Daratumumab for patients with myeloma with early or late relapse after initial therapy: subgroup analysis of CASTOR and POLLUX.

ABSTRACT: High-risk multiple myeloma (MM) is often defined based on cytogenetic abnormalities, but patients who relapse early after initial therapy are considered a functional high-risk group. In the phase 3 CASTOR and POLLUX studies, daratumumab plus bortezomib/dexamethasone (D-Vd) or lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS), regardless of cytogenetic risk, and achieved higher rates of complete response or better (≥CR) and minimal residual disease (MRD) negativity vs that with Vd/Rd alone in relapsed/refractory MM. Post hoc analyses of CASTOR and POLLUX evaluated patient subgroups with 1 prior line of therapy based on timing of progression/relapse (early or late) after initiation of first line of therapy. PFS consistently favored the daratumumab-containing regimens across subgroups using both a 24- and 18-month early-relapse cutoff. In the CASTOR/POLLUX pooled data set, daratumumab reduced the risk of disease progression or death by 65% (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.26-0.48; P < .0001) in the early-relapse (<24 months) subgroup and by 65% (HR, 0.35; 95% CI, 0.26-0.47; P < .0001) in the late-relapse (≥24 months) subgroup. OS also favored the daratumumab-containing regimens in both the early-relapse (HR, 0.62; 95% CI, 0.45-0.86; P = .0036) and late-relapse (HR, 0.67; 95% CI, 0.48-0.93; P = .0183) subgroups in the pooled population using a 24-month cutoff. Rates of ≥CR and MRD negativity (10-5) were higher with daratumumab vs control, regardless of progression/relapse timing. Although daratumumab is unable to fully overcome the adverse prognosis of early relapse, our results support the use of daratumumab for patients with 1 prior line of therapy, including for those who progress/relapse early after initial therapy and are considered to have functional high-risk MM. These trials were registered at www.clinicaltrials.gov as #NCT02136134 (CASTOR) and #NCT02076009 (POLLUX).

Ibrutinib Efficacy, Safety, and Pharmacokinetics in Chinese Patients with Relapsed or Refractory Waldenström's Macroglobulinemia: A Multicenter, Single-Arm, Phase 4 Study.

INTRODUCTION: Waldenström's macroglobulinemia (WM) is a rare malignant B cell lymphoma which occurs in around 1-2% of all hematologic tumors. Ibrutinib was approved in China for WM on the basis of two global pivotal studies which enrolled no Chinese patients. The aim of this study was to determine the efficacy, safety, and pharmacokinetics of ibrutinib in Chinese patients with relapsed or refractory (r/r) WM. METHODS: This was an open-label, single-arm, multicenter phase 4 study conducted across five sites in China. Enrolled patients with clinicopathological confirmed WM received ibrutinib 420 mg once daily orally until disease progression or unacceptable toxicity. The primary endpoint was major response rate (MRR, partial response [PR], or better) according to the modified consensus criteria from the Sixth International Workshop on WM. RESULTS: Seventeen patients were enrolled; at data cutoff (March 19, 2022), MRR was 64.7% (90% confidence interval [CI] 42.0-83.4) and overall response rate was 100% (90% CI 83.8-100.0). One (5.9%) patient achieved very good PR, 10 (58.8%) achieved PR, and six (35.3%) achieved minor response. The median duration of response (PR or better) was 14.8 months (95% CI 10.8-not estimable [NE]). Median progression-free survival was 18.4 months (95% CI 12.9-NE). All patients experienced at least one treatment-emergent adverse event (TEAE) related to the study drug, and grade ≥ 3 TEAEs were reported in 13 (76.5%) patients. There were no TEAEs leading to dose reduction or death. The median model estimated maximum plasma concentration and area under the plasma concentration-time curve during 24 h after dosing at steady state were 40.5 ng/mL and 204 ng·h/mL, respectively. CONCLUSIONS: Ibrutinib demonstrated durable responses in Chinese patients with r/r WM. Treatment was well tolerated with no new safety signals compared with the pivotal global studies. Ibrutinib exposure was also comparable between Chinese and non-Chinese patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04042376.

Anisotropic Nonlocal Damping in Ferromagnet/α-GeTe Bilayers Enabled by Splitting Energy Bands.

The understanding and manipulation of anisotropic Gilbert damping is crucial for both fundamental research and versatile engineering and optimization. Although several works on anisotropic damping have been reported, no direct relationship between the band structure and anisotropic damping was established. Here, we observed an anisotropic damping in Fe/GeTe manipulated by the symmetric band structures of GeTe via angle-resolved photoemission spectroscopy. Moreover, the anisotropic damping can be modified by the symmetry of band structures. Our Letter provides insightful understandings of the anisotropic Gilbert damping in ferromagnets interfaced with Rashba semiconductors and suggests the possibility of manipulating the Gilbert damping by band engineering.

