EVIDENCE meta-analysis: evaluating minimal residual disease as an intermediate clinical end point for multiple myeloma.

Estimating progression-free survival (PFS) and overall survival superiority during clinical trials of multiple myeloma (MM) has become increasingly challenging as novel therapeutics have improved patient outcomes. Thus, it is imperative to identify earlier end point surrogates that are predictive of long-term clinical benefit. Minimal residual disease (MRD)-negativity is a common intermediate end point that has shown prognostic value for clinical benefit in MM.

Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma.

In the primary analysis of the phase III COLUMBA study, daratumumab by subcutaneous administration (DARA SC) demonstrated non-inferiority to intravenous administration (DARA IV) for relapsed or refractory multiple myeloma (RRMM). Here, we report the final analysis of efficacy and safety from COLUMBA after a median of 29.3 months follow-up (additional 21.

Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA.

We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (≥CR) with MRD-negative status and progression-free survival (PFS).

Sustained minimal residual disease negativity in newly diagnosed multiple myeloma and the impact of daratumumab in MAIA and ALCYONE.

In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone [D-Rd]) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone [D-VMP]). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE.

Results of a Time and Motion Survey Regarding Subcutaneous versus Intravenous Administration of Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma.

Purpose: Daratumumab (DARA) is a humanized anti-CD38 monoclonal antibody and approved as monotherapy or in combination with standard of care regimens for the treatment of multiple myeloma (MM). DARA intravenous (IV) administration is time-consuming; availability of DARA subcutaneous (SC) is expected to reduce this burden. A time and motion survey was undertaken to elicit healthcare providers' (HCPs') understanding of the workflow and time estimates for administration of DARA IV and SC (beyond treatment time) in patients with relapsed/refractory MM.

Subcutaneous daratumumab in Asian patients with heavily pretreated multiple myeloma: subgroup analyses of the noninferiority, phase 3 COLUMBA study.

The phase 3 COLUMBA study demonstrated noninferiority of subcutaneous daratumumab (DARA SC) to intravenous daratumumab (DARA IV) in relapsed or refractory multiple myeloma. We present a subgroup analysis of Asian patients from COLUMBA. Eligible patients had ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were double refractory.

Evaluation of Cardiac Repolarization in the Randomized Phase 2 Study of Intermediate- or High-Risk Smoldering Multiple Myeloma Patients Treated with Daratumumab Monotherapy.

Introduction: Daratumumab is a CD38-targeting monoclonal antibody that has demonstrated clinical benefit for multiple myeloma. Daratumumab inhibition of CD38, which is expressed on immune cell populations and cardiomyocytes, could potentially affect cardiac function. This QTc substudy of the phase 2 CENTAURUS study investigated the potential effect of intravenous daratumumab monotherapy on QTc prolongation and other electrocardiogram (ECG) parameters, including concentration-QTc effect modeling.

Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients.

We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.

Greater treatment satisfaction in patients receiving daratumumab subcutaneous vs. intravenous for relapsed or refractory multiple myeloma: COLUMBA clinical trial results.

Purpose: The phase III COLUMBA study evaluated daratumumab (DARA) intravenous (IV) and subcutaneous (SC) in patients with relapsed or refractory multiple myeloma. Here, we report patient-reported satisfaction with therapy (SWT) in COLUMBA.

Methods: DARA IV or DARA SC was administered weekly (cycles 1-2), every 2 weeks (cycles 3-6), and every 4 weeks (cycles 7 +).

Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial.

Background: Intravenous daratumumab for treatment of patients with multiple myeloma involves a lengthy infusion that affects quality of life, and infusion-related reactions are common. Subcutaneous daratumumab is thought to be easier to administer and to cause fewer administration-related reactions. In this study (COLUMBA), we tested the non-inferiority of subcutaneous daratumumab to intravenous daratumumab.

Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, open-label, multicenter, phase 2 study (CENTAURUS).

Current guidelines for smoldering multiple myeloma (SMM) recommend active monitoring until the onset of multiple myeloma (MM) before initiating treatment or enrollment in a clinical trial. Earlier intervention may delay progression to MM. In CENTAURUS, 123 patients with intermediate-risk or high-risk SMM were randomly assigned to daratumumab 16 mg/kg intravenously on extended intense (intense), extended intermediate (intermediate), or short dosing schedules.

