A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial.

We conducted a randomized, controlled trial comparing thalidomide-prednisone as maintenance therapy with observation in 332 patients who had undergone autologous stem cell transplantation with melphalan 200 mg/m2. The primary end point was overall survival (OS); secondary end points were myeloma-specific progression-free survival,progression-free survival, incidence of venous thromboembolism, and health-related quality of life (HRQoL). With a median follow-up of 4.1 years, no differences in OS between thalidomide-prednisone and observation were detected (respective 4-year estimates of 68% vs 60%, respectively; hazard ratio = 0.77; P = .18); thalidomide-prednisone was associated with superior myeloma-specific progression-free survival and progression-free survival (for both outcomes, the 4-year estimates were 32% vs 14%; hazard ratio = 0.56; P < .0001) and more frequent venous thromboembolism (7.3% vs none; P = .0004). Median survival after first disease recurrence was 27.7 months with thalidomide-prednisone and 34.1 months in the observation group. Nine second malignancies were observed with thalidomide-prednisone versus 6 in the observation group. Those allocated to thalidomide-prednisone reported worse HRQoL with respect to cognitive function, dyspnea, constipation, thirst, leg swelling, numbness, dry mouth, and balance problems. We conclude that maintenance therapy with thalidomide-prednisone after autologous stem cell transplantation improves the duration of disease control, but is associated with worsening of patient-reported HRQoL and no detectable OS benefit.

Lenalidomide plus melphalan without prednisone for previously untreated older patients with multiple myeloma: a phase II trial.

BACKGROUND: We conducted a phase II trial that evaluated the tolerability and efficacy of combining lenalidomide with melphalan in previously untreated patients with multiple myeloma who were not candidates for autologous stem cell transplantation. METHODS: After a run-in phase of 6 patients, we planned to conduct a randomized phase II selection-design trial that assessed 2 dose levels of lenalidomide, given days 1 to 21, combined with melphalan, given days 1 to 4, and every 28 days. Planned doses of melphalan were 9 mg/m(2)/d and respective doses of lenalidomide were 10 and 20 mg/d (M9L10 and M9L20). Coprimary endpoints were the frequency of dose-limiting Planned doses of melphalan were 9 mg/m(2)/d and respective doses of lenalidomide were 10 and 20 mg/d (M9L10 and M9L20). toxicities (DLT) and complete response (CR). RESULTS: Four patients received M9L10; all experienced DLTs, which resulted in closure of this cohort. When using the same schedule, we then sequentially tested M6L10 (melphalan 6 mg/m(2) on days 1 to 4 and lenalidomide 10 mg/d on days 1 to 21 every 28 days) (6 patients), M4L15 (melphalan 4 mg/m(2) on days 1 to 4 and lenalidomide 15 mg/d on days 1 to 21 every 28 days) (6 patients), and M5L10 (melphalan 5 mg/m(2) days 1 to 4 and lenalidomide 10 mg/d days 1 to 21 every 28 days) (34 patients). In each cohort, the DLT endpoint was reached because of severe and prolonged hematologic toxicity. At the final dose level, M5L10, 20 of 27 patients experienced DLTs within their first 3 cycles; among 10 patients who received at least 6 cycles, none achieved a CR. CONCLUSIONS: Combining lenalidomide plus melphalan without prednisone is associated with substantial hematologic toxicity that precludes cyclical administration of adequate drug doses.

A phase 2 study of platinum and gemcitabine in patients with advanced salivary gland cancer: a trial of the NCIC Clinical Trials Group.

BACKGROUND: Salivary gland cancers are rare, histologically diverse, and varied in their biologic behavior and responsiveness to systemic therapy. To the authors' knowledge, there currently is no standard chemotherapy for these tumors, but cisplatin-based regimens are often used. This phase 2 trial evaluated the combination of gemcitabine with cisplatin (carboplatin in those with protocol-defined contraindications to cisplatin). METHODS: Fit, consenting adult patients had advanced, metastatic, or locoregionally recurrent salivary gland cancer (any histologic subtype) that was not suitable for radiation or surgery. Therapy was comprised of gemcitabine at a dose of 1000 mg/m(2) administered intravenously on Days 1 and 8, and cisplatin at a dose of 70 mg/m(2) on Day 2, of a 21-day cycle. If carboplatin was substituted, it was administered on Day 1, targeted to an area under the concentration-time curve of 5 mg/mL/s. Response was assessed every 2 cycles according to Response Evaluation Criteria In Solid Tumors. Patients received up to 6 cycles. The primary endpoint was objective response. A 2-stage design was used, with a response rate of 45% required to declare the regimen active. RESULTS: Thirty-three eligible patients were enrolled, of whom 30 were response evaluable. Eight objective responses were observed (1 complete and 7 partial) for a response rate of 24% (95% confidence interval, 11-42%), with responses observed in all histologic subtypes. Toxicity was within that expected for this combination. CONCLUSIONS: This regimen did not meet the predefined criteria to be declared active in advanced salivary gland cancers. Enrollment of patients with these rare cancers into well-designed clinical trials remains an urgent priority.

Transient lipopolysaccharide-induced cytokine responses in the maternal serum and amniotic fluid of the guinea pig.

OBJECTIVE: The aim of this study was to characterize the pregnant guinea pig cytokine time course following a maternal inflammatory insult. STUDY DESIGN: Pregnant guinea pigs (n = 34) were injected intraperitoneally with 100 microg/kg lipopolysaccharide (LPS) at 70% gestation and euthanized at 24 hours, 48 hours, or 5 days. Control animals were euthanized at 70% gestation without LPS exposure. Interleukin (IL)-6, IL-1beta, and tumor necrosis factor-alpha (TNF-alpha) were quantified in the maternal serum and amniotic fluid by an enzyme-linked immunosorbent assay. RESULTS: IL-6 and IL-1beta concentrations were elevated in the maternal serum at 24 hours and returned to control levels by 5 days. In the amniotic fluid, IL-6 peaked at 48 hours and IL-1beta at 24 hours. TNF-alpha levels were not significantly increased. CONCLUSION: Maternal intraperitoneal LPS injection produces transient increases in cytokine concentrations in the maternal serum and amniotic fluid within 5 days, further implicating the cytokines as mediators of fetal white matter damage.

Dose-dependent lipopolysaccharide-induced fetal brain injury in the guinea pig.

OBJECTIVE: This study determined whether a lipopolysaccharide (LPS) dose-dependent increase in fetal brain injury occurs to further characterize the relationship between maternal inflammation and fetal brain injury. STUDY DESIGN: Pregnant guinea pigs (n = 59) at 70% gestation were injected intraperitoneally with 1, 5, 25, 50, 100, 200, or 300 microg LPS per kilogram of maternal body weight or an equivalent volume of vehicle. Animals were killed 7 days later. Maternal serum and amniotic fluid samples were assayed for proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 using enzyme-linked immunosorbent assay kits. Fetal brains (n = 72) were stained for evidence of cell death with NeuroTACS stain. RESULTS: Seven days after LPS injections, cytokine concentrations in maternal serum and amniotic fluid were not different (P > .05) from controls. Levels of cell death in all brain regions examined were highest following the maternal administration of 300 mug/kg LPS (P < .05). The dose effect was brain region-dependent (P < .05). CONCLUSION: A threshold of maternal infection/inflammation exists, beyond which demonstrable fetal brain injury may result.