Transposon DNA sequences facilitate the tissue-specific gene transfer of circulating tumor DNA between human cells.

The exchange of genes between cells is known to play an important physiological and pathological role in many organisms. We show that circulating tumor DNA (ctDNA) facilitates cell-specific gene transfer between human cancer cells and explain part of the mechanisms behind this phenomenon. As ctDNA migrates into the nucleus, genetic information is transferred. Cell targeting and ctDNA integration require ERVL, SINE or LINE DNA sequences. Chemically manufactured AluSp and MER11C sequences replicated multiple myeloma (MM) ctDNA cell targeting and integration. Additionally, we found that ctDNA may alter the treatment response of MM and pancreatic cancer models. This study shows that retrotransposon DNA sequences promote cancer gene transfer. However, because cell-free DNA has been detected in physiological and other pathological conditions, our findings have a broader impact than just cancer. Furthermore, the discovery that transposon DNA sequences mediate tissue-specific targeting will open up a new avenue for the delivery of genes and therapies.

Enhancing Therapeutic Efficacy and Safety of Immune Checkpoint Inhibition for Bladder Cancer: A Comparative Analysis of Injectable vs. Intravesical Administration.

Bladder cancer (BC) presents a significant global health burden, characterized by high recurrence rates post-initial treatment. Gender differences in BC prevalence and response to therapy emphasize the importance of personalized treatment strategies. While Bacillus Calmette-Guérin (BCG) remains a cornerstone of BC therapy, resistance poses a challenge, necessitating alternative strategies. Immune checkpoint inhibitors (ICIs) have shown promise, yet systemic toxicity raises concern. Intravesical administration of ICIs offers a potential solution, with recent studies demonstrating the feasibility and efficacy of intravesical pembrolizumab. Although systemic toxicity remains a concern, its localized administration may mitigate adverse events. Additionally, liposomal delivery of ICIs exhibits promises in enhancing drug penetration and reducing toxicity. Novel imaging modalities compatible with Vesical Imaging-Reporting and Data System (VI-RADS) and capable of predicting high-grade bladder cancer can aid the pre-operative shared decision making of patient and surgeon. Future research should focus on refining treatment approaches, optimizing dosing regimens, and leveraging advanced imaging techniques to improve patient outcomes. In conclusion, intravesical immunotherapy presents a promising avenue for BC treatment, offering enhanced therapeutic effectiveness while minimizing systemic toxicity. Continued research efforts are essential to validate these findings and optimize intravesical immunotherapy's role in BC management, ultimately improving patient outcomes.

Pembrolizumab and low-dose, single-fraction radiotherapy for patients with relapsed or refractory multiple myeloma: a prospective, single-centre, single-group, open-label, phase 2 pilot trial in the USA.

BACKGROUND: Currently, the use of radiotherapy alone for people with multiple myeloma is limited to palliation of pain, pending fracture, and control of spinal-cord compression. Single immune-checkpoint inhibitors, such as anti-programmed death-1 (anti-PD1), have not been successful. We aimed to evaluate the activity and safety of the combination of pembrolizumab and low-dose, single-fraction, hypofractionated radiotherapy to treat patients with relapsed or refractory multiple myeloma. METHODS: For this prospective, single-centre, single-group, open-label, phase 2 trial, we recruited patients with relapsed or refractory multiple myeloma from the Winship Cancer Institute (Emory University, Atlanta, GA, USA). Key inclusion criteria were aged 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, relapsed or refractory multiple myeloma as indicated by progression under International Myeloma Working Group (IMWG) criteria, and adequate candidacy for both pembrolizumab and radiotherapy. Baseline and post-treatment assessments were serial bone-marrow biopsy, peripheral blood collections, staging, serial serum and urine paraprotein analysis, serial PET-CT imaging, and a physical examination. On day 1, patients received hypofractionated 8 gray in 1 fraction (8 Gy/1 fx) radiotherapy to either symptomatic or progressing extra-osseous or osseous myeloma sites. Patients also received pembrolizumab (200 mg/kg intravenously) on day 2 or 3, then once every 3 weeks (±7 days) for 2 years or until progressive disease, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death. Dose reduction and interruptions were not allowed. The primary outcome was acute toxicity defined as grade 3 or worse toxicity at 3 months within the radiated site when used in combination with pembrolizumab. All patients were analysed per protocol and included in safety analyses. This trial is registered on ClinicalTrials.gov (NCT03267888); it is completed and closed to accrual. FINDINGS: 32 patients were screened between June 1, 2018, and Sept 2, 2022, and 25 were enrolled in the trial and treated on protocol. Of the 25 treated patients, 11 (44%) were female and 14 (56%) were male. 19 (76%) patients were White and six (24%) were Black or African American. Toxicity, as the primary outcome, was deemed to be acceptable as no grade 4 or 5 adverse events were observed. At 3-month follow-up, eight (32%) of 25 patients had treatment benefit (one had stable disease, three had partial response, two had very good partial response, and two had complete response). There was no grade 3 or worse radiation-related toxicity within irradiated volumes. One (4%) patient of the 25 who received combination treatment had a grade 3 pembrolizumab-related adverse event. There were no treatment-related deaths. INTERPRETATION: Combination treatment of low-dose, single-fraction radiotherapy with pembrolizumab was safe, with early promise of response activity. Our approach could be an option for patients with relapsed or refractory multiple myeloma who have not responded to previous treatment. Larger trials to substantiate our findings are needed. FUNDING: Merck Sharp & Dohme.

