Pomalidomide, dexamethasone, and daratumumab in Japanese patients with relapsed or refractory multiple myeloma after lenalidomide-based treatment.

In cohort C of the phase 2 MM-014 trial, the efficacy and safety of pomalidomide, dexamethasone, and daratumumab therapy were investigated in 18 Japanese patients with relapsed/refractory multiple myeloma (RRMM) after their most recent regimen of lenalidomide-based therapy (NCT01946477). Patients received oral pomalidomide (4 mg daily), oral dexamethasone (20-40 mg weekly), and intravenously infused daratumumab (16 mg/kg). Median age was 67.5 years. All patients received prior lenalidomide per protocol; 89% received prior bortezomib. Twelve patients (67%) had lenalidomide-refractory disease, and 6 (33%) had lenalidomide-relapsed disease. Ten patients (56%) had only 1 prior treatment line. As of August 3, 2020, 15 patients (83%) were still on treatment; median follow-up was 8.1 months. Three patients (17%) discontinued treatment (2 for adverse events; 1 for major protocol deviation). Overall response rate (primary endpoint) was 83% (very good partial response or better, 61%). All patients had ≥ 1 grade 3/4 treatment-emergent adverse events, most commonly neutropenia (78%; febrile, 6%), leukopenia (28%), and lymphopenia (22%). Grade 3/4 infections occurred in 17%; 11% had pneumonia. In Japanese patients with RRMM, a triplet regimen of pomalidomide, dexamethasone, and daratumumab after early-line lenalidomide treatment failure showed high efficacy and safety consistent with the known safety profile.

Pomalidomide, dexamethasone, and daratumumab immediately after lenalidomide-based treatment in patients with multiple myeloma: updated efficacy, safety, and health-related quality of life results from the phase 2 MM-014 trial.

Patients with relapsed/refractory multiple myeloma (RRMM) need proven subsequent therapies after early-line lenalidomide treatment failure. The phase 2 MM-014 trial (NCT01946477) investigated pomalidomide, dexamethasone, and daratumumab after 1 to 2 prior treatment lines (62.5%, 1 prior line) in patients with RRMM and prior lenalidomide (75.0%, lenalidomide refractory). With a median follow-up of 28.4 months, overall response rate was 77.7% (52.7% achieved very good partial response or better) and median progression-free survival was 30.8 months. For patients with lenalidomide-refractory disease, these outcomes were 76.2%, 47.6%, and 23.7 months, respectively. No new safety signals were observed; 64.3% experienced grade 3/4 neutropenia. Health-related quality of life was preserved or trended toward improvement through 12 treatment cycles. Pomalidomide, dexamethasone, and daratumumab given immediately after early-line lenalidomide-based treatment continues to demonstrate safety and efficacy, supporting pomalidomide-dexamethasone as a foundation of combination therapy in RRMM and providing evidence that the immunomodulatory agent class delivers benefit after lenalidomide treatment failure.

Association of Morbid Progression With Overall Survival Among Patients With Multiple Myeloma: Validation of the Progression-free Survival Endpoint.

INTRODUCTION: Multiple myeloma (MM) is an incurable malignancy, marked by end-organ damage that is frequently irreversible. Progressive disease (PD) can be defined as morbid PD, associated with new-onset hypercalcemia, renal insufficiency, anemia, or lytic bone lesions (CRAB symptoms), or as asymptomatic biochemical progression. The frequency of morbid versus asymptomatic PD and its effect on survival is unknown. Our aim was to determine the incidence of morbid PD, and to evaluate if this influences survival. PATIENTS AND METHODS: Data from 2 phase III trials of transplant-ineligible patients with newly diagnosed MM were included in a post hoc analysis. RESULTS: Of 2082 patients enrolled, 1243 (59.7%) experienced PD. At first progression, 543 (43.7%) patients had morbid PD; 12 (2.2%) had hypercalcemia, 271 (49.9%) had renal insufficiency, 370 (68.1%) developed anemia, and 79 (14.5%) developed new or enlarged bone lesions. A total of 700 (56.3%) patients had asymptomatic PD. Patients with morbid PD had worse second progression-free survival (PFS) versus patients with asymptomatic biochemical PD (median second PFS, 11.5 months vs. 20.0 months; hazard ratio, 1.63; 95% confidence interval, 1.43-1.85; P < .0001) and worse overall survival (OS) (median OS, 23.2 months vs 39.3 months; hazard ratio, 1.51; 95% confidence interval, 1.30, 1.74; P < .0001). CONCLUSIONS: Morbid PD occurs frequently and is associated with inferior second PFS and OS. As CRAB symptoms may not reverse with therapy, morbid PD is a meaningful event, and its association with a shortened PFS adds validity to PFS as a relevant endpoint in patients with MM.