Surface coupling in Bi2Se3 ultrathin films by screened Coulomb interaction.

Single-particle band theory has been very successful in describing the band structure of topological insulators. However, with decreasing thickness of topological insulator thin films, single-particle band theory is insufficient to explain their band structures and transport properties due to the existence of top and bottom surface-state coupling. Here, we reconstruct this coupling with an equivalently screened Coulomb interaction in Bi2Se3 ultrathin films. The thickness-dependent position of the Dirac point and the magnitude of the mass gap are discussed in terms of the Hartree approximation and the self-consistent gap equation. We find that for thicknesses below 6 quintuple layers, the magnitude of the mass gap is in good agreement with the experimental results. Our work provides a more accurate means of describing and predicting the behaviour of quasi-particles in ultrathin topological insulator films and stacked topological systems.

Dual Topology of Dirac Electron Transport and Photogalvanic Effect in Low-Dimensional Topological Insulator Superlattices.

Dual topological insulators, simultaneously protected by time-reversal symmetry and crystalline symmetry, open great opportunities to explore different symmetry-protected metallic surface states. However, the conventional dual topological states located on different facets hinder integration into planar opto-electronic/spintronic devices. Here, dual topological superlattices (TSLs) Bi2 Se3 -(Bi2 /Bi2 Se3 )N with limited stacking layer number N are constructed. Angle-resolved photoelectron emission spectra of the TSLs identify the coexistence and adjustment of dual topological surface states on Bi2 Se3 facet. The existence and tunability of spin-polarized dual-topological bands with N on Bi2 Se3 facet result in an unconventionally weak antilocalization effect (WAL) with variable WAL coefficient α (maximum close to 3/2) from quantum transport experiments. Most importantly, it is identified that the spin-polarized surface electrons from dual topological bands exhibit circularly and linearly polarized photogalvanic effect (CPGE and LPGE). It is anticipated that the stacked dual-topology and stacking layer number controlled bands evolution provide a platform for realizing intrinsic CPGE and LPGE. The results show that the surface electronic structure of the dual TSLs is highly tunable and well-regulated for quantum transport and photoexcitation, which shed light on engineering for opto-electronic/spintronic applications.

Overall Survival With Daratumumab, Lenalidomide, and Dexamethasone in Previously Treated Multiple Myeloma (POLLUX): A Randomized, Open-Label, Phase III Trial.

PURPOSE: With the initial analysis of POLLUX at a median follow-up of 13.5 months, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly prolonged progression-free survival versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the time of final analysis for overall survival (OS). METHODS: POLLUX was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned 1:1 to D-Rd or Rd until disease progression or unacceptable toxicity. After positive primary analysis and protocol amendment, patients receiving Rd were offered daratumumab monotherapy after disease progression. RESULTS: Significant OS benefit was observed with D-Rd (hazard ratio, 0.73; 95% CI, 0.58 to 0.91; P = .0044) at a median (range) follow-up of 79.7 months (0.0-86.5). The median OS was 67.6 months for D-Rd compared with 51.8 months for Rd. Prespecified analyses demonstrated an improved OS with D-Rd versus Rd in most subgroups, including patients age ≥ 65 years and patients with one, two, or three prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and refractoriness to their last prior line of therapy or a proteasome inhibitor. The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with D-Rd versus Rd were neutropenia (57.6% v 41.6%), anemia (19.8% v 22.4%), pneumonia (17.3% v 11.0%), thrombocytopenia (15.5% v 15.7%), and diarrhea (10.2% v 3.9%). CONCLUSION: D-Rd significantly extended OS versus Rd alone in patients with RRMM. To our knowledge, for the first time, our findings, together with the OS benefit observed with daratumumab plus bortezomib and dexamethasone in the phase III CASTOR trial, demonstrate OS improvement with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02076009 [POLLUX]).

Overall Survival With Daratumumab, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma (CASTOR): A Randomized, Open-Label, Phase III Trial.

PURPOSE: At the primary analysis of CASTOR (median follow-up, 7.4 months), daratumumab plus bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival versus bortezomib and dexamethasone (Vd) alone in relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the final analysis for overall survival (OS). METHODS: CASTOR was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned to Vd (up to eight cycles) with or without daratumumab (until disease progression). After positive primary analysis and protocol amendment, patients receiving Vd were offered daratumumab monotherapy after disease progression. RESULTS: At a median (range) follow-up of 72.6 months (0.0-79.8), significant OS benefit was observed with D-Vd (hazard ratio, 0.74; 95% CI, 0.59 to 0.92; P = .0075). Median OS was 49.6 months with D-Vd versus 38.5 months with Vd. Prespecified subgroup analyses demonstrated an OS advantage with D-Vd versus Vd for most subgroups, including patients age ≥ 65 years and patients with one or two prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and prior bortezomib treatment. The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with D-Vd versus Vd were thrombocytopenia (46.1% v 32.9%), anemia (16.0% v 16.0%), neutropenia (13.6% v 4.6%), lymphopenia (10.3% v 2.5%), and pneumonia (10.7% v 10.1%). CONCLUSION: D-Vd significantly prolonged OS in patients with RRMM, with the greatest OS benefit observed in patients with one prior line of therapy. To our knowledge, our results, together with the OS benefit observed with daratumumab plus lenalidomide and dexamethasone in the phase III POLLUX study, demonstrate for the first time an OS benefit with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02136134 [CASTOR]).

