Clinical activity of arsenic trioxide for the treatment of multiple myeloma

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Abstract

Arsenic has been used since ancient times as a therapeutic agent. However, until recently its use in modern medicine has been restricted to the treatment of a limited number of parasitic infections. In the early 1990s, reports from China described impressive results with arsenic trioxide in patients with de novo, relapsed, and refractory acute promyelocytic leukemia (APL). Other investigators subsequently confirmed these results leading to approval of its use for relapsed or refractory APL in the United States. Investigations of this agent have demonstrated that its efficacy in APL and preclinical tumor models is dependent upon a number of mechanisms, including induction of apoptosis, effects on cellular differentiation, cell cycling, and tumor angiogenesis. Subsequent preclinical studies showed significant activity of arsenic trioxide in multiple myeloma (MM). Based on this, in a phase II trial, we have evaluated the activity of arsenic trioxide in 14 patients with relapsed MM, refractory to conventional salvage therapy. With the dose and schedule used, treatment with arsenic trioxide produced responses in three patients and prolonged stable disease in a fourth patient, with the longest response lasting 6 weeks. Although treatment was reasonably well tolerated, in these patients with extensive prior therapy, 11 developed cytopenia, five associated with infectious complications and three developed deep vein thromboses. The results of this small trial support further investigation of this novel drug for the treatment of patients with relapsed or refractory MM.

Introduction

MM is a malignancy of committed, follicular center B cells1 with a median age at onset of 63 years.2 Despite numerous chemotherapy options including high-dose therapy and autologous stem cell transplantation, MM remains an incurable disease. There is significant variation in the survival of patients with MM; prognostic variables that identify groups with widely different survival rates include β2-microglobulin level, plasma cell-labeling index, plasmablastic morphology, serum LDH levels, C-reactive protein and cytogenetics.3 Relapsed or chemotherapy-resistant MM remains a serious clinical problem requiring novel therapeutic options.

Molecular and preclinical studies suggest that arsenic trioxide may be effective in various cancers. Initial studies from China reported remarkable clinical efficacy of arsenic trioxide therapy in patients with de novo and relapsed APL.4 Single-agent chemotherapy with arsenic trioxide produced complete remissions in eight of 11 (72.7%) patients presenting with newly diagnosed APL, without causing myelosuppression.5 Unlike all-trans retinoic acid therapy (ATRA), long-term arsenic trioxide therapy produced molecular remissions in salvage patients relapsing after remissions induced by ATRA and chemotherapy.6

Although the exact mechanism of antitumor activity for arsenic trioxide is unknown, it has been shown to inhibit cell proliferation and induce apoptosis in a spectrum of malignant B cell lines including myeloma cells.7,8 At pharmacologic concentrations, arsenic trioxide dose- and time-dependently inhibits survival and growth of several different human myeloma cell lines.9,10 These experimental studies with MM cell lines and in a xenograft models suggest that arsenic trioxide may interrupt several key mechanisms of myeloma cell growth and survival and perhaps be effective in patients with MM forming the rationale for a phase II trial of arsenic trioxide in patients with relapsed or resistant MM.

Materials and methods

Clinical protocol

Patients with relapsed or resistant MM and at least one prior cycle of high-dose chemotherapy with autologous stem cell rescue were eligible for enrollment on this protocol. Patients were required to have normal renal and hepatic function. Exclusion criteria included a history of grand mal seizures, active infection, pregnancy, or breastfeeding. Written informed consent was required, and the protocol was reviewed and approved by the institutional review board of the University of Arkansas for Medical Sciences.

Treatment with arsenic trioxide

Patients meeting eligibility criteria received a 2-h daily intravenous infusion of arsenic trioxide 0.15 mg/kg for 60 days (the same dosage used in the treatment of APL). Patients were evaluated for response, defined as a reduction in myeloma paraprotein at days 30 and 60. Treatment was continued for an additional 30 days in patients showing a response. Retreatment was initiated in responders between 3 and 6 weeks after first treatment.

Statistical analysis

The primary efficacy variable was response to therapy as reflected in the serum ‘M’ protein level. Objective responses were a ≥50% reduction, and minor responses a ≥25% reduction in M-protein. Duration of progression-free survival in responders was a secondary efficacy variable. Safety was assessed by a numerical tabulation of adverse events assessed in accordance with the NCI Common Toxicity Criteria, version 2 (found at Http://ctep.info.nih.gov), eg grade I neutropenia is defined as an absolute neutrophil count (ANC) of 1500–>2000/mm3, grade 2 when ANC is 1000–<1500/mm3, grade 3 is 500–<1000/mm3 and grade 4 is when ANC is <500/mm3.

Results

Patient characteristics

Fourteen high-risk patients with extensive prior therapy were enrolled (Table 1). Patients had advanced disease; 11 patients had CRP >2.5 mg/l and 10 patients had >30% bone marrow plasmacytosis. All but one patient had a history of at least two high-dose induction therapies followed by autologous peripheral blood stem cell transplants. Following relapse after high-dose therapy, 11 of 14 patients had undergone two additional salvage therapies with combinations such as DCEP (dexamethasone, cyclophosphamide, etoposide, and cis-platinum) and thalidomide. Ten of 14 patients had stage III disease. Cytogenetic abnormalities were present in 13 of 14 patients, and nine of 14 evaluable patients had chromosome 13 abnormalities.

