Susanna Jacobus

Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial

BACKGROUND High-dose dexamethasone is a mainstay of therapy for multiple myeloma. We studied whether low-dose dexamethasone in combination with lenalidomide is non-inferior to and has lower toxicity than high-dose dexamethasone plus lenalidomide. METHODS Patients with untreated symptomatic myeloma were randomly assigned in this open-label non-inferiority trial to lenalidomide 25 mg on days 1-21 plus dexamethasone 40 mg on days 1-4, 9-12, and 17-20 of a 28-day cycle (high dose), or lenalidomide given on the same schedule with dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle (low dose). After four cycles, patients could discontinue therapy to pursue stem-cell transplantation or continue treatment until disease progression. The primary endpoint was response rate after four cycles assessed with European Group for Blood and Bone Marrow Transplant criteria. The non-inferiority margin was an absolute difference of 15% in response rate. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00098475. FINDINGS 445 patients were randomly assigned: 223 to high-dose and 222 to low-dose regimens. 169 (79%) of 214 patients receiving high-dose therapy and 142 (68%) of 205 patients on low-dose therapy had complete or partial response within four cycles (odds ratio 1.75, 80% CI 1.30-2.32; p=0.008). However, at the second interim analysis at 1 year, overall survival was 96% (95% CI 94-99) in the low-dose dexamethasone group compared with 87% (82-92) in the high-dose group (p=0.0002). As a result, the trial was stopped and patients on high-dose therapy were crossed over to low-dose therapy. 117 patients (52%) on the high-dose regimen had grade three or worse toxic effects in the first 4 months, compared with 76 (35%) of the 220 on the low-dose regimen for whom toxicity data were available (p=0.0001), 12 of 222 on high dose and one of 220 on low-dose dexamethasone died in the first 4 months (p=0.003). The three most common grade three or higher toxicities were deep-vein thrombosis, 57 (26%) of 223 versus 27 (12%) of 220 (p=0.0003); infections including pneumonia, 35 (16%) of 223 versus 20 (9%) of 220 (p=0.04), and fatigue 33 (15%) of 223 versus 20 (9%) of 220 (p=0.08), respectively. INTERPRETATION Lenalidomide plus low-dose dexamethasone is associated with better short-term overall survival and with lower toxicity than lenalidomide plus high-dose dexamethasone in patients with newly diagnosed myeloma. FUNDING National Cancer Institute, Rockville, MD, USA.

Double-Blind, Randomized Trial of Docetaxel Plus Vandetanib Versus Docetaxel Plus Placebo in Platinum-Pretreated Metastatic Urothelial Cancer

PURPOSE Vandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with docetaxel was assessed in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy. PATIENTS AND METHODS The primary objective was to determine whether vandetanib 100 mg plus docetaxel 75 mg/m(2) intravenously every 21 days prolonged progression-free survival (PFS) versus placebo plus docetaxel. The study was designed to detect a 60% improvement in median PFS with 80% power and one-sided α at 5%. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Overall survival (OS), overall response rate (ORR), and safety were secondary objectives. RESULTS In all, 142 patients were randomly assigned and received at least one dose of therapy. Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = .9). ORR and OS were not different between both arms. Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhea (7% v 0%). Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months. CONCLUSION In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR, or OS. The toxicity of vandetanib plus docetaxel was greater than that for vendetanib plus placebo. Single-agent vandetanib activity was minimal.

Moving Beyond the Hazard Ratio in Quantifying the Between-Group Difference in Survival Analysis

In a longitudinal clinical study to compare two groups, the primary end point is often the time to a specific event (eg, disease progression, death). The hazard ratio estimate is routinely used to empirically quantify the between-group difference under the assumption that the ratio of the two hazard functions is approximately constant over time. When this assumption is plausible, such a ratio estimate may capture the relative difference between two survival curves. However, the clinical meaning of such a ratio estimate is difficult, if not impossible, to interpret when the underlying proportional hazards assumption is violated (ie, the hazard ratio is not constant over time). Although this issue has been studied extensively and various alternatives to the hazard ratio estimator have been discussed in the statistical literature, such crucial information does not seem to have reached the broader community of health science researchers. In this article, we summarize several critical concerns regarding this conventional practice and discuss various well-known alternatives for quantifying the underlying differences between groups with respect to a time-to-event end point. The data from three recent cancer clinical trials, which reflect a variety of scenarios, are used throughout to illustrate our discussions. When there is not sufficient information about the profile of the between-group difference at the design stage of the study, we encourage practitioners to consider a prespecified, clinically meaningful, model-free measure for quantifying the difference and to use robust estimation procedures to draw primary inferences.