International Myeloma Working Group immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell-engaging bispecific antibodies in multiple myeloma.

Multiple myeloma remains an incurable disease, despite the development of numerous drug classes and combinations that have contributed to improved overall survival. Immunotherapies directed against cancer cell-surface antigens, such as chimeric antigen receptor (CAR) T-cell therapy and T-cell-redirecting bispecific antibodies, have recently received regulatory approvals and shown unprecedented efficacy. However, these immunotherapies have unique mechanisms of action and toxicities that are different to previous treatments for myeloma, so experiences from clinical trials and early access programmes are essential for providing specific recommendations for management of patients, especially as these agents become available across many parts of the world. Here, we provide expert consensus clinical practice guidelines for the use of bispecific antibodies for the treatment of myeloma. The International Myeloma Working Group is also involved in the collection of prospective real-time data of patients treated with such immunotherapies, with the aim of learning continuously and adapting clinical practices to optimise the management of patients receiving immunotherapies.

Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk.

In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]). Among 123 D-KRd patients, 43.1%, 37.4%, and 19.5% had 0, 1, or ≥2 HRCAs. Among 120 D-RVd patients, 55.8%, 28.3%, and 10.8% had 0, 1, or ≥2 HRCAs. Rates of complete response or better (best on study) for 0, 1, or ≥2 HRCAs were 90.6%, 89.1%, and 70.8% for D-KRd, and 90.9%, 78.8%, and 61.5% for D-RVd. At median follow-up (MASTER, 31.1 months; GRIFFIN, 49.6 months for randomized patients/59.5 months for safety run-in patients), MRD-negativity rates as assessed by next-generation sequencing (10-5) were 80.0%, 86.4%, and 83.3% for 0, 1, or ≥2 HRCAs for D-KRd, and 76.1%, 55.9%, and 61.5% for D-RVd. PFS was similar between studies and superior for 0 or 1 versus ≥2 HRCAs: 36-month PFS rates for D-KRd were 89.9%, 86.2%, and 52.4%, and 96.7%, 90.5%, and 53.5% for D-RVd. These data support the use of daratumumab-containing regimens for transplant-eligible NDMM with HCRAs; however, additional strategies are needed for ultra-high-risk disease (≥2 HRCAs). Video Abstract.

Health-related quality of life in transplant-eligible patients with newly diagnosed multiple myeloma treated with daratumumab, lenalidomide, bortezomib, and dexamethasone: Patient-reported outcomes from GRIFFIN.

