ORLANDO, Fla.—Continuous lenalidomide treatment (MPR-R: melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance) achieved a higher overall response rate (ORR) as well as better quality and more rapid responses than melphalan and prednisone (MP) in transplant-ineligible patients with newly diagnosed multiple myeloma.

Furthermore, compared with fixed-duration regimens of MP and MPR, MPR-R resulted in an unprecedented reduction in risk of progression with a manageable safety profile, suggesting that continuous lenalidomide therapy with MPR-R is superior to regimens of limited duration by providing sustained disease control in this patient population, said Antonio Palumbo, MD, of the University of Torino, Torino, Italy.

The prospective phase 3 study (MM-015) enrolled 459 patients aged ≥65 years, median age 71 years,  with newly diagnosed multiple myeloma who were stratified by age and International Staging System (ISS) stage and randomized to receive MPR-R, MPR, or MP. During double-blind treatment, patients received melphalan 0.18 mg/kg (days 1-4), prednisone 2 mg/kg (days 1-4), with or without lenalidomide 10 mg/day (days 1-21) for 9, 28-day cycles. Following 9 cycles of MPR, patients received maintenance lenalidomide (10 mg/day, days 1-21) or placebo until disease progression. Patients in the MP arm received placebo until disease progression. Patients with progressive disease (PD) could enroll in the open-label extension phase and receive lenalidomide at 25 mg/day (days 1-21) with or without dexamethasone at 40 mg/day (days 1-4, 9-12, 17-20), Dr. Palumbo said in an oral presentation during the 52nd American Society of Hematology Annual Meeting and Exposition.

The primary comparison for this trial was MPR-R vs MP. Data presented represent results of a preplanned interim analysis at 70% of events (median follow-up 21 months). Compared with MP, MPR-R resulted in a higher ORR (77% vs 50%; P<0.001) and higher rates of complete response (16% vs 4%; P<0.001) and very good partial response (VGPR) or better (32% vs 12%; P<0.001). Responses, which were more rapid in patients receiving MPR-R vs MP (median 2 vs 3 months; P<0.001), improved over time.

Overall, MPR-R reduced risk of disease progression by 58% vs MP (hazard ratio [HR] = 0.423, P<0.001), with a higher 2-year progression-free survival (PFS) rate (55% vs 16%). PFS was extended in patients receiving continuous lenalidomide therapy vs fixed-duration MP regardless of gender, ISS stage (1/2 vs 3), kidney function (creatinine clearance ≥60 vs <60 mL/min), or baseline β2-microglobulin (≤5.5 vs >5.5 mg/L).

Dr. Palumbo said a landmark analysis comparing MPR-R and MPR was initiated at the beginning of cycle 10. Maintenance lenalidomide was found to result in a 69% reduced risk of progression vs placebo (HR = 0.314, P<0.001). In addition, regardless of induction response (≥VGPR or PR), patients who received maintenance lenalidomide had longer PFS vs placebo. Patients relapsing during MPR-R had similar second-line treatment duration (median 55 weeks) compared with those relapsing while on placebo following MPR (median 68 weeks) or MP (54 weeks).

Additionally, PD rates during the open-label extension phase were similar across all treatments (13% for each). Thus, outcomes of patients who relapse following continuous lenalidomide are similar to outcomes of those who relapse following fixed-duration regimens, suggesting that maintenance lenalidomide is not associated with more aggressive relapse. Follow-up remains too short to identify significant OS differences among the 3 groups; the 1-year OS is about 93%-93% and 2-year OS is 91%-92.

MPR-R had a manageable safety profile, with minimal cumulative toxicities. Discontinuation rates due to adverse events (AEs) were 20% for those treated with MPR-R and 8% with MP. Grade 3/4 neutropenia, thrombocytopenia, and anemia occurred in 71%, 38%, and 24% of patients receiving MPR-R and 30%, 14%, and 17% of those receiving MP; no grade 3/4 peripheral neuropathy was observed. Maintenance lenalidomide was as well tolerated as placebo, with few grade 3/4 AEs. During maintenance treatment, low rates of thrombocytopenia (3% vs 2%), neutropenia (2% vs 0%), deep vein thrombosis (1% vs 0%), and fatigue (1% vs 0%) were observed.

MPR-R is a new standard treatment option and is highly active in patients 65-75 years of age. Continuous lenalidomide treatment achieved an unprecedented PFS, with a median PFS of 31 months.

Off Label Use: Lenalidomide is not approved for first line use in multiple myeloma.