Bispecifics, trispecifics, and other novel immune treatments in myeloma.

Despite recent advances in treatment, relapses in multiple myeloma (MM) are inevitable. Off-the-shelf immunotherapeutics represent a promising avenue for research, with various classes of agents under development and several demonstrating deep and durable responses in patients who have exhausted all available therapies. Antibody-drug conjugates (ADCs) seek to improve on naked monoclonal antibodies by delivering a cytotoxic payload directly to tumor cells while largely limiting systemic effects. Belantamab mafodotin, a B-cell maturation antigen (BCMA)-targeted ADC, has shown response rates >30% in a phase 2 trial of highly refractory patients and is being investigated in a variety of settings and combinations. Several other ADCs are in earlier stages of development that target cell surface antigens that are internalized, including BCMA, CD38, CD46, CD56, CD74, and CD138. Bispecifics are designed to bring cytotoxic immune effector cells into proximity with tumor cells, and several agents have shown high response rates in early trials. Current targets include BCMA, CD38, GPRC5d, and FCRH5, and all of these seek to engage T cells through CD3. Bispecifics targeting natural killer (NK) cells through CD16 are still in preclinical development. Trispecific antibodies may represent an advance over bispecifics by providing a T-cell costimulatory signal such as CD28, or alternatively, dual MM antigens to increase specificity of NK or T-cell targeting. This is an area of active preclinical research at this time. Lastly, designed ankyrin repeat proteins, which are small antibody-mimetic proteins with high target-binding affinity, have the potential to block multiple pathways at once and provide stimulatory signals to the immune system

Selinexor in relapsed/refractory multiple myeloma.

Multiple myeloma (MM) represents an incurable hematologic malignancy. Despite significant advances over the past decade, with the advent of multiple new classes of anti-myeloma agents, including immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies, patients ultimately relapse. Selinexor is a first-in-class exportin-1 inhibitor with activity in these multiply relapsed and refractory patients. Although the current Food and Drug Administration (FDA) approval is for the doublet of Selinexor in combination with dexamethasone, ongoing clinical trials are evaluating a number of combination regimens. These triplet and quadruplet, selinexor-based, regimens are showing significant activity in triple-class refractory patients. With appropriate combination drug choice, drug dosing, and supportive measures, patients with previously no viable options for therapy, now have multiple potential regimens to control their disease

The Matching Function and Nonlinear Business Cycles

The Cobb-Douglas matching function is ubiquitous in labor search and matching models, even though it imposes a constant matching elasticity that is unlikely to hold empirically. To examine the implications of this discrepancy, this paper uses a general constant returns to scale matching function to derive conditions that show how the cyclicality of the matching elasticity affects the shape of the job finding rate as a function of productivity and amplifies or dampens nonlinear labor market dynamics. It then shows that modest variation in the matching elasticity, consistent with recent estimates, significantly affects higher order moments and optimal policy. This motivates research that can provide greater clarity on the matching function specification

Evaluation of Operation IceBridge quick-look snow depth estimates on sea ice

We evaluate Operation IceBridge (OIB) ‘quick-look’ (QL) snow depth on sea ice retrievals using in situ measurements taken over immobile first-year ice (FYI) and multi-year ice (MYI) during March of 2014. Good agreement was found over undeformed FYI (-4.5 cm mean bias) with reduced agreement over deformed FYI (-6.6 cm mean bias). Over MYI, the mean bias was -5.7 cm but 54% of retrievals were discarded by the OIB retrieval process as compared to only 10% over FYI. Footprint scale analysis revealed a root mean square error (RMSE) of 6.2 cm over undeformed FYI with RMSE of 10.5 cm and 17.5 cm in the more complex deformed FYI and MYI environments. Correlation analysis was used to demonstrate contrasting retrieval uncertainty associated with spatial aggregation and ice surface roughness

Conservation Status of the Longhead Darter, Percina macrocephala, in Kinnicock Creek, Kentucky

Percina macrocephala, the Longhead Darter, is rare throughout its range and endangered in Kentucky. One population in Kentucky occurs in Kinniconick Creek, Lewis County, and prior to this study was known from only a few specimens, mostly collected in 1981. In summer and early fall of 2007 and 2008, 55 reaches, spanning 54 stream km of Kinniconick Creek, were surveyed by snorkeling, electrofishing, or seining for P. macrocephala. We encountered 104 individuals of P. macrocephala in a 50 stream km segment from just below the town of Kinniconick to the town of Garrison. Fifteen of the 55 sampled reaches contained P. macrocephala. Most individuals were encountered in a middle section between the confluences of Laurel Fork and Town Branch; this area also contained many young-of-the-year, indicating successful reproduction and recruitment. Although we judge this species to be rare to uncommon in most of Kinniconick Creek, it is locally common in the middle section, and the population seems to be stable and perhaps the most robust in the state. We conservatively estimate a total population of 2000-5000 in the stream. Because this population appears to be migratory, and exhibits source-sink dynamics, it is susceptible to anthropogenic barriers (e.g., culvert crossings) that prevent movements

The Coastal Convective Interactions Experiment (CCIE): understanding the role of sea breezes for hailstorm hotspots in Eastern Australia

