Citations

Abstract 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 Methods All prospective interventional clinical trials for SMM, including published studies, meeting abstracts, and unpublished trials listed on ClinicalTrials.gov up to April 1, 2023, were identified.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.

Abstract Identifying individuals at risk for short-term fracture is essential to offer prompt beneficial treatment, especially since many fractures occur in those without osteoporosis by DXA-aBMD. We evaluated whether deficits in bone microarchitecture and density predict short-term fracture risk independent of the clinical predictors, DXA-BMD and FRAX. We combined data from eight cohorts to conduct a prospective study of bone microarchitecture at the distal radius and tibia (by HR-pQCT) and 2-year incidence of fracture (non-traumatic and traumatic) in 7327 individuals (4824 women, 2503 men, mean 69 ± 9 years). We estimated sex-specific hazard ratios (HR) for associations between bone measures and 2-year fracture incidence, adjusted for age, cohort, height, and weight, and then additionally adjusted for FN aBMD or FRAX for major osteoporotic fracture. Only 7% of study participants had FN T-score ≤ −2.5, whereas 53% had T-scores between −1.0 and −2.5 and 37% had T-scores ≥−1.0. Two-year cumulative fracture incidence was 4% (296/7327). Each SD decrease in radius cortical bone measures increased fracture risk by 38%-76% for women and men. After additional adjustment for FN-aBMD, risks remained increased by 28%-61%. Radius trabecular measures were also associated with 2-year fracture risk independently of FN-aBMD in women (HRs range: 1.21 per SD for trabecular separation to 1.55 for total vBMD). Decreased failure load (FL) was associated with increased fracture risk in both women and men (FN-aBMD ranges of adjusted HR = 1.47-2.42). Tibia measurement results were similar to radius results. Findings were also similar when models were adjusted for FRAX. In older adults, FL and HR-pQCT measures of cortical and trabecular bone microarchitecture and density with strong associations to short-term fractures improved fracture prediction beyond aBMD and FRAX. Thus, HR-pQCT may be a useful adjunct to traditional assessment of short-term fracture risk in older adults, including those with T-scores above the osteoporosis range.

The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease provide strategies for the prevention, diagnosis, and treatment of venous thromboembolism (VTE) in adult patients with cancer. VTE is a common and life-threatening condition in patients with cancer, and its management often requires multidisciplinary efforts. The NCCN panel is comprised of specialists spanning various fields, including cardiology, hematology, medical oncology, internal medicine, interventional radiology, and pharmacology. The content featured in this issue specifically addresses the evaluation and recommended treatment options outlined in the NCCN Guidelines for the diverse subtypes of cancer-associated VTE.

Abstract Background We evaluated the association of achieving endoscopic outcomes at week 12 of induction with improvements in clinical outcomes and quality of life (QoL) at week 52 of maintenance in patients with moderately to severely active Crohn’s disease (CD) treated with upadacitinib (UPA). Methods This post hoc analysis evaluated data from 2 phase 3 induction trials (NCT03345836 and NCT03345849) and 1 maintenance (NCT03345823) trial. Clinical responders to 12-week induction therapy with UPA who also received 52-week maintenance treatment with UPA were included. Endoscopic response, remission, healing, and ulcer-free endoscopy were assessed at week 12. Meaningful improvements in clinical and QoL outcomes were evaluated at week 52. Results A significantly greater proportion of patients who achieved an endoscopic response at the end of induction, compared with patients who did not, attained Crohn’s Disease Activity Index (CDAI) remission (52.0% vs 34.6%; P ≤ .01), corticosteroid-free CDAI remission (50.0% vs 30.9%), Inflammatory Bowel Disease Questionnaire remission (52.6% vs 30.3%), and meaningful improvements in Functional Assessment of Chronic Illness Therapy—Fatigue response (46.7% vs 25.9%), overall work impairment (47.1% vs 26.5%), and daily activity impairment (53.3% vs 34.1%) (all P < .05) at week 52. Similar findings were observed for patients who achieved endoscopic remission, endoscopic healing, and ulcer-free endoscopy at the end of induction vs those who did not. Conclusions Early improvement in endoscopic outcomes after UPA induction treatment was associated with long-term meaningful improvements in clinical outcomes and QoL in patients with CD. Clinical Registration number U-EXCEED induction trial (NCT03345836), U-EXCEL induction trial (NCT03345849), and U-ENDURE maintenance trial (NCT03345823).

