A plain language summary of the final analysis of the GRIFFIN study of daratumumab plus lenalidomide, bortezomib, and dexamethasone for people with newly diagnosed multiple myeloma.

What Is This Summary About?: This summary describes the final analysis of the GRIFFIN study. In this study, participants were newly diagnosed with a type of blood and bone marrow cancer called multiple myeloma, had never received any treatment, and were able to undergo an autologous stem cell transplant. The GRIFFIN study looked at adding the drug daratumumab (D) to a combination of standard treatments called RVd (lenalidomide [R], bortezomib [V], and dexamethasone [d]) during the treatment phases induction and consolidation, followed by daratumumab and lenalidomide (D-R) maintenance.

Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study.

No randomized trial has directly compared daratumumab and lenalidomide (D-R) maintenance therapy versus standard-of-care lenalidomide (R) alone post-transplant. Here, we report the primary results of the phase 3 AURIGA study evaluating D-R versus R maintenance in NDMM patients who were in ≥very good partial response, minimal residual disease (MRD; threshold 10-5) positive, and anti-CD38 naïve post-transplant. Patients were randomized 1:1 to D-R or R maintenance for up to 36 cycles.

Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN.

The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]).

Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk.

In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]).

Health-related quality of life in transplant-eligible patients with newly diagnosed multiple myeloma treated with daratumumab, lenalidomide, bortezomib, and dexamethasone: Patient-reported outcomes from GRIFFIN.

In the phase 2 GRIFFIN trial (ClinicalTrials.gov identifier: NCT02874742), daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) improved depth of response and progression-free survival (PFS) versus lenalidomide, bortezomib, and dexamethasone (RVd) alone in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) collected using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30-item (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module 20-item (QLQ-MY20), and EuroQol 5-Dimension 5-Level (EQ-5D-5L) tools on day 1 of cycles 1, 2, and 3; on day 21 of cycle 4 (end of induction therapy); on day 1 of cycle 5; on day 21 of cycle 6 (end of posttransplant consolidation therapy); and at months 6, 12, 18, and 24 of maintenance therapy.

Post hoc analysis of daratumumab plus lenalidomide, bortezomib and dexamethasone in Black patients from final data of the GRIFFIN study.

Due in part to racial disparities and underrepresentation in clinical studies, optimal therapies for Black patients with multiple myeloma remain undefined. This final analysis of GRIFFIN by race showed that the addition of daratumumab (D) to lenalidomide/bortezomib/dexamethasone (RVd) provides clinical benefit among both Black and White transplant-eligible newly diagnosed patients compared with RVd alone. However, Black patients were more likely to discontinue ≥1 drug due to treatment-emergent adverse events.

Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial.

Background: Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone (D-RVd) in the GRIFFIN study improved the stringent complete response rate by the end of consolidation in transplantation-eligible patients with newly diagnosed multiple myeloma. Here, we report the findings of the predefined final analysis.

Methods: GRIFFIN was an open-label, randomised, active-controlled, phase 2 trial done in 35 research centres in the USA.

Stem Cell Mobilization Yields with Daratumumab- and Lenalidomide-Containing Quadruplet Induction Therapy in Newly Diagnosed Multiple Myeloma: Findings from the MASTER and GRIFFIN Trials.

For eligible patients with newly diagnosed multiple myeloma (NDMM), standard of care includes induction therapy followed by autologous stem cell transplantation (ASCT). Daratumumab as monotherapy and in combination treatment is approved across multiple lines of therapy for multiple myeloma (MM), and lenalidomide is an effective and commonly used agent for induction and maintenance therapy in MM. However, there is concern that lenalidomide and daratumumab given as induction therapy might impair mobilization of stem cells for ASCT.

Daratumumab plus lenalidomide, bortezomib and dexamethasone in newly diagnosed multiple myeloma: Analysis of vascular thrombotic events in the GRIFFIN study.

Patients with multiple myeloma are at increased risk of vascular thromboembolic events (VTEs). This post hoc analysis evaluated VTEs in the randomised phase 2 GRIFFIN study (ClinicalTrials.gov Identifier: NCT02874742) that investigated lenalidomide/bortezomib/dexamethasone (RVd) ± daratumumab (D).

Initial surgical and clinical experience with the Nucleus CI532 slim modiolar electrode in the UK.

Objective: The goal of this work is to describe the first experience in the UK with the slim pre-curved perimodiolar electrode Nucleus CI532 in a continuous series of patients in terms of surgical and clinical reliability and early performance outcomes.

Method: In this retrospective review we describe the complication rate (including electrode array tip fold-over), NRT thresholds, hearing preservation, power efficiency and CI performance outcomes in a continuous series of 40 cochlear implants CI532 performed between October 2016 and November 2017 in 17 adults and 13 children with severe to profound hearing loss.