Prognostic factors for hyperdiploid-myeloma: effects of chromosome 13 deletions and IgH translocations

Chromosomal hyperdiploidy is the defining genetic signature in 40–50% of myeloma (MM) patients. We characterize hyperdiploid-MM (H-MM) in terms of its clinical and prognostic features in a cohort of 220 H-MM patients entered into clinical trials. Hyperdiploid-myeloma is associated with male sex, kappa immunoglobulin subtype, symptomatic bone disease and better survival compared to nonhyperdiploid-MM (median overall survival 48 vs 35 months, log-rank P=0.023), despite similar response to treatment. Among 108 H-MM cases with FISH studies for common genetic abnormalities, survival is negatively affected by the existence of immunoglobulin heavy chain (IgH) translocations, especially those involving unknown partners, while the presence of chromosome 13 deletion by FISH did not significantly affect survival (median overall survival 50 vs 47 months, log-rank P=0.47). Hyperdiploid-myeloma is therefore a unique genetic subtype of MM associated with improved outcome with distinct clinical features. The existence of IgH translocations but not chromosome 13 deletion by FISH negatively impacts survival and may allow further risk stratification of this population of MM patients.

Clinical and biological significance of RAS mutations in multiple myeloma

Primary genetic abnormalities in myeloma (MM) such as trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19 and 21 associated with hyperdiploid MM and translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14q32 and three main recurrent partners: MMSET/FGFR3, CCND1 and c-MAF are already present in the pre-malignant monoclonal gammopathy of undetermined significance (MGUS) stage.1 Some patients with these genetic abnormalities may remain as MGUS for many years without transforming to MM, suggesting that they are involved in clonal initiation but do not mediate malignant transformation.

