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Thalidomide in Blood Cancers: Disappointing Results

Date: March 15, 2024

Thalidomide has an infamous historical connotation. Most of us remember "thalidomide babies" born a several decades ago, babies that were horribly malformed and disfigured because their mothers were prescribed thalidomide during pregnancy. More recently, thalidomide and its newer analog "Revlimid" have gained good press as potential therapeutic agents in treating blood cancers. Revlimid has shown encouraging efficacy in Multiple Myeloma, and it is undergoing clinical trials in CLL as well. I understand several of our CLL expert centers are attempting to recruit patients into Revlimid based trials.

The article below should give some pause, I think. This Reuters review describes the results published in the latest issue of the prestigious New England Journal of Medicine. A very large (668 patients), randomized double-arm study has shown that while adding thalidomide to the therapy mix did indeed get higher response statistics, it did nothing for increasing the overall survival of patients. This is a credible and well conducted study and the results are disappointing to say the least. As patients trying to maximize our lives, what matters to us is overall survival - who cares about response statistics if they do not track increased survival?

Incidentally, the illusory advantage of higher response statistics carried the penalty of higher risk of deep vein thrombosis (blood clots deep in the veins, potentially capable of initiating a stroke, for example), as well as resistance to salvage therapy when the remissions ended. And oh yes, before I forget, there was the usual higher incidence of peripheral neuropathy, something that is always seen in using thalidomide or its analogs.

Please remember that this article describes results obtained with thalidomide, and not its more recent kissing cousin Revlimid (lenalidomide). Hopefully, Revlimid will not disappoint in a similar fashion. Nevertheless, these are not encouraging results. Extrapolating from efficacy in multiple myeloma to CLL is a big leap. Add to that these new results that improved response statistics do not add up to improved survival, and I am now less a fan of thalidomide than I was before. Ladies and gents, the devil is in the details, look carefully before you sign on the dotted line for early stage clinical trials! That is good advice for any new drug, and I think it is now even more valid for thalidomide and its analogs.

Be well,

Chaya
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Press Report

Adding Thalidomide to Myeloma Therapy of Little Benefit

Reuters Health Information 2024. © 2024 Reuters Ltd.

NEW YORK (Reuters Health) Mar 08 - Adding thalidomide to high-dose therapy for multiple myeloma makes complete responses more likely and increases event-free survival, but does not improve overall survival and has considerable toxicity, new research shows.

Melphalan-based high-dose therapy has been shown to improve the survival of multiple myeloma. However, it was unclear if adding thalidomide, an agent with activity against advanced and refractory disease, to this therapy could further improve outcomes.

To investigate, Dr. Bart Barlogie, from the University of Arkansas for Medical Sciences in Little Rock, and colleagues assessed the outcomes of 668 patients who were randomized to receive two cycles of melphalan-based therapy, supported by hematopoietic-cell transplantation, with or without thalidomide.

The researchers' findings appear in The New England Journal of Medicine for March 9th.

After a median follow-up period of 42 months, the complete response rate in the thalidomide group was 62%, significantly higher than the 43% rate noted in the control group (p < 0.001), the authors state. Similarly, the 5-year event-free survival rate in the thalidomide group was also higher, 56% vs. 44% (p = 0.01).

Now for the bad news.

Due in part to a lower response rate to salvage therapy, the addition of thalidomide did not improve overall survival; both groups had a 5-year overall survival rate of about 65%. The median survival period after relapse in the thalidomide group was 1.1 years compared with a period of 2.7 years in the control group (p = 0.001).

Deep vein thrombosis occurred in 34% of thalidomide-treated patients compared with 18% of controls (p < 0.001). Treatment with low-molecular-weight heparin did not eliminate the elevated risk. Other adverse events seen more often in the thalidomide group included peripheral neuropathy, syncope, bowel obstruction, tremor and neutropenia.

"These results indicate that contrary to a widely held belief, a complete response is not a valid surrogate for overall survival in clinical trials," Dr. Michele Cavo and Dr. Michele Baccarani, from the University of Bologna in Italy, comment in a related editorial.

"The higher rate of failure to respond to salvage therapy in the thalidomide group needs to be investigated further," they suggest, "especially with respect to the salvage potential of new drugs in patients who had received thalidomide as initial treatment."

N Engl J Med 2024;354:1021-1030,1076-1078.
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