Daratumumab, Bortezomib, and Dexamethasone versus Bortezomib and Dexamethasone in Chinese Patients With Relapsed or Refractory Multiple Myeloma: Updated Analysis of LEPUS.

BACKGROUND: In the phase 3 LEPUS study, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Here, we report updated efficacy and safety results from LEPUS. PATIENTS AND METHODS: Chinese patients with ≥ 1 prior line of therapy were randomized 2:1 to bortezomib (1.3 mg/m2) and dexamethasone (20 mg) for eight cycles ± daratumumab (16 mg/kg) until disease progression. The primary endpoint was progression-free survival (PFS). RESULTS: In total, 211 patients were randomized to D-Vd (n = 141) or Vd (n = 70). At a 25.1-month median follow-up, D-Vd prolonged PFS versus Vd (median, 14.8 vs. 6.3 months; hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.24-0.51; P < .00001). PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib (HR, 0.36; 95% CI, 0.25-0.53), patients who were refractory to last prior line of therapy (HR, 0.42; 95% CI, 0.27-0.65), and patients with high-risk cytogenetics (HR, 0.41; 95% CI, 0.23-0.71). Overall response rate (84.7% vs.66.7%; P = .00314) and rates of very good partial response or better (71.5% vs. 34.9%; P < .00001) and complete response or better (40.1% vs 14.3%; P = .00016) were higher with D-Vd versus Vd. No new safety concerns were identified. CONCLUSIONS: In this updated analysis, D-Vd maintained significant efficacy benefits versus Vd alone and demonstrated a consistent safety profile, further supporting the use of D-Vd as a standard of care in Chinese patients with RRMM.

[Spatial and temporal variations of the responses of radial growth of Larix gmelinii to climate in the Daxing'anling Mountains of Northeast China]. / å¤§å ´å®‰å²­å ´å®‰è½å¶æ¾å¾„å‘ç”Ÿé•¿å¯¹æ°”å€™å“åº”çš„æ—¶ç©ºå˜åŒ–.

Following the distribution characteristics of Larix gmelinii in Daxing'anling Mountains, nine sampling sites along a latitude gradient were set up to analyze the spatial difference and temporal dynamic in the responses of radial growth of L. gmelinii to climate. Overall, the radial growth of L. gmelinii was positively correlated with the standardized precipitation evapotranspiration index (SPEI) in summer (June to August), summer precipitation, February SPEI, and February preci-pitation, but was negatively correlated with the March temperature. Spatially, in the southern area of the region with higher annual average temperature, the radial growth of L. gmelinii had a significant positive correlation with February SPEI. In the northern area with lower annual average tempera-ture, the radial growth of L. gmelinii was negatively correlated with the temperature in March. Temporally, the growth-climate relationship for L. gmelinii was unstable. In the area with higher annual average temperature, the positive effects of SPEI and precipitation, as well as the negative effects of temperature in summer on growth significantly enhanced with climate warming. In the area with lower annual average temperature, the negative response of growth to March temperature enhanced more obviously. Such a result indicated that climate change would alter growth-climate relationship, with great spatial variations. Our results suggested that radial growth of L. gmelinii would be limited in the future climate of warm and dry in the Daxing'anling Mountains. The growth of L. gmelinii might obviously decline in south due to summer water deficit and winter drought, and might be inhibited in north because of warm and dry winter.

Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Chinese Patients with Relapsed or Refractory Multiple Myeloma: Phase 3 LEPUS (MMY3009) Study.