In the phase 2 GRIFFIN trial (ClinicalTrials.gov identifier: NCT02874742), daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) improved depth of response and progression-free survival (PFS) versus lenalidomide, bortezomib, and dexamethasone (RVd) alone in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) collected using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30-item (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module 20-item (QLQ-MY20), and EuroQol 5-Dimension 5-Level (EQ-5D-5L) tools on day 1 of cycles 1, 2, and 3; on day 21 of cycle 4 (end of induction therapy); on day 1 of cycle 5; on day 21 of cycle 6 (end of posttransplant consolidation therapy); and at months 6, 12, 18, and 24 of maintenance therapy. Meaningful improvements from baseline were seen in most of the PRO scales with both treatments after consolidation and were sustained for at least 2 years of maintenance treatment. Large reductions from baseline (~20 points) were especially observed in pain symptoms for both treatment groups, although these were numerically higher for patients receiving D-RVd during the majority of the time points. In addition, improvements in key scales, such as global health status, fatigue symptoms, and physical functioning, were also seen with both D-RVd and RVd. These improvements in health-related quality of life contribute to the totality of evidence supporting the improvement in clinical outcomes such as response rates and PFS with D-RVd in induction, consolidation, and maintenance therapy in TE patients with NDMM.

Post hoc analysis of daratumumab plus lenalidomide, bortezomib and dexamethasone in Black patients from final data of the GRIFFIN study.

Due in part to racial disparities and underrepresentation in clinical studies, optimal therapies for Black patients with multiple myeloma remain undefined. This final analysis of GRIFFIN by race showed that the addition of daratumumab (D) to lenalidomide/bortezomib/dexamethasone (RVd) provides clinical benefit among both Black and White transplant-eligible newly diagnosed patients compared with RVd alone. However, Black patients were more likely to discontinue ≥1 drug due to treatment-emergent adverse events. In summary, these findings suggest a benefit of D-RVd front-line therapy among Black and White patients and underscore the importance of equitable treatment access for all patients.

Cargo selective vesicle tethering: The structural basis for binding of specific cargo proteins by the Golgi tether component TBC1D23.

The Golgi-localized golgins golgin-97 and golgin-245 capture transport vesicles arriving from endosomes via the protein TBC1D23. The amino-terminal domain of TBC1D23 binds to the golgins, and the carboxyl-terminal domain of TBC1D23 captures the vesicles, but how it recognizes specific vesicles was unclear. A search for binding partners of the carboxyl-terminal domain unexpectedly revealed direct binding to carboxypeptidase D and syntaxin-16, known cargo proteins of the captured vesicles. Binding is via a threonine-leucine-tyrosine (TLY) sequence present in both proteins next to an acidic cluster. A crystal structure reveals how this acidic TLY motif binds to TBC1D23. An acidic TLY motif is also present in the tails of other endosome-to-Golgi cargo, and these also bind TBC1D23. Structure-guided mutations in the carboxyl-terminal domain that disrupt motif binding in vitro also block vesicle capture in vivo. Thus, TBC1D23 attached to golgin-97 and golgin-245 captures vesicles by a previously undescribed mechanism: the recognition of a motif shared by cargo proteins carried by the vesicle.

Divergence of variant binding/neutralizing antibodies following SARS-CoV-2 booster vaccines in myeloma: Impact of hybrid immunity.

We characterized virus-neutralization and spike-binding antibody profiles in myeloma patients following monovalent or bivalent-SARS-CoV-2 booster vaccination. Vaccination improves the breadth of binding antibodies but not neutralization activity against current variants. Hybrid immunity and immune imprinting impact vaccine-elicited immunity.

Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial.

