Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma

Abstract

Background: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown.

Methods: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival.

Results: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P = 0.55); 42.0% and 46.8%, respectively, had a complete response or better (P = 0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65).

Conclusions: Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.).

Figure 1.. Screening, Randomization, Treatment, and Follow-up.

Of the 77 patients who did not meet eligibility criteria, 32 did not have measurable disease or had minimal measurable disease, 9 did not have end‑organ damage as defined by the CRAB criteria (i.e., hypercalcemia, renal insufficiency, anemia, or bone lesions), 26 had laboratory values outside permitted cutoff levels, 4 had exceeded the limit of previous therapy, and 6 had screening failure. Of the 24 patients who discontinued the trial for other reasons, 9 had another complicating disease, 8 had insurance issues, 4 discontinued because of physician decision, 2 were unable to adhere to the trial protocol, and 1 had received an alternative therapy. The 76 patients who did not receive lenalidomide maintenance therapy included the 55 patients who had not received melphalan and undergone autologous stem‑cell transplantation (ASCT). Of the 31 patients in the RVD (lenalidomide, bortezomib, dexamethasone)–alone group who discontinued the trial therapy for other reasons, 10 (2 before maintenance therapy) had received therapy outside the trial protocol for another cancer, 2 (1 before maintenance therapy) had received therapy outside the trial protocol for multiple myeloma, 4 (2 before maintenance therapy) had a treatment delay of more than 6 weeks, 7 (4 before maintenance therapy) withdrew consent, 1 had other reasons for discontinuation before maintenance therapy, and 7 had missing data. Of the 39 patients in the transplantation group who discontinued the trial therapy for other reasons, 13 (1 before maintenance therapy) had received therapy outside the trial protocol for another cancer, 2 (1 before maintenance therapy) had received therapy outside the trial protocol for multiple myeloma, 15 (4 before maintenance therapy) had a treatment delay of more than 6 weeks, 5 (2 before maintenance therapy) withdrew consent, and 4 had missing data.

Figure 2.. Kaplan–Meier Curves for Progression-free Survival and Overall Survival in the Intention-to-Treat Population.

Panel A shows progression‑free survival among patients who received RVD alone and among those who received RVD plus transplantation. In the RVD‑alone group, of 189 events of disease progression or death, 1 death occurred in the absence of disease progression. In the transplantation group, of 139 events, 11 deaths occurred in the absence of disease progression. Panel B shows the Kaplan–Meier analysis of overall survival in the two groups; there were 90 deaths in the RVD‑alone group and 88 deaths in the transplantation group. In both panels, tick marks indicate censored data.