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The thalidomide-melphalan-prednisone regimen that is given to multiple myeloma patients newly diagnosed between the ages of 65 and 75 can be used in the very elderly as well, according to interim results of the placebo-controlled Intergroupe Francophone du Myelome 01-01 trial in patients 75 years of age and older.
An intent-to-treat analysis showed a trend toward better overall survival in patients who received thalidomide with melphalan and prednisone. Based on interim data, lead author Dr. Cyrille Hulin estimated their median overall survival to be 45 months vs. 28 months for a control group given a placebo instead of thalidomide.
Median progression-free survival was significantly longer with the three-drug combination: 24 months vs. 19 months (P = .004), Dr. Hulin reported. "Melphalan-prednisone-thalidomide is an effective combination with acceptable toxicity in patients with multiple myeloma who are older than 75 years of age, and these patients [achieve] a significant improvement in progression-free survival," said Dr. Hulin of the Intergroupe Francophone du Myelome.
The study is the first large, double-blind, randomized trial to examine this combination of agents in the older old—a population that accounts for a third of all those with multiple myeloma, according to a discussion by Dr. Sagar Lonial. "This really is a landmark study that's been done in a difficult patient population, and I think it really does potentially set the standard for a number of studies that we're going to be looking at in the future," said Dr. Lonial of the Winship Cancer Institute at Emory University in Atlanta.
The IFM 01-01 protocol called for all patients to receive 12 6-week cycles of melphalan 0.2 mg/kg daily and prednisone 2 mg/kg on days 1 through 4. In addition, they were evenly randomized to receive a placebo or 100 mg daily of thalidomide in two capsules for 72 weeks. No maintenance treatment was given, but everyone received clodronate. Those who had a recent thrombosis were excluded.
Randomization began in April 2002 and closed after enrollment of 232 patients. Dr. Jean-Luc Harousseau presented a planned interim analysis based on the first 200 patients, who were evenly randomized to the placebo and thalidomide arms. Slightly more than half were women. The median age was 79 years; one-third of the cohort was over age 80. On clinical assessment 60% presented with significant comorbidities.
After completing therapy, 61% of patients who were given thalidomide had a partial response, and 22% had a very good partial response. The comparable rates for the placebo group were 30% and 8%, respectively. Complete response was achieved in 7% with thalidomide and 1% for placebo, Dr. Hulin added. At 12 months, 61% of the thalidomide arm enjoyed a partial response—almost double the rate in the placebo arm.
Since the protocol started, 93 patients have died: 54 in the placebo arm and 39 in the thalidomide arm. There was, however, little difference in the causes of death, including myeloma and toxicity.
Eighty-five patients withdrew from each arm. Toxicity was the primary cause of withdrawal in the thalidomide arm (53%), while disease progression was the primary cause in the placebo group (60%). Nonetheless, Dr. Hulin said that despite the high withdrawal rate, toxicity was acceptable in this population. Among side effects causing withdrawal, he cited, were peripheral neuropathy (11); thrombosis (7); or hematologic (7), neurologic (7), cardiac (3), and other adverse events (10). Causes of 13 toxicity-related withdrawals in the placebo arm included hematologic events (5), peripheral neuropathy (3), and non-peripheral neurological complications (2). There was a single case of thrombosis.
Although grade 3/4 neutropenia was higher in the thalidomide arm (21% vs. 9%), Dr. Hulin described it as manageable. "Four-fifths of patients in the [thalidomide arm] were able to tolerate treatment at least during the initial 6 months, and 65% were able to tolerate it for more than 1 year," he said, adding that the level of peripheral neuropathy was acceptable and not surprising.
Dr. Hulin suggested neurotoxicity might be reduced by shortening duration of thalidomide treatment. In addition, low-molecular-weight heparin or aspirin prophylaxis could reduce thrombosis, he said, concluding "melphalan-prednisone-thalidomide could be the reference treatment for all patients older than 65 years with newly diagnosed myeloma."
Regarding the toxicity, Dr. Lonial noted that almost 30% of the cohort had peripheral neuropathy at baseline "and objective testing that was performed in this excellent study is further corroboration that we really need to look at baseline neuropathy if we're going to assess the neuropathic potential of our novel agents. Seeing that 18% of patients in the MP-placebo arm had grade 1 peripheral neuropathy is a very important finding."
Hulin C. et al. Comparison of melphalan-prednisone-thalidomide (MP-T) to melphalan-prednisone (MP) in patients 75 years of age or older with untreated multiple myeloma (MM). Preliminary results of the randomized, double-blind, placebo controlled IFM 01-01 trial. Abstract 8001.
Commentary |
The treatment of elderly patients with multiple myeloma remains a challenge. Finding a regimen that is effective and that obviates the need for stem cell transplant is important. The results with melphalan, prednisone, and thalidomide are encouraging in this study of patients aged 75 and older. Though toxicity was considered acceptable, it is critical that clinicians be aware of the side effect profile of this triple combination, and that they employ strategies to minimize morbidity. Neurotoxicity, observed in 18 of 45 patients who dropped out of the trial because of toxicity, might be reduced by shortening the duration of thalidomide Low-molecular weight heparin or aspirin might be given prophylactically to reduce the risk of deep vein thrombosis, which was observed in 7 of 45 patients who dropped out. Other regimens may be equally effective, especially lenalidomide plus low-dose dexamethasone, as seen in ECOG E4A03 and reported by Rajkumar and colleagues. In that study, 1-year survival was 96.5%, and 95% in patients 65 and older—unprecedented in phase III trials in newly diagnosed patients. That said, I consider melphalan/prednisone/thalidomide a reasonable strategy to use in older patients. — Steven T. Rosen, M.D.
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