Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma.

Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week).

Abiraterone acetate and prednisolone for metastatic castration-resistant prostate cancer failing androgen deprivation and docetaxel-based chemotherapy: a phase II bridging study in Korean and Taiwanese patients.

Objectives: To evaluate the safety and efficacy of abiraterone acetate and prednisolone in Korean and Taiwanese patients with metastatic castration-resistant prostate cancer not responding to docetaxel-based chemotherapy.

Methods: In this single-arm study, 82 metastatic castration-resistant prostate cancer patients who failed docetaxel-based chemotherapy were treated with abiraterone (1000 mg, once daily) and prednisolone (5 mg, twice daily). Patients achieving a prostate-specific antigen decline ≥ 50% were considered as responding.

Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors.

Purpose: Bone complications of metastatic disease, including skeletal-related events (SREs), impair patients' functioning and quality of life. In a randomized, phase 3 trial of 1,776 patients with metastases from solid tumors (except breast or prostate) or multiple myeloma, denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs. This ad hoc analysis reports outcomes in the subgroup of 1,597 patients with solid tumors, excluding patients with multiple myeloma.

NADPH inhibits [2Fe-2S] cluster protein transfer from diabetes drug target MitoNEET to an apo-acceptor protein.

MitoNEET (mNT) is the founding member of the recently discovered CDGSH family of [2Fe-2S] proteins capable of [2Fe-2S] cluster transfer to apo-acceptor proteins. It is a target of the thiazolidinedione (TZD) class of anti-diabetes drugs whose binding modulate both electron transfer and cluster transfer properties. The [2Fe-2S] cluster in mNT is destabilized upon binding of NADPH, which leads to loss of the [2Fe-2S] cluster to the solution environment.

Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.

Purpose: This study compared denosumab, a fully human monoclonal anti-receptor activator of nuclear factor kappa-B ligand antibody, with zoledronic acid (ZA) for delaying or preventing skeletal-related events (SRE) in patients with advanced cancer and bone metastases (excluding breast and prostate) or myeloma.

Patients And Methods: Eligible patients were randomly assigned in a double-blind, double-dummy design to receive monthly subcutaneous denosumab 120 mg (n = 886) or intravenous ZA 4 mg (dose adjusted for renal impairment; n = 890). Daily supplemental calcium and vitamin D were strongly recommended.

An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma.

RANKL is a key mediator of osteoclast differentiation, activation, and survival. Preclinical data suggest that aberrant production and activation of osteoclasts may influence proliferation of multiple myeloma (MM) cells in the bone marrow. Reports have also shown that inhibiting RANKL may have a direct effect on RANK-expressing myeloma cells and a therapeutic role in treating the disease.

Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure.

Bone metastases place patients at increased risk of skeletal-related events (SREs), including pathologic fractures, spinal cord compression, severe pain requiring radiotherapy or surgery, and hypercalcemia, because of increased osteoclast-mediated bone resorption. Denosumab, a fully human monoclonal antibody, decreases bone resorption by inhibiting RANKL, which mediates osteoclast activity. We compared the effects of denosumab in two phase 2 studies in patients with bone metastases naive to intravenous bisphosphonate therapy (IV BP; n = 255) and those with elevated levels of the bone resorption marker urinary N-telopeptide (uNTX) despite ongoing IV BP treatment (n = 111).

A phase I/II study of arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of relapsed or refractory multiple myeloma.

Purpose: This multicenter, open-label, phase I/II dose escalation study assessed the safety/tolerability and initial efficacy of arsenic trioxide/bortezomib/ascorbic acid (ABC) combination therapy in patients with relapsed/refractory multiple myeloma.

Experimental Design: Enrolled in six cohorts, patients were given arsenic trioxide (0.125 or 0.

Arsenic compounds in the treatment of multiple myeloma: a new role for a historical remedy.

Arsenic compounds have been used since ancient times to treat a wide variety of ailments. Although the use of arsenic to treat hematologic cancers has been documented since the 19th century, widespread use of arsenic compounds in patients with hematologic malignancies did not occur until the 1990s, when several groups in China reported impressive clinical response rates in patients with acute promyelocytic leukemia who had received arsenic trioxide. Subsequently, clinical studies conducted in the United States confirmed earlier reports, and arsenic trioxide was approved by the Food and Drug Administration for the treatment of relapsed/refractory acute promyelocytic leukemia.

Treatment for myeloma bone disease.

Multiple myeloma (MM) is a B cell malignancy characterized by enhanced bone loss commonly associated with diffuse osteopenia, focal lytic lesions, pathologic fractures, hypercalcemia, and bony pain. Bone destruction in MM results from asynchronous bone turnover wherein increased osteoclastic bone resorption is not accompanied by a comparable increase in bone formation. Consequently, patients with MM frequently require radiation therapy, surgery, and analgesic medications.

Efficacy and safety of melphalan, arsenic trioxide and ascorbic acid combination therapy in patients with relapsed or refractory multiple myeloma: a prospective, multicentre, phase II, single-arm study.

We assessed the safety and efficacy of melphalan, arsenic trioxide (ATO) and ascorbic acid (AA) (MAC) combination therapy for patients with multiple myeloma (MM) who failed more than two different prior regimens. Patients received melphalan (0.1 mg/kg p.

Myeloma bone disease and treatment options.

Multiple myeloma (MM) is a B-cell malignancy characterized by enhanced bone loss commonly associated with a diffuse osteopenia, focal lytic lesions, pathologic fractures, hypercalcemia, and bony pain. Bone destruction in MM results from asynchronous bone turnover wherein increased osteoclastic bone resorption is not accompanied by a comparable increase in bone formation. Recent characterization of osteoclast-activating factors (OAFs), receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL)-osteoprotegerin-RANK system, and inhibitors of Wnt signaling have provided a better understanding of myeloma bone disease in molecular level.

Serum pleiotrophin levels are elevated in multiple myeloma patients and correlate with disease status.

Pleiotrophin (PTN), a tightly regulated angiogenic and mitogenic heparin-binding protein, is markedly elevated in a variety of aggressive solid tumours. The role of PTN in haematological malignancies, however, has not been previously evaluated. This study demonstrated that PTN serum levels were elevated in multiple myeloma (MM) patients when compared with healthy subjects (P < 0.

Purification and characterization of a cyclooxygenase-2 and angiogenesis suppressing factor produced by human fibroblasts.

Cyclooxygenase-2 (COX-2) is an inducible enzyme that plays an important role in several pathophysiological processes, including inflammation, angiogenesis, and tumorigenesis. We have recently observed that COX-2 induction is restrained in proliferating fibroblasts. The mechanism by which this occurs is unclear.

Dynamic regulation of cyclooxygenase-2 promoter activity by isoforms of CCAAT/enhancer-binding proteins.

To elucidate the mechanism by which isoforms of CCAAT/enhancer-binding proteins regulate cyclooxygenase-2 expression, we determined by a novel technique binding of six isoforms of this transactivator to two sequence-specific CCAAT/enhancer-binding protein (-132/-125) and cyclic AMP (-59/-53) regulatory elements in human foreskin fibroblasts treated with phorbol 12-myristate 13-acetate for 4 h. The delta isoform bound to these two elements at basal state, which was displaced by full-length as well as two truncated beta isoforms, a 41-kDa liver-enriched activating protein and a 16-kDa liver-enriched inhibitory protein, after phorbol ester stimulation. Kinetic analysis shows time-dependent changes in beta and delta binding that were concordant with time-dependent increase in cyclooxygenase-2 induction.