Lenalidomide Maintenance in Transplant-Eligible Myeloma Population Still Debated

February 2014 Vol 7, No 1, Special Issue ASH 2013 Payers' Perspectives in Oncology - Multiple Myeloma
Caroline Helwick

New Orleans, LA—The FIRST (Frontline Investigation of Rev­limid plus Dexamethasone versus Standard Thalidomide) trial in transplant-ineligible patients demonstrated the benefit of continuous lenalidomide (Revlimid). However, studies in younger, transplant-eligible patients yielded conflicting results, especially in terms of an overall survival (OS) advantage, according to Mayo Clinic investigators, who performed a systematic review and meta-analysis of existing outcomes data—and updated with data presented at ASH 2013—to evaluate the role of maintenance therapy with lenalidomide.

They identified 4 randomized controlled trials that met the inclusion criteria—IFM 2005-02, CALGB 100104, MM-015, and RV-MM-PI209—involving 1935 patients who received lenalidomide 10-mg daily, after induction or transplant, and continued until progression.

PFS but Not OS Benefit
“All 4 studies showed an improvement in PFS [progression-free survival], with an overall 51% reduction in risk of progression (P <.001),” reported Preet Paul Singh, MD, Division of Hematology, Mayo Clinic, Rochester. “There was modest [but nonsignificant] improvement in OS with lenalidomide maintenance, with 2 studies showing a benefit and 2 not showing one, resulting in a modest 23% reduction in risk.”

However, the use of lenalidomide maintenance was also associated with a 62% increase in the risk of second primary malignancies (P = .006), a 4.9-fold increased risk of neutropenia (P <.001), a 2.7-fold increase in thrombocytopenia (P <.001), a 2.3-fold increased risk of fatigue (P = .01), and a 3.2-fold increase in venous thromboembolism (P = .02).

“The subset of patients benefitting the most from lenalidomide maintenance is not yet defined, and the risks and benefits should be discussed with all patients,” Dr Singh said.

Updated IFM 2005-02 Analysis
A new analysis of the multiple myeloma (MM) IFM 2005-02 trial presented at the meeting confirmed that len­alidomide maintenance prolongs PFS after stem-cell transplantation but does not improve OS.

IFM 2005-02 was a randomized, placebo-controlled phase 3 trial that investigated the efficacy of lenalidomide maintenance after transplantation in 614 patients with MM (aged <65 years) who had not progressed after first-line stem-cell transplant. The patients were randomized to main­tenance with lenalidomide 10-mg to 15-mg daily or to placebo until disease progression.

In the new analysis, the median PFS from randomization was 46 months with lenalidomide and 24 months with placebo (P <.001), but despite the longer 77-month follow-up, the median OS was still not significantly improved with maintenance lenalidomide, being approximately 80 months in each arm (P = .80).

“The discrepancy between PFS and OS was still present,” said Michel Attal, MD, of Toulouse, France. “This is possibly attributed to the shorter survival time after first disease progression in the maintenance arm than is observed in patients receiving placebo.”

Dr Attal called attention to the median second PFS, which was the time from the first progression to the second progression. In this scenario, the placebo arm was superior, with a median second PFS of 24 months versus 13 months with lenalidomide (P = .001).

Second primary malignancies were also almost twice as high in the lenalidomide arm, and the rates of severe neutropenia were 3 times higher.

The meaning of these findings, according to Dr Attal, is that “the benefit of lenalidomide maintenance is an early benefit, occurring in the first 2 years,” after which resistance emerges and creates “a late negative impact of maintenance.”

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