Thalidomide Maintenance Following High Dose Therapy in Multiple Myeloma: A UK Myeloma Forum Phase 2 Study.

Thalidomide has an established place in the induction therapy of myeloma and more recently, information on its potential as a maintenance agent after autografting has started to become available. Its value in this setting is being tested in a prospective, randomised manner in the UK MRC Myeloma IX trial. As a prelude to that study, we set up this pilot investigation in 2001. We examined thalidomide monotherapy as maintenance in stable patients, commencing 3 months post high dose melphalan. We evaluated the long-term tolerance of thalidomide at 5 doses; 50mg, 100mg, 200mg, 250mg and 300mg. Patients were not anticoagulated. 100 patients were recruited between Nov. 2001 and Feb. 2004, 20 in each cohort. End points were disease progression and toxicity. Information is available for tolerance, side effects, disease status and quality of life. Median follow up is 23.5 months (range 4 to 48). 75 patients have now stopped thalidomide, 68% due to side effects, 29% for disease progression and 3% for other reasons. 10 patients have died, 9 from relapsed or progressive myeloma and 1 from bladder cancer. Overall, the estimated median time to disease progression (PFS) is 35 months. There was an improvement in PFS for those who managed to tolerate thalidomide for >6 months, which became highly significant if taken for >12 months (median 20 months if taken for <12 months vs. not reached if taken >12 months, p=0.0006). Higher doses of thalidomide were impractical with only 8% sustaining a dose of 300 mg. There was, however a non-significant improvement in PFS for those taking >150 mg suggesting a possible dosage effect. The best outcome was seen in the group of patients who achieved a CR only after the initiation of thalidomide. It is possible that this selects a group whose disease is thalidomide-sensitive. Peripheral neuropathy was the commonest reason for discontinuing thalidomide (34 patients). 15 further patients continued on the drug but experienced mild neuropathic symtoms. Most (but not all) who stopped the drug reported improvement in their neuropathy and none deteriorated. Other common side effects were lethargy/somnolence, constipation, rashes, pruritis and dry skin. One patient in the 100 mg cohort experienced a deep vein thrombosis, which occurred two weeks after starting the drug. Two patients suffered from hypothyroidism. QOL was assessed using the QLQ-C30 and QLQ-MY24 questionnaires at baseline and then 3 monthly. Most patients recorded low symptom levels and gradually improving levels of function. There were few striking changes in QOL. The analysis is confounded by the clear impact of side effects i.e. the fact that most patients stopped the drug if problems occurred. In conclusion, thalidomide can be used in maintenance after autograft but many patients fail to tolerate it long-term and doses >200mg are rarely practical. There is no excess of thrombosis in this setting. Side effects, particularly peripheral neuropathy, led to discontinuation in over 2 thirds of patients at the median follow up of 23.5 months but this may be long enough to gain benefit for some. PFS is improved in those who can stay on the drug for at least 6 and preferably 12 months. Of interest, the patients who failed to achieve CR post autograft but went on to get a CR on thalidomide did particularly well.