Thalidomide Beneficial for Older Multiple Myeloma PatientsKey Words
Multiple myeloma, thalidomide, melphalan, prednisone. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Summary
In this phase III clinical trial, older patients – most over the age of 65 – with previously untreated multiple myeloma did significantly better than a comparison group when thalidomide was added to the conventional chemotherapy melphalan plus prednisone (MP). These results provide the first solid evidence of thalidomide’s effectiveness in this group of elderly patients.
Source
The Lancet, March 11, 2006 (see the journal abstract)
(Lancet. 2006 Mar 11;367(9513):825-31)
Background
Multiple myeloma occurs when a type of white blood cell called a plasma cell starts reproducing uncontrollably. The excess plasma cells crowd out healthy blood cells in the bone marrow (the spongy tissue inside large bones), causing pain and gradually destroying the bone.
Melphalan and prednisone (MP) used together have been the standard chemotherapy drugs used to treat multiple myeloma for many years. Since the late 1990s, the addition of thalidomide has proven effective in both relapsed and newly diagnosed myeloma patients. Thalidomide appears to affect the blood supply that fuels the growth of tumors, but may fight cancer in other ways as well. Thalidomide is approved for this use by the U.S. Food and Drug Administration, and in its current form no longer carries risks that once made it infamous for damage to unborn babies.
Another type of treatment, stem cell transplantation, can put some patients’ multiple myeloma into remission, but many older patients are unable to tolerate this form of high-dose cancer treatment, which poses risks of infection, anemia, and damage to vital organs such as the liver. Thus younger patients have a better five-year survival rate than do the majority of people diagnosed with multiple myeloma, who are older and medically disqualified from stem cell transplant.
Doctors generally treat older, newly diagnosed multiple myeloma patients with thalidomide plus MP, but clinical trial evidence to support this approach has been lacking.
The Study
Between January 2002 and May 2005, researchers with this phase III trial enrolled patients with newly diagnosed multiple myeloma who were older than age 64 or not medically able to undergo stem cell transplantation. The patients were randomly assigned to receive either MP plus thalidomide or MP alone. The study, which took place at multiple Italian sites, was not blinded, meaning that both patients and doctors knew who was receiving which treatment.
A preliminary analysis of the trial’s data showed a statistically significant improvement in response rate for the MP plus thalidomide group, so the trial was stopped in May 2005 for ethical reasons. The final results were based on the 255 patients who had been followed for more than the minimally required six months.
Of the 72 patients in the MP-only group and the 129 patients in the MP plus thalidomide group, only seven were younger than age 65.
All patients took MP pills daily for one week in every four, for a total of 24 weeks. Patients in the experimental group took an additional thalidomide pill every day throughout the 24 weeks, and then continued to take the drug thereafter for maintenance until they relapsed. Patients receiving MP only were permitted to begin taking thalidomide if their disease returned before the study was over. Because of a high rate of blood clotting in the thalidomide group, the anticoagulant drug Enoxaparin® was given to patients enrolled after December of 2003.
The study was conducted by the Italian Multiple Myeloma Network (GIMEMA). The principal investigator was Antonio Palumbo, M.D. of the Università di Torino in Italy. Pharmion Corporation supplied free thalidomide for the study.
Results
The median follow-up times were 17.6 months for survivors in the thalidomide group and 15.2 months for the MP-only group. At the two-year mark, 54 percent of the thalidomide group were alive without their disease having progressed or returned (event-free survival) compared to only 27 percent of the MP-only group.
Researchers measured patients’ response to treatment by monitoring the amount of a protein in their bodies that corresponds to the presence of multiple myeloma. Complete or near-complete responses were seen in 36 patients who took thalidomide (27.9 percent), compared to nine who did not (7.2 percent).
Because the study was stopped early, it was not possible to reliably determine whether the thalidomide treatment helped patients live longer overall, though there was a trend – not yet statistically significant – toward better overall survival for the experimental group.
Adverse events were higher with thalidomide, causing the deaths of 11 patients (eight percent) compared to six in the MP-alone group. Nearly half (48 percent) of those taking thalidoimide experienced serious toxicity, compared to 25 percent of those taking MP-alone.
Though thalidomide patients were permitted to continue taking the drug after the six-month primary treatment, on average they were only able to take it for eight months altogether because of the increased toxicity. During initial treatment, about a third of patients discontinued taking thalidomide, and more than a third had their dosage reduced.
Toxicities that were significantly worse for the thalidomide patients included blood clotting in the legs, peripheral neuropathy, pneumonia and other infections, and constipation.
Comments
Although thalidomide is already widely used as the initial treatment for elderly multiple myeloma patients, these results provide solid evidence that it should become the standard of care, said Shaji K. Kumar, M.D., of the Mayo Clinic, who called it an “historic moment in myeloma therapy,” in an accompanying Comment.
“This is the first definitive trial in this older population,” said Michael Bishop, M.D., of the National Cancer Institute’s Center for Cancer Research, “and the event-free results are highly encouraging. Hopefully, as the data mature, we will be able to see a clear advantage in overall survival as well.”
Limitations
As noted, adding thalidomide to MP significantly increases toxicity. In addition, the effectiveness of thalidomide may diminish over time.
“The best treatment for multiple myeloma is a moving target these days,” said Bishop. “There is evidence that many patients between 60 and 70 can tolerate and will certainly benefit from autologous stem cell transplants." Early results on bortezomib (Velcade®) as initial therapy, alone or in combination with dexamethasone, are also promising, he said, and a newer version of thalidomide called lenalidomide is also under study.
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