Rodriguez, Cesar

Introduction Talquetamab (Tal) is a bispecific antibody therapy approved for patients with relapsed/refractory multiple myeloma (MM), targeting both GPRC5D x CD3 receptors. Clinical studies demonstrate that Tal creates deep and durable responses, but less is known about the patient experience. This study aimed to explore the experiences of patients from the patient and physician perspectives to help understand what to expect with this first-in-class novel therapy. Methods This qualitative study consisted of two components. First, patients with documented use of Tal were identified and recruited through the HealthTree Cure Hub. Individual patients then took part in 2-hour, semi-structured virtual interviews. Patients were asked to discuss their experiences 1-2 months prior to starting Tal and 4-5 months after beginning therapy. Patients discussed GPRC5D-related symptoms (including oral, skin-related, and nail-related symptoms), overall impact, and satisfaction. Participants were US adults diagnosed with MM who took Tal for at least 4 months, either in a clinical trial or commercial setting. Interviews were conducted February-April 2024. Second, patients and physicians gathered in a facilitated roundtable discussion to review findings and generate ideas for symptom management. The roundtable lasted 2.5 hours and took place in Chicago, IL in May 2024. Results Eight men and 4 women (n=12) aged 52-79 years participated in the interviews. Interviewed participants were mostly white (84%) and college-educated (84%). Seven (58%) received Tal in a clinical trial, and 9 were still receiving Tal. Roundtable participants included 3 patients (2 male, 1 female; all white and college educated), and 3 physicians with Tal experience. In the interviews, patients reported high overall satisfaction, with most (75%) rating their satisfaction an 8 or higher on a 10-point scale. Satisfaction was largely driven by the effectiveness of therapy, with all reporting clinical improvements in their MM disease. Patients reported improvements in their energy/strength and decreased fatigue. They also reported increased physical activities and ability to work, volunteer, or engage in hobbies. Physicians affirmed these findings as consistent with their observations and noted they are also very satisfied with Tal. Oral symptoms such as distorted taste/loss of taste and dry mouth were common with varying severity. Although all interviewees (n=12) reported taste symptoms (typically starting within the first month of therapy), five said their symptoms fully improved (3 after 1 year on treatment, and 2 after stopping treatment), and 4 experienced partial recovery. Ten lost weight, but most (92%) maintained adequate nutrition. Patients and physicians suggested coping strategies including diet modifications, use of strong flavors (e.g., spices, cinnamon), monitoring weight, prioritizing adequate calories, using mouthwashes/lozenges, drinking water while eating, taking small bites, and consuming foods that are easier to swallow. They also noted that it is important to educate patients on expected symptoms before starting the treatment. Skin- and nail-related symptoms were also common but less impactful on quality of life. All patients (n=12) experienced skin- and nail-related symptoms, but most considered these symptoms mild. Skin-related symptoms such as dry skin and skin exfoliation occurred once and typically lasted 1-2 months. Nail symptoms were primarily cosmetic, and the duration varied. Suggested management strategies include skin moisturizers, nail thickeners/hardeners, keeping nails short, and wearing protective gloves. Physicians noted it's helpful to reassure patients that nail loss is not harmful. Overall, GPRC5D-related symptoms were not treatment-limiting, and no patients had to miss a dose due to these symptoms. Patients perceived these symptoms as bearable but noted the treatment was effective at controlling the disease. Conclusions This study described patient experiences and reflected how patients perceive the benefit/risk profile of talquetamab. Symptoms were perceived as bearable and high satisfaction scores were driven by strong clinical effectiveness. Patients and physicians agreed that real-world feedback from patients, practical tips, and management strategies are vitally important for patients and physicians using this novel therapy.

Introduction: Peripheral arterial disease (PAD) is caused by a lack of blood flow to the musculature relative to its metabolism which results in pain. PAD impacts up to 20% of patients around the world. PAD involves macrovascular and microvascular dysfunction. Near-infrared spectroscopy (NIRS) measures muscle oxygenation levels and assesses microvascular function. The standard of care for diagnosing PAD is the ankle-brachial index (ABI), which assesses macrovascular disease, and the 6-minute walk test (6MWT), which measures gait speed and claudication. NIRS has the potential to monitor progression of PAD. Hypothesis: NIRS measurement of muscle oxygenation, during a standard test of vascular occlusion and post-occlusive hyperemia, the vascular occlusion test (VOT), is predictive of PAD severity as determined by ABI and 6MWT. Methods: We studied 24 patients diagnosed with PAD. The mean age of the patients was 71.3 years, including 54% (n=13) males and 46% (n=11) females. The VOT consisted of rest, occlusion, and reperfusion phases each lasting 5 min (15 min total). Muscle oxygen saturation levels were recorded at 2 hertz. For every patient, 6 features were extracted from the VOT data using computational methods. The VOT features from 15 patients were used to train function-fitting neural network models to predict ABI and 6MWT Continuous Distance. The models were then used to predict ABI and 6MWT Continuous Distance from the VOT features of 9 test patients not used in the training, Results: For patients in the test set, the ABI and 6MWT Continuous Distance predicted by the models differed from the actual measurements by 14%±13% and 15%±17%, respectively (Figure 1). For patients in the training set, the ABI and 6MWT Continuous Distance predicted by the models differed from the actual measurements by 0±0% and 12%±11%, respectively (Figure 1). Conclusion: The VOT has the potential to predict the ABI and 6MWT Continuous Distance of patients diagnosed with PAD, suggesting that the VOT can be automated and used to monitor the severity of PAD. With more data from both healthy patients and PAD patients, and improvement of the model, we anticipate that the VOT will complement ABI and 6MWT in the diagnosis and monitoring of PAD.

