Importance Numerous studies have evaluated the prognostic value of minimal residual disease (MRD) in multiple myeloma (MM). Most studies were small and varied in terms of patient population, treatment, and MRD assessment methods. Objective To evaluate the utility of MRD detection in patients with newly diagnosed MM. Data Sources A Medline search was conducted for articles published in English between January 1990 and January 2016. Study Selection Eligible studies reported MRD status and progression-free survival (PFS) or overall survival (OS) in ≥ 20 patients following treatment. Among 405 articles identified, 21 met the initial eligibility criteria and were included in the analysis. Data Extraction and Synthesis Information on patient characteristics, treatment, MRD assessment, and outcomes were extracted using a standard form. Main Outcome Measures The impact of MRD status on PFS and OS was assessed by pooling data from relevant trials. Data were adjusted to allow for different proportions of patients with MRD in different studies, and analyzed using the Peto method. Forest plots were created based on Cox model analysis. Other pre-specified research questions were addressed qualitatively. Results Fourteen studies (n = 1,273) provided data on the impact of MRD on PFS, and 12 studies (n = 1,100) on OS. Results were reported specifically in patients who had achieved conventional complete response (CR) in 5 studies for PFS (n = 574) and 6 studies for OS (n = 616). MRD-negative status was associated with significantly better PFS overall (Hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.36–0.48; P < .0001) and in studies specifically looking at CR patients (HR 0.44; 95% CI 0.34–0.56; P < .0001). OS was also favorable in MRD-negative patients overall (HR 0.57; 95% CI 0.46–0.71; P < .0001) and in CR patients (HR 0.47; 95% CI 0.33–0.67; P < .0001). Tests of heterogeneity found no significant differences among the studies for PFS and OS. Conclusions and Relevance MRD-negative status after treatment for newly diagnosed MM is associated with long-term survival. These findings provide quantitative evidence to support the integration of MRD assessment as an endpoint in clinical trials of MM.

Overproduction of VLDL (very-low-density lipoprotein) particles is an important cause of FCHL (familial combined hyperlipidaemia). It has been shown recently that VLDL production is driven by the amount of hepatic fat. The present study was conducted to determine the prevalence of fatty liver in relation to the different fat compartments and lipid parameters in FCHL. A total of 68 FCHL patients, 110 normolipidaemic relatives and 66 spouses underwent ultrasound of the abdominal region to estimate the amount of subcutaneous, visceral and hepatic fat. Skinfold callipers were used to measure subcutaneous fat of the biceps, triceps, subscapular and supra-iliacal regions. Fatty liver was observed in 18% of the spouses, 25% of the normolipidaemic relatives and 49% of the FCHL patients. After adjustment for age, gender and body mass index, the prevalence of fatty liver was significantly higher in FCHL patients compared with spouses [OR (odds ratio), 3.1; P=0.03], and also in the normolipidaemic relatives compared with spouses (OR, 4.0; P=0.02), whereas no differences were observed between FCHL patients and normolipidaemic relatives (OR, 0.8; P=0.58). In the normolipidaemic relatives and FCHL patients combined, both visceral fat mass and subcutaneous abdominal fat were independent predictors of fatty liver (P<0.001 for both fat compartments; FCHL status corrected). Of interest, fatty liver stages were correlated with both VLDL-apoB (apolipoprotein B) and VLDL-triacylglycerols (triglycerides) in a representative subset (n=69) of patients and relatives (r(2)=0.12, P=0.006; and r(2)=0.18, P=0.001 respectively). These results show that fatty liver is a central aspect of FCHL, i.e. patients and normolipidaemic relatives. Both visceral and subcutaneous adiposity contribute to its 3-4-fold higher risk in FCHL.

Objective-The present study addresses the presence of distinct metabolic phenotypes in familial combined hyperlipidemia (FCHL) in relation to small dense low-density lipoprotein (sd LDL) and very low-density lipoprotein (VLDL) subclasses. Methods and Results-Hyperlipidemic FCHL relatives (nϭ72) were analyzed for LDL size by gradient gel electrophoresis. Pattern B LDL (sd LDL, particle size Ͻ258 Å) and pattern A LDL (buoyant LDL, particle size Ն258 Å) were defined. Analyses showed bimodal distribution of LDL size associated with distinct phenotypes. Subjects with predominantly large, buoyant LDL showed a hypercholesterolemic phenotype and the highest apo B levels. Subjects with predominantly sd LDL showed a hypertriglyceridemic, low high-density lipoprotein (HDL) cholesterol phenotype, with moderately elevated apoB, total cholesterol level, and LDL cholesterol level. Subjects with both buoyant LDL and sd LDL (pattern AB, nϭ7) showed an intermediate phenotype, with high normal plasma triglycerides. VLDL subfraction analysis showed that the sd LDL phenotype was associated with a 10-times higher number of VLDL1 particles of relatively lower apo AI and apo E content, as well as smaller VLDL2 particles, in combination with increased plasma insulin concentration in comparison to pattern A. Key Words: sd LDL Ⅲ apolipoprotein B Ⅲ triglycerides Ⅲ insulin resistance Ⅲ VLDL F amilial combined hyperlipidemia (FCHL) is a metabolic disease, delineated as a genetic disorder of lipid metabolism almost 3 decades ago. 1 It is associated with a 2-to 5-fold increased risk of premature coronary artery disease. 1,2 Despite recent progress, the genetic and metabolic backgrounds of FCHL have not been elucidated in detail. Subjects with FCHL present with a complex phenotype whose expression is influenced by genetic, metabolic, and environmental factors. [3][4][5][6] Affected FCHL relatives are viscerally obese, 2,4,7 hyperinsulinemic, 3 insulin-resistant, 5,7 and can show a number of abnormalities in lipid metabolism: hypercholesterolemia and/or hypertriglyceridemia, elevated apolipoprotein B (apoB) levels, small dense low-density lipoprotein (sd LDL), and decreased plasma high-density lipoprotein (HDL) cholesterol concentrations. Conclusions-TheVery low-density lipoprotein (VLDL) and LDL consist of distinct, physicochemically heterogenic subclasses. 8 A practical characterization of the LDL profile divides it into two major phenotypes: pattern A, characterized by a preponderance of large, buoyant particles, with peak particle diameter Ն258 Å, and pattern B, characterized by predominance of sd LDL particles, with peak particle diameter Ͻ258 Å. In the population, sd LDL phenotype and the concurrent metabolic abnormalities (relative hypertriglyceridemia and low HDL cholesterol) have been designated the atherogenic lipoprotein phenotype, 9 consistent with its association with an increased risk of coronary artery disease. 9,10 Furthermore, pattern B LDL has been recognized as a feature of the metabolic syndrome 11 and is characteristic for i...

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