Continuous Treatment with Lenalidomide Plus Low-Dose Dexamethasone (Ld) Versus Ld Induction Followed By Autologous Stem Cell Transplant (ASCT) in Patients with Newly Diagnosed Multiple Myeloma (NDMM): A Pooled Analysis of Two Randomized Clinical Trials

Background: High-dose chemotherapy followed by ASCT remains the standard of care for patients aged ≤75 years with NDMM. The ability of novel agents, such as lenalidomide and bortezomib, to produce treatment response rates comparable to those seen with ASCT has raised questions about the necessity for upfront ASCT in transplant-eligible NDMM patients. This analysis aimed to compare the efficacy and safety of continuous Ld versus Ld+ASCT in patients with NDMM.

Methods: Data were pooled from two randomized clinical trials (NCT01731886 and NCT00807599) that compared Ld alone versus Ld+ASCT in NDMM patients aged ≤75 years. Patients received four 28-day cycles of Ld (lenalidomide 25mg daily on days 1–21; dexamethasone 40mg on days 1, 8, 15, and 22) followed by stem-cell mobilization and collection, and either a) Arm A: continuous Ld (an additional 4 cycles +/- lenalidomide maintenance in NCT01731886, or continuous lenalidomide at the last tolerated dose until disease progression plus dexamethasone 20mg for 1 year following treatment initiation in NCT00807599); or b) Arm B: ASCT conditioned with high-dose melphalan, and followed by lenalidomide maintenance therapy. In both trials, patients were withdrawn if they developed progressive disease (PD) at any time, or had stable disease (SD) after cycle 4 of Ld induction. We evaluated overall response rate (ORR; defined as a partial response or better), progression-free survival (PFS), overall survival (OS), and adverse event (AE) incidence rates, focusing on those randomized patients who responded to 4 cycles of Ld induction.

Results: Sixty patients were enrolled into NCT01731886, and 63 into NCT00807599. The analysis included a total of 85 patients who had been randomized and achieved a response to 4 cycles of Ld induction: 41 in Arm A, and 44 in Arm B. Mean ages in Arm A versus Arm B were 61.8 versus 61.7 years; median (range) follow-up times were 3.97 (0.27–6.19) versus 3.71 (0.16–5.66) years. Baseline cytogenetic risk profiles were similar overall, although Arm A contained a higher percentage of intermediate-risk patients (17.1% versus 11.4%). More than half of all patients included in the analysis had International Staging System stage 1 disease: 63.4% of patients in Arm A, and 47.7% of those in Arm B. Median PFS was similar with the two treatment approaches: 4.3 versus 4.4 years (Figure 1; p = 0.9107). OS also did not differ significantly between the two arms (Figure 2). As expected, both treatment regimens were well tolerated. Clinically significant grade 3 and 4 AEs occurring outside of the transplant period included the following: anemia (17.1% Arm A versus 15.9% Arm B); neutropenia (36.6% versus 38.6%); thrombocytopenia (17.1% versus 18.4%); infectious complications (14.6% versus 27.3%); thromboembolic events (7.3% versus 6.8%); and secondary malignancies (7.3% versus 4.5%).

Conclusions: The findings of this pooled analysis suggest that, in transplant-eligible patients responsive to Ld induction, continuous Ld results in similar PFS and OS to Ld+ASCT. Larger phase III trials addressing this question are awaited.

Figure 1

Figure 2