Results of Total Therapy 2 (TT 2), a phase III randomized trial, to determine the role of thalidomide (THAL) in the upfront management of multiple myeloma (MM)

Authors: B. Barlogie, G. Tricot, J. Shaughnessy, E. Rasmussen, F. Zhan, E. Anaissie, M. Zangari, G. Talamo, J. Zeldis, J. Crowley


Background: THAL’s efficacy in end-stage MM justified its evaluation in the context of up-front therapy with TT 2.

Methods: Untreated patients with MM, stratified by B2M and plasma cell labeling index (PCLI), were randomized to -/+ THAL, administered until relapse. 668 patients were enrolled to test whether added THAL would increase 5-yr EFS from 40% to 50% (primary endpoint; 80% power, 2-sided 0.05 level test). DSMB approved release of results in March 2005.

Results: 345/323 patients were randomized to -/+ THAL. Median age, 57yrs; B2M >=4mg/L, 31%; albumin <3.5g/dL, 18%; PCLI >=1%, 14%; abnormal cytogenetics (CA), 30%. Median follow-up is 35 mos; 85% completed 1st and 67% 2nd transplant. THAL increased CR from 43% to 62% (p<0.001), with similar CR durations; 5-yr EFS was superior on THAL (55% vs. 40%; p=0.029, stratified log-rank); 5-yr OS was similar (68% vs 63%; p=0.90), due to shorter post-relapse OS on THAL arm (p=0.001). Of 382 patients with FISH data for amplification of 1q21/CKS1B (amp1q21) and deletion 13q14/Rb (del13), independent negative PF for OS/EFS were CA (p<0.001), amp1q21 (p<0.001/0.003), del 13 (p=0.031/<0.001), LDH>=190U/L (p=0.012/0.005) and albumin<3.5g/dL (p<0.001); adjusting for these PF, THAL was still significantly positive for EFS (p<0.001). R2 for OS was 46% (39% solely due to the 3 genetic PF), indicating that an unprecedented high level of outcome variability had been accounted for.

Conclusions: (1) THAL in TT2 improves CR and EFS, as yet without apparent benefit for OS;
(2) genetic parameters, relevant to cell cycle check point control, dominate among PF. Further follow-up is required to determine whether genetic subgroups benefit from THAL.