Immunomodulation in Pomalidomide, Dexamethasone, and Daratumumab-Treated Patients with Relapsed/Refractory Multiple Myeloma.

PURPOSE: Addition of daratumumab to pomalidomide and low-dose dexamethasone (LoDEX) is a safe and effective combination for relapsed/refractory multiple myeloma treatment. We sought to better understand immune combinational benefit of pomalidomide and daratumumab with LoDEX. PATIENTS AND METHODS: Immunophenotypic changes were analyzed in peripheral blood from longitudinal sampling of patients treated with this triplet regimen from cohort B of the CC4047-MM-014 phase II trial (NCT01946477). RESULTS: Consistent with the daratumumab mechanism, treatment led to decreased natural killer (NK) and B cells. In contrast, pronounced increases occurred in activated and proliferating NK and T cells, appreciably in CD8+ T cells, along with reduction in naïve and expansion of effector memory compartments. Timing of T-cell changes correlated with pomalidomide dosing schedule. Enhanced activation/differentiation did not result in increased exhausted T-cell phenotypes or increases in regulatory T cells. Similar immune enhancements were also observed in patients previously refractory to lenalidomide. CONCLUSIONS: These data support a potential mechanism for enhanced immune-mediated cytotoxicity in which daratumumab-mediated NK-cell diminution is partially offset by pomalidomide effects on the remaining NK-cell pool. Furthermore, daratumumab antimyeloma activity and elimination of CD38+ T cells (regulatory/activated) provide a rationale for therapeutic combination with direct tumoricidal activity and immunomodulation of pomalidomide-directed T-cell enhancements. These data highlight enhancements in immune subpopulations for the combination of daratumumab with pomalidomide and potentially with next-generation cereblon-targeting agents.

Pomalidomide, dexamethasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment.

Patients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need of effective therapies. The safety and efficacy of pomalidomide, low-dose dexamethasone, and daratumumab was evaluated in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM) after one to two prior treatment lines in the phase 2 MM-014 study. Patients received pomalidomide 4 mg daily from days 1-21 and dexamethasone 40 mg weekly (28-day cycles). Daratumumab 16 mg/kg was administered per label. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. Per protocol, all patients (N = 112) had received lenalidomide in their most recent prior regimen (75.0% lenalidomide refractory). ORR was 77.7% (76.2% in lenalidomide-refractory patients); median follow-up was 17.2 months. Median PFS was not reached (1-year PFS rate 75.1%). The most common hematologic grade 3/4 treatment-emergent adverse event was neutropenia (62.5%). Grade 3/4 infections were reported in 31.3% of patients, including 13.4% with grade 3/4 pneumonia. These results demonstrate the safety and efficacy of pomalidomide-based therapy as early as second line in patients with RRMM, even immediately after lenalidomide failure, indicating that switching from the immunomodulatory agent class is not necessary.

Pomalidomide plus low-dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure.

Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In cohort A of the phase 2 MM-014 trial, we examined the safety and efficacy of pomalidomide plus low-dose dexamethasone immediately after lenalidomide-based treatment failure in patients with RRMM and two prior lines of therapy. Pomalidomide 4 mg was given on days 1 to 21 of 28-day cycles. Dexamethasone 40 mg (20 mg for patients aged >75 years) was given on days 1, 8, 15 and 22 of 28-day cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. The intention-to-treat population comprised 56 patients; all received prior lenalidomide (87·5% lenalidomide refractory) and 39 (69·6%) received prior bortezomib. ORR was 32·1% (28·2% in the prior-bortezomib subgroup). Median PFS was 12·2 months (7·9 months in the prior-bortezomib subgroup). Median OS was 41·7 months (38·6 months in the prior-bortezomib subgroup). The most common grade 3/4 treatment-emergent adverse events were anaemia (25·0%), pneumonia (14·3%) and fatigue (14·3%). These findings support earlier sequencing of pomalidomide-based therapy in lenalidomide-pretreated patients with RRMM, including those who have become refractory to lenalidomide. Trial registration: www.ClinicalTrials.gov identifier NCT01946477.

