1 Service dHématologie, CHU de Pierre Bénite, Lyon; 2 Service dHématologie, CHU de Saint Etienne, Saint Etienne; 3 Service de Médecine, Centre Léon Bérard, Lyon; 4 IRI Servier, Courbevoie, France
Received 21 May 2002; revised 24 October 2002; accepted 20 November 2002
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Abstract |
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Patients with relapsing or refractory multiple myeloma have poor prognosis. Few compounds are active in these patients and response duration remains short. We report the results of an open phase II trial evaluating the efficacy and safety of fotemustine monotherapy.
Patients and methods:
Twenty-one patients with relapsing (17) or refractory (four) multiple myeloma received fotemustine 100 mg/m2 on an outpatient basis on days 1 and 8 of the induction cycle, followed after a 6-week rest period by fotemustine 100 mg/m2 every 3 weeks until progression or unacceptable toxicity. Fotemustine pharmacokinetics during the first day of induction was compared between patients with normal or abnormal renal function.
Results:
Five of 20 eligible patients had an objective response giving an intention-to-treat response rate of 25% [95% confidence interval (CI) 6% to 44%] and a 35.7% response rate (95% CI 11% to 61%) in the 14 patients having received at least four injections of fotemustine. The median time to objective response was 8.9 months. The median times to progression and survival were 13.8 and 23.1 months, respectively, with a 2-year survival rate of 49%. The main toxicity was myelosuppression with grade 34 neutropenia and thrombocytopenia in 66% and 71% of patients, respectively. There was one toxic death by sepsis after induction. The pharmacokinetic parameters in renal-impaired patients were not significantly different from those in patients with normal renal function with a similar incidence of grade 34 toxicity in both groups.
Conclusions:
Fotemustine as a single agent has definite activity in patients with relapsing or refractory multiple myeloma, with acceptable toxicity and can be administered at conventional doses in patients with mild or moderate renal impairment.
Key words: fotemustine, multiple myeloma, pharmacokinetic, phase II
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Introduction |
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The identification of new compounds active in myeloma thus remains a priority. Various combination chemotherapy regimens have been evaluated, including VAD (vincristine, doxorubicin, dexamethasone) and VBAP (vincristine, carmustine, doxorubicin, prednisone)/VBAP (vincristine, melphalan, cyclophosphamide, prednisone) [57]. None of these combination regimens has proven to yield higher response rates than the classical melphalanprednisone combination first used by Alexanian [8, 9]. However, non-alkylating regimens such as VAD are preferred in non-elderly patients due to receive high-dose therapy with stem-cell support, in order to preserve the bone marrow during induction therapy. Complete responses are rarely observed with these combination chemotherapy regimens, and the most effective regimen today in patients with multiple myeloma remains high-dose melphalan.
Various alkylating agents have been investigated in myeloma patients, including melphalan, cyclophosphamide and carmustine [10, 11]. The most widely used drug today is melphalan, either by repeated oral administration or as high-dose therapy. Fotemustine is a chloroethylnitrosourea that has demonstrated significant antitumour activity in patients with melanoma and glioma [12, 13], but which has not been tested in patients with multiple myeloma. The toxicity spectrum of this alkylating agent is characteristic, with delayed thrombocytopenia and little or no mucositis. In the scope of this trial, we sought to determine the antitumour efficacy and tolerance to fotemustine as a single agent in patients with relapsing or refractory multiple myeloma. We also evaluated the effect of renal impairment on the pharmacokinetics of fotemustine in these patients.
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Patients and methods |
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Protocol design and regimen
All patients had routine evaluations before treatment, including physical examination, skeletal X-ray, bone marrow biopsy, bone marrow aspirate, electrocardiogram and chest X-ray. The haematological and biochemical profile including complete blood cell counts, tests for renal and liver functions, calcaemia, serum and urine M component concentration, and serum levels of immunoglobulins, ß2-microglobulin, C-reactive protein and lactate dehydrogenase were analysed.
Fotemustine was supplied by Servier Laboratories (Orléans, France). Based on patient body surface area, the total fotemustine dose to be administered was diluted in 250 ml isotonic glucose and immediately administered as a 1-hour i.v. infusion, protected from light. The treatment plan consisted of an induction cycle with fotemustine 100 mg/m2 administered on an outpatient basis on days 1 and 8, followed by a 6-week rest period. In non-progressive patients, a maintenance therapy was initiated with one i.v. administration of fotemustine 100 mg/m2 every 3 weeks until progression or unacceptable toxicity, with a maximum of 16 administrations, including the two induction administrations. During maintenance treatment, the dose of fotemustine was to be delayed or reduced according to haematological and non-haematological toxicity. A delay >2 weeks and any irreversible World Health Organization (WHO) or Union Internationale Contre le Cancer (UICC) grade 3 or 4 toxicities (except for grade 3 or 4 alopecia, or grade 3 vomiting) led to a permanent discontinuation of treatment.
Response and toxicity evaluation
The antitumour activity was assessed 7 weeks after the first infusion of fotemustine, then every 6 weeks (every two administrations) with serum and urine M component measurement. A complete remission (CR) was defined as the absence of M component in serum and urine (confirmed by immunofixation) and <5% of plasma cells in bone marrow aspirate with no increase or new bone lesions, disappearance of symptoms and normalisation of calcaemia and cytopenias. Partial remission (PR) was defined as a reduction of 50% in M component in serum and urine or a reduction of
75% of Bence Jones Protein. Minor response (MR) corresponded to a reduction of M component between 25% and 49%. The M component reduction was to be associated with clinical improvement, normalisation of hypercalcaemia and the absence of signs of progressive disease. Progressive disease (PD) or relapse was defined as a confirmed increase of M component, progression of bone lesions, appearance or worsening of symptoms, cytopenias, renal failure or hypercalcaemia. Patients who did not meet the criteria of response or PD were noted as stable disease (SD). Toxicity was graded according to WHO criteria.
