short report
Thalidomide maintenance following high-dose therapy in multiple myeloma: a UK myeloma forum phase 2 study
Sylvia Feyler,1 Andy Rawstron,2 Graham Jackson,3 John A. Snowden,4 Kim Cocks5 and Roderick J. Johnson1 1
St James University Hospital, Leeds,
2
Haematological Malignancy Diagnostic Service, Leeds General Infirmary, Leeds, 3 Department of
Haematology, Royal Victoria Hospital, Newcastle Upon Tyne, 4Department of Haematology, Sheffield Teaching Hospitals NHS Trust, Sheffield, and 5Clinical Trials Research Unit, University of Leeds, Leeds, UK Received 18 May 2007; accepted for publication 13 July 2007 Correspondence: Dr Roderick Johnson, Department of Haematology, St James
Summary Thalidomide maintenance has unresolved issues regarding dosage and toxicity. We evaluated this in five dose cohorts in 100 patients. At a median follow-up of 32Æ3 months, 23 patients had stopped thalidomide for disease progression, 54 for side effects. 3-year overall and progression-free survival was 76% and 41% respectively. Dosage did not influence disease outcome but greatly affected toxicity. Fifteen patients converted from partial remission to complete remission on thalidomide at a median of 13Æ5 months. Maintenance doses >200 mg were largely unachievable and peripheral neuropathy was the main toxicity. Lower doses enabled more patients to stay on the drug for a useful period of time. Keywords: thalidomide, myeloma, maintenance, stem cell transplantation, toxicity.
University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. E-mail:
[email protected]
Despite therapeutic advances, myeloma remains largely incurable with current therapies. High-dose melphalan-based autografting (HDM) is a standard of care, results in good disease control and increases median survival (Child et al, 2003). Attempts to improve on this using interferon maintenance have met with limited success and significant toxicity. Thalidomide is established therapy in relapsed and refractory disease, both as a single agent (Glasmacher et al, 2006) and in combination with chemotherapy (Kyriakou et al, 2005). More recently, it has become part of standard induction treatment in combination with Dexamethasone and other chemotherapy agents (Rajkumar et al, 2006; Richardson & Anderson, 2006). Attempts to postpone relapse or progression after autograft by employing thalidomide as maintenance therapy appear feasible and safe (Santos et al, 2004). However, higher doses of thalidomide in the maintenance setting can lead to intolerable toxicities and high discontinuation rates (Stewart et al, 2004). As a pilot study to the UK Medical Research Council (MRC) Myeloma IX trial, a phase II study was initiated, using thalidomide at five different doses following HDM, with the aim of assessing safety and toxicity in this particular setting and to establish an appropriate dosing schedule. Secondary aims were to document the length of time patients could
tolerate the drug, the long-term side effect profile and evidence of efficacy.
Patients and methods One hundred patients were recruited from 17 centres in the UK between November 2001 and February 2004. Patients with non-progressive disease, 3 months postautograft (HDM 200 mg/m2) were eligible. They were sequentially allocated to five, dose-escalating cohorts: 20 patients in each, at thalidomide doses of 50, 100, 200, 250 and 300 mg. All patients started at 50 mg daily and escalated at two weekly intervals to the target dose for their cohort. No anticoagulation was used. Data were collected for disease status, side effect profile, tolerance and quality of life using the QLQ C30 questionnaire. Study endpoints were disease progression or withdrawal of thalidomide (for toxicity or any other reason). Dose reductions were allowed at the discretion of the treating clinician and were recorded. Baseline characteristics were similar in all five cohorts (Table Ia). Median age at diagnosis was 58 years with a range of 36–69 years. There was a male predominance, with 62% male and 38% female patients. In all, 67% of patients were
ª 2007 The Authors Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 139, 429–433 doi:10.1111/j.1365-2141.2007.06817.x
Short Report Table Ia. Patient characteristics Cohort
50 mg
100 mg
200 mg
250 mg
300 mg
ALL
No. patients Age at transplant, years (range) Gender (%) Male Female Stage (%) I II III Unknown Diagnosis to HDT (months) Response to HDT* CR PR MR No. prior therapies 1 2 3 or more
20 58Æ5 (40–66)
20 56Æ5 (51–66)
21 56(36–69)
20 61 (40–67)
19 57 (40–69)
100 58 (36–69)
55 45
70 30
57 43
60 40
68 32
62 38
20 10 65 5 8 (6–28)
30 0 70 0 8 (5–122)
19 14 43 24 8 (4–31)
5 5 85 5 8 (3–71)
15 5 75 5 7 (4–106)
18 7 67 8 8 (3–122)
40 50 10
25 75 0
19 76 5
45 55 0
42 53 5
34 62 4
85 10 5
65 30 5
57 24 19
70 20 10
84 5 11
72 18 10
HDT, high dose therapy; CR, complete response; PR, partial response; MR, minimal response.