Introduction: Peripheral artery disease (PAD), an atherosclerotic disease of the peripheral arteries, also results in microvascular dysfunction. PAD patients are recommended to undergo supervised walking and medical management; however, compliance with supervised walking programs is limited due to inconvenience and pain, necessitating alternative non-pharmacological interventions. We have shown that daily muscle stretching improved microvascular function in aged rats. This prompted us to study the effect of daily muscle stretching on microvascular function of the calf muscles in PAD patients. Methods: A randomized, single-blinded study was conducted on 24 PAD patients. Patients were assigned to either stretching or placebo stretching using a dorsiflexion splint (Image 1) for 30 min/day, 5 days/wk for 4 wks. Calf muscle oxygen saturation (smO 2 ) was recorded using near-infrared spectroscopy during the six-minute walking test (6MWT) before (Visit 1) and after (Visit 2) stretching or placebo stretching. The percentage decrease in smO 2 (from baseline) at minute 1 (Δ1) and minute 2 (Δ2) of the 6MWT was determined. Two-way ANOVA was used to compare Δ1 and Δ2 between the stretching and placebo stretching groups. Results: The mean age of the patients was 74.1±11.4 yrs with 52% (13/23) males. There was no significant difference in the changes in smO 2 during the 6MWT at either minute 1 (Δ1: 44.1±7.3% vs 27.1±7.0%, p=0.12) or minute 2 (Δ2: 78.7±8.2% vs 58.1±7.9%, p=0.08) between the stretching group and placebo stretching group at Visit 1. In contrast, at Visit 2, there was a significantly greater change in smO 2 at minute 2 (D2: 83.1±8.2% vs 51.3±7.9%, p=0.008) in the stretching group compared to the placebo stretching group with a trend towards a statistically greater change in smO 2 at minute 1 (Δ1: 39.0±7.3% vs 20.4±7.0%, p=0.06) (Image 2). Conclusion: Daily stretching of the calf muscles for 4 weeks is associated with increased oxygen extraction by the calf muscles during walking.

Background: Although recently available immune-based approaches in multiple myeloma produce high response rates, curative outcomes have not yet been achieved, which highlights the need for new agents that further activate the immune system without increasing toxicity. ORIC-533 is a highly potent and selective, orally bioavailable, small molecule inhibitor of CD73, an enzyme expressed by various cell types, including immune cells and which catalyzes the generation of adenosine from adenosine monophosphate (AMP) (Allard 2019). Adenosine itself is highly immunosuppressive, diminishing activity of a range of immune cell types, including T, NK, and dendritic cells (Young 2014). By blocking adenosine production from AMP via inhibition of CD73, ORIC-533 has demonstrated the ability to restore and enhance immune function. Multiple myeloma (MM) patient bone marrow (BM) contains multiple cell types that also express CD73, including immune cells, cancer-associated fibroblasts, mesenchymal stem cells, and endothelial cells (Allard 2019). Moreover, elevated adenosine levels in the MM BM niche correlate with disease progression (Horenstein 2016; Yang 2020). We have previously observed that CD73-mediated adenosine activity suppresses the cytolytic antitumor immune function in the MM BM milieu (Ray 2022). ORIC-533 treatment reduced adenosine production, overcame this immune suppression with evidence of restored DC-mediated priming and activated cytotoxic CD8 + T-cell function, and significantly enhanced immune cell cytolytic behavior against RRMM tumor cells in autologous patient ex vivo experiments (Junttila 2022), making ORIC-533 a potential immunotherapy for patients with MM. Methods: ORIC-533-01 (NCT05227144) is an ongoing i3+3 Phase 1b dose escalation study in patients with RRMM. The primary objectives are to determine single agent safety/tolerability and pharmacokinetics (PK) of ORIC-533 to select the RP2D. Pharmacodynamic assessments include measurement of CD73 functional activity in serum and BM, as well as enumeration of immune cell subsets and activation state in blood and BM. Patients are also evaluated for clinical efficacy using IMWG criteria. Results: As of 23 June 2023, 17 patients received ORIC-533 once daily across 4 dose levels (400 mg to 1600 mg). All patients were triple-class refractory, 88% were penta-refractory, and 59% also received prior anti-BCMA/CD3 bispecific therapy or anti-BCMA CAR-T therapy. Overall, ORIC-533 was very well tolerated, with 5 patients experiencing a total of 10 treatment-related adverse events (TRAEs). Fatigue was the only G3 AE and the only TRAE seen in more than 1 patient (1 event each of G3 and G2); all other events seen in 1 patient each, were G1 or G2 in severity, and of no specific system organ class. No dose limiting toxicities, no Grade ≥4 TRAEs, and no treatment-related serious adverse events have been observed. PK showed increased exposure with dose with a plasma half-life of ~24 hrs. Soluble CD73 enzymatic activity was nearly completely inhibited by C1D15 in serum of all patients across all dose levels, while the largest relative suppression in surface CD73 activity in BM cells was observed at the highest dose level. There was also evidence for increases in the abundance of circulating NK and CD8+ T cells after 1 treatment cycle, with preliminary evidence of enhanced CD8+ T-cell activation at the highest dose levels tested in both peripheral blood and BM. In addition, early evidence of single agent clinical activity was observed. Conclusions: ORIC-533 has demonstrated an acceptable safety profile and preliminary evidence of immune activation in a heavily pretreated RRMM patient population. Enrollment is ongoing and updated data will be presented.