Table 1 Patient characteristics (n = 14)

Efficacy

Responses are summarized in Table 2. Three patients responded to a single infusion cycle; two patients had >50% reduction in M protein, one of which with >75% reduction. One additional patient had >25% reduction with a total response rate of 21%. The duration of response was 6 weeks for the patients with 25% and 50% reductions in ‘M’ protein; the patient with the 75% response died 1 week post-therapy of infection- and disease-related complications. Eight patients were considered non-responders, and three patients progressed while on the protocol. One patient who did not achieve a definitive response, nonetheless experienced prolonged stable disease. Bone marrow cytoreduction was not monitored in all patients. However, in one responding patient no change in bone marrow plasmacytosis was observed. Five of the non-responders and one patient who relapsed after response to therapy with arsenic trioxide had alternate salvage therapies (ie transplant, high-dose cyclophosphamide, dexamethasone with or without thalidomide) without effect.

Table 2 Responses

Adverse events

Toxicities (grades 3–5) in this patient group were somewhat different from those reported in patients treated with arsenic trioxide for APL. Eleven patients developed neutropenia with WBC <1000 cells/mm3 requiring growth factor support, while five of these patients developed infectious complication. Three patients experienced deep vein thrombosis (two were catheter related), two reported extreme fatigue, and five developed infections (pneumonia, Candida septicemia, and/or bacteremia). Due to progressive disease and/or limited tolerance only five patients were able to receive 60 days of treatment.

Discussion

Since its introduction in the 1960s, combination therapy with intermittent courses of melphalan and prednisone has been the standard chemotherapy for patients with MM with the median survival of 3 years or less.11 With the introduction of high-dose chemotherapy, response rates as well as event-free and overall survival have improved.12 A randomized trial of 200 previously untreated patients, the Intergroupe Français du Myélome (IMF-90), demonstrated a response rate of 81% in patients treated with high-dose therapy and autologous bone marrow transplantation vs a 57% response in patients treated with conventional chemotherapy (P < 0.001).11 High-dose therapy with stem cell support was also superior with respect to the number of complete responses (22% vs 5%), event-free (28% vs 10%; P = 0.01), and overall 5-year survival (52% vs 12%; P = 0.03). Treatment-related mortality was similar in both groups. The superiority of high-dose chemotherapy with stem cell support has also been subsequently confirmed in other studies.13,14 However, despite the improvements in response and survival, MM remains an incurable malignancy for the majority of patients. Therefore, new treatment strategies are required. Treatment modalities under various stages of investigation include immunotherapy, chemokine/cytokine manipulation, inhibition of angiogenesis, and strategies targeted at bone marrow microenvironment. Although some advances have been made in this area with thalidomide and bisphosphonates, arsenic trioxide targets multiple mechanisms of disease progression in patients with MM and offers an important new avenue of investigation.

In the present study, arsenic trioxide administered in accordance with the protocol that was successfully used to induce remission in patients with APL, produced responses in three of 14 patients who had failed high-dose chemotherapy and two different salvage regimens. In addition, another patient experienced stable disease for over 6 months. The patient with the best response died within a week of completion of therapy due to complications related to the disease; the other two patients had a 6-week duration of response. Although the rate and duration of response were low, this very resistant patient population had failed all previous therapies and also failed to respond to salvage maneuvers attempted following arsenic trioxide therapy.15 Although arsenic trioxide was otherwise well tolerated, we observed unexpected toxicity in the form of cytopenias that may have been related to the limited bone marrow reserve after autotransplant and/or advanced disease. In the APL population, arsenic trioxide is not associated with significant myelosuppression.6,14 Normal hematologic values were also not an entry criterion in our study; the substantial cytopenias observed in 80% of patients in the present study may reflect the marginal bone marrow reserve in these heavily pretreated population. In a different study of arsenic trioxide in patients with a variety of advanced hematologic malignancies, patients who entered the study with pre-existing myelosuppression experienced exacerbation of the condition during treatment, while patients with relatively normal blood counts did not.16,17 Additionally, the majority of patients in this study had undergone at least one high-dose chemotherapy with stem cell support, while none of the APL patients had such therapy. It is possible that the damage to the marrow and the stromal elements may add to the higher risk for development of cytopenias and explain the discrepancy between treatment toxicities in APL and multiple myeloma.

In conclusion, despite improved response rates achieved with high-dose chemotherapy and stem cell transplantation, MM remains a largely incurable malignancy. Preclinical data and the current clinical trial support a potential role for arsenic trioxide in the therapy of patients with relapsed or resistant MM. Subsequent studies should assess dose and scheduling adjustments for more prolonged administration, as well as combination therapy with ascorbic acid, interferon-α and dexamethasone. Additional basic research is needed to determine the exact mechanisms responsible for the actions of arsenic trioxide in patients with MM, particularly the effects of this novel agent on angiogenesis. Finally, recent clinical experience demonstrating significant efficacy and acceptable toxicities with arsenic trioxide, even in pediatric patients with APL, provides a strong rationale for the use of this agent in MM patients earlier in their disease.

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Acknowledgements

This work was done at University of Arkansas for Medical Sciences, Myeloma and Transplantation Medical Center. This study was supported in part by an unrestricted educational grant from Cell Therapeutics, Inc.

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Correspondence to NC Munshi.

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Munshi, N., Tricot, G., Desikan, R. et al. Clinical activity of arsenic trioxide for the treatment of multiple myeloma. Leukemia 16, 1835–1837 (2002) doi:10.1038/sj.leu.2402599

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Keywords

  • arsenic trioxide
  • antiangiogenesis
  • apoptosis
  • multiple myeloma

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