Intranasal mometasone furoate therapy for allergic rhinitis symptoms and rhinitis-disturbed sleep.

BACKGROUND: Allergic rhinitis (AR) and related nasal congestion cause rhinitis-disturbed sleep (RDS). Intranasal corticosteroids reduce nasal congestion and improve sleep quality in AR but have not been extensively studied in RDS. OBJECTIVE: To evaluate the efficacy of mometasone furoate nasal spray (NS) on nasal symptoms, nasal patency, sleep variables, quality of life, and daytime functioning in perennial AR (PAR) and concomitant RDS. METHODS: In this double-blind 4-week study, 30 adults with PAR and moderate RDS were randomized 2:1 to receive mometasone furoate NS, 200 microg, or placebo each morning. The primary end point was the apnea-hypopnea index. Secondary outcome measures included changes in total nasal symptom score (TNSS), nighttime symptom score, daytime peak nasal inspiratory flow, nighttime flow limitation index, Rhinoconjunctivitis Quality of Life Questionnaire-Standardized (RQLQ-S) score, Epworth Sleepiness Scale score, and Work Productivity and Activities Impairment-Allergy Specific (WPAI-AS) questionnaire score. Analysis of covariance was used for all efficacy end points. RESULTS: The apnea-hypopnea index at study end was not statistically significantly different between groups. However, mometasone furoate NS therapy significantly improved morning (P = .04) and evening (P = .01) TNSSs, morning (P = .049) and evening (P = .03) nasal obstruction/blockage/congestion, daily peak nasal inspiratory flow (P = .03), flow limitation index (P = .02), Epworth Sleepiness Scale score (P = .048), RQLQ-S score (P = .03), and 2 of 5 WPAI-AS domains. Among patients receiving mometasone furoate NS, TNSS improvements were significantly correlated with improved work- and non-work-related productivity. CONCLUSIONS: In patients with PAR and RDS, mometasone furoate NS use improved nasal symptoms, sleepiness, and impairment in daily activities. Correlated reduced nasal symptoms and improved performance suggest that improving AR symptoms with mometasone furoate NS administration can benefit sleep and daytime functioning.

Loratadine provides early symptom control in seasonal allergic rhinitis.

Allergic rhinitis (AR) affects approximately 500 million people worldwide, and prevalence is increasing. Second-generation nonsedating antihistamines are first-line treatments for seasonal AR (SAR). This study was performed to evaluate early SAR symptom relief with second-generation antihistamines through a retrospective analysis of previously published data. In this study, 835 subjects aged 12-60 years with a > or = 2-year history of SAR were randomized to receive loratadine, 10 mg, once daily; fexofenadine, 60 mg, twice daily; or placebo for 7 days. Each subject recorded the severity of five symptoms of SAR on a scale of 0-3. This primary post hoc efficacy analysis was the mean change from baseline in daily average A.M./P.M. reflective and instantaneous total symptom score (TSS) on days 2 and 3. Significantly greater mean reductions from baseline were shown with loratadine compared with fexofenadine in average A.M./P.M. reflective TSS on days 2 (-3.51 versus -2.84, respectively; p < 0.002) and 3 (-3.80 versus -3.19, respectively; p = 0.007) and in average A.M./P.M. instantaneous TSS on day 3 (-3.68 versus -3.15, respectively; p = 0.022). Similar results were noted in average A.M./P.M. reflective and instantaneous total nasal symptom scores and for 10 of 20 individual symptom time points (p < 0.05). Loratadine was significantly more effective than placebo for all time points (p < 0.001). Early, sustained symptom relief was seen with loratadine, suggesting that it may be more effective for treating SAR symptoms.