A phase III Eastern Cooperative Oncology Group (ECOG) trial (E1A060) comparing melphalan, prednisone, and thalidomide (Thalomid) with melphalan, prednisone, and lenalidomide (Revlimid) in elderly patients with untreated multiple myeloma found that at the end of the induction period, patients receiving melphalan, prednisone, and lenalidomide had “a statistically superior” quality of life.
“Much of this difference appears attributable to lower neuropathy rates with lenalidomide than with thalidomide,” A. Keith Stewart, MBChB, of Mayo Clinic Arizona in Scottsdale, and colleagues reported in Blood. There were no statistical or clinically relevant differences in response rates, progression-free survival, or overall survival.
A total of 306 patients enrolled: 154 in the melphalan, prednisone, and thalidomide arm and 152 in the melphalan, prednisone, and lenalidomide arm. “Seven cooperative groups contributed, with 66% of patients coming from 33 participating ECOG centers,” the researchers noted.
“Eligible patients required a confirmed diagnosis of multiple myeloma as well as evidence of end-organ damage at the time of diagnosis. Patients were ≥ 65 years and had declined alternative treatment or were < 65 years and were not candidates for autologous stem cell transplantation or had declined transplant,” the investigators explained. The median age of the study participants was 75.7 years. ECOG performance status ≤ 2 was required.
For induction therapy, patients received either 9 mg/m2 of melphalan and 100 mg of prednisone orally on days 1 to 4 with 100 mg of thalidomide daily or 5 mg/m2 of melphalan and 100 mg of prednisone orally on days 1 to 4 with 10 mg of lenalidomide orally on days 1 to 21. The authors explained that they used “the designation melphalan, prednisone, and lenalidomide to delineate the lower doses of melphalan that can be coadministered as well as continuous use of lenalidomide, with a hypothesis that melphalan, prednisone, and lenalidomide would be noninferior and possibly superior in terms of toxicity and survival outcomes.”
Patients continued on therapy for 12 28-day cycles followed by 100 mg of thalidomide or 10 mg of lenalidomide daily until progression or unacceptable toxicity. “Mean duration of overall treatment (induction and maintenance) was 15.6 months on melphalan, prednisone, and thalidomide and 14.9 months on melphalan, prednisone, and lenalidomide for the entire study cohort,” the authors noted.
Survival Findings
The median follow-up was 40.7 months. For the primary intention-to-treat analysis, the median progression-free survival observed was 21.0 months for patients receiving melphalan, prednisone, and thalidomide vs 18.7 months for those receiving melphalan, prednisone, and lenalidomide (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.64–1.09; P = .186). Overall survival was 52.6 months with melphalan, prednisone, and thalidomide vs 47.7 months with melphalan, prednisone, and lenalidomide (HR, 0.88; 95% CI, 0.63–1.24; P = .476). “Per-protocol response rates were 63.6% (melphalan, prednisone, and thalidomide) and 59.9% (melphalan, prednisone, and lenalidomide; P = .557),” the investigators reported.
Toxicity
“Both regimens proved toxic,” the authors wrote. “At least 58% of melphalan, prednisone, and lenalidomide patients and 73% of melphalan, prednisone, and thalidomide patients experienced grade 3 toxicity, and half the patients discontinued treatment before finishing 12 months of planned induction therapy, with toxicity being the primary reason (42%) for stopping treatment.”
Patients receiving melphalan, prednisone, and thalidomide had significantly higher ≥ grade 3 nonhematologic toxicity, 59.5% vs 40.0% receiving melphalan, prednisone, and lenalidomide (P = .001). “There was also a notable age effect in the melphalan, prednisone, and thalidomide arm,” the investigators noted, with 47.2% of those > 75 years experiencing a grade ≥ 3 adverse event vs 35.6% of patients < 75 years. “This difference in tolerability by age was not significant in melphalan, prednisone, and lenalidomide patients,” the authors wrote.
Grade ≥ 3 events occurring in > 5% of patients included anemia, leukopenia, lymphopenia, neutropenia, fatigue, constipation, and dyspnea (in the melphalan, prednisone, and thalidomide arm only). Deep vein thrombosis or pulmonary embolism was observed in 8.8% of the melphalan, prednisone, and thalidomide patients and 6.7% of the melphalan, prednisone, and lenalidomide patients. Second malignancies occurred in 18 melphalan, prednisone, and thalidomide patients and 14 melphalan, prednisone, and lenalidomide patients. ■
Stewart AK, et al: Blood 126:1294-1301, 2015.
