Pomalidomide, Bortezomib, and Dexamethasone in Lenalidomide-Pretreated Multiple Myeloma: A Subanalysis of OPTIMISMM by Frailty and Bortezomib Dose Adjustment.

INTRODUCTION: A proportion of patients with multiple myeloma (MM) are older and/or have comorbidities, requiring dose adjustments. Data from OPTIMISMM (NCT01734928) supported the use of pomalidomide, bortezomib, and dexamethasone (PVd) for treating relapsed/refractory MM. This subanalysis of OPTIMISMM assessed outcome by frailty and/or bortezomib dose adjustment. METHODS: Patient frailty (nonfrail vs. frail) was classified using age, Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status. Data from patients requiring a bortezomib dose reduction, interruption, and/or withdrawal during PVd treatment were assessed. RESULTS: Among 559 patients, 93 of 281 (33.1%) and 93 of 278 (33.5%) patients who received PVd and bortezomib and dexamethasone (Vd), respectively, were frail. Overall response rate (ORR) and median progression-free survival (PFS) were higher in nonfrail vs. frail with PVd treatment (ORR, 82.8% vs. 79.6%; PFS, 14.7 vs. 9.7 months); significantly higher than with Vd regardless of frailty. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were higher with PVd vs. Vd, regardless of frailty. Discontinuations of PVd were lower in nonfrail vs. frail patients (19.2% vs. 30.1%); the median duration of treatment was similar (DoT; 8.8 vs. 8.9 months, respectively). Patients who received PVd with a bortezomib dose adjustment (n = 240) had a longer median DoT (9.3 vs. 4.5 months) and PFS (12.1 vs. 8.4 months) vs. those without. CONCLUSION: Frail patients treated with PVd demonstrated a higher ORR and a longer PFS and DoT vs. Vd, despite a higher frequency of grade ≥ 3 TEAEs leading to pomalidomide, bortezomib, and/or dexamethasone discontinuation. Therefore, PVd treatment may improve patient outcomes, regardless of frailty.

CXCL8 Antagonist Improves Diabetic Nephropathy in Male Mice With Diabetes and Attenuates High Glucose-Induced Mesangial Injury.

Inflammation is recognized as a crucial contribution to diabetic nephropathy (DN). CXCL8 binds to its CXC chemokine receptors (CXCR1 and CXCR2) for recruiting neutrophil infiltration and initiates tissue inflammation. Therefore, we explored the effect of CXCR1 and CXCR2 inhibition on DN. This was achieved by CXCL8(3-72)K11R/G31P (G31P), an antagonist of CXCL8 that has exhibited therapeutic efficacy in inflammatory diseases and malignancies. In this study, we found that renal leukocyte accumulation and rapid increases of CXCL8 occurred in high-fat diet/streptozocin-induced diabetic mice. G31P effectively reduced urine volume, urine albumin/creatinine ratio, blood urea nitrogen, and creatinine clearance rate in mice with diabetes. In addition, renal histopathologic changes including mesangial expansion, glomerulosclerosis, and extracellular matrix deposition were partially moderated in G31P-treated diabetic mice. Furthermore, G31P attenuated renal inflammation and renal fibrosis of diabetic mice by inhibiting proinflammatory and profibrotic elements. G31P also inhibited high glucose-induced inflammatory and fibrotic factor upregulation in human renal mesangial cells. At the molecular level, G31P inhibited activation of CXCR1/2 downstream signaling JAK2/STAT3 and ERK1/2 pathways in in vitro and in vivo experiments. Our results suggest blockade of CXCR1/2 by G31P could confer renoprotective effects that offer potential therapeutic opportunities in DN.