A phase 1b study of once-weekly carfilzomib combined with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma.

Twice-weekly carfilzomib with lenalidomide-dexamethasone (Rd) is an effective regimen for newly diagnosed multiple myeloma (NDMM). Here we evaluated once-weekly carfilzomib with Rd (once-weekly KRd) in NDMM patients. The NDMM patients were enrolled regardless of transplant eligibility. Patients received carfilzomib on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on carfilzomib days (also day 22 for cycles 1-8) for ≤18, 28-day cycles. Enrollment initiated in a carfilzomib 20/70 mg/m2 (20 mg/m2 on cycle one, day 1; 70 mg/m2 thereafter) NDMM dose-expansion arm, which was suspended because of serious adverse events. After evaluation of dose-limiting toxicities in a two-step-up dose-evaluation cohort, an NDMM dose-expansion arm (carfilzomib 20/56 mg/m2 ) was opened. Fifty-one NDMM patients were enrolled in dose-finding and dose-expansion cohorts. Results are presented for the carfilzomib 56 mg/m2 NDMM dose-expansion arm (n = 33). The grade ≥ 3 treatment-emergent AE (TEAE) rate was 63.6%. Twenty-five patients underwent stem cell collection; 18 proceeded to auto stem cell transplant, and five resumed KRd on study after autoSCT. The overall response rate (ORR) based on best overall response by cycle four was 97.0% (≥very good partial response [VGPR], 69.7%) in the NDMM 20/56 mg/m2 cohort. In patients who did not receive autoSCT (n = 15), the median number of cycles was 16.0; ORR was 93.3% (≥VGPR, 80.0%). At a median follow-up of 8.1 months, median progression-free survival was not reached. Once-weekly KRd (carfilzomib 56 mg/m2 ) had a favorable safety profile and promising activity in NDMM, supporting the use of this regimen in this setting.

Weekly carfilzomib, lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: A phase 1b study.

Twice-weekly carfilzomib (27 mg/m2 ) with lenalidomide-dexamethasone (KRd) is a standard-of-care in relapsed or refractory multiple myeloma (RRMM). This phase 1b study evaluated KRd with once-weekly carfilzomib in RRMM. Patients received carfilzomib (30-minute infusion; 56 or 70mg/m2 ) on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on days 1, 8, 15, and 22 (day 22 omitted for cycles 9+) of 28-day cycles. Primary objective was safety/tolerability; efficacy was a secondary objective. Fifty-six RRMM patients enrolled: 22 during dose evaluation (56-mg/m2 , n = 10; 70-mg/m2 , n = 12) and 34 during dose expansion (all initiated dosing at 70 mg/m2 ). After 2 fatal adverse events (AEs) during 70-mg/m2 dose expansion, dosage reduction to 56 mg/m2 was permitted. Results are presented for carfilzomib 56-mg/m2 (n = 10) and 70-mg/m2 groups (dose evaluation/expansion; n = 46). Median carfilzomib dose was 53.2 mg/m2 (56-mg/m2 group) and 62.4 mg/m2 (70-mg/m2 group). Grade ≥3 AE rates were 70.0% (56 mg/m2 ) and 69.6% (70 mg/m2 ). Overall response rates were 90.0% (56 mg/m2 ) and 89.1% (70 mg/m2 ); ≥very good partial response rates were 50.0% (56 mg/m2 ) and 73.9% (70 mg/m2 ). Once-weekly KRd was active with acceptable toxicity in RRMM, supporting further evaluation of this regimen.

Associations between genetic variants in the ACE, AGT, AGTR1 and AGTR2 genes and renal function in the Multi-ethnic Study of Atherosclerosis.

BACKGROUND/AIMS: Some studies suggest that polymorphisms in angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II type I receptor (AGTR1) and angiotensin II type II receptor (AGTR2) genes may contribute to renal function variation. METHODS: Genotyping for single nucleotide polymorphisms (SNPs) in these candidate genes was performed in 2,847 participants from four racial/ethnic groups (African American, Chinese, White and Hispanic) without known cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. SNP and haplotype analyses were performed to determine associations between genotypes and cross-sectional renal function measurements, including urine albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) using serum creatinine and cystatin C. RESULTS: Twenty-four ACE SNPs, 10 AGT SNPs, 15 AGTR1 SNPs and 6 AGTR2 SNPs were typed successfully. After adjusting for ancestry, age and gender, 3 SNPs (AGT M235T, AGT rs2148582 and AGTR1 rs2131127) showed associations with an empiric p value <0.05 with the same phenotype in multiple racial/ethnic groups, suggesting replication. The AGT M235T SNP has been shown previously to be associated with diabetic and hypertensive nephropathy. CONCLUSIONS: These data suggest that genetic polymorphisms in the renin-angiotensin system are associated with renal phenotypes in the general population, but that many associations differ across racial/ethnic groups.

Replication of calpain-10 genetic association with carotid intima-media thickness.