Results: Preliminary data from these groups reveals some low-frequency hearing preservation in the CI532 group although none of the patients were conventional hearing preservation candidates.

Discovery of novel potent imidazo[1,2-b]pyridazine PDE10a inhibitors.

Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo.

Benzo[d]imidazole Transient Receptor Potential Vanilloid 1 Antagonists for the Treatment of Pain: Discovery of trans-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol (Mavatrep).

Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a benzo[d]imidazole platform that evolved from a biaryl amide lead. This design composes three sections: a 2-substituted 5-phenyl headgroup attached to the benzo[d]imidazole platform, which is tethered at the two position to a phenyl tail group. Optimization of this design led to the identification of 4 (mavatrep), comprising a trifluoromethyl-phenyl-vinyl tail.

Cochlear implantation in a patient with combined renal and liver transplantation.

Objective And Importance: Patients who have undergone solid organ transplantation and continuing immunosuppressant medication are at a higher risk of wound problems and infections following cochlear implantation. This risk is theoretically even further increased in multi-organ transplant recipients due to the increased doses of immunosuppressive medications that these patients are administered.

Clinical Presentation And Intervention: Here, we present the first reported case of successful cochlear implantation in a patient who had previously undergone successful combined liver and kidney transplant.

Colony-stimulating factor-1 receptor inhibitors for the treatment of cancer and inflammatory disease.

FMS is the exclusive receptor tyrosine kinase for colony-stimulating factor-1 (CSF-1, also known as M-CSF), which regulates the survival, proliferation, differentiation, and function of macrophage lineage cells. Since CSF-1 is over-expressed in many tumors and at sites of inflammation, small molecule inhibitors of CSF-1 appear to offer an attractive strategy for reducing macrophage numbers associated with cancer as well as autoimmune and inflammatory disease, such as rheumatoid arthritis (RA). Numerous FMS inhibitors with structurally distinct chemotypes have been developed and exhibit potent in vitro activity, but only a limited number of compounds have progressed clinically due to poor selectivity.

Small-molecule inhibitors of the p53-HDM2 interaction for the treatment of cancer.

Background: The hdm2 oncogene product, HDM2 (also known as MDM2), is an ubiquitin protein ligase that suppresses the transcriptional activity of the tumor suppressor p53 and promotes its degradation. Approximately 50% of all human tumors harbor mutations or deletions in the TP53 gene. In the remaining half of all human cancers that express the wild-type protein, aberrations of p53 regulators such as HDM2 account for p53 inhibition.

Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif.

2-Cyano-6-fluorophenylacetamide was explored as a novel P2 scaffold in the design of thrombin inhibitors. Optimization around this structural motif culminated in 14, which is a potent thrombin inhibitor (K(i)=1.2nM) that exhibits robust efficacy in canine anticoagulation and thrombosis models upon oral administration.

Inhibitory effect of statins on renal epithelial-to-mesenchymal transition.

Background/aim: Recent studies have suggested that statins may play a role in the protection against renal failure which is independent of cholesterol reduction. Activation of RhoGTPases is a key step in renal tubular cells' epithelial-to-mesenchymal transition (EMT) which contributes to renal interstitial fibrosis. We hypothesized that statins could act by inhibiting the synthesis of the isoprenoids, such as geranylgeranyl pyrophosphate, which is essential for membrane attachment and biological activity of RhoGTPases, RhoA and Rac1.

RhoGTPase activation is a key step in renal epithelial mesenchymal transdifferentiation.

ESRD is characterized by an interstitial infiltrate of inflammatory cells in association with tubular atrophy, epithelial mesenchymal transdifferentiation (EMT), and interstitial fibrosis. Human proximal tubular epithelial cells (HK2 cells) undergo EMT in response to activated PBMC conditioned medium (aPBMC-CM), showing acquisition of a fibroblastoid morphology, increased fibronectin-EDA (EDA) expression, loss of junctional E-cadherin localization, and cytokeratin 19 (K19) expression. The signaling pathway(s) that regulates EMT in response to aPBMC-CM is not well understood.

Oncostatin M, a cytokine released by activated mononuclear cells, induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathway activation.

Interactions between inflammatory infiltrates and resident tubular epithelial cells may play important roles in the development of tubulointerstitial fibrosis, by promoting epithelial cell-myofibroblast transdifferentiation (EMT). Human proximal tubular epithelial cells transdifferentiated to myofibroblasts after treatment with activated PBMC conditioned medium. mRNA and protein levels for alpha-smooth muscle actin, collagen I, and fibronectin EDA(+) (markers for the myofibroblastic phenotype) were increased, whereas those for E-cadherin and cytokeratin 19 (markers for the epithelial phenotype) were decreased.