Clinical and pharmacokinetic phase II study of fotemustine in refractory and relapsing multiple myeloma patients

C. Dumontet1,+, J. Jaubert2, C. Sebban3, F. Bouafia1, C. Ardiet3, B. Tranchand3, E. Berger4, C. Lucas4, D. Guyotat2 and B. Coiffier1

1 Service d’Hématologie, CHU de Pierre Bénite, Lyon; 2 Service d’Hématologie, 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


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

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 3–4 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 3–4 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


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The prognosis of stage II or III myeloma has improved considerably during the past 20 years. The introduction of high-dose therapy with stem cell support has been shown to improve overall survival in a randomised trial, in comparison with conventional combination therapy [1]. Whereas overall survival was considered to be ~2 years before such treatments were introduced, it has now been shown in large series that the overall survival is greater than 5 years [2, 3]. Despite these improvements, all patients with multiple myeloma eventually relapse and the vast majority will die from their disease. The recent introduction of thalidomide in the anti-myeloma armamentarium has raised great enthusiasm [4]. Because it is easy to administer and fairly well tolerated, this compound has provided high response rates in patients with advanced disease. However, all patients will eventually relapse and the neurotoxicity due to prolonged administration of this compound remains problematic.

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 melphalan–prednisone 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.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient eligibility
Eligible patients were required to have histologically-confirmed multiple myeloma according to Southwest Oncology Group (SWOG) criteria [14], refractory (non-responding patients who progressed under treatment) or in first or second relapse after standard or high-dose chemotherapy. Only adult patients with progressive disease and a measurable monoclonal (M) component in the serum or urine were enrolled. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status <=2, a life expectancy >3 months, no radiotherapy, immunotherapy, steroid therapy or chemotherapy within the last 4 weeks before study entry (6 weeks for nitrosoureas), calcaemia <3 mmol/l, adequate blood cell counts (polynuclear neutrophils >=1.5 x 109/l and platelets >=100 x 109/l) and adequate hepatic function (transaminases, alkaline phosphatase and bilirubin <=2.5 x upper limit of normal). Presentation with renal failure did not disqualify patients from eligibility, provided the serum creatinine level was <=300 µmol/l after correction of dehydration or hypercalcaemia. All patients gave written informed consent.

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 concentration–time 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 Kaplan–Meier 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.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
From March 1997 to June 1998, 21 patients were included in three French centres after Ethics Committee approval. Patient characteristics at inclusion are summarised in Table 1. There were 14 men and seven women with a median age of 64 years (range 48–76). Twenty patients had advanced disease according to SWOG criteria and the majority of patients had a good performance status. Four patients were classified as having refractory disease, while 17 had relapsing disease, including nine patients in second relapse. Twenty patients had previously been treated with an alkylating agent: nitrosourea in 12 patients, cyclophosphamide in 16 patients and melphalan in 19 patients. Eight of them had received high-dose melphalan supported by autologous peripheral haematopoietic stem cells (with total body irradiation in four patients). One patient was not eligible due to a non-measurable M component. Median time between initial diagnosis and initiation of fotemustine was 41.5 months (range 4.6–74.6). Ten patients had impaired renal function (calculated CrCl <60 ml/min; range 33.8–58.7), while 10 patients had normal renal function (calculated CrCl >=60 ml/min) and one patient could not be evaluated for renal function because of missing data.


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Table 1. Patient characteristics
 
Treatment administration
One hundred and seventy-nine infusions of fotemustine were administered during the study period and the median number of fotemustine infusions delivered per patient was seven (range 2–16). All patients received the first two injections of the induction cycle at full dose. Sixteen patients received at least one maintenance cycle. Fourteen patients receiving at least four injections were evaluable for the per protocol efficacy analysis. Six patients completed the 16 planned administrations of fotemustine. The reasons for treatment discontinuation during the study treatment are listed in Table 2. The main reasons for discontinuation were progressive disease in seven patients and treatment-related adverse events in five patients. After the induction cycles, five patients did not receive maintenance treatment for the following reasons: one patient refused further treatment, one died of septic shock during aplasia, one because of persistent thrombocytopenia and two because of progressive disease. Overall, 87 of 137 maintenance cycles (63.5%) were administered with a delay of >7 days and/or at a dose decreased by >=20%, which in 83 cycles was due to haematological toxicities. The median cumulative dose per patient was 600 mg/m2 (range 200–1600). Due to delays and/or dose reductions, the median absolute dose intensity of fotemustine was 27 mg/m2/week (range 15.8–32.1) and the median relative dose intensity [defined as actual delivered dose (mg/m2/week) divided by the planned dose (mg/m2/week) over the entire course of treatment and including all cycles] was 87.9% (range 48.5–101.8).


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Table 2. Treatment administration
 
Response and outcome
Five patients had an objective response after at least four injections of fotemustine with a reduction of M component >=50%, leading to a response rate of 35.7% [95% confidence interval (CI) 11% to 61%] in the 14 evaluable patients (Table 3). Two patients had a MR, four patients had SD and three patients progressed. In the 20 eligible patients, the objective response rate was 25% (95% CI 6% to 44%) (Table 3). The median time to partial response was 8.9 months (range 5–12.1 months). Patients with a PR had already at least a MR after a median of 4.8 months (range 2.2–5.8), i.e. after six fotemustine injections (range 2–8). Partial and minor responses were obtained in five of 16 patients with relapsed disease and in two of four patients with refractory disease. The main characteristics and outcome of the responding patients are shown in Table 4. All of these patients had previously been treated with melphalan-containing regimens. Responses were seen both in patients previously treated with autologous transplantation (two PR out of eight patients) and patients not previously treated with transplantation (three PR and two MR).