BACKGROUND: Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone (D-RVd) in the GRIFFIN study improved the stringent complete response rate by the end of consolidation in transplantation-eligible patients with newly diagnosed multiple myeloma. Here, we report the findings of the predefined final analysis. METHODS: GRIFFIN was an open-label, randomised, active-controlled, phase 2 trial done in 35 research centres in the USA. Patients had newly diagnosed multiple myeloma with measurable disease by M protein or free light chain, were aged 18-70 years, had an ECOG performance score of 0-2, and were eligible for autologous haematopoietic stem-cell transplantation (HSCT). Patients were randomly assigned (1:1) to four D-RVd or RVd induction cycles, autologous HSCT, two D-RVd or RVd consolidation cycles, and lenalidomide with or without daratumumab maintenance therapy for 2 years. Patients received 21-day cycles of oral lenalidomide (25 mg on days 1-14), subcutaneous bortezomib (1·3 mg/m2 on days 1, 4, 8, and 11), oral dexamethasone (40 mg weekly) with or without intravenous daratumumab (16 mg/kg weekly, cycles 1-4; day 1, cycles 5-6). Maintenance therapy (28-day cycles) was oral lenalidomide (10 mg on days 1-21) with or without daratumumab (16 mg/kg intravenously every 4 or 8 weeks, or 1800 mg subcutaneously monthly). Patients could continue lenalidomide maintenance after study treatment completion. The primary endpoint was stringent complete response rate by the end of consolidation in the response-evaluable population, and has already been reported. Here we report updated stringent complete response rates and secondary outcomes including progression-free survival and overall survival. The trial is registered with ClinicalTrials.gov (NCT02874742) and ended on April 8, 2022. FINDINGS: Between Dec 20, 2016, and April 10, 2018, 104 patients were randomly assigned to the D-RVd group and 103 were randomly assigned to the RVd group; most patients were White (85 [82%] in the D-RVd group and 76 [74%] in the RVd group) and male (58 [56%] in the D-RVd group and 60 [58%] in the RVd group). At a median follow-up of 49·6 months (IQR 47·4-52·1), D-RVd improved rates of stringent complete response (67 [67%] of 100] vs 47 [48%] of 98]; odds ratio 2·18 [95% CI 1·22-3·89], p=0·0079), and 4-year progression-free survival was 87·2% (95% CI 77·9-92·8) for D-RVd versus 70·0% (95% CI 55·9-80·3) for RVd, with a hazard ratio (HR) of 0·45 (95% CI 0·21-0·95, p=0·032) for risk of disease progression or death with D-RVd. Median overall survival was not reached for either group (HR 0·90 [95% CI 0·31-2·56], p=0·84). The most common grade 3-4 treatment-emergent adverse events in the D-RVd versus RVd groups were neutropenia (46 [46%] of 99 vs 23 [23%] of 102), lymphopenia (23 [23%] vs 23 [23%]), leukopenia (17 [17%] vs eight [8%]), thrombocytopenia (16 [16%] vs nine [9%]), pneumonia (12 [12%] vs 14 [14%]), and hypophosphataemia (ten [10%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 46 (46%) of 99 patients in the D-RVd group and in 53 (52%) of 102 patients in the RVd group. One patient in each treatment group reported a treatment-emergent adverse event that resulted in death (bronchopneumonia in the D-RVd group; cause unknown in the RVd group); neither was related to study treatment. No new safety concerns occurred with maintenance therapy. INTERPRETATION: Addition of daratumumab to RVd improved the depth of response and progression-free survival in transplantation-eligible patients with newly diagnosed multiple myeloma. These results justify further evaluation in phase 3 studies. FUNDING: Janssen Oncology.

Divergence of variant binding/neutralizing antibodies following SARS-CoV-2 booster vaccines in myeloma: Impact of hybrid immunity.

We characterized virus-neutralization and spike-binding antibody profiles in myeloma patients following monovalent or bivalent-SARS-CoV-2 booster vaccination. Vaccination improves the breadth of binding antibodies but not neutralization activity against current variants. Hybrid immunity and immune imprinting impact vaccine-elicited immunity.

Regulation of antigen-specific T cell infiltration and spatial architecture in multiple myeloma and premalignancy.

Entry of antigen-specific T cells into human tumors is critical for immunotherapy, but the underlying mechanisms are poorly understood. Here, we combined high-dimensional spatial analyses with in vitro and in vivo modeling to study the mechanisms underlying immune infiltration in human multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS). Clustered tumor growth was a feature of MM but not MGUS biopsies, and this growth pattern was reproduced in humanized mouse models. MM biopsies exhibited intralesional as well as spatial heterogeneity, with coexistence of T cell-rich and T cell-sparse regions and the presence of areas of T cell exclusion. In vitro studies demonstrated that T cell entry into MM clusters was regulated by agonistic signals and CD2-CD58 interactions. Upon adoptive transfer, antigen-specific T cells localized to the tumor site but required in situ DC-mediated antigen presentation for tumor entry. C-type lectin domain family 9 member A-positive (CLEC9A+) DCs appeared to mark portals of entry for gradients of T cell infiltration in MM biopsies, and their proximity to T cell factor 1-positive (TCF1+) T cells correlated with disease state and risk status. These data illustrate a role for tumor-associated DCs and in situ activation in promoting the infiltration of antigen-specific T cells in MM and provide insights into spatial alterations in tumor/immune cells with malignant evolution.

