In a phase III trial reported in The New England Journal of Medicine, Antonio Palumbo, MD, Chief of the Myeloma Unit at the University of Turin, Italy, and colleagues found that high-dose melphalan plus autologous stem cell transplantation improved progression-free survival and overall survival compared with MPR (melphalan, prednisone, and lenalidomide [Revlimid]) consolidation. They also found that lenalidomide maintenance vs no maintenance improved progression-free survival in multiple myeloma patients aged ≤ 65 years.1
Study Details
In this open-label trial, 402 patients aged ≤ 65 years with newly diagnosed multiple myeloma from 62 centers in Israel and Italy received induction therapy consisting of four 28-day cycles of lenalidomide at 25 mg/d on days 1 to 21 plus dexamethasone at 40 mg/d on days 1, 8, 15, and 22 and were randomly assigned between November 2007 and July 2009 to high-dose melphalan plus autologous stem cell transplant or MPR consolidation and to lenalidomide maintenance vs no maintenance. Cyclophosphamide and granulocyte colony-stimulating factor (Neupogen) were used for stem cell mobilization.
At the end of induction, randomization was revealed for the total of 273 patients without progressive disease during induction/mobilization who remained eligible for consolidation therapy and received high-dose melphalan 200 mg/m2 for two 4-month cycles followed by autologous stem cell transplant (n = 141) or MPR consolidation (n = 132). Of these, a total of 251 received randomized treatment with lenalidomide maintenance after high-dose melphalan consolidation (n = 67) or MPR consolidation (n = 59) or no lenalidomide maintenance after high-dose melphalan (n = 68) or MPR (n = 57).
MPR consolidation consisted of six 28-day cycles of melphalan at 0.18 mg/kg on days 1 to 4, prednisone at 2 mg/kg on days 1 to 4, and lenalidomide at 10 mg on days 1 to 21. Lenalidomide maintenance consisted of 10 mg on days 1 to 21 of each 28-day cycle. Patients with progressive disease during induction or consolidation were treated according to local standards and remained in the trial for outcome evaluations. The primary endpoint was progression-free survival.
Survival From Diagnosis
Median follow-up was 51.2 months. Among all enrolled patients, median progression-free survival from time of diagnosis was 54.7 months in patients who received high-dose melphalan plus lenalidomide maintenance, 37.4 months in those receiving high-dose melphalan without maintenance, 34.2 months in those receiving MPR plus lenalidomide maintenance, and 21.8 months in those receiving MPR without maintenance. The respective 5-year overall survival rates were 78.4%, 66.6%, 70.2%, and 58.7%.
Survival From Start of Consolidation
Among the 273 patients eligible for the consolidation phase, median progression-free survival from the start of consolidation was 43.0 months in the high-dose melphalan/autologous stem cell transplant group vs 22.4 months in the MPR consolidation group (hazard ratio [HR] = 0.44, P < .001) and 4-year overall survival was 81.6% vs 65.3% (HR = 0.55, P = .02). The progression-free survival benefit associated with high-dose melphalan was consistent across all patient subgroups.
Survival From Start of Lenalidomide Maintenance
Among the 251 patients eligible for the maintenance period, median progression-free survival from the start of maintenance was 41.9 months with lenalidomide maintenance vs 21.6 months without maintenance (HR = 0.47, P < .001). Three-year overall survival was nonsignificantly prolonged with lenalidomide maintenance (88.0% vs 79.2%, HR = 0.64, P = .14). The beneficial effect of lenalidomide maintenance on progression-free survival was consistent in all subgroups except patients with stage III disease (P = .04 for interaction between stage and treatment).
The investigators found no significant differences in progression-free survival between the lenalidomide maintenance and no-maintenance groups in the comparison of high-dose melphalan vs MPR (P = .99 for interaction) or between the high-dose melphalan and MPR groups in the comparison of lenalidomide maintenance vs no maintenance (P = 0.93 for interaction).
Among patients with relapse, 3-year overall survival from time of relapse was similar in the four treatment groups. In the MPR group, 63% of patients received high-dose melphalan at relapse.
Toxicity
Grade 3 or 4 adverse events that were significantly more common with high-dose melphalan (all P < .001) included neutropenia (94.3% vs 51.5%), thrombocytopenia (93.6% vs 8.3%), gastrointestinal events (18.4% vs 0%), infections (16.3% vs 0.8%), and systemic events (12.8% vs 1.5%).
Grade 3 or 4 adverse events that were more common with lenalidomide maintenance vs no maintenance included neutropenia (23.3% vs 0%, P < .001), infections (6.0% vs 1.7%, P = .09), and dermatologic events (4.3% vs 0%, P = .03).
Treatment was discontinued due to adverse events in 4% of patients during induction and in 0.7% during high-dose melphalan treatment and 3.0% during MPR treatment. Adverse events led to lenalidomide dose reduction in 14.7% of patients and discontinuation in 5.2%.
Second primary cancers were observed in 0.3% of patients during induction, in no patients during high-dose melphalan or MPR consolidation, and in 4.3% of both the lenalidomide maintenance and no-maintenance groups during the maintenance period.
Conclusions
The investigators concluded:
[W]e found that consolidation therapy with high-dose melphalan, as compared with MPR, improved progression-free and overall survival, although at a cost of increased toxicity. Our findings confirm that high-dose melphalan remains the more effective therapeutic option in patients with newly diagnosed multiple myeloma. We also found that maintenance therapy with lenalidomide, as compared with no maintenance therapy, significantly reduced the risk of disease progression. ■
Disclosure: The study was funded by Celgene. For full disclosures of the study authors, visit www.nejm.org.
Reference
1. Palumbo A, Cavallo F, Gay F, et al: Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 371:895-905, 2014.
