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Len Maintenance in MM
Lenalidomide Now Approved for Maintenance in Myeloma

Released: April 25, 2017

Expiration: April 24, 2018

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After years of research, we finally have some clarity on maintenance therapy for myeloma, at least for patients who have received autologous stem cell transplantation (ASCT). In February 2017, the FDA approved lenalidomide as maintenance therapy in this setting. However, this approval addresses an issue many experts have already accepted: Maintenance therapy improves outcomes after transplantation. Even so, the expanded indication for lenalidomide in myeloma is likely to influence clinical practice in important ways. Below, I address some questions regarding this new approval.

What were the concerns that delayed adoption of lenalidomide as maintenance therapy?
The delay in adoption and approval of lenalidomide as a maintenance therapy was likely related to limited data on the survival benefit of this treatment approach in the post-transplantation setting. The FDA approval clearly highlights the clinical benefit associated with maintenance therapy with lenalidomide. This approval also demonstrated that a benefit exists despite a higher rate of second primary malignancies with lenalidomide maintenance. A large meta-analysis of 3 clinical trials (CALGB 100104 from the United States, IFM 2005-02 from France, and the GIMEMA study from Italy) demonstrated a significant improvement in both PFS and OS with the addition of lenalidomide maintenance after ASCT. Although this meta-analysis showed significantly higher rates of second primary malignancies (hematologic HR: 2.03, P = .015; and solid tumor HR: 1.71, P = .032), the competing risk of death is outweighed by the benefit of maintenance lenalidomide, supporting its use in these patients. These results are quite impressive, even in an era where many patients receive multiple lines of therapy, and highlight that choices early in the disease course can have a significant long-term effect by delaying disease progression and extending survival.

Who doesn’t appear to benefit as much from post-ASCT lenalidomide?
In the trials that led to this recent approval, patients with high-risk disease appeared to benefit less from lenalidomide maintenance therapy (HR: 1.18 in the meta-analysis). This reflects similar findings in other trials that included high-risk patients; newer data suggest that high-risk patients may benefit more from combination maintenance therapy with lenalidomide plus a proteasome inhibitor. Nooka and colleagues evaluated 45 consecutive patients with high-risk cytogenetics—that is, patients with del(17p), del(1p), t(4;14), t(14;16), or presentation as PCL—and showed that combination maintenance/consolidation with RVD following ASCT resulted in 96% of patients achieving VGPR or better as best response, with 51% achieving stringent CR.

What is the effect on postrelapse salvage therapy?
Many of the large randomized myeloma trials published in the past 4 years for the treatment of early relapse used lenalidomide/dexamethasone as the control arm, but those patients generally had not received lenalidomide maintenance. Given what is likely to be widespread adoption of lenalidomide maintenance, approaches for early relapse will start to include either a proteasome inhibitor (bortezomib, ixazomib, or carfilzomib) or pomalidomide, as many patients will already be resistant to lenalidomide at the time of first relapse. More data are needed from phase III trials of non-lenalidomide–based salvage therapies to improve outcomes in the expanding population of patients with early relapse.

What is the benefit for patients?
Many large data sets have demonstrated that patients with myeloma who receive modern induction therapy followed by ASCT and lenalidomide maintenance have a median PFS approaching 5 years. This is a welcome improvement, but it creates additional questions: Do all patients need lenalidomide until progression? How will the evolving role of minimal residual disease testing influence duration of therapy? Of most importance, how will new immunotherapies be used once patients are in a deep remission? Might immunotherapy be the key to long-term control, allowing patients to discontinue therapy?

These and many other questions will require in-depth and complex phase III trials to answer, but for now, the news is fantastic for patients—the longer we are able to keep our patients in first remission, the more time we have to generate additional data and develop agents to manage early relapse.

Be sure to try our interactive treatment decision aid to help you select optimal maintenance therapy for your patients with myeloma. This tool was designed by my colleagues (Kenneth Anderson MD; Carol Ann Huff, MD; Shaji Kumar, MD; and Suzanne Lentzsch, MD, PhD) and me to help you rapidly select individualized treatment options using pull-down menu options in the online tool, based on your patient’s specific disease characteristics.

Share your thoughts on the new approval of lenalidomide as maintenance therapy for myeloma in the comment box below!

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