Long CR Duration With Total Therapy 3 for Myeloma

ASCO—Efficacy was high and mortality was low with Total Therapy 3 (TT3), the latest version of Total Therapy for myeloma from Bart Barlogie, MD, PhD, and colleagues at the Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock. Dr. Barlogie reported the results of the phase II study at the 43rd Annual Meeting of the American Society of Clinical Oncology (abstract 8020).

Total Therapy 3, like Total Therapy 2 (TT2), includes tandem transplants with melphalan 200 mg/m². For TT3, in keeping with the "total" therapy concept of including all active available agents, the investigators added bortezomib (Velcade) to induction and consolidation therapy with DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide), and included bortezomib in the first-year maintenance regimen (VDT once monthly). Second and third year maintenance was T plus D (Thal/Dex once monthly).

Also, he said, the protocol schedule was modified to shorten the induction from four to two phases and to give Thal/Dex to cover the drug-free phases of TT2 "to suppress myeloma survival signals during marrow recovery and thus reduce the relapse rate."

The study included 303 patients with newly diagnosed myeloma; median follow-up is 24 months. The median age of the patients was 59 years, but Dr. Barlogie noted that 28% of the patients were over age 65. Protocol compliance was "remarkably high" with TT3, he said: 94% of patients completed the first transplant and 83% the second transplant.

Study Results

With TT3 at 24 months, about 60% of patients had achieved a complete remission (CR) and 80% had a near-CR. Overall survival at 24 months was 87% and event-free survival 84%, an improvement over that seen with TT2 (75%). Importantly, he said, CR duration counted from the onset of CR is 91% at 24 months. "I have never before seen these kinds of encouraging, albeit early, results with a flat curve across 2 to 3 years," he said. Overall, he said, TT3 was significantly better than TT2 historical controls for onset and duration of CR and for event-free survival. Overall survival data are still immature.

Despite the complexity and intensity of the therapy, the cumulative treatment-related mortality at 24 months was only 5%, he noted. Toxicities greater than grade 2 were sensory neuropathy and thromboembolic events.

Gene Expression Profiles

Gene expression profile (GEP) information was available for 91% of patients in the TT3 study: 85% low risk and 15% high risk. Overall survival was significantly higher for low-risk GEP patients on TT3 than for high-risk patients (91% vs 70%, P = .0002). Event-free survival was also significantly higher (90% vs 58%) as was CR duration (94% vs 60%).

In these TT3 patients with GEP information, compared with historical TT2 patients with such information, there was a major improvement in event-free survival in low-risk patients (P = .002), compared with low-risk TT2 patients, as well as in the smaller high-risk subgroup (P = .05). CR duration was also significantly superior among low-risk TT3 patients vs low-risk TT2 patients (P = .01). "I was very impressed with the fairly straight low-risk TT3 line," he said.

Importantly, Dr. Barlogie said, with TT3, there was no difference in outcome whether or not patients had the FGFR3 t(4;14) translocation, once GEP risk score was accounted for. This abnormality has been considered a poor prognostic factor. "GEP risk overrides the prognostic implications of FGFR3 t(4;14)," he said. A comparison of low-risk TT3 and TT2 patients with this translocation showed superior overall survival for the TT3 patients. There was also a trend toward superior survival with TT3 in the FGFR3/MMSET t(4;14) subgroup (P = .06).

"It appears that bortezomib contributes, at last in part, to the advantage in event-free survival and CR duration in the GEP low-risk group, and to the better overall survival of the t(4;14) translocation subgroup, compared with TT2," Dr. Barlogie commented.

Finally, repeat gene array analysis of purified myeloma cells and unseparated bone marrow biopsies 48 hours after a test dose of bortezomib in a small group of patients showed downregulation of a microenvironment gene termed MAG-1, and this was associated with superior survival. "These data indicate that an alteration early on of the bone marrow microenvironment by bortezomib does have potentially long lasting consequences," Dr. Barlogie said.