Bart Barlogie, MD, PhD, Elias J. Anaissie, MD, John D. Shaughnessy Jr., PhD, Frits van Rhee, MD, PhD, Mauricio Pineda-Roman, MD, Jeff Haessler, MD, Klaus A. Hollmig, MD, Yazan Alsayed, MD, Sarah Waheed, MD, Monica Graziutti, MD, Elias Kiwan, MD and John Crowley, PhD

We have previously reported on the remarkable activity of the TT3 program that incorporated both bortezomib (V) and thalidomide (T) into the up-front management of 303 patients. TT3 consisted of  2 cycles each of induction prior to and of dose-reduced consolidation therapy with VTD-PACE (cisplatin, doxorubicin, cyclophosphamide, etoposide) after melphalan 200mg/m2 (M200)-based tandem transplants, followed by maintenance therapy for 3 years with VTD and, in later stages, VRD (substituting T for lenalidomide, R). Characteristics included a median age of 59yr (range, 33-75yr), B2M >=4mg/L in 37%, albumin <3.5g/dL in 26%, ISS stages II and III in 33% and 21%, cytogenetic abnormalities (CA) in 33% and gene expression profiling (GEP)-defined high-risk MM in 15% of the 275 patients with such data. With a median follow-up of 39 months, 4-yr overall survival (OS) and event-free survival (EFS) estimates were 78% and 71%, respectively, including 84% and 77% among the 85% with GEP-defined low-risk MM contrasting with 43% and 33% in the remainder with high-risk MM (both p<0.0001). Near-CR and CR, attained in 86% and 63%, were sustained at 4 years from response onset in 78% and 87%, which pertained to 83% and 90% with low-risk MM but to only 44% and 57% with high-risk MM (all p <0.0001). These results were corroborated in a TT3 extension trial (TT3E) that enrolled 175 additional patients, comprising higher proportions of CA (42%) and GEP-defined high-risk MM (21%). Two-year estimates of OS and EFS are 85% and 85%, with 94% and 92% in low-risk patients versus 61% and 62% in high-risk MM (p=0.0001, p=0.0003); the 2-yr estimate of remaining in CR is 93% including 100% in low-risk and 77% in high-risk MM (p=0.01). Multivariate analysis of features linked to OS in TT3 included GEP-defined high-risk, CA, B2M and LDH elevation, collectively accounting for 41% of outcome variability by R2 statistics; the corresponding R2 values for EFS and n-CR duration were 38% and 39%. Compared to the predecessor trial, TT2, that evaluated the role of T in a randomized trial design in 668 patients, TT3 data were superior for OS (p=0.08), EFS (<0.0001), n-CR duration (p<0.0001) and CR duration (p=0.0002). In the low-risk subgroup, EFS (p=0.0001), n-CR duration (p<0.0001) and CR duration (Figure 1a; p=0.0002) all were superior in TT3 versus TT2; whereas, in the high-risk MM group, outcomes remained poor also with TT3 despite superior EFS (Figure 1b; p=0.03). Based on these data, we have now started a GEP-risk-based algorithm of assigning separate therapies to good-risk (TT4) and poor-risk MM (TT5). As the TT3 results for low-risk are difficult to improve upon, TT4 randomizes patients between standard TT3 and TT3-LITE that employs only 1 cycle each of induction and consolidation (with anticipated further improvement in compliance) and 4-day-fractionated M50x4 to enable the addition of VTD and thus exploit synergistic drug interactions to occur. In order to sustain tolerable effective therapies for at least 3 years and prevent recurrence from previous drug-free or insufficiently effective phases in TT3, TT5 for high-risk MM employs less dose-intense and more dose-dense highly synergistic combination therapy, utilizing M10-VTD-PACE for induction, M80 (in 4 daily fractions of M20) plus VRD-PACE tandem transplants, separated by 2 cycles of M20 (in 4 daily fractions of M5) plus VTD-PACE, and followed by 2 years of monthly alternating R-VD and M-VD.

Figure 1a: Superior CR duration with TT3 v TT2 in GEP-low-risk MM:

Figure 1b: Superior event-free survival with TT3 v TT2 in GEP-high-risk MM: