Thalidomide has been used since 1997 in the treatment of myeloma. Remarkable efficacy has been observed both alone and in combination with dexamethasone and other drugs. Strangely, only recently have comparative trials been completed to show the clear added benefit of thalidomide and the drug still awaits formal FDA approval for myeloma treatment.

Two recent studies have lead to some confusion about thalidomide efficacy. In the first study from the Little Rock team in Arkansas (Barlogie, et al NEJM 354(10); 1021-30, March 9^th, 2006) thalidomide was given throughout the treatment course to half the patients undertaking the Total Therapy 2 double transplant protocol. The patients receiving thalidomide throughout the disease course had higher initial complete response rates (62% versus 43%) and a higher percentage of patients in remission at 5 years (56% versus 44%), but the ultimate overall survival was the same as in patients not receiving thalidomide initially. What does this mean?

The problems in interpreting this result are several. Firstly, 83% of the patients not receiving thalidomide initially did receive it as soon as they relapsed. The primary comparison is therefore between early use of thalidomide versus later use of thalidomide. One interpretation is that both are good, in that the overall survival in both patient groups is over 5 years even for patients > 65 years old. However, secondly it is truly difficult to sort out the impact of thalidomide in the setting of such a complex multi-drug and multi-procedure protocol. But, the use of thalidomide did not appear to be detrimental to the overall outcome although important side effects such as neuropathy and DVTs (deep vein thrombosis or clotting episodes) are a concern with early continuous use of thalidomide in a multi-drug protocol. This study therefore provides mostly an important caution about study design when a critical endpoint to be evaluated is the overall patient survival. Other studies are required to better address the role of thalidomide in this type of complex transplant setting and several have been ongoing to be reported very soon.

Separately a much simpler study from the Torino group in Italy shows a clear benefit for thalidomide (Palumbo, et al Lancet 367: 825-31, March 11^th, 2006.) This study evaluates the value of the addition of thalidomide 100 mg daily to the standard melphalan/ prednisone (M/P) regimen used for older patients aged 60-85 years. 129 patients received the additional thalidomide and 126 patients received M/P alone. The combined competely plus partial response rate with MPT was 76% versus 47.6% for the MP alone without added thalidomide. In this case, although there were some increased toxicities as one might expect (neuropathy, DVTs, infection risk) especially early in treatment, the initial benefit was sustained. In this case, there was an overall trend to both longer remissions (p 0.0006) as well as longer survival. Again, the interpretation of survival was complicated by use of thalidomide in MP patients at relapse (21%) as well as the higher up front risks with the new MPT combination. Recommendations are now made for anticoagulant therapy, preventative antibiotics and lower doses of thalidomide to reduce toxicities and risks. Overall, there is remarkable benefit with thalidomide in this trial, which has led to several other larger randomized trials, which have confirmed the advantages of adding (with due cautions) thalidomide to the standard melphalan/ prednisone regimen.

Thus, as they say, the devil is in the details! One has to look closely to assess the results of new trials. The bottom line for now is that thalidomide continues to show remarkable benefit. As with every drug careful advice is required about the details of thalidomide use including the dosage, preventative medications, such as blood thinners and antibiotics, as well as the most appropriate timing and setting to use the drug. The clear benefit of thalidomide plus dexamethasone as frontline therapy in patients proceeding to stem cell harvesting and transplantation is, for example, well established. As always, myeloma patients need to seek as much information as possible about the appropriate use of drugs in their only personal situation.