August 1, 2016

Jason M. Broderick

Maintenance lenalidomide following frontline treatment with high-dose melphalan and autologous stem cell transplant reduced the risk of death by 26% versus placebo or no maintenance in patients with multiple myeloma.

Philip McCarthy, MD

Maintenance lenalidomide (Revlimid) following frontline treatment with high-dose melphalan and autologous stem cell transplant (ASCT) reduced the risk of death by 26% versus placebo or no maintenance in patients with multiple myeloma, according to a meta-analysis presented at the 2016 ASCO Annual Meeting.

The analysis included pooled data from 1209 patients with newly diagnosed multiple myeloma enrolled across 3 phase III randomized trials: CALGB (Alliance) 100104, IFM 2005-02, and GIMEMA-RVMM-PI-209. The 7-year overall survival (OS) rate was 62% with maintenance lenalidomide versus 50% in patients who did not receive the therapy.

“Lenalidomide maintenance following autologous stem cell transplant can now be considered a standard of care for people with multiple myeloma,” Philip McCarthy, MD, senior author on the meta-analysis and principal investigator of the CALGB study said in a statement released during the ASCO meeting.

“The improvements over the last decade in terms of both survival and quality of life for patients with this disease are striking, and very encouraging,” added McCarthy, who is director of Blood & Marrow Transplant at Roswell Park Cancer Institute.

In the pooled analysis, 605 patients had been randomized between 2005 and 2009 to lenalidomide maintenance and 604 patients received placebo or no maintenance. Baseline characteristics were well balanced between the 2 arms. Eighty-two percent of patients received single ASCT and 18% received tandem ASCT. Following induction therapy and ASCT, a complete response (CR) or very good partial response (VGPR) was reached by 55% of the patients.

At a median follow-up of 80 months, the median OS had not been reached in the maintenance lenalidomide arm versus 86 months in the control arm (HR, 0.74; 95% CI, 0.62-0.89; P = .001). The researchers estimated this represents a 2.5-year OS benefit with maintenance lenalidomide. The reduction in the risk of death with lenalidomide was 14% (HR, 0.86; 95% CI, 0.65-1.15) in patients who had a partial response or less to induction treatment and ASCT, and 30% (HR, 0.70; 95% CI, 0.54-0.90) in patients who achieved a CR or VGPR.

The 5-year OS rate was 71% with maintenance lenalidomide versus 66% in the control arm. The 6-year OS rates were 65% versus 58%, respectively.

The OS benefit observed in the pooled analysis is consistent with previously reported progression-free survival data, which showed that in each of the phase III studies, maintenance lenalidomide reduced the risk of disease progression or death by approximately 50%.

"Lenalidomide has consistently demonstrated improvement in progression-free survival in this setting," lead author of the IFM study, Michel Attal, MD, University of Toulouse, said in a statement released during the ASCO conference. "The improved overall survival shown by this meta-analysis further supports the positive benefit-risk ratio observed in the individual phase III studies."

The risk of developing a hematologic or solid tumor second primary malignancy (SPM) was higher in patients receiving lenalidomide, with hazard ratios of 2.03 (95% CI, 1.14-3.61; P = .015) and 1.71 (95% CI, 1.04-2.79; P = .032), respectively. There were 36 hematologic SPMs in the lenalidomide cohort compared with 17 in the control group. Cases of solid tumor SPMs were 43 and 25, respectively.

McCarthy noted, however, that, “The overall survival benefit of lenalidomide maintenance outweighs the risk of developing an SPM.”

IFM 2005-02 was a phase III double-blind trial in which treatment-naïve patients with multiple myeloma who had received induction chemotherapy and ASCT were randomized in a 1:1 ratio to consolidation lenalidomide (25 mg/day on days 1-21 of each 28-day cycle, for 2 cycles) followed by placebo or maintenance lenalidomide (10 mg/day induction dose increased to 15 mg/day at 3 months if tolerated). The study was conducted at 78 centers in France, Belgium, and Switzerland, and had a primary endpoint of posttrantplant PFS.

In the the double-blind, open-label phase III GIMEMA-RVMM-PI-209 trial, newly diagnosed patients with multiple myeloma who received standard induction with lenalidomide plus dexamethasone were then treated with ASCT or MPR (melphalan, prednisone, and lenalidomide), followed by maintenance lenalidomide or no treatment. The trial was conducted at 62 locations in Italy and Israel. The primary objective was PFS and the secondary outcome measure was the efficacy and safety of maintenance lenalidomide.

Commenting on the pooled analysis results, the lead investigator of the GIMEMA study, Antonio Palumbo, MD, of the University of Torino, said, “The results of this meta-analysis reinforce the long-term benefit that lenalidomide maintenance therapy has demonstrated in myeloma patients who receive an autologous stem cell transplant within the large, phase III studies individually.”

Attal M, Palumbo A, Holstein SA, et al. Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): a meta-analysis (MA) of overall survival (OS). J Clin Oncol 34, 2016 (suppl; abstr 8001).

The doubled-blind phase III CALGB (Alliance) 100104 trial randomized patients with multiple myeloma to maintenance lenalidomide or placebo after first-line chemotherapy and ASCT. Lenalidomide was started at 10 mg daily and elevated to 15 mg daily at 3 months for patients who tolerated the initial treatment. The trial was conducted at 47 locations in the United States. The primary endpoint was time to tumor progression.