Abstract Fibrolamellar carcinoma (FLC) is a rare, usually lethal primary liver tumor that affects children, adolescents and young adults. Sequencing of FLC tumors in hepatocytes reveals that in 99% of the patients there is one recurrent genomic alteration: A deletion of 400 kB. This produces DNAJB1::PRKACA, a fusion of the first exon of DNAJB1 with the 2nd – 10th exons of PRKACA, the catalytic subunit of protein kinase A (PKA). PKA exists as a holoenzyme of two catalytic subunits and two regulatory subunits. The regulatory subunit both inhibits the catalytic and localizes it in the cell. Calibrated mass spectrometry shows that in normal liver there is always an excess of regulatory>catalytic subunits, but in the adjacent FLC tumor tissue there is an excess of catalytic>regulatory subunits. Different biochemistry assays and proximity ligation reveal both free catalytic, unbound to regulatory subunits, and an increase of kinase activity in the tumor cells. Much of the increase of catalytic subunit is in the nucleus. Transducing primary human hepatocytes (PHH) with DNAJB1::PRKACA is sufficient to recapitulate the transcriptome of FLC tumors. Transduction of PHH with just the wt PRKACA is also sufficient to recapitulate the transcriptome of FLC tumors. Thus, just increasing the level of kinase is sufficient, there is nothing special about the fusion domain. From our tissue repository we have four patients who have a tumor that looks like FLC but does not have a fusion to the catalytic subunit. The only alteration in these patients is loss of regulatory subunit. The transcriptome of these patient tumors is indistinguishable from that of classic DNAJB1::PRKACA FLC in hepatocytes. Additionally, we have a few dozen patients who have either DNAJB1::PRKACA or another fusion, ATP1B1::PRKACA in the ductal cells of their liver (producing cholangiocarcinomas) or ductal cells of their pancreas (producing IOPN, Intraductal Oncolytic Pancreatic Neoplasms). The transcriptome of these patients clusters with the transcriptome of the FLC patients with DNAJB1::PRKACA in the hepatocytes. A functional precision medicine drug repurposing screen found that the EC50 of the response of freshly resected tumors from patients to a wide panel of drugs is the same as that of FLC patients with DNAJB1::PRKACA in their hepatocytes. Based on sequencing one could conclude that patients with deletion of regulatory subunit in the hepatocytes, or expression of DNAJB1::PRKACA in the hepatocytes, or expression of DNAJB1::PRKACA or ATP1B1::PRKACA in the cholangiocytes or pancreatic ductal cells are at least three distinct diseases. An analysis of the cell biological changes reveals that they all of an increase of the ratio of catalytic:regulatory subunit, they have an increase of catalytic subunit in the nucleus, and these all result in the same changes of transcriptome and the same drug-response profile. Thus, looking beyond sequencing to the cellular changes leads to a different conclusion, that maybe they should be considered the same disease. Citation Format: Sanford Simon, Mahsa Shirani, David Requena, Denise Ng, Gadi Lalazar, Solomon Levin, Michael S. Torbenson, Aatur D. Singhi, Henrik Molina, Charles M. Rice, Philip Coffino, Barbara A. Lyons. Precision medicine for the fusion protein driven cancer, fibrolamellar carcinoma (FLC): Beyond sequencing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B022.

