 addresses the anthropological inability of sinful humans to fulfill the law was nearly universal. This interpretation, however, has recently faced serious ...criticisms. One of the most influential alternative readings is that Gal 3:10-14 primarily addresses the issue of Israel's corporate curse. I argue, however, that there are problems with this interpretation, despite its current popularity. A carefully nuanced version of the anthropological view provides a more satisfying reading of the text.
Autologous chimeric antigen receptor T-cell (CAR-T) therapies targeting B-cell maturation antigen (BCMA) have revolutionized the field of multiple myeloma in the same way that the Ford Model T ...revolutionized the original CAR world a century ago. However, we are only beginning to understand how to improve the efficacy and usability of these cellular therapies. In this review, we explore three automotive analogies for innovation with BCMA CAR-T therapies: stronger engines, better mileage, and hassle-free delivery. Firstly, we can build stronger engines in terms of BCMA targeting: improved antigen binding, tools to modulate antigen density, and armoring to better reach the antigen itself. Secondly, we can improve "mileage" in terms of response durability through
CAR design and
immune manipulation. Thirdly, we can implement hassle-free delivery through rapid manufacturing protocols and off-the-shelf products. Just as the Model T set a benchmark for car manufacturing over 100 years ago, idecabtagene vicleucel and ciltacabtagene autoleucel have now set the starting point for BCMA CAR-T therapy with their approvals. As with any emerging technology, whether automotive or cellular, the best in innovation and optimization is yet to come.
J. Andrew Cowan challenges the popular theory that Luke sought to boost the cultural status of the early Christian movement by emphasising its Jewish roots – associating the new church with an ...ancient and therefore respected heritage. Cowan instead argues that Luke draws upon the traditions of the Old Testament and its supporting texts as a reassurance to Christians, promising that Jesus’ life, his works and the church that follow legitimately provide fulfilment of God’s salvific plan. Cowan’s argument compares Luke’s writings to two near-contemporaries, Dionysius of Halicarnassus and T. Flavius Josephus, both of whom emphasized the ancient heritage of a people with cultural or political aims in view, exploring how the writings of Luke do not reflect the same cultural values or pursue the same ends. Challenging assumptions on Luke’s supposed attempts to assuage political concerns, capitalize on antiquity, and present Christianity as an inner-Jewish sect, Cowan counters with arguments for Luke being critical of over-valuing tradition and defining the Jewish people as resistant to God and His messages. Cowan concludes with the argument that the apostle does not strive for legitimisation of the new church by previous cultural standards, but instead provides theological reassurance to Christians that God’s plan has been fulfilled, with implications for broader debate.
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