Subcutaneous daratumumab (DARA SC) versus active monitoring in patients (pts) with high-risk smoldering multiple myeloma (SMM): Randomized, open-label, phase 3 AQUILA study

Background: Standard of care for SMM includes active monitoring until progression to multiple myeloma (MM); however, recent evidence suggests pts with high-risk features may benefit from early treatment. DARA is a human IgGκ monoclonal antibody targeting CD38 that is approved as monotherapy for relapsed/refractory MM (RRMM) or in combination with standard of care for RRMM or newly diagnosed MM. Results from the phase 3 COLUMBA study showed that DARA SC demonstrated similar efficacy to intravenous (IV) DARA but with a lower rate of infusion-related reactions and shorter administration time. Based on the promising single-agent activity observed with IV DARA in intermediate- or high-risk SMM pts during the phase 2 CENTAURUS study, we hypothesized that DARA SC may delay progression to MM versus active monitoring in pts with high-risk SMM. Methods: AQUILA is an ongoing, randomized, open-label, multicenter phase 3 study of DARA SC versus active monitoring in pts with high-risk SMM. DARA SC (DARA 1,800 mg + recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; Halozyme]) is administered by manual injection over approximately 5 minutes at alternating locations on the abdomen weekly in Cycles 1 and 2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter until 39 cycles (28 days/cycle), up to 36 months, or until disease progression. Eligibility criteria include confirmed diagnosis of SMM for ≤5 years, factors indicating high risk of progression to MM (clonal bone marrow plasma cells [BMPCs] ≥10% and ≥1 of the following: serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8 to 50% to < 60% with measurable disease), and ECOG performance status ≤1. The primary endpoint is progression-free survival (PFS), assessed by an independent review committee, with disease progression defined according to International Myeloma Working Group diagnostic criteria for MM. Secondary endpoints include time to biochemical or diagnostic (SLiM-CRAB) progression, overall response rate, complete response rate, duration of response, time to response, time to first-line treatment for MM, PFS on first-line treatment for MM (PFS2), overall survival, and incidence of MM with adverse prognostic features. The study completed enrollment on May 6, 2019; 390 pts have been randomly assigned to DARA SC or active monitoring. The primary efficacy analysis will be performed after approximately 165 PFS events have been observed

Sintering high tungsten content W-Ni-Fe heavy alloys by microwave radiation

This paper presents a detailed study of microwave (MW) sintering of W-Ni-Fe heavy alloys (WHAs) with tungsten (W) content 90 to 98 mass pct (Ni and Fe mass ratio of 7 to 3) in comparison with conventional (CV) hydrogen sintering. Experimental results show that WHAs were MW sintered to fully dense (≥99 pct of theoretical) when heated to sintering temperatures at a heating rate of 50 K/min to 80 K/min (50 C/min to 80 C/min) and isothermally held for 2 to 10 minutes, with sintering cycle times of only 25 to 35 minutes (excluding the cooling time). The desired microstructures of finer W grains, more matrix phases, and lower W contiguity (in 95W and 98W) were produced compared to the counterparts by CV sintering. Such microstructural features offered the alloys excellent tensile properties: ultimate tensile strengths (UTS) 1080 to 1110 MPa and tensile elongation 22.1 to 26.8 pct in 90 to 95W, and UTS 920 MPa and elongation 11.2 pct in 98W. MW sintering appeared to be more effective in fabricating WHAs with W content ≥95 pct. It was observed that the superior UTS with MW-sintered alloys was mainly due to the fast heating and shortened isothermal holding times. Prolonged sintering led to substantial grain coarsening as a result of faster tungsten grain growth in MW sintering, and consequently deteriorated the tensile properties. The grain growth rate constant K achieved was calculated to be 5.1 μm3/s for MW sintering compared to 2.9 μm3/s for CV sintering. Fast heating and short isothermal holding times are thus suggested for the fabrication of WHAs by MW sintering