In 2012, three randomized placebo-controlled trials reported that maintenance treatment with lenalidomide (Revlimid) in multiple myeloma resulted in a significant increase in progression-free survival. Two of these trials examined the efficacy of maintenance therapy with lenalidomide after stem cell transplantation, and the other examined the efficacy of maintenance therapy after conventional melphalan-based therapy. One post-transplantation study conducted in the United States found an improvement in overall survival, but no survival benefit was seen in the other trials. All three studies showed a significant increase in the incidence of second cancers. The publication of these findings has generated some controversy. Some experts endorsed conventional maintenance therapy (at least in the post-transplant clinical setting), while others felt that further data should be obtained before the above therapies could be recommended. Instead of clarifying this issue, the frequent interpretive updates on these studies in subsequent meetings have added new misconceptions. In this issue, we focus on these findings in the post-transplant clinical context. At the outset of the publication of these studies, experts pointed out the reasons for caution. We need more data to clarify whether all patients need to receive lenalidomide maintenance therapy after transplantation. This remains the current attitude. The background of the study is post-transplant maintenance therapy. Autologous stem cell transplantation therapy did not cure multiple myeloma, but rather prolonged overall survival. Subsequently, three randomized trials found that the timing of stem cell transplantation (early transplantation vs. transplantation at first relapse) did not affect overall survival, but we generally always prefer early stem cell transplantation because it leads to a longer window of time without treatment or without toxic events. Routine maintenance therapy, even with oral agents or well-tolerated drugs, reduces the above time window, which is actually what makes early autologous stem cell transplantation so attractive. The fact that maintenance therapy is of indefinite duration and can continue until disease progression means that myeloma patients are required to remain on medication for life, whereas the median survival of young standard-risk patients has exceeded 10 years. A clear benefit in overall survival would also support the above pathway, especially if treatment is reasonable and well tolerated. Chronic granulocytic leukemia is a good example of this. However, at least for now, we simply do not have convincing long-term data on survival benefit. Even the U.S. studies that have found a survival benefit have not been available to all subgroups of patients. Some patients will also suffer from the treatment. Next, let’s explore a major misconception. There are two very similar trials, one done in the US and the other by the French IFM, but only the US trial found an improvement in survival. A common explanation is that the French trial terminated the trial after 2 years of maintenance treatment, whereas in the US trial maintenance treatment continued until disease progression. This is an incorrect interpretation. The median duration of maintenance treatment at the time the US trial was counted was nearly 2 years, which is much shorter than the duration of maintenance treatment in the French trial. It is true that the rule of the IFM trial was to discontinue maintenance treatment as soon as a second cancer risk was identified (median treatment duration of 2 years), but this is not a reason for the lack of survival benefit. What exactly are the reasons for the survival differences in these two trials? There are many possible reasons, but at least two deserve detailed discussion. One is that 35% of the patients in the US trial had received lenalidomide induction therapy, and all of these patients had a significant survival benefit. No significant survival benefit was seen in patients who did not receive lenalidomide induction. How should this effect be explained? Patients who did not respond to lenalidomide induction therapy or who exhibited unnecessary toxicities were excluded. On the other hand, patients in the trial who were found to have a clear survival benefit were those who received lenalidomide induction prior to randomization and were most likely to achieve remission from this treatment and tolerate it well. A second reason for the lack of a survival benefit in the French IFM trial was that all patients treated with autologous stem cell transplantation were given 2 months of lenalidomide consolidation therapy. Some believe this was a problem in the French trial, but experts say they disagree. A more plausible explanation is that if two months of consolidation therapy helped improve survival, why was this effect not seen with the subsequent 4 years of maintenance therapy? After all, two months of consolidation therapy is low in toxicity, carries little risk of second cancers, and is much less expensive. The fact that lenalidomide maintenance therapy increased the risk of second cancers in all three trials is another cause for concern. These risk values were about 7% in the lenalidomide group compared to 3% in the placebo group. In the transplantation setting, lenalidomide can be used for a short period of time after the administration of high-dose melphalan-based therapy, and melphalan-based therapy is not first-line therapy, so lenalidomide can be used until disease progression without causing a significant increase in the risk of second cancers. The clear benefit of survival may offset the risk of second cancer, but simply delaying progression does not offset this risk. Although the risk of progression in multiple myeloma is much higher than the risk of second cancers, the two are not comparable, as progression is only the definition of a biochemical indicator of myeloma and can be treated once detected, whereas a fatal second cancer is much more serious. The remaining cancers can be addressed by a longer follow-up, and another Italian trial could provide the answer. We will also follow the results of an ongoing randomized trial done by the Eastern Oncology Collaborative Group that explores the duration of maintenance treatment: two years vs. continuing until disease progression. In the meantime, we must make some judgments based on some of the incomplete data available. After a careful risk-benefit assessment by the Mayo Clinic, the panel made the following recommendation: For standard-risk patients, sequential 2-month lenalidomide consolidation therapy after autologous stem cell transplantation is recommended. The results of the French trial showed no effect on overall survival with or without lenalidomide maintenance therapy using this strategy. After 2 months of consolidation therapy, lenalidomide maintenance therapy is recommended if it is clear that the patient can produce remission to lenalidomide and does not achieve very good partial or complete remission. These patients are the specific subgroup identified in the U.S. trial as having a survival benefit. As for the duration of maintenance therapy, experts recommend a maximum of 2 years. Beyond this, we do not have randomized comparable data to evaluate the value of extended maintenance therapy, but the French trial has clearly demonstrated that it increases the risk of second cancers, and the randomization process of this trial is trustworthy. For intermediate-risk and high-risk patients, experts recommend a maintenance regimen based on bortezomib (Vanco) as the preferred treatment based on the results of several recent trials. Myeloma is a cytogenetically heterogeneous complex solid tumor, and individualized treatment should be attempted to maximize benefit and minimize harm to patients.