Stem cell mutations can be detected in myeloma patients years before onset of secondary leukemias.

Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/t-MDS) are secondary hematologic malignancies associated with poor prognosis, warranting insights into their predisposing conditions and cells of origin. We identified patients with myeloma who developed t-AML/t-MDS and analyzed their stem and progenitor cells collected years before the onset of secondary disease. We demonstrate that aberrant stem cells with high CD123 expression can be detected long before the onset of overt leukemia.

Correction to: A Rapid and Robust Protocol for Reduced Representation Bisulfite Sequencing in Multiple Myeloma.

The text highlighted in bold in the below line in Chapter 13 has been replaced as given below. "Chapter 13 Page no. 186.

A Comparison of Radiographic Joint Space Width Measurements Versus Ultrasonographic Assessment of Cartilage Thickness in Children with Juvenile Idiopathic Arthritis.

Objective: Joint space narrowing (JSN) is a measurable outcome of tissue degeneration in arthritis. JSN is usually assessed by conventional radiography. Ultrasonographic (US) measurement of joint cartilage thickness has been validated in healthy children, and US measurement of the distal femoral cartilage has been validated in a group of patients with juvenile idiopathic arthritis (JIA).

Genome Wide Mapping of Methylated and Hydroxyl-Methylated Cytosines Using a Modified HpaII Tiny Fragment Enrichment by Ligation Mediated PCR Tagged Sequencing Protocol.

Here we describe a method for genome wide investigation of methylation and hydroxymethylation status of cytosines. This protocol is an improvement of the HELP-tagging protocol previously described by Suzuki et al. It involves the glucosylation of 5-hydroxymethylcytosines (5-hmC) with β-glucosyl transferase (β-GT), thus rendering them resistant to digestion by MspI.

Prednisolone Effects on Urine Cross-Linked N-Telopeptides of Type I Collagen (Ntx) Diurnal Rhythms in Children.

Background: Recently, methods for mimicking endogenous cortisol rhythms hereby potentially reducing the risk of systemic adverse effects of exogenous corticosteroids have been patented. Methods for sensitive detection of adverse effects on bone turnover of various doses, administration routes and regimens of exogenous corticosteroids have been patented. Urine cross-linked Ntelopeptides of Type I collagen (Ntx) have been established as a sensitive bone resorption marker and urine levels of Ntx have been found to exhibit a distinct diurnal rhythm.

Joint cartilage thickness and automated determination of bone age and bone health in juvenile idiopathic arthritis.

Background: BoneXpert is an automated method to calculate bone maturation and bone health index (BHI) in children with juvenile idiopathic arthritis (JIA). Cartilage thickness can also be seen as an indicator for bone health and arthritis damage. The objective of this study was to evaluate the relation between cartilage thickness, bone maturation and bone health in patients with JIA.

The timing of administration of exogenous glucocorticoid affects 24hour growth hormone secretion in children.

Unlabelled: Exogenous glucocorticoids may suppress linear growth by affecting the diurnal secretory rhythm of GH.

Objective: To assess whether the timing of exogenous glucocorticoid administration affects GH secretion in children.

Design: Four girls and four boys aged 10.

Nasopharyngeal amyloidoma with osteolytic lesions leading to diagnosis of systemic light-chain amyloidosis.

Amyloidomas of the head and neck region are uncommon and generally considered a benign localized form of amyloidosis. Here, we describe "the unusual case of a young man" with a nasopharyngeal mass and osteolytic lesions caused by systemic light-chain amyloidosis treated successfully with a combined surgical and chemotherapy approach.

Multi-subgroup gene screening using semi-parametric hierarchical mixture models and the optimal discovery procedure: Application to a randomized clinical trial in multiple myeloma.

This article proposes an efficient approach to screening genes associated with a phenotypic variable of interest in genomic studies with subgroups. In order to capture and detect various association profiles across subgroups, we flexibly estimate the underlying effect size distribution across subgroups using a semi-parametric hierarchical mixture model for subgroup-specific summary statistics from independent subgroups. We then perform gene ranking and selection using an optimal discovery procedure based on the fitted model with control of false discovery rate.