Lenalidomide in Older Multiple Myeloma Patients

For patients 65 to 75 years of age newly diagnosed with multiple myeloma who were ineligible for transplant, treatment with lenalidomide maintenance therapy extended the time before relapse in a recent study [N Engl J Med. 2012;366(19):1759-1769].

The phase 3, multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of induction therapy with melphalan-prednisone-lenalidomide followed by lenalidomide maintenance (MPR-R), compared with melphalan-prednisone-lenalidomide (MPR) or melphalan–prednisone (MP) followed by placebo. The study, conducted at 82 centers in Europe, Australia, and Israel, recruited patients from February 2007, to September 2008.

Patients were randomized in a 1:1:1 ratio to receive MPR-R (n=152), MPR (n=153), or MP (n=154) and were stratified according to age (65-75 years vs >75) and International Staging System stage. Approximately two thirds of the patients completed induction treatment. Baseline characteristics were well balanced among the 3 treatment arms, with the exception of a higher Karnofsky performance-status score in the MP group than in the MPR-R and MPR groups.

Median age was 71 years; 111 patients (24%) were >75 years of age. A high percentage of patients had International Staging System stage III, indicating more severe disease (48%-51% in the 3 treatment groups). The median follow-up period was 30 months. The primary end point was progression-free survival. Secondary end points included response rate, overall survival rate, and adverse events.

The MPR-R regimen consisted of induction with nine 9 28-day cycles of melphalan (at a dose of
0.18 mg per kilogram of body weight on days 1-4), prednisone (2 mg per kilogram on days 1-4), and lenalidomide (10 mg on days 1-21), followed by lenalidomide maintenance (10 mg on days 1-21 of each 28-day cycle) until disease progression or the development of unacceptable rates of adverse effects. The MPR group received the same MPR induction, followed by placebo, and the MP group received MP induction (at the same doses and on the same schedule as the MPR regimen), with placebo during induction and maintenance. All patients received aspirin thromboprophylaxis (75 mg-100 mg daily) during induction.

The median progression-free survival was significantly longer in the MPR-R treatment arm (31 months), compared with MPR (14 months; hazard ratio [HR], 0.49; P<.001) and MP (13 months; HR, 0.40; P<.0001). The progression-free survival benefit associated with MPR-R was observed in patients 65 to 75 years of age, but not in those >75 years of age (P=.001 for treatment-by-age interaction). After induction therapy, a landmark analysis showed a 66% reduction in the rate of progression with MPR-R, compared with MPR (HR, 0.34; P<.001). The 3-year rate of invasive second primary tumors was lowest with MP at 3%, compared with 7% for each MPR-R and MPR treatment groups.

Response rates were better with MPR-R and MPR (77% and 68%, respectively vs 50% with MP; P<.0001 and P=.002, respectively, for the comparison with MP). The 3-year overall survival rate was 70% with MPR-R, 62% with MPR, and 66% with MP. During induction, the most frequent adverse events were hematologic; grade 4 neutropenia was reported in 35% (n=52), 32% (n=49), and 8% (n=12) of the patients in the MPR-R, MPR, and MP groups, respectively. Grade 4 thrombocyctopenia occurred in 11% (n=17), 12% (n=19), and 4% (n=6) of patients in the MPR-R, MPR, and MP groups, respectively.

Although benefits of MPR are less evident in older patients, “lenalidomide maintenance extends progression-free survival regardless of age,” the researchers concluded.