The coastal convective interactions experiment (CCIE's) integration of climatological analysis with an intensive field campaign has provided an opportunity for revealing some of the complexities surrounding thunderstorm hotpots in complex physical settings like SEQ. For the CCIE climatological analysis, a continuous 18-yr (July 1997 to June 2015) volumetric reflectivity radar dataset was sourced from the 1.9° S-band weather radar located at Marburg, 50 km west of Brisbane. A cell-based analysis of this archive was performed using a MATLAB implementation of the identification, tracking, and selected analysis algorithms from the Weather Decision Support System-Integrated Information (WDSS-II). The 10-min interval of the Marburg radar volumes creates significant spatial discontinuities between MESH grids from an individual thunderstorm. A preliminary analysis indicates a strong relationship between the presence of the sea breeze and the Boonah hailstorm hotspot, but further analysis is needed to isolate the additional influence of synoptic and topographic drivers. Furthermore, fine-scale field observations of the sea-breeze?thunderstorm interaction events have begun to shed some light on the meteorology of thunderstorm hotspots in South East Queensland (SEQ)

A multimodal dialog approach to mental state characterization in clinically depressed, anxious, and suicidal populations.

BACKGROUND: The rise of depression, anxiety, and suicide rates has led to increased demand for telemedicine-based mental health screening and remote patient monitoring (RPM) solutions to alleviate the burden on, and enhance the efficiency of, mental health practitioners. Multimodal dialog systems (MDS) that conduct on-demand, structured interviews offer a scalable and cost-effective solution to address this need. OBJECTIVE: This study evaluates the feasibility of a cloud based MDS agent, Tina, for mental state characterization in participants with depression, anxiety, and suicide risk. METHOD: Sixty-eight participants were recruited through an online health registry and completed 73 sessions, with 15 (20.6%), 21 (28.8%), and 26 (35.6%) sessions screening positive for depression, anxiety, and suicide risk, respectively using conventional screening instruments. Participants then interacted with Tina as they completed a structured interview designed to elicit calibrated, open-ended responses regarding the participants feelings and emotional state. Simultaneously, the platform streamed their speech and video recordings in real-time to a HIPAA-compliant cloud server, to compute speech, language, and facial movement-based biomarkers. After their sessions, participants completed user experience surveys. Machine learning models were developed using extracted features and evaluated with the area under the receiver operating characteristic curve (AUC). RESULTS: For both depression and suicide risk, affected individuals tended to have a higher percent pause time, while those positive for anxiety showed reduced lip movement relative to healthy controls. In terms of single-modality classification models, speech features performed best for depression (AUC = 0.64; 95% CI = 0.51-0.78), facial features for anxiety (AUC = 0.57; 95% CI = 0.43-0.71), and text features for suicide risk (AUC = 0.65; 95% CI = 0.52-0.78). Best overall performance was achieved by decision fusion of all models in identifying suicide risk (AUC = 0.76; 95% CI = 0.65-0.87). Participants reported the experience comfortable and shared their feelings. CONCLUSION: MDS is a feasible, useful, effective, and interpretable solution for RPM in real-world clinical depression, anxiety, and suicidal populations. Facial information is more informative for anxiety classification, while speech and language are more discriminative of depression and suicidality markers. In general, combining speech, language, and facial information improved model performance on all classification tasks

Subcutaneous daratumumab and hyaluronidase-fihj in newly diagnosed or relapsed/refractory multiple myeloma.

Daratumumab, a human immunoglobulin G1 kappa monoclonal antibody that targets CD38, is currently approved as monotherapy and in varying combinations with approved anti-myeloma regimens in both newly diagnosed multiple myeloma and relapsed refractory multiple myeloma. Originally developed for intravenous administration, the subcutaneous formulation of daratumumab (daratumumab and hyaluronidase-fihj) was recently approved by the US Federal Drug Administration and European Commission in 2020. In clinical trials, compared with the intravenous formulation, subcutaneous daratumumab (Dara-SC) has significantly shorter administration time (median first dose 7 h versus 3-5 min, respectively), lower rates of infusion-related reactions (median first dose 50% versus less than 10%, respectively), and lower volume of infusion (median 500-1000 ml versus 15 ml, respectively). Otherwise, the pharmacokinetics, safety profile, and efficacy are comparable. This review summarizes the pivotal trials that led to the approval of Dara-SC, highlights important clinical considerations for the use of Dara-SC, and provides practical guidelines for the administration of Dara-SC in the clinic

Bispecific Antibodies in Multiple Myeloma: Present and Future.

UNLABELLED: Despite many recent advances in therapy, there is still no plateau in overall survival curves in multiple myeloma. Bispecific antibodies are a novel immunotherapeutic approach designed to bind antigens on malignant plasma cells and cytotoxic immune effector cells. Early-phase clinical trials targeting B-cell maturation antigen (BCMA), GPRC5D, and FcRH5 have demonstrated a favorable safety profile, with mainly low-grade cytokine release syndrome, cytopenias, and infections. Although dose escalation is ongoing in several studies, early efficacy data show response rates in the most active dose cohorts between 61% and 83% with many deep responses; however, durability remains to be established. Further clinical trial data are eagerly anticipated. SIGNIFICANCE: Overall survival of triple-class refractory multiple myeloma remains poor. Bispecific antibodies are a novel immunotherapeutic modality with a favorable safety profile and impressive preliminary efficacy in heavily treated patients. Although more data are needed, bispecifics will likely become an integral part of the multiple myeloma treatment paradigm in the near future. Studies in earlier lines of therapy and in combination with other active anti-multiple myeloma agents will help further define the role of bispecifics in multiple myeloma