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Table 3. Best responses after at least four administrations in the eligible and evaluable patient populations
 

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Table 4. Characteristics and outcome of responders
 
With a median follow-up of 22.6 months, eight patients had died of progressive disease, one of toxicity and two from other causes considered unrelated to the study drug. Among the nine surviving patients, seven showed progressive disease while one patient remained stable after 33 months and another patient remained in partial response after 29 months. Both of these patients had received 16 doses of fotemustine. The estimated median time to progression was 13.8 months in the eligible patient population (range 1.3–33+) (Figure 1) and the estimated median survival was 23.1 months (range 1.6–36.3+) (Figure 2). The estimated 2-year progression-free survival and overall survival were 22% and 49%, respectively.



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Figure 1. Time to progression for 20 eligible patients with multiple myeloma since initiating treatment. Median time to progression was 13.8 months.

 


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Figure 2. Survival curve for all 20 eligible patients. Median survival from start of therapy was 23.1 months.

 
Toxicity
All of the 21 patients included were assessable for toxicity. The main toxicities were grade 3–4 leucopenia, neutropenia and thrombocytopenia in 13, 14 and 15 patients, respectively. This occurred mainly after the first two injections with 12 patients experiencing a grade 3–4 neutropenia (57%) and 14 a grade 3–4 thrombocytopenia (67%) (Table 5). During the induction cycle, the median times to nadir were 45 days (range 26–66) and 38 days (range 28–49) for neutropenia and thrombocytopenia, respectively. The median duration of grade 3–4 toxicities was 14 days for neutropenia (range 1–21) and thrombocytopenia (range 1–76). Three patients were hospitalised for grade 3 neutropenic fever and one patient died consequently due to a septic shock associated with grade 4 neutropenia on day 66 after the first dose of fotemustine. No other severe treatment-related adverse events were noted except for grade 3 haemorrhage with favourable outcome associated with grade 3 thrombocytopenia in one patient, and grade 3 mucositis in one patient. Overall, five patients discontinued treatment because of adverse events deemed related to the study drug: three patients for thrombocytopenia, one patient because of grade 2 cardiac failure after a cumulative dose of 800 mg/m2 (14 doses of fotemustine) and one patient for toxic death (due to neutropenic sepsis).


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Table 5. Haematological toxicity
 
Pharmacokinetic results
Twenty patients were evaluable for the pharmacokinetic analysis, 10 with normal renal function (mean Cockcroft CrCl 82.3 ± 12.3 ml/min; range 66.7–112.3) and 10 with abnormal renal function (mean Cockcroft CrCl 44.1 ± 8.7 ml/min; range 33.8–58.7). As shown in Table 6, patients with impaired renal function tended to be older than patients with normal renal function (67.8 versus 62.8 years) with a lower mean body weight (59.7 versus 76.1 kg). After a 100 mg/m2 dose of fotemustine, the Cmax, AUC and t1/2 in renal function-impaired patients were not significantly different from those of patients with normal renal function (P = 0.494, 0.967 and 0.338, respectively). Moreover, when analysed continuously rather than comparing the two groups, no correlation was found between CrCl and fotemustine clearance (R2 = 0.0757). The safety profile appeared to be similar in the two groups of patients; in particular, regarding the incidence of grade 3–4 neutropenia and thrombocytopenia and grade 3–4 extra-haematological toxicity during the induction cycle (Table 6).


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Table 6. Fotemustine pharmacokinetic parameters according to renal function
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This multicentre open phase II study evaluating single-agent fotemustine treatment in patients with refractory or relapsing multiple myeloma confirmed the antitumour effect of fotemustine in this population, with a 25% overall response rate among 20 eligible patients on an intention-to-treat basis and a 35.7% response rate in 14 patients having received at least four injections of fotemustine. Given the fact that 95% of patients had received prior alkylating therapy, including eight patients who had received high-dose melphalan, this response rate is particularly remarkable. The striking features of antitumour activity were the delayed response, with a median time to objective response of 8.9 months, and a prolonged time to progression (13.8 months). Pharmacokinetic analyses performed in these patients, including 10 patients with impaired renal function, showed that fotemustine pharmacokinetics is not changed by renal dysfunction and therefore can be safely administered at full dose to patients with mild or moderate renal failure.

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-{alpha}, 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 granulocyte–macrophage 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.


    Acknowledgements
 
This work was supported by the Institut de Recherches Internationales Servier, Courbevoie, France.


    Footnotes
 
+ Correspondence to: Dr C. Dumontet, Service d‘Hématologie, Centre Hospitalier Lyon Sud, 69495 Pierre Bénite Cedex, France. Tel: +33-4-78-861679; Fax: +33-4-78-866566; E-mail: charles.dumontet{at}chu-lyon.fr Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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19. Knaut EH, Crowley JJ, Wade JL et al. Evaluation of topotecan in resistant and relapsing multiple myeloma: a Southwest Oncology Group study. J Clin Oncol 1998; 16: 589–592.[Abstract]

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