BACKGROUND: Daratumumab plus bortezomib/dexamethasone (D-Vd) significantly improved outcomes versus Vd in patients with relapsed or refractory multiple myeloma (RRMM) in the phase 3 CASTOR study. We report the results of a prespecified interim analysis of the phase 3 LEPUS study of D-Vd versus Vd in Chinese patients with RRMM. PATIENTS AND METHODS: Chinese patients with ≥ 1 prior line of therapy were randomized 2:1 to receive 8 cycles (21 days/cycle) of bortezomib (1.3 mg/m2 subcutaneously) and dexamethasone (20 mg orally/intravenously) ± daratumumab (16 mg/kg intravenously). The primary endpoint was progression-free survival (PFS). RESULTS: A total of 211 patients were randomized (D-Vd, 141; Vd, 70). After an 8.2-month median follow-up, D-Vd significantly prolonged PFS versus Vd (median, not reached vs. 6.3 months; hazard ratio, 0.28; 95% confidence interval, 0.17-0.47; P < .00001) and significantly improved the rates of overall response (83% vs. 65%; P = .00527), ≥ very good partial response (65% vs. 33%; P = .00002), ≥ complete response (33% vs. 11%; P = .00079), and minimal residual disease negativity (10-5 sensitivity; 22% vs. 3%; P = .0002). The PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib treatment and with high-risk cytogenetics. Thrombocytopenia (D-Vd, 51%; Vd, 37%), lymphopenia (44%; 29%), and lung infection (30%; 22%) were the 3 most common grade 3/4 treatment-emergent adverse events. Although patients in both treatment groups experienced higher rates of grade 3/4 lymphopenia and infections versus patients in CASTOR, the safety profile was generally consistent with that of CASTOR. CONCLUSION: These data support the use of D-Vd in Chinese patients with RRMM.

The miR-28-5p-CAMTA2 axis regulates colon cancer progression via Wnt/ß-catenin signaling.

BACKGROUND: Colon cancer is the third most commonly diagnosed cancer with high morbidity and mortality. Calmodulin-binding transcription activator 2 (CAMTA2) belongs to the calmodulin-binding transcription activator protein family. The functional role of CAMTA2 in colon cancer development remains unclear. Our research found out that CAMTA2 was high-level expressed in colon cancer, and the upregulated CAMTA2 expression was markedly correlated with poor survival. Functional experiments showed that knockdown of CAMTA2 repressed colon cancer cell proliferation/migration in vitro and attenuated proliferation in vivo. In additional, CAMTA2 expression was controlled by miR-28-5p via posttranscriptional regulation and miR-28-5p expression was reversely correlated with CAMTA2 expression in colon cancer. Moreover, enforced miR-28-5p expression downregulated the expression of CAMTA2 significantly and the restoration of CAMTA2 expression abolished the inhibitory effect of miR-28-5p on colon cancer cell proliferation and metastasis. Mechanistically, overexpression of miR-28-5p suppressed Wnt/ß-catenin signaling and the inhibitory could be partly abolished by overexpression of CAMTA2. In summary, our findings reveal that miR-28-5p/CAMTA2 axis plays a critical role in human colon cancer, which might be a promising diagnosis and therapeutic target for colon cancer treatment.

[Interspecific difference of relationship between radial growth and climate factor for Larix olgensis and Picea jezoensis var. komarovii in Changbai Mountain, Northeast China.] / 长白山落叶松与鱼鳞云杉生长-æ°”å€™å ³ç³»çš„ç§é—´å·®å¼‚.

To clarify the responses of radial growth of different tree species to climate change and its stability, we explored the relationships between radial growth and climate factors of larch (Larix olgensis) and spruce (Picea jezoensis var. komarovii) distributed at high altitude (1600-1750 m) on the northern slope of Changbai Mountain, using the chronological method. The results showed that the growth of larch was significantly positively correlated with the maximum temperature in June and negatively correlated with the precipitation in June. The radial growth of spruce was significantly positively correlated with the maximum temperature in May. Results from redundancy analysis showed that larch growth was mainly affected by summer temperature, while spruce growth was significantly restricted by spring temperature. During 1959-2014, the relationship between larch growth and summer temperature was relatively stable. For spruce, the correlation between radial growth and spring temperatures had gradually weakened since 1986, mainly due to the growth slowdown because of decreased maximum air temperature. Our results provide theoretical references for predicting the growth response of conifers at Changbai Mountain region in the context of climate change.

A novel bowel necrosis classification system and examination of patient outcomes in incarcerated groin hernia patients.

The objective of this study was to determine a classification system for BN in incarcerated groin hernia patients and to explore the possible relationship between BN staging and patient outcomes. Incarcerated groin hernia patients treated with emergency bowel resection from January 2008 to December 2013 were screened for inclusion in a prospective study. A novel three-stage classification system was proposed for BN (BN stages I-III) and correlations between adverse events (AEs) and mortality with BN stage were determined. A total of 108 patients were included, with 71, 26, and 11 patients in BN stages I, II, and III, respectively. AEs, which included wound and intra-abdominal infections and other systemic complications, increased with higher BN stage (all P < 0.05). Mortality increased with BN stage, with 2.8%, 7.7%, and 27.3% at BN stages I, II, and III, respectively (P < 0.05). The proposed BN staging system can objectively reflect the degree of bowel damage and its corresponding adverse outcomes.