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 0.250 mg/kg), bortezomib (0.7, 1.0, or 1.3 mg/m(2)), and a fixed dose of ascorbic acid (1 g) i.v. on days 1, 4, 8, and 11 of a 21-day cycle for a maximum of eight cycles. The primary end point was safety/tolerability of the ABC regimen. RESULTS: Twenty-two patients (median age, 63 years) were enrolled, having failed a median of 4 (range, 3-9) prior therapies. One occurrence of grade 4 thrombocytopenia was observed. One patient had asymptomatic arrhythmia and withdrew from the study. Objective responses were observed in 6 (27%) patients, including two partial responses and four minor responses. Median progression-free survival was 5 months (95% confidence interval, 2-9 months), and median overall survival had not been reached. The 12-month progression-free survival and overall survival rates were 34% and 74%, respectively. One (minor response) of six patients receiving the lowest dose of bortezomib (0.7 mg/m(2)) and 5 (2 partial responses and 3 minor responses) of 16 patients receiving the higher doses (1.0 or 1.3 mg/m(2)) responded. CONCLUSIONS: The ABC regimen was well tolerated by most patients, and it produced preliminary signs of efficacy with an objective response rate of 27% in this heavily pretreated study population. These findings warrant further clinical evaluation of the ABC combination for treatment of relapsed/refractory multiple myeloma.

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. The recent development of minimally invasive surgical procedures such as kyphoplasty allows patients with myeloma with vertebral compression fractures to have immediate improvement in their quality of life with shorter hospital stays. Bisphosphonates are specific inhibitors of osteoclastic activity, and these agents have been evaluated in patients with MM with bone disease during the past 15 years. Monthly i.v. infusions of either pamidronate or zoledronic acid have reduced the skeletal complications among patients with MM and are now a mainstay of myeloma therapy. Orally administered bisphosphonates, in contrast, have shown little ability to slow the development of skeletal complications in these patients. Although preclinical studies suggest that nitrogen-containing bisphosphonates have potent antitumor effects, clinical trials will be necessary, probably at higher doses given more slowly, to establish their possible antitumor effects clinically. Moreover, recent advances in the use of bone-seeking radiopharmaceuticals make these attractive therapeutic candidates to combine with bisphosphonates or radiosensitizing drugs (e.g., bortezomib) to achieve a synergistic effect. As our understanding of the pathophysiology of myeloma bone disease continues to grow, new target therapies will continue to emerge, offering new and more advanced options for the management of myeloma bone disease.

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.o.), ATO (0.25 mg/kg i.v.) and AA (1 g i.v) on days 1-4 of week 1, ATO and AA twice weekly during weeks 2-5 and no treatment during week 6 of cycle 1; during cycles 2-6, the schedule remained the same except ATO and AA were given twice weekly in week 1. Objective responses occurred in 31 of 65 (48%) patients, including two complete, 15 partial and 14 minor responses. Median progression-free survival and overall survival were 7 and 19 months respectively. Twenty-two patients had elevated serum creatinine levels (SCr) at baseline, and 18 of 22 (82%) showed decreased SCr levels during treatment. Specific grade 3/4 haematological (3%) or cardiac adverse events occurred infrequently. Frequent grade 3/4 non-haematological adverse events included fever/chills (15%), pain (8%) and fatigue (6%). This steroid-free regimen was effective and well tolerated in this heavily pretreated group. These results indicate that the MAC regimen is a new therapeutic option for patients with relapsed or refractory MM.

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. The development of minimally invasive surgical procedures such as kyphoplasty and vertebroplasty allows myeloma patients with vertebral compression fractures to have immediate improvement in quality of life and shorter hospital stays. Monthly intravenous infusion of either pamidronate or zoledronic acid have reduced the skeletal complications among MM patients and are now a mainstay of myeloma therapy. Orally administered bisphosphonates, in contrast, have shown little ability to slow the development of skeletal complications in these patients. Although pre-clinical studies suggest nitrogen-containing bisphosphonates have potent anti-tumor effects, clinical trials will be necessary, probably at higher doses given more slowly, to establish their possible anti-tumor effects clinically. As our understanding of the pathophysiology of myeloma bone disease continues to increase, new target therapies will continue to emerge offering new and more advanced options for the management of myeloma bone disease.

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 < 0.0001). Serum levels of this protein significantly increased during progression of disease, and decreased during response to anti-MM therapy (P < 0.001). These results suggest that serum PTN may be a new biomarker for monitoring the disease status and therapeutic response of MM patients.

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. The use of arsenic compounds in the treatment of multiple myeloma (MM) is supported by the proposed mechanisms of action underlying the antitumor activity of arsenic and by preclinical studies showing antiproliferative and cytotoxic activities in cell culture and animal models. Moreover, clinical studies of arsenic compounds, particularly arsenic trioxide-based regimens, have shown that this drug is clinically active in patients with relapsed/refractory MM. Combination studies with other antimyeloma agents have shown evidence of synergy with arsenic trioxide. Furthermore, arsenic trioxide-based regimens in MM appear to be well tolerated, particularly with regard to cardiac toxicity. The activity and tolerability observed in clinical studies promise to make arsenic-based chemotherapy a viable treatment option for patients whose disease does not respond to or who cannot tolerate other chemotherapy regimens.