Clinical significance of TP53 mutation in myeloma

The p53 tumor suppressor is a critical regulator of tissue homeostasis, and its inactivation at the gene or protein level confers cellular properties conducive for oncogenesis and cancer progression. Furthermore, p53 inactivation has been associated with resistance to therapy. Indeed, the p53 response is deficient in 450% of cancers mainly through gene mutation. In contrast to other solid tumors and carcinomas, TP53 mutations are rare in multiple myeloma (MM), a malignancy characterized by clonal plasma cells secreting monoclonal immunoglobulin. Previous studies of TP53 mutations in MM were hampered by clinical heterogeneity in the study cohorts and the relatively small sample size (all with o100 patients). These studies reported a prevalence of TP53 mutation ranging from 0 to 20%. However, it is not always obvious whether the study cohorts consist of newly diagnosed or relapsed patients. This is important as the prevalence of TP53 mutations increases with more advance disease (even this is not clearly defined and seemed to include Durie–Salmon stage III and plasma cell leukemia) and is very prevalent in HMCLs. Furthermore, these studies generally limit their investigation to exons 5–9, whereas several studies in other cancers have shown that mutations can occur in other exons. At present, the prognostic importance of TP53 mutations in myeloma is unknown. In this study, we comprehensively define the prevalence of TP53 mutations in newly diagnosed myeloma patients by screening genomic DNA from unsorted whole bone marrow from a large cohort of patients entered into an Eastern Cooperative Oncology Group clinical trial E9486/E9487 (n1⁄4 561) using conformation sensitive gel electrophoresis (CSGE). A total of 268 patients, based on sample availability, were included in our current study. These patients had extensive follow-up information with median follow-up of survivors 4.8 years and only 4.5% (n1⁄4 25) of the cohort alive at the time of our analysis, resulting in negligible censoring. Fluorescent in situ hybridization (FISH) studies using the cytoplasmic immunoglobulin-FISH technique in this cohort of patients has been previously reported. Polymerase chain reaction primers were designed to amplify 11 DNA fragments from exon 1 to 11 (exon 1: CCA TGT GCT CAA GAC TGG C, CGA GCT GAA AAT ACA CGG AG; exon 2: CAG GAG TGC TTG GGT TGT, CCC ACA GGT CTC TGC TAG G; exon 3: CTG TGG GAA GCG AAA AT, GAT GGG TGA AAA GAG CAG TCA; exon 4: GGG CTG AGG ACC TGG T, ACA GGA AGC CTA AGG GTG AAG; exon 5: TTG CTG CCG TGT TCC A, CAA CCA GCC CTG TCG TCT CT; exon 6: GGC TGG AGA GAC GAC AGG G, ATC TCA TGG GGT TAT AGG GAG; exon 7: TTG CCA CAG GTC TCC C, ATG GAA GAA ATC GGT AAG AG; exon 8: TTT AAA TGG GAC AGG TAG GAC, CTT ACC TCG CTT AGT GCT; exon 9: GGG AGC ACT AAG CGA GGT A, CAA CCA GGA GCC ATT GTC TTT; exon 10: TTG CTT TTG TAC CGT CAT AA, ACA GCT GCC TTT GAC CAT; exon 11: GCA CAG ACC CTC TCA CTC ATG TGA, AGA CCC AAA ACC CAA AAT G). The primers were optimized and grouped into three multiplex reactions. These groups had to be compatible according to primer length, MgCl2 concentration and annealing temperature. Multiplex one contained exons 4, 7, 8 and 10; multiplex two contained exons 1, 3, 5 and 9; and multiplex three contained exons 2, 6, 7 and 11. The radiolabeled amplicons were run through 15% mild denaturing 0.4 mm polyacrylamide gel for 4 h at 40 W. The gel was dried and placed on a photoimager screen for analysis. Abnormal banding patterns were subsequently directly sequenced. It appears that TP53 mutations are relatively rare in newly diagnosed patients as only nine of the 268 samples (3%) tested were positive for mutations. The actual prevalence may be slightly higher if one considers the sensitivity of CSGE (10%) and the fact that non-purified bone marrow samples are used (bone marrow samples were all collected before the availability of practical CD138þ cell sorting). However, the median plasma cell infiltration of the cohort is 40% (range 20–95%) with 70% of patients having more than 30% of plasma cells in the bone marrow. Only three of the mutations are point mutations, and majority resulted in premature termination and a predicted truncated protein product (Table 1). Seven of the nine mutations occurred in the DNA-binding domain, where the majority of reported TP53 mutations occur. However, we did not see any mutations in codons 175, 245, 248, 249, 273 and 282 that accounts for 28% of all TP53 mutations in cancers. In addition, we found several mutations outside exons 5–9 (all previous studies only examined exons, 5–9). None of the mutations are known polymorphism and all of them are predicted to alter protein structure and function. Therefore, the spectrum of TP53 mutations is broad and not typical of other malignancies. We also examined the association between the presence of TP53 mutations and other clinical features and common genetic abnormalities using the Fisher’s exact test. The presence of TP53 mutations was associated with presence of soft tissue plasmacytoma (37 versus 7%, P1⁄4 0.018). Unlike previous studies that found TP53 mutation to be more common in advance stage MM, we could not confirm this because the distribution of International Staging System (ISS) stage is relatively even, although clearly the total number of patients with an abnormality is quite small to draw firm conclusions. As our analysis was conducted in newly diagnosed and pretreatment samples, it provides a better baseline for examining the relation between TP53 mutation and disease stage. The presence of TP53 mutations was significantly associated with 17p13 deletions as five of the nine patients (56%) with mutation also had 17p13 hemizygous loss (versus 10%, P1⁄4 0.01). This is consistent with previous observations in other malignancies that many tumors that harbor TP53 mutations also show loss of heterozygosity. In those patients with only 17p13 hemizygous loss, it would be important to assess how the p53 pathway is affected and whether the other allele of p53 is suppressed by other means such as epigenetic mechanisms. These studies are currently being conducted in our laboratory. Patients with TP53 mutations were also enriched for primary translocations, such as t(11;14), t(4;14) and t(14;16) (67 versus 24%, P1⁄4 0.014). In contrast, there was no association with D13 or hyperdiploid status. We also report for the first time the prognostic significance of TP53 mutations. The presence of TP53 mutations was associated with very poor survival of only one and a half years (Figure 1). We have previously reported the short survival associated with 17p13 deletions in this cohort of patients. We did not report on the difference in outcome for those with 17p13 deletions and Letters to the Editor