Shifting Sociodemographic Characteristics of a Phase I Clinical Trial Population at an NCI-Designated Comprehensive Cancer Center in the Southeast.

Racial and ethnic minority populations are consistently under-represented in oncology clinical trials despite comprising a disproportionate share of a cancer burden. Phase I oncology clinical trials pose a unique challenge and opportunity for minority inclusion. Here we compared the sociodemographic characteristics of patients participating in phase 1 clinical trials a National Cancer Institute ( NCI)-designated comprehensive center to all patients at the center, patients with new cancer diagnosis in metropolitan Atlanta and patients with new cancer diagnoses in the state of Georgia. From 2015 to 2020, 2325 patients (43.4% female, 56.6% male) consented to participate in a phase I trial. Grouped self-reported race distribution was 70.3% White, 26.2% Black, and 3.5% other. Of new patient registrations at Winship Cancer Institute (N = 107 497) (50% F, 50% M), grouped race distribution was 63.3% White, 32.0% Black, and 4.7% other. Patients with new cancer diagnoses in metro Atlanta from 2015 to 2016 (N = 31101) were 58.4% White, 37.2% Black, and 4.3% other. Race and sex distribution of phase I patients was significantly different than Winship patients (P < .001). Over time, percent of White patients decreased in both phase I and Winship groups (P = .009 and P < .001, respectively); percentage of females did not change in either group (P = .54 phase I, P = .063 Winship). Although phase I patients were more likely to be White, male, and privately ensured than the Winship cohort, from 2015 to 2020 the percentage of White patients in phase I trials and among all new patients treated at Winship decreased. The intent of characterizing existing disparities is to improve the representation of patients from racial and ethnic minority backgrounds in phase I clinical trials.

Impact of Black Race on Peripheral Neuropathy in Patients With Newly Diagnosed Multiple Myeloma Receiving Bortezomib Induction.

PURPOSE: The incidence of multiple myeloma (MM) is two to three times higher in Black patients compared with other races, making it the most common hematologic malignancy in this patient population. Current treatment guidelines recommend the combination of a proteasome inhibitor, an immunomodulatory agent, and a corticosteroid as preferred induction therapy. Bortezomib use comes with the risk of peripheral neuropathy (PN) and potential need for dose reduction, therapy interruption, and additional supportive medications. Known risk factors for bortezomib-induced peripheral neuropathy (BIPN) include diabetes mellitus, previous thalidomide, advanced age, and obesity. We aimed to determine the potential association between Black race and incidence of BIPN. PATIENTS AND METHODS: We identified a cohort of 748 patients with newly diagnosed MM who received induction with bortezomib, lenalidomide, and dexamethasone from 2007 to 2016. One hundred forty Black patients were matched with 140 non-Black patients on age, sex, BMI, and route of bortezomib administration. Incidence of BIPN was a binary event defined as new use of a neuropathy medication, bortezomib dose reduction, dose omission, or discontinuation because of PN. RESULTS: The incidence of BIPN was higher in Black patients (46%) compared with non-Black patients (34%; P = .05) in both univariate (odds ratio [OR], 1.61; 95% CI, 1.00 to 2.61; P = .052) and multivariable analyses (OR, 1.64; 95% CI, 1.01 to 2.67; P = .047). No significant differences in BIPN were seen when stratified by route of administration. CONCLUSION: These data indicate that Black race is an independent risk factor for the development of BIPN. Additional prevention strategies, close monitoring, and appropriate supportive care measures are warranted for these patients.

BCMA CAR-T induces complete and durable remission in refractory plasmablastic lymphoma.

