The efficacy of low dose thalidomide in refractory/relapsed myeloma—a retrospective audit

The treatment options for many elderly patients with multiple myeloma once they have failed first line therapy are limited by an unacceptable incidence of myelosuppressive or other side effects. Thalidomide is an active agent with response rates in myeloma of 30 – 50% [1], increasing in relapsed patients up to 77% by the addition of agents with known activity in this disease [2]. There is conflicting evidence as to whether higher doses (over 400 mg daily) of thalidomide improve response and outcome [3,4]. However, at the higher dosages side-effects are a significant problem with few patients tolerating doses above 400 mg daily for any length of time [5]. In view of the lack of support of any given dosing strategy for thalidomide [6], the clear dose related toxicity and with both the evidence for synergy with dexamethasone [2,7] and the recorded activity at very low doses [8] we adopted a low dose combination protocol in our practise, reserving escalation of the thalidomide dose for patients who failed to respond. Dexamethasone as a single agent can cause considerable morbidity in elderly patients and so this has been given once weekly as part of this combination. Treatment consisted of thalidomide at a dose of 50 mg given on alternate days together with weekly dexamethasone (20 mg). Patients remained on this schedule for a minimum of 2 months and the dose of thalidomide was escalated if there was no evidence of response. Twenty-nine patients with proven multiple myeloma have been treated (17 female, 12 male); the median age of this group was 69 years (range 49 – 83). In all but one case, patients had received prior therapy for myeloma (see Table I). Of 29 patients, 18 in our study remained on 50 mg thalidomide on alternate days with dexamethasone 20 mg once a week, six escalated to 50 mg daily or 100 mg on alternate days, three to 100 mg daily and two patients to 200 mg daily. In all cases dexamethasone continued at 20 mg weekly. Twenty-two patients (75%) demonstrated a significant fall in paraprotein. By EBMT criteria [9] one patient with non-secretory myeloma had a complete response, 12 out of the 22 responders had a partial response and nine a minimal response. The median duration of treatment among the responders is 12 months (3 – 28), with two-thirds of patients still on their initial starting regimen at the time of writing this report. The median time to response was 10 weeks, but the median duration of response has not been reached. Of the 22 responders, 12 also had a normalization of their peripheral blood counts with no concomitant treatment with any growth factors. Ten (45%) developed side effects to the thalidomide. Half of these patients were on thalidomide 50 mg on alternate days, while four were on 100 mg daily and one patient on 200 mg daily. The median duration of treatment before the onset of symptoms was 14 months (6 – 28). The predominant side effect reported (eight of 10 patients) was peripheral neuropathy with tingling and numbness of the feet in most cases and in one case of the hands. This was mild, WHO Grade I or Grade II. One patient developed retinal vein thrombosis and another developed a pulmonary embolus. Mild constipation was a side effect in two patients. In nine out of the 10 patients the side effects were thought significant enough to warrant stopping the thalidomide.