research paper
Thalidomide-dexamethasone versus Interferon-alphadexamethasone as maintenance treatment after ThaDD induction for multiple myeloma: a prospective, multicentre, randomised study
Massimo Offidani,1 Laura Corvatta,2 Claudia Polloni,1 Maria-Novella Piersantelli,1 Silvia Gentili,1 Piero Galieni,2 Giuseppe Visani,2 Francesco Alesiani,2 Massimo Catarini,2 Marino Brunori,2 Arduino Samori,2 Maurizio Burattini,2 Riccardo Centurioni,2 Mario Ferranti,2 Luciano Giuliodori,2 Marco Candela,2 Anna Mele,2 Monica Marconi2 and Pietro Leoni1 1
Clinica di Ematologia Azienda Ospedaliero-
Universitaria, Ospedali Riuniti Ancona, and 2
Marche Multiple Myeloma Network, GEMaMM,
Ancona, Italy
Received 22 August 2008; accepted for publication 30 September 2008 Correspondence: Massimo Offidani, Clinica di Ematologia Ospedali Riuniti Ancona, Via Conca, 71, 60020 Ancona. E-mail:
[email protected]
Summary Maintenance therapy was explored in multiple myeloma (MM) patients after conventional thalidomide, dexamethasone and pegylated liposomal doxorubicin (ThaDD). Patients with newly or relapsed MM obtaining at least minor response after 6 ThaDD courses, were randomised to receive a-interferon (IFN) 3 MU 3 times a week or thalidomide 100 mg daily until relapse. Both groups also received pulsed dexamethasone 20 mg 4 d a month. Fifty-one patients were randomized in the IFN-dexamethasone (ID) arm and 52 in the thalidomide-dexamethasone (TD) arm. The characteristics of two groups were similar. A significantly better 2-years progression-free survival (PFS; 63% vs. 32%; P = 0Æ024) and overall survival (84% vs. 68%; P = 0Æ030) was observed in the thalidomide arm. In high-risk patients and in those achieving less than very good partial response after induction, TD fared better in term of PFS. Main side effects were peripheral neuropathy and constipation in TD group, fatigue, anorexia and haematological toxicity in ID arm. There was a 21% probability of discontinuation at 3 years in the thalidomide arm and 44% in the IFN arm (P = 0Æ014). Low-dose thalidomide plus pulsed low-dose dexamethasone after conventional thalidomide combination-based therapy was also feasible in the long term, enabling significantly better residual disease control if compared with a standard maintenance therapy. Keywords: multiple myeloma, thalidomide, interferon, maintenance.
Multiple Myeloma (MM) is an incurable malignant plasma cell disorder. Despite improvements in the treatment of MM by high-dose chemotherapy and autologous transplantation, and more recently, by newer drugs, MM patients will ultimately progress and die from their disease. Therefore, all attempts to prolong the duration of remission and thereby possibly increase survival with a maintenance therapy may still be an appealing approach, taking care that this does not have a significant impact on patient quality of life. Two meta-analyses demonstrated that maintenance therapy with a-Interferon significantly prolongs progression-free survival (PFS) and overall survival (OS) of patients with MM treated with standard chemotherapy (Fritz & Ludwig, 2000; The Myeloma Trialists’ Collaborative Group, 2001). Moreover, Salmon et al (1998) demonstrated that a-Interferon plus steroids allowed a
significantly better PFS when used as maintenance therapy after response to Vincristine, Doxorubicin and dexamethasone. Therefore, after conventional chemotherapy, a-Interferon with or without steroids has been considered the standard maintenance therapy to date. The availability of novel agents such, as thalidomide, lenalidomide and bortezomib, particularly in combination with steroids and chemotherapy, has increased both the rate and the quality of response to induction therapy (San-Miguel et al, 2008). This should make residual disease control easier after initial or subsequent remissions. Therefore, this biological-based strategy directed at targeting the stromal-tumour cell interaction is now also considered promising in the maintenance setting given that it may be even more effective in the phase of minimal residual disease.
ª 2008 The Authors First published online 25 November 2008 Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 653–659 doi:10.1111/j.1365-2141.2008.07495.x
M. Offidani et al Whilst many studies are running with these new agents, Thalidomide is the most studied agent in the maintenance setting so far. The published studies are heterogeneous and all in the context of maintenance therapy after auto transplantation (Stewart et al, 2004; Attal et al, 2006; Barlogie et al, 2006; Spencer et al, 2007). They showed a benefit in terms of response rate and survival although long-term feasibility is questionable. This is the first prospective, multicentre, randomised study in which thalidomide was administered as maintenance therapy following conventional treatment including new drugs.
