Superior results of Total Therapy 3 (2003-33) in gene expression profiling-defined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance

Abstract

The Total Therapy 3 trial 2003-33 enrolled 303 newly diagnosed multiple myeloma patients and was noted to provide superior clinical outcomes compared with predecessor trial Total Therapy 2, especially in gene expression profiling (GEP)-defined low-risk disease. We report here on the results of successor trial 2006-66 with 177 patients, using bortezomib, lenalidomide, and dexamethasone maintenance for 3 years versus bortezomib, thalidomide, and dexamethasone in year 1 and thalidomide/dexamethasone in years 2 and 3 in the 2003-33 protocol. Overall survival (OS) and event-free survival (EFS) plots were super-imposable for the 2 trials, as were onset of complete response and complete response duration (CRD), regardless of GEP risk. GEP-defined high-risk designation, pertinent to 17% of patients, imparted inferior OS, EFS, and CRD in both protocols and, on multivariate analysis, was the sole adverse feature affecting OS, EFS, and CRD. Mathematical modeling of CRD in low-risk myeloma predicted a 55% cure fraction (P < .001). Despite more rapid onset and higher rate of CR than in other molecular subgroups, CRD was inferior in CCND1 without CD20 myeloma, resembling outcomes in MAF/MAFB and proliferation entities. The robustness of the GEP risk model should be exploited in clinical trials aimed at improving the notoriously poor outcome in high-risk disease.

Figure 1

Clinical outcomes in 2003-33 and 2006-66 trials. Overall survival (OS; A) and event-free survival (EFS; B) from initiation of therapy, as well as timing of onset of complete response (CR) from treatment start (C). Complete response duration (CRD) was measured from onset of CR (D).

Figure 2

Clinical outcomes in 2003-33 and 2006-66 trials according to gene expression profiling (GEP)–defined risk. (A-D) Low-risk disease: OS (A), EFS, (B), CR onset (C), and CRD (D). (E-H) High-risk disease: OS (E), EFS, (F), CR onset (G), and CRD (H).

Figure 3

Mathematical model for GEP-defined low-risk and high-risk myeloma, compatible with a cure fraction for low-risk disease of 55% (CR rate of 63% times 87.6%).

Figure 4

Clinical outcomes in 2003-33 and 2006-66 trials combined for patients with GEP-derived molecular subgroups. OS (A), EFS, (B), CR onset (C), and CRD (D). Subgroup designations are CD-1, CD-2, MMSET/FGFR3, MAF/MAFB, hyperdiploidy, low bone disease, myeloid, and proliferation. Similar colors were used for similar curves (blue represents favorable; yellow, CD-1; and red, unfavorable). P values for individual colors, or 1 color versus the rest.