At the Second International Congress on Leukemia, Lymphoma, and Myeloma, recently held in Istanbul, Turkey, researchers summarized the clinical results of Total Therapy trials. Total Therapy, which combines multiple-drug regimens with stem cell transplants, represents significant progress in the fight against myeloma, and its high success rates hold promise for an eventual cure.

In the Total Therapy 1 (TT1) trial, patients received chemotherapy drug regimens of VAD, CTX (cyclophosphamide), and EDAP, as well as the chemotherapeutic agent melphalan (Alkeran), to destroy cancer cells in preparation for stem cell transplant. After undergoing two stem cell transplants to re-infuse bone marrow that the chemotherapy had destroyed, patients received interferon to help maintain any cancer remission.

As of February 2009, 51 of the original 231 TT1 patients were still alive, with a median follow-up of 14 years. The median durations of event-free survival (EFS) and overall survival (OS) were 2.6 and 5.7 years, respectively. Throughout the trial, metaphase cytogenetic abnormalities, which reflect irregular chromosome numbers in the tumor cells, were consistently predictive of poor prognosis.

In Total Therapy 2 (TT2), 668 patients received the same form of double transplant as in TT1, but their preparatory chemotherapy regimens consisted of four cycles of VAD, DCEP, CAD, and DCEP. Additionally, half of the patients received thalidomide (Thalomid) and all patients received dexamethasone (Decadron) the first year post-transplant, as well as indefinite interferon maintenance therapy.

With a median follow-up of eight years, 378 TT2 patients are currently alive, 253 have been event-free, and 81 have consistently been in complete remission (CR). The median duration of overall survival was 9.7 years, but those receiving thalidomide enjoyed significantly greater 10-year estimates for both event-free and overall survival. Thalidomide conferred EFS and OS estimates of 38 and 57 percent, respectively, while TT2 regimens lacking thalidomide only enjoyed rates of 24 and 41 percent, respectively.

Results analysis confirmed a variety of biological markers that correlated to poorer prognosis. Tumor chromosomal abnormalities, elevated levels of B2M and LDH, and low albumin levels all helped predict the outcome of a shorter survival period. In addition, tumors with high-risk gene expression, as revealed through genetic expression profiling, corresponded to less favorable outcomes.

In the final trial, Total Therapy 3 (TT3), patients received functionally similar regimens to TT2 as well as the addition of Velcade (bortezomib). In addition, half of the patients received thalidomide (TT3A), while those in TT3B received Revlimid (lenalidomide). At 3.1 years post-treatment, the predicted five-year overall survival rate is currently 71 percent.

As in TT2, tumors with high-risk genetic profiles correlated to poorer prognoses in TT3. At four years out, 48 percent of