Lenalidomide improved progression-free survival after first-line induction therapy but increased risk for second cancers.

Response rates and remission durations have improved for patients with multiple myeloma since the advent of more effective induction regimens and autologous stem-cell transplant (ASCT) consolidation. Nonetheless, most patients experience disease progression within 3 to 4 years. To assess the role of maintenance lenalidomide after initial therapy to improve progression-free survival (PFS), investigators conducted three phase III, multicenter, randomized, double-blind, placebo-controlled trials involving previously untreated multiple myeloma patients.

In an industry-supported study by Palumbo and colleagues, 459 patients (aged 65) with newly diagnosed, symptomatic disease who were ineligible for ASCT were randomized to one of three regimens: melphalan plus prednisone followed by placebo (MP), MP plus lenalidomide (Revlimid; 10 mg of on days 1–21 of 28-day cycle) for 9 cycles followed by placebo (MPR), or MPR induction followed by the same dosage of lenalidomide until relapse or unacceptable toxicity (MPR-R). At median follow-up of 30 months, median PFS was longer with MPR-R (31 months) than with MPR (14 months; P<0.001) or MP (13 months; P<0.001); PFS benefit was achieved by patients aged 65 to 75 but not by those older than 75. Overall survival (OS) was not improved with lenalidomide. The rate of grade 4 neutropenia was higher with lenalidomide versus without (32%–35% vs. 8%), as was the 3-year rate of second primary cancers (7% vs. 3%).

In an industry-supported study by Attal and colleagues, 614 patients (aged <65) without disease progression after induction therapy and ASCT were randomized to placebo or lenalidomide (10 mg daily for 3 months, increased to 15 mg if tolerated) until relapse or unacceptable toxicity. At median follow-up of 30 months, the median PFS was longer with lenalidomide than with placebo (41 vs. 23 months; P<0.001). OS was not improved with lenalidomide. At median follow-up of 45 months, the rate of second primary cancers was higher with lenalidomide than with placebo (3.1 vs. 1.2 per 100 person-years; P=0.002).

In a study by McCarthy and colleagues, 460 patients (aged <71) who achieved stable disease or partial or complete remission at 100 days after ASCT were randomized to placebo or lenalidomide (10 mg daily, dose-adjusted to 5–15 mg as tolerated) until relapse. After a planned interim analysis at median follow-up of 18 months showed a benefit for lenalidomide, 86 of the 128 patients remaining on placebo crossed over to lenalidomide. At a median follow-up of 34 months, the median time to disease progression (the primary outcome) was longer with lenalidomide than with placebo (46 vs. 27 months; P<0.001). The rate of OS at 3 years was higher with lenalidomide than with placebo (88% vs. 80%; 2-sided P=0.03). The rate of grade 3 or 4 neutropenia was higher with lenalidomide than with placebo (P<0.001), as was the cumulative incidence of a second primary cancer (P=0.008).

Comment: Each of these trials showed that lenalidomide improved PFS, and one showed that it improved OS. Further analysis and longer follow-up will be important to better assess toxicities (especially the increased risk for second malignancies) and the response to further therapy in patients with disease progression after lenalidomide maintenance. The benefit of lenalidomide maintenance versus lenalidomide therapy at the time of progression is also of interest, especially for patients in complete remission after initial induction. As an editorialist noted, it is necessary to consider the high cost of lenalidomide. In aggregate, these important phase III trials establish maintenance lenalidomide as an option for myeloma patients who respond to first-line induction therapy.

Source:  Journal Watch Oncology and Hematology