OBJECTIVE: Diabetes and atherosclerosis may share common genetic determinants. A prior study in Hispanics found association of haplotypes in the diabetes gene calpain-10 (CAPN10) with carotid artery intima-media thickness (CIMT). This study sought to replicate this association in an independent cohort. METHODS: Four CAPN10 SNPs were genotyped and haplotypes determined in 487 Hispanic Americans from 143 families ascertained via an index case with hypertension. CIMT was measured from B-mode ultrasound, and glycemic traits quantified from euglycemic clamps. Association of SNPs and haplotypes with CIMT was determined. RESULTS: The minor alleles of SNP-56 and SNP-63 were associated with increased CIMT in dominant and additive models. The association of haplotype 1112 with increased CIMT was replicated. No associations with fasting insulin, insulin secretion, or insulin sensitivity were observed. CONCLUSIONS: CAPN10 association with CIMT was replicated, further supporting its role as a common genetic determinant of diabetes and atherosclerosis in Hispanics.

Loss of the Y chromosome: an age-related or clonal phenomenon in acute myelogenous leukemia/myelodysplastic syndrome?

CONTEXT: The clinical association between loss of the Y chromosome and acute myelogenous leukemia and myelodysplastic syndrome (AML/MDS) has been debated because both phenomena are related to aging. A prior publication suggests that loss of the Y chromosome in more than 75% of cells may indicate a clonal phenomenon that could be a marker for hematologic disease. OBJECTIVE: To evaluate the relationship between loss of the Y chromosome and AML/MDS. DESIGN: A retrospective review of cytogenetic reports of 2896 male patients ascertained from 1996 to 2007 was performed. Results were stratified based on the percentage of cells missing the Y chromosome and were correlated with patients' ages and bone marrow biopsy reports through logistic regression analysis with adjustment for age. RESULTS: Loss of the Y chromosome was found in 142 patients. Of these, 16 patients demonstrated myeloid disease, with 2 cases of AML and 14 cases of MDS. An increased incidence (P < .05) of AML/MDS was seen only in the group composed of 8 patients with complete loss of the Y chromosome in all karyotyped cells (1 case of AML and 7 cases of MDS). CONCLUSION: Loss of the Y chromosome appears to be primarily an age-related phenomenon. However, in individuals in which all cells on cytogenetic analysis showed loss of the Y chromosome, there was a statistically significant increase in AML/MDS, suggesting that the absence of any normal-dividing cells in a bone marrow analysis may be indicative of AML/MDS.

Carotid intima-media thickness (cIMT) cosegregates with blood pressure and renal function in hypertensive Hispanic families.

BACKGROUND: Carotid intima-media thickness (cIMT) is commonly used as a surrogate for atherosclerosis. Since cIMT is correlated with hypertension and microalbuminuria, we tested the hypothesis that there is a genetic basis for the observed relationship between cIMT, blood pressure (BP), and renal function within high risk families. METHODS: Six hundred and three nondiabetic individuals from 149 Hispanic American families (HA) were ascertained via a hypertensive parent. Phenotyping included cIMT, BP, anthropometrics, and renal function, which was assessed by urine microalbumin, blood urea nitrogen (BUN), serum creatinine (Cr), and Cr clearance (Ccr). A variance components approach was used to estimate trait heritabilities and decompositions of their phenotypic correlations. RESULTS: Significant heritabilities (P<0.0001 for each) were found for cIMT, body mass index, BP, and the renal function traits. There were significant phenotypic correlations within family members, with positive correlations between cIMT and systolic BP (SBP), and urine microalbumin and Ccr, and negative correlations among cIMT, BUN, and Cr; these remained significant after correction for BP, but not after correction for urine microalbumin. Partitioned into genetic and environmental correlations, genetic correlations were significant between cIMT and each of SBP, urine microalbumin, Ccr, BUN, and Cr, respectively, while there were significant environmental correlations between cIMT and each of BUN, Cr, and Ccr. The genetic and environmental correlations were unchanged when adjusted for BP, but were no longer significant when adjusted for urine microalbumin. CONCLUSIONS: There is substantial genetic contribution to SBP, renal function, and cIMT in these high risk Hispanic families. Subclinical atherosclerosis shares common genetic determinants with SBP and, independently, with measures of renal function.

Evaluating gene x gene and gene x smoking interaction in rheumatoid arthritis using candidate genes in GAW15.

We examined the potential gene x gene interactions and gene x smoking interactions in rheumatoid arthritis (RA) using the candidate gene data sets provided by Genetic Analysis Workshop 15 Problem 2. The multifactor dimensionality reduction (MDR) method was used to test gene x gene interactions among candidate genes. The case-only sample was used to test gene x smoking interactions. The best predictive model was the single-locus model with single-nucleotide polymorphism (SNP) rs2476601 in gene PTPN22. However, no clear gene x gene interaction was identified. Substantial departure from multiplicativity was observed between smoking and SNPs in genes CTLA4, PADI4, MIF, and SNPs on chromosome 5 and one haplotype of PTPN22. The strongest evidence of association was identified between the PTPN22 gene and RA status, which was consistently detected in single SNP association, gene x gene interaction and gene x smoking interaction analyses.