Thalidomide, The Phoenix, Arises Again

The story of thalidomide, the notorious teratogenic drug developed in Germany and sold around the world from 1957 to 1961 as a treatment for morning sickness, continues to unfold. By now most are familiar with thalidomide's history, how it caused phocomelia and other severe birth defects in over 10,000 babies, how it was never approved in the United States thanks to the insight and viligance of an FDA employee named Frances Kelsey, M.D., Ph.D., and how it has been approved now to treat certain types of cancer. Will its legacy be one of more than just shame?

Elderly patients with an aggressive form of blood cancer lived about 20 months longer when given the drug thalidomide as part of their treatment, French researchers said on Friday.

To me the question has already been asked and answered - this French study only serves to add more evidence to the conclusion that thalidomide is a valuable tool in the fight against multiple myeloma.

Between May 22, 2000, and Aug 8, 2005, 447 previously untreated patients with multiple myeloma, who were aged between 65 and 75 years, were randomly assigned to receive either melphalan and prednisone (MP; n=196), melphalan and prednisone plus thalidomide (MPT; n=125), or reduced-intensity stem cell transplantation using melphalan 100 mg/m2 (MEL100; n=126). The primary endpoint was overall survival.

French oncologists have been leading the way in much of myeloma research. This study, from the Intergroupe Francophone du Myélome, is hot off the press from the October 6th issue of The Lancet.

After a median follow-up of 51.5 months (IQR 34.4-63.2), median overall survival times were 33.2 months (13.8-54.8) for MP, 51.6 months (26.6-not reached) for MPT, and 38.3 months (13.0-61.6) for MEL100. The MPT regimen was associated with a significantly better overall survival than was the MP regimen (hazard ratio 0.59, 95% CI 0.46-0.81, p=0.0006) or MEL100 regimen (0.69, 0.49-0.96, p=0.027).

Translation: adding the oral immunomodulatory drug thalidomide to the standard chemotherapy regimen of melphalan and prednisone stretches the medical statistic known as median overall survival from 33 months to 52 months. To a medical oncologist this is considered a major improvement in survival and an excuse to raise hopes for elderly patients with myeloma.

The downside, as one might guess, are the side effects of the drug. Not all patients can tolerate thalidomide in the dose requested by their doctors. It can cause rash, constipation and sedation. Three out of four patients who take thalidomide for 12 months develop peripheral neuropathy and it is not possible yet to predict who is at risk for this complication at the initiation of therapy.

Nevertheless, this doesn't damper my enthusiasm for thalidomide as a significant improvement in the care of the myeloma patient, especially patients over the age of 65. My only prediction is that well before this century comes to a close thalidomide will once again be shelved, perhaps for good - not because of its toxicity, but because it will have been upstaged by one of a dozen or more new compounds. In fact, one derivative of thalidomide, called lenalidomide, has already been approved as a second line therapy in multiple myeloma.

What are the secrets to improving the outcome of patients with myeloma? We don't know half of them yet, but our scientist friends are happy to help slow learners like me understand current myeloma research by drawing a little cartoon delineating the work lying ahead. Here is one example, courtesy of CA: A Cancer Journal for Clinicians:

(Gulp) - I think it's time to curl up with something a little less cerebral...goodnight, all.