Abstract Although complete remission rates in adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have improved over the last 2 decades, it is still inferior to that of the pediatric population, and once in remission, the risk of relapse is still high. Furthermore, although pediatric-inspired chemotherapy regimens have improved long-term outcomes for adolescents and young adults, these intensive chemotherapy regimens are not well tolerated in older patients and are associated with higher morbidity and mortality. Immunotherapeutic agents offer a potential opportunity to improve response and decrease relapse without increasing toxicity. The incorporation of rituximab (anti-CD20 monoclonal antibody) into chemotherapy regimens has been shown to improve outcomes. The treatment of BCP-ALL in adults has been transformed with the approval of inotuzumab ozogamicin (anti-CD22 antibody-drug conjugate), blinatumomab (CD3/CD19 bispecific antibody construct), and chimeric antigen receptor T cells for relapsed or refractory disease and of blinatumomab for measurable residual disease (MRD)–positive remission. More recently, studies of inotuzumab and blinatumomab have shown promising results when used up front either with or without multiagent chemotherapy. Blinatumomab has also been shown in a randomized trial to provide a survival benefit in patients with MRD-negative first remission when added to chemotherapy, which recently led to its additional US Food and Drug Administration approval for use in consolidation. In this review, we highlight the evolution of chemoimmunotherapy-based treatment approaches in the management of treatment-naïve BCP-ALL.

Abstract Nicotine exposure in the context of smoking or vaping worsens airway function. Although nicotinic acetylcholine receptors (nAChRs) are commonly thought to exert effects through the peripheral nervous system, we previously showed that airway smooth muscle (ASM) expresses them, particularly α7 subtype nAChR (α7nAChR), with functional effects on contractility and metabolism. However, the mechanisms of nAChR regulation and downstream effects in ASM are not fully understood. Using ASM cells from people without asthma versus people with mild to moderate asthma, we tested the hypothesis that nAChR-specific endoplasmic reticulum (ER) chaperones, resistance to inhibitors of cholinesterase 3 (RIC-3) and transmembrane protein 35A (TMEM35A) promote cell surface localization of α7nAChR with downstream influence on its functionality: effects exacerbated by inflammation. We found that mild to moderate asthma and exposure to proinflammatory cytokines relevant to asthma promote chaperone and α7nAChR expression in ASM. Downstream, ER stress was linked to nicotine/α7nAChR signaling, where RIC-3 and TMEM35 regulate nicotine-induced ER stress, intracellular Ca2+ regulation, and ASM cell proliferation. Overall, our data highlight the importance α7nAChR chaperones in mediating and modulating nicotine effects in ASM toward airway contractility and remodeling.

Waldenström macroglobulinemia (WM) is a B-cell lymphoma characterized by the presence of bone marrow lymphoplasmacytic infiltration and circulating monoclonal immunoglobulin M protein. The clinical presentation of WM is variable, ranging from gradually progressive cytopenias, organomegaly, fatigue, B symptoms, and peripheral neuropathy to the more emergent presentation with symptomatic hyperviscosity, cryoglobulinemia, hemolytic anemia–associated symptoms, acquired von Willebrand disease or acquired hemophilia–associated bleeding. Approximately 1 in 5 patients with WM are asymptomatic at diagnosis and classified as having smoldering WM, not requiring WM-directed therapy. Although WM typically has an indolent, relapsing-remitting course, the outcomes are heterogeneous. The prognosis of patients with WM is known to be impacted by certain clinical and laboratory features at initial presentation, with advanced age, elevated serum lactate dehydrogenase, and low serum albumin unfavorably affecting the outcome. Although complications such as histologic transformation or light and/or heavy chain (AL/ALH) amyloidosis are infrequent, their occurrence adversely influences the disease course. The International Prognostic Staging System for WM (IPSS-WM) is a validated model, often used in clinical practice, but needs to be reexamined in the current era. The discovery of the recurrent MYD88 L265P gain-of-function point mutation and the subclonal CXCR4 mutations has helped improve our understanding of the WM biology, and the prognostic impact of these mutations is under evaluation, with somewhat inconsistent findings thus far across studies. This review discusses the clinical presentation, diagnostic criteria, and prognostic markers of WM.

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel’s recommendations regarding the age at which to initiate screening in average-risk individuals and those with increased risk based on personal history of childhood, adolescent, and young adult cancer.