Durie–Salmon stage 3 at diagnosis, 7% stage 2 and 18% stage 1. Median time from diagnosis to autograft was 8 months (range 3–122). Seventy-two percent had received only one prior mode of treatment, the majority being VAD (vincristine, adriamycin and dexamethasone) or VAD-like regimens leading up to their autograft. No patient was treated with thalidomidecontaining regimens prior enrolment into the study. In all, 18% received two prior modalities of treatment and 10% three or more. At study entry 34% of patients had achieved a complete remission (CR), 62% a partial remission (PR) and 4% were minimal responders according to the EBMT criteria of response (Blade et al, 1998).
Results and discussion Long-term tolerance and toxicity of thalidomide maintenance At a median follow-up of 32Æ3 months (range 9–48), 77 of 100 patients had discontinued thalidomide, 23 because of disease progression, 53 because of side effects and one patient because of funding issues. The median time on the drug for the whole group was 14 months (range 0Æ5–37). The 53% of patients who stopped thalidomide solely due to side effects (i.e. with no evidence of disease progression) stayed on the drug for an average of 10 months (range 0Æ5–26). Fifty-six precent of patients were able to tolerate it for >12 months. The length of time on thalidomide was strongly dose-dependent, as shown in Fig 1A. Regarding toxicity, peripheral neuropathy was the most common problem (72% overall) and led to discontinuation of 430
thalidomide in 34 patients. Thirty-eight patients experienced grade 1–2 neuropathy but managed to continue therapy. These data were in keeping with other long-term observations showing that after 1 year of treatment, up to 75% of patients suffer peripheral neuropathy, a third of cases being of grade 3 or 4 (Tosi et al, 2005). Other common side effects were general lethargy/somnolence (42 patients), constipation (33 patients), rashes (27 patients), dizziness (nine patients), mild dyspnoea (seven patients) and hypothyroidism (four patients). Two patients suffered from deep vein thromboses (although one was no longer on thalidomide at the time). No pulmonary emboli were reported. Other rare side effects included oedema, cramps, sicca symptoms, headaches, erectile dysfunction, bradycardia, anxiety, tremor, depression, tinnitus and deafness. A summary of the side effects is shown in Table Ib. Taken together, these findings showed that thalidomide is a practical option as maintenance therapy postautograft but only around half of patients will tolerate it beyond 1 year – even if their disease remains stable. Doses of 200 mg and above were associated with major toxicity and can rarely be taken long-term. This supports the findings of a Canadian study, where entry into the 400 mg maintenance arm had to be closed because of treatment-related toxicity (Stewart et al, 2004). In a phase 2 study (Sahebi et al, 2006), the median tolerated dose of thalidomide in the maintenance setting postautograft was also confirmed at 200 mg. Peripheral neuropathy was the main and most important adverse event and lead to discontinuation in almost one third of the patients and some degree of morbidity in three quarters. The incidence of thrombosis was very low at 2% (one during and one after thalidomide therapy). This contrasts with the
ª 2007 The Authors Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 139, 429–433
Short Report
(A)
P = 0·001
P = 0·31
(B)
Fig 1. (A) Duration of thalidomide treatment. Left panel: time on the intended dose (mg). Right panel: time on any dose (mg). (B) Progression-free survival by achieved dose. The probabilities of progression-free survival in patients taking 1 yr) thalidomide therapy in patients with multiple myeloma. European Journal of Haematology, 74, 212–216.
Zangari, M., Anaissie, E., Barlogie, B., Badros, A., Desikan, R., Gopal, A.V., Morris, C., Toor, A., Siegel, E., Fink, L. & Tricot, G. (2001) Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood, 98, 1614–1615.
ª 2007 The Authors Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 139, 429–433
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