Pharmacokinetic analysis
Heparinised (or EDTA) blood samples were drawn via a peripheral vein prior to and then 60 and 150 min after the beginning of fotemustine infusion. After quick centrifugation at low temperature, the plasma was immediately transferred to sample tubes and kept frozen at 20°C or 80°C until analysis. A reverse-phase high-performance liquid chromatography (HPLC) technique, as described by Gordon et al. [15], was used for determination of fotemustine levels in plasma. Pharmacokinetics were determined using Bayesian estimation. The main evaluation criteria were the area under the plasma concentrationtime curve (AUC), peak concentration at the end of infusion (Cmax) and elimination half-life (t1/2).
Statistical analysis
The primary end points of the study were the best overall response rate and safety. Based on an estimated overall response rate of 20%, 14 evaluable patients were necessary to confirm activity with a ß-risk 5% [16]. Patients were considered to be evaluable for response after they had received at least four administrations of fotemustine. The best overall response rate was determined for the evaluable population and for all eligible patients. Secondary efficacy end points were time to progression and survival. The time to progression and survival were calculated according to the method of KaplanMeier from the first day of treatment until progression or death. Toxicity and tolerance were evaluated in patients having received at least one dose of study treatment. Pharmacokinetic results were compared in patients with normal or abnormal renal function, according to their creatinine clearance (CrCl) calculated using the Cockcroft and Gault formula [17]. The effects of impaired renal function on the pharmacokinetics of fotemustine (AUC, Cmax and t1/2) were compared statistically using one factor analysis of variance.
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Results |
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Discussion |
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The response rates observed with fotemustine in patients with relapsed and refractory disease compares favourably to those reported in recent studies with other new agents used as single-agent therapy. Vinorelbine evaluated in 40 patients relapsing after one or two conventional chemotherapies or after one high-dose chemotherapy yielded a response rate of 12.5% of patients on an intention-to-treat basis and 17.1% in the evaluable population (one CR and four PR in 29 evaluable patients) [18]. The response rate was dramatically improved when vinorelbine was combined with high-dose dexamethasone [18]. In 43 patients with resistant and relapsing multiple myeloma treated with topotecan, the response rate was 16% in the intention-to-treat population and 18% in the evaluable patients (seven PRs in 39 evaluable patients) [19]. Recently, oral idarubicin administered in 14 heavily-pretreated patients yielded an objective response in two patients (14% RR) [20]. Immuno-modulating drugs, such as interferon-, have been shown to yield an overall response rate of 20% in patients with refractory multiple myeloma [21].
The VAD regimen (high-dose pulsed dexamethasone and continuous 4-day infusions of doxorubicin and vincristine sulfate) has been evaluated in patients with myeloma in first relapse, yielding overall response rates of 40% [5, 6]. Unfortunately, this regimen has significant toxicity related to infection, gastrointestinal bleeding, hypercortisolism and cytopenia, and many patients with relapsed disease are not suitable candidates for therapy of this intensity. The use of high-dose treatment, with or without granulocytemacrophage colony-stimulating factor (GM-CSF) and autologous stem cell support in patients resistant to VAD-based regimens, is reported to result in remissions in 30% of patients, but disappointingly, the median remission duration and survival were only 3 and 6 months, respectively [22]. Encouraging results in relapsing or refractory patients have been reported with thalidomide administered per os in 84 previously-treated patients with refractory myeloma [4]. Single-agent thalidomide yielded an overall response rate of 32% and the 12-month event-free survival and overall survival rates were 22% and 58%, respectively. Neurotoxicity is most likely to be the dose-limiting toxicity, particularly in patients having received vinca-alkaloids.
The main toxicity of fotemustine observed in this study was haematological and was mostly observed after the induction treatment. The incidence of high-grade thrombocytopenia and leucopenia were higher in this population receiving injections of 100 mg/m2 every 2 weeks than in other phase II studies using fotemustine alone (100 mg/m2 weekly for 3 weeks) in metastatic malignant melanoma [13] or in supratentorial malignant glioma [12]. This is due to the fact that the patients in this study were heavily pretreated, including 20 patients having received alkylating treatment, and had significant bone marrow infiltration when fotemustine was initiated. Although not routinely administered in this study, prophylactic antifungal and antiviral therapy should be considered in patients receiving fotemustine for multiple myeloma. Other severe treatment-related adverse events were infrequent, although there was one toxic death. Another schedule testing fotemustine on an every 3-week schedule is currently ongoing in order to improve the haematological tolerance.
In conclusion, fotemustine has definite activity as a single agent in refractory or relapsing multiple myeloma, even in patients having received prior treatment with melphalan or nitrosoureas. Moreover, fotemustine can be administered at the standard/recommended dose levels in patients with mild to moderate renal impairment. It should be emphasised that fotemustine is probably most suited to patients with slow progressive disease, given the delay to response. Furthermore fotemustine is an alkylating agent, and stem cell collection, when considered, should be performed prior to fotemustine administration. Fotemustine should be evaluated in the scope of combination regimens, either with non-alkylating antimitotics, high-dose steroids, immunotherapy or antiangiogenic compounds. High-dose fotemustine with stem cell support has already been administered to patients with high-grade glioma [23] and could also constitute an interesting complement or alternative to high-dose melphalan, since its delayed toxicity profile and the lack of mucositis allows treatment on an outpatient basis.
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Acknowledgements |
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Footnotes |
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References |
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