Although a cure for multiple myeloma is still not possible in most patients, maintenance of a prolonged progression-free interval with minimal toxicity is an important goal in the management of this disease. The median overall survival among patients who required therapy before 1996 was approximately 3 years.23
In the era of new agents and autologous hematopoietic stem-cell transplantation, the median overall survival after transplantation is close to 8 years.23,24
In this study, 85% of patients in the lenalidomide group and 77% of patients in the placebo group were alive at a median follow-up of nearly 3 years.
Several strategies have been implemented to improve the response to primary therapy since it correlates with the outcome.25–27
Patients with multiple myeloma who have complete remission after primary therapy appear to have a longer time to progression, resulting in prolonged overall survival, although patients with a very good partial response (>90% reduction in myeloma protein) may have excellent outcomes.25
Maintenance of disease control without clinically significant progression and dose-limiting toxic effects, as well as tolerability for the patient, may also translate into prolonged overall survival. Lenalidomide maintenance may increase the time to progression in patients who do not have complete remission after induction therapy and transplantation, thus generating outcomes similar to those for patients with complete remission. Although the response criteria of the International Myeloma Working Group were not used for all patients in this study, the results are consistent with those of previous studies with respect to response and outcome.
Diagnostic cytogenetic abnormalities in multiple myeloma have been associated with the outcome.28
Cytogenetic analysis was not required for enrollment in this study; however, a review of available data is ongoing. We expect this information to better define populations that would benefit most from lenalidomide maintenance therapy. Patients with disease progression before day 100 after autologous hematopoietic stem-cell transplantation (4% of the patients who were registered in our study) were not eligible to undergo randomization. We cannot conclusively say whether induction regimens with multiple drugs could overcome progressive disease and whether this group of patients would benefit from maintenance therapy after transplantation.
Consolidation therapy after induction therapy and transplantation is one strategy that improves outcomes. Consolidation appears to be most effective in inducing complete remission in patients with residual disease.29,30
Consolidation therapy is more intensive than maintenance therapy, often with toxic effects. In this study, lenalidomide maintenance as a form of prolonged therapy, as compared with placebo, prolonged the time to progression and increased overall survival.
Despite its demonstrated efficacy, thalidomide maintenance therapy has been limited by neurotoxicity, with up to 75% of patients discontinuing maintenance therapy.7–12
Other studies have shown that lenalidomide and bortezomib used as maintenance therapy are better tolerated, with clinically significant efficacy for long-term maintenance after autologous hematopoietic stem-cell transplantation.31,32
In this issue of the Journal,
Attal et al.33
also report a significantly prolonged time to disease progression with lenalidomide maintenance therapy after autologous hematopoietic stem-cell transplantation. A related article by Palumbo et al.34
describes a significantly prolonged time to disease progression with lenalidomide maintenance therapy after the use of low-dose induction therapy. These three studies show the usefulness of lenalidomide maintenance therapy for prolonging the time to disease progression in both patients who have undergone stem-cell transplantation and those who have not. The study reported by Attal et al.33
did not show an overall survival benefit, a finding that could be due to differences in induction (use or nonuse of lenalidomide-based induction therapy) and consolidation (use or nonuse of more alkylator-based chemotherapy) before transplantation, the use of lenalidomide consolidation therapy in both groups after transplantation, the use of two transplantations in some patients, and the discontinuation of maintenance therapy.33
Longer follow-up and additional studies may clarify the different findings.
A major concern during maintenance therapy is toxicity that limits long-term use and the ability to receive future treatment after disease progression or that results in life-threatening disorders. Acute myeloid leukemia or the myelodysplastic syndrome has been reported in patients with multiple myeloma who did not undergo transplantation and were treated with melphalan.35,36
An observational bias is unlikely to explain these findings because of the rapid development of acute myeloid leukemia and, to a lesser extent, the my-elodysplastic syndrome. A recent report by the Swedish Cancer Registry described an increased incidence of these disorders in patients with multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS).37
The finding that acute myeloid leukemia or the myelodysplastic syndrome occurs in untreated patients with MGUS suggests that these plasma-cell disorders are associated with a hematopoietic stem-cell or microenvironmental defect in addition to an effect of chemotherapy exposure. Multiple myeloma is also associated with solid-tumor cancers.38
In this study, the increase in second primary solid-tumor cancers in the lenalidomide group was not associated with a specific tumor type, and the cause was uncertain. Close monitoring of blood counts, as indicated by the study guidelines, and standard screening for cancers are recommended.
In conclusion, this study suggests that lenalidomide maintenance therapy until disease progression is feasible for prolonged administration. The increase in time to progression led to early study unblinding, and despite the crossover, benefits with respect to progression and overall survival were seen in patients receiving lenalidomide maintenance therapy, especially those who had received lenalidomide-based induction therapy. It remains to be determined whether the incorporation of other new agents with lenalidomide will further increase the time to disease progression and overall survival.