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

Berenson, James R.; Boccia, Ralph V.; Siegel, David S.; Bozdech, Marek J.; Bessudo, Alberto; Stadtmauer, Edward A.; Pomeroy, J. Talisman; Steis, Ronald G.; Flam, Marshall S.; Lutzky, Jose; Jilani, Syed; Volk, Joseph; Wong, Siu-Fun; Moss, Robert A.; Patel, Ravi; Ferretti, Delina; Russell, Kit; Louie, Robert; Yeh, Hong‐Zen; Swift, Regina A.

doi:10.1111/j.1365-2141.2006.06280.x

Cited by 69 publications

(41 citation statements)

References 53 publications

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“…The overall response rates in these combined regimens vary widely between 12 and 100% (6)(7)(8). It is necessary to identify novel combinations of ATO with other drugs, to offer novel mechanisms for treating MM.…”

Section: Introductionmentioning

confidence: 99%

Synergistic effects of valproic acid and arsenic trioxide on RPMI8226 cells in vitro and the possible underlying mechanisms

Wang

Zhang

2012

Molecular Medicine Reports

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Abstract. The aim of the present study was to investigate the synergistic effects of valproic acid (VPA) and arsenic trioxide (ATO) on the proliferation of RPMI8226 cells and the possible underlying mechanisms. Cell apoptosis was assessed by flow cytometry. The mRNA expression levels were analyzed by semi-quantitative polymerase chain reaction, and the protein expression levels were analyzed by western blotting. The histone acetylation and methylation states of the gene promoters were detected using a chromatin immunoprecipitation technique. The apoptotic rates of the RPMI8226 cells in the combined drug groups were significantly increased compared with those of the single drug groups (P<0.05). The mRNA and protein expression levels of Bcl-2 and the expression levels of HDAC1 mRNA and H3K9me2 protein decreased significantly in the combined groups compared with the single drug groups. The mRNA and protein expression levels of Bax, Caspase 8, Caspase 9 and LSD1, and the protein expression of acetylated H3 increased significantly in the combination groups compared with the single drug groups. Histone methylation and acetylation of the Bcl-2 and bax gene promoters were increased in the combination groups compared with the single drug groups. VPA and ATO had synergistic effects on the proliferation of RPMI8226 cells, which may have been associated with the decreased expression of Bcl-2 and the increased expression levels of Bcl-2-associated X protein, Caspase 8 and Caspase 9. Therefore, the expression levels of the Bcl-2 gene family may have been regulated by the levels of gene promoter methylation and acetylation. IntroductionMultiple myeloma (MM) is a plasma cell disorder, characterized by anemia, renal disease, lytic bone disease, and immune dysfunction. MM is one of the most common types of hematological malignancy in China (1). Although currently approved treatments for newly diagnosed MM, including high-dose chemotherapy followed by autologous transplantation, and novel drugs, including proteasome inhibitors and immunomodulatory agents (IMiDs), have led to increased survival rates, the majority of patients will eventually relapse and become refractory to treatment (2). Therefore, patients with relapsed or refractory MM have an unmet requirement for safe and efficacious novel therapies.Arsenic trioxide (ATO) has been suggested as an option for the treatment of relapsing or refractory MM. In vitro, ATO has been found to induced myeloma cell apoptosis, and monotherapy with ATO results in partial response rates between 0 and 17%, and minimal responses between 7 and 33%, resulting in mean overall response rates of 30% for treatment of myeloma (3-5).In order to improve the treatment response rates in patients with MM, ATO has been combined with other novel drugs, including proteasome inhibitors, IMiDs and dexamethsone, for the treatment of MM. The overall response rates in these combined regimens vary widely between 12 and 100% (6-8). It is necessary to identify novel combinations of ATO with other drugs, to offer nov...

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Section: Introductionmentioning

confidence: 99%

Synergistic effects of valproic acid and arsenic trioxide on RPMI8226 cells in vitro and the possible underlying mechanisms

Wang

Zhang

2012

Molecular Medicine Reports

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“…The ABC regimen may offer an active, yet tolerable, therapeutic option for older patients with relapsed or refractory multiple myeloma who are unable to endure other chemotherapy or steroid-based regimens. In addition, the combination of melphalan, arsenic, and bortezomib may be worthwhile to evaluate given the promising results of this ABC study and those of other phase I and II trials showing that melphalan/arsenic trioxide and melphalan/bortezomib combination treatment are also well tolerated and have significant clinical activity (48,50).…”

Section: Discussionmentioning

confidence: 99%

A Phase I/II Study of Arsenic Trioxide/Bortezomib/Ascorbic Acid Combination Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma

Berenson

Matous

Swift

et al. 2007

Clinical Cancer Research

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119

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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 (1g) 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) of16 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.

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“…20 In contrast, the combination of As 2 O 3 with other anti-cancer therapeutic agents showed promising results for MDS as well as MM in phase II studies. [21][22][23][24] As 2 O 3 in clinically relevant doses generally does not induce myelosuppression, which is a good complement to conventional cytotoxic agents. This feature, together with the multiple molecular pathways targeted by arsenic, supports the potential role of As 2 O 3 as an adjuvant with other chemotherapy.…”

Section: As 2 O 3 As Single-compound Adjunct Therapymentioning

confidence: 99%

Supplements for immune enhancement in hematologic malignancies

Sze¹,

Chan²

2009

Hematology

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This brief review aims to discuss the various cellular immunological aspects and related mechanisms of the use of specific components from traditional herbal medicines. We begin with lessons learned from thalidomide as an effective single drug with multiple mechanisms of action to treat multiple myeloma. Examples of "supplements" or integrative therapy will be drawn from arsenic trioxide, medicinal mushrooms including Coriolus vesicular and Ganoderma lucidum, followed by the discussion of beta-glucans affecting various immunological important cellular subsets. Different classes of compounds may enhance distinct immune cell populations that might contribute to a multi-targeted holistic effects on anti-cancer treatment. Finally, we conclude by highlighting an herbal formulation PHY906 as a potential adjunct to chemotherapy that might become one of the first US Food and Drug Administration (FDA) approved oral herbal medicines for anti-cancer adjunct treatment.

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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

Cited by 69 publications

References 53 publications

Synergistic effects of valproic acid and arsenic trioxide on RPMI8226 cells in vitro and the possible underlying mechanisms

Synergistic effects of valproic acid and arsenic trioxide on RPMI8226 cells in vitro and the possible underlying mechanisms

A Phase I/II Study of Arsenic Trioxide/Bortezomib/Ascorbic Acid Combination Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma

Supplements for immune enhancement in hematologic malignancies

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