Neoadjuvant Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin With Pegfilgrastim Support in Muscle-Invasive Urothelial Cancer: Pathologic, Radiologic, and Biomarker Correlates

PURPOSE In advanced urothelial cancer, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) results in a high response rate, less toxicity, and few dosing delays. We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive urothelial cancer (MIUC). PATIENTS AND METHODS Patients with cT2-cT4, N0-1, M0 MIUC were enrolled. Four cycles of ddMVAC were administered, followed by radical cystectomy. The primary end point was pathologic response (PaR) defined by pathologic downstaging to ≤ pT1N0M0. The study used Simons optimal two-stage design to evaluate null and alternative hypotheses of PaR rate of 35% versus 55%. Secondary end points included toxicity, disease-free survival (DFS), radiologic response (RaR), and biomarker correlates, including ERCC1. RESULTS Between December 2008 and April 2012, 39 patients (cT2N0, 33%; cT3N0, 18%; cT4N0, 3%; cT2-4N1, 43%; unspecified, 3%) were enrolled. Median follow-up was 2 years. Overall, 49% (80% CI, 38 to 61) achieved PaR of ≤ pT1N0M0, and we concluded this regimen was effective. High-grade (grade ≥ 3) toxicities were observed in 10% of patients, with no neutropenic fevers or treatment-related death. One-year DFS was 89% versus 67% for patients who achieved PaR compared with those who did not (hazard ratio [HR], 2.6; 95% CI, 0.8 to 8.1; P = .08) and 86% versus 62% for patients who achieved RaR compared with those who did not (HR, 4.1; 95% CI, 1.3 to 12.5; P = .009). We found no association between serum tumor markers or ERCC1 expression with response or survival. CONCLUSION In patients with MIUC, neoadjuvant ddMVAC was well tolerated and resulted in significant pathologic and radiologic downstaging.

Genomic variation in myeloma: design, content, and initial application of the Bank On A Cure SNP Panel to detect associations with progression-free survival

BackgroundWe have engaged in an international program designated the Bank On A Cure, which has established DNA banks from multiple cooperative and institutional clinical trials, and a platform for examining the association of genetic variations with disease risk and outcomes in multiple myeloma.We describe the development and content of a novel custom SNP panel that contains 3404 SNPs in 983 genes, representing cellular functions and pathways that may influence disease severity at diagnosis, toxicity, progression or other treatment outcomes. A systematic search of national databases was used to identify non-synonymous coding SNPs and SNPs within transcriptional regulatory regions. To explore SNP associations with PFS we compared SNP profiles of short term (less than 1 year, n = 70) versus long term progression-free survivors (greater than 3 years, n = 73) in two phase III clinical trials.ResultsQuality controls were established, demonstrating an accurate and robust screening panel for genetic variations, and some initial racial comparisons of allelic variation were done. A variety of analytical approaches, including machine learning tools for data mining and recursive partitioning analyses, demonstrated predictive value of the SNP panel in survival. While the entire SNP panel showed genotype predictive association with PFS, some SNP subsets were identified within drug response, cellular signaling and cell cycle genes.ConclusionA targeted gene approach was undertaken to develop an SNP panel that can test for associations with clinical outcomes in myeloma. The initial analysis provided some predictive power, demonstrating that genetic variations in the myeloma patient population may influence PFS.

Relationship between serum adiponectin and prostate cancer grade

Obesity is associated with prostate cancer (PCA) grade, but the mechanism behind this relationship is not understood. Adiponectin is an adipokine that has been linked with the development of hormonally sensitive carcinomas, including prostate cancer. We evaluated the relationship between serum adiponectin and Gleason score (GS) in a prospective series of patients seen in a single institution.

Response to docetaxel/carboplatin-based chemotherapy as first- and second-line therapy in patients with metastatic hormone-refractory prostate cancer

To evaluate the efficacy of docetaxel/carboplatin (DC)‐based chemotherapy as first‐ and second‐line chemotherapy for patients with hormone‐refractory prostate cancer (HRPC).