Plasmablastic lymphoma (PBL) is a rare subtype of aggressive large B-cell lymphoma, with a dismal prognosis despite aggressive therapies. New approaches are needed for those with refractory disease. PBL expresses antigens similar to multiple myeloma (MM), including B-cell maturation antigen (BCMA). Chimeric antigen receptor T-cell (CAR-T) therapy directed against BCMA has shown efficacy for the treatment of heavily pretreated MM with low rates of grades 3 and 4 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in a phase Ib/II trial (A Study of JNJ-68284528, a CAR-T Directed Against BCMA in Participants With Relapsed or Refractory Multiple Myeloma (CARTITUDE-1), NCT03548207). However, data for the use of BCMA CAR-T for treating PBL are lacking.We report a challenging case of multiple refractory PBL that emerged from B-cell acute lymphoblastic leukemia in an adolescent who failed to respond to an allogeneic hematopoietic cell transplant. The patient developed rapidly advancing disease despite withdrawal of immunosuppression, treatment with etoposide, ibrutinib, and daratumumab, prompting consideration of BCMA CAR-T (under emergency investigational new drug (eIND)). The patient achieved a complete remission (CR), without recurrent acute graft versus host disease (GVHD), CRS or ICANS after BCMA CAR-T therapy. BCMA CAR-T expansion was detected in vivo, peaking on day 15. The patient remains in CR for more than a year post CAR-T therapy, supporting consideration of immunotherapy for future patients with refractory PBL, a disease with few treatment options.

Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody.

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48-250 µg/kg tested to date (n = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6-56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2-27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date.

Treating Lower Urinary Tract Symptoms in Older Adults: Intravesical Options.

This article provides an overview of the diagnosis and the treatment of lower urinary tract symptoms in older adults complicated by the neurodegenerative changes in the micturition reflex and further confounded by age-related decline in hepatic and renal clearance raising the propensity of adverse drug reactions. The first-line drug treatment for lower urinary tract symptoms, orally administered antimuscarinics, fails to reach the equilibrium dissociation constant of muscarinic receptors even at their maximum plasma concentration and tends to evoke a half-maximal response at a muscarinic receptor occupancy of just 0.206% in the bladder with a minimal difference from exocrine glands, which raises the adverse drug reaction risk. On the contrary, intravesical antimuscarinics are instilled at concentrations 1000-fold higher than the oral maximum plasma concentration and the equilibrium dissociation constant erects a downhill concentration gradient that drives passive diffusion and achieves a mucosal concentration around ten-fold lower than the instilled concentration for a long-lasting occupation of muscarinic receptors in mucosa and sensory nerves. A high local concentration of antimuscarinics in the bladder triggers alternative mechanisms of action and is supposed to engage retrograde transport to nerve cell bodies for neuroplastic changes that underlie a long-lasting therapeutic effect, while an intrinsically lower systemic uptake of the intravesical route lowers the muscarinic receptor occupancy of exocrine glands to lower the adverse drug reaction relative to the oral route. Thus, the traditional pharmacokinetics and pharmacodynamics of oral treatment are upended by intravesical antimuscarinics to generate a dramatic improvement (~ 76%) noted in a meta-analysis of studies enrolling children with neurogenic lower urinary tract symptoms on the primary endpoint of maximum cystometric bladder capacity as well as the secondary endpoints of filling compliance and uninhibited detrusor contractions. The therapeutic success of intravesical multidose oxybutynin solution or oxybutynin entrapped in the polymer for sustained release in the pediatric population bodes well for patients with lower urinary tract symptoms at the other extreme of the age spectrum. Though generally used to predict oral drug absorption, Lipinski's rule of five can also explain the ten-fold lower systemic uptake from the bladder of positively charged trospium over oxybutynin, a tertiary amine. Chemodenervation by an intradetrusor injection of onabotulinumtoxinA is merited for patients with idiopathic overactive bladder discontinuing oral treatment because of a lack of efficacy. However, age-related peripheral neurodegeneration potentiates the adverse drug reaction risk of urinary retention that motivates the quest of liquid instillation, delivering larger fraction of onabotulinumtoxinA to the mucosa as opposed to muscle by an intradetrusor injection can also probe the neurogenic and myogenic predominance of idiopathic overactive bladder. Overall, the treatment paradigm of lower urinary tract symptoms in older adults should be tailored to individual's overall health status and the risk tolerance for adverse drug reactions.