Long-Term Outcome of a Prospective Randomized Trial Comparing Continuous Lenalidomide/Dexamethasone with Lenalidomide/Dexamethasone Induction, MEL140 with Autologous Blood Stem Cell Transplantation and Single Agent Lenalidomide Maintenance in Patients of Age 60-75 Years with Newly Diagnosed Multiple Myeloma

Background: Lenalidomide/dexamethasone has been approved as a standard treatment in multiple myeloma and is applied preferentially in older patients with comorbidities. The addition of daratumumab to this therapy is the best treatment option today for patients who are not transplant eligible. Intensity-reduced high-dose melphalan (MEL140) with autologous transplantation also is an effective treatment option for older patients who are transplant eligible but may not tolerate full dose high-dose melphalan (MEL200). A combination of MEL140 with lenalidomide/dexamethasone potentially could produce a better outcome compared with lenalidomide/dexamethasone alone.

Methods: In this trial (DSMM XIII; EudraCT-No: 2008-004083-39) patients of age 60-75 years with newly diagnosed multiple myeloma who had symptomatic and measurable disease were randomly assigned to either (A1) 3 cycles of lenalidomide (25 mg po d1-21/28d) with low-dose dexamethasone (40 mg po d1, d8, d15, d22/28d), followed by stem cell mobilization and then further lenalidomide/dexamethasone cycles until progression or (A2) 3 cycles of lenalidomide/dexamethasone as induction, followed by stem cell mobilization, intensity-reduced high-dose melphalan 140 mg/m2 (MEL140) (single or double) with autologous blood stem cell transplantation and lenalidomide maintenance with 10 mg daily until progression. At randomization, patients were stratified according to age (60-70 years vs 71-75 years) and ISS stage (I, II vs III). The primary endpoint was progression-free survival, and secondary endpoints included safety, response rates and overall survival. Here, we report the long-term outcome.

Results: 348 patients were included into the study and 339 patients could be analysed per intention-to-treat (ITT). Patient characteristics were well balanced between treatment arms. For all patients, median age was 68 years (range 60 – 75), 29% were older than 70 years, 36.5% had ISS stage I, 35.6% ISS stage II, and 27.9% ISS stage III.

After a median follow-up of 68 months, the median progression-free survival (PFS) was 40 months for A1 (169 patients) and 33 months for A2 (170 patients) (HR 1.16; p=0.19) in the ITT analysis. The median overall survival (OS) was 87 months for A1 and 96 months for A2 (HR 1.04; p=0.81). A prespecified per-protocol (PP) analysis was defined to include patients who received at least 6 months of study treatment (also including patients with progressive disease or death during this time period). In this PP analysis the median PFS was 42 months for A1 (139 patients) and 36 months for A2 (131 patients) (HR 1.15; p=0.27); the median OS was 89 months for A1 and 96 months for A2 (HR 1.01; p=0.96). In arm A2, 115 patients (68%) received one or two transplants. For transplanted patients, median PFS was 40 months and median OS was 114 months.

Second primary malignancies (SPMs) were observed in 24 patients in arm A1 (skin 12, solid tumor 11, hematologic 1) and in 20 patients in arm A2 (skin 5, solid tumor 11, hematologic 4).

Conclusion: In the intention-to-treat population, the combination of MEL140 with lenalidomide/dexamethasone induction and lenalidomide single agent maintenance was not superior to continuous lenalidomide/dexamethasone treatment. Subgroup analyses with a focus on the role of transplant will be presented at the meeting.

Sponsor: Gesellschaft für Medizinische Innovation in der Hämatologie/Onkologie – GMIHO