Mann–Whitney U-test if they were proportional or continuous variables, respectively. PFS and OS were calculated from the date of randomization to the date of progression or death for any cause, and death for any causes, respectively. The curves were plotted according to the Kaplan–Meier method and they were compared by logrank test. A P < 0Æ05 (two-sided) was considered significant. All statistical analyses were performed with the Statistical Package for the Social Sciences (spss) software (SPSS Science, Chicago, IL, USA).
Results Methods Patients characteristics Study design and treatment modalities Elderly de novo or relapsing MM patients were enrolled in a prospective phase II multicentre study to receive ThaDD (Thalidomide 100 mg/d continuously, dexamethasone 40 mg on days 1–4 and 9–12, pegylated liposomal Doxorubicin 40 mg/m2 on day 1 every 28 d). Patients baseline evaluation, inclusion/exclusion criteria, treatment modalities, response criteria, toxicity criteria and follow-up have been previously described elsewhere (Offidani et al, 2006a,b). Patients presenting at least a minor response after six courses of ThaDD induction therapy were included in a subsequent phase III randomised study and received either standard treatment with a-Interferon 3 MU · 3/week or an experimental treatment with Thalidomide 100 mg/d until the next recurrence or until serious side effects. Both groups were given also dexamethasone 20 mg/d · 4 d every month. According to National Cancer Institute toxicity criteria, version 3 (http://ctep.cancer.gov/ forms/CTCAEv3.pdf), dose reduction was allowed for grade £2 toxicity, while temporary or definite therapy discontinuation was required for grade ‡3 toxicity. During maintenance with thalidomide, antithrombotic prophylaxis by fixed-dose warfarin was at the discretion of attending physician. Unfavourable cytogenetics were defined as any abnormalities observed by fluorescence in situ hybridization analysis except the absence of abnormalities, t(11;14) and hyperdip loidia. Fifty patients were required in each group to ensure a 20% difference in the 2-years TTP with 80% power and 5% a error. The analysis was performed on an intention to treat basis. Randomisation was determined by the coordinating centre (Ancona, Italy) and sent to the other centres by e-mail after each patient’s eligibility was confirmed. The study was approved by the local Ethical Committees and conducted according to the provisions of the Declaration of Helsinki.
Statistical methods Characteristics of patients were compared by chi-square test (or Fischer exact test) for contingency tables or by 654
One hundred and forty-seven patients were enrolled in the ThaDD protocol and 103 patients were randomised in to the maintenance study. Forty-four patients were not randomised; of these, 17 patients did not complete induction therapy, 10 died prior to randomization, 11 did not achieve a minor response, 5 were removed due to toxicity and 1 underwent an allogeneic transplantation. Fifty-one patients were randomised to the Interferon-dexamethasone (ID) arm and the other 52 patients to the Thalidomide-dexamethasone (TD) arm. The two groups of patients were matched for main prognostic factors such as age, serum b2-microglobulin, serum albumin, International Staging System (ISS) score, serum C-reactive protein, cytogenetics, response to therapy and first remission duration for relapsed patients. Furthermore, in both arms, a similar number of patients had relapsed (22 vs. 23) or undergone previous autologous transplantation (10 vs. 10) (Table I).
Response to induction and during maintenance Detailed postinduction response rate for both randomisation arms are given in Table II. In summary, we observed a very good partial remission (VGPR) or better in 57% of randomized ID patients and 54% in those randomised for TD (P = 0Æ410). During the follow-up of the patients undergoing maintenance therapy, both the ID and TD regimens slightly improved the response obtained by induction. Finally at least VGPR or better response was obtained in 61% and 61Æ5% of patients in the ID and TD arm respectively (Table II).
Time to progression and overall survival After a median maintenance follow-up of 30 months in both arms, 30 ID patients (60%) relapsed vs. 17 (33%) TD patients (P = 0Æ009). PFS was significantly higher in the TD arm versus the ID arm (P = 0Æ024) (Fig 1). The 2-year PFS probabilities amounted to 32% in the ID arm vs. 63% in the TD arm. When disease progressed, patients received bortezomib-based salvage therapy mostly within controlled study. Two-years OS probability was significantly better in the TD arm compared to the ID arm (84% vs. 68%; P = 0Æ030) (Fig 1).
ª 2008 The Authors Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 144, 653–659
Thalidomide Maintenance in MM Patients Table I. Baseline characteristics of patients. ID No = 51
Table II. Best response to induction and during maintenance therapies. TD No = 52 ID No (%) 34/18 71 (52–83) 36 7 8 1 30 12 10 16 21 15
Best response after ThaDD regimen CR 17 (33) nCR 5 (10) VGPR 7 (13Æ5) PR 16 (31Æ5) MR 6 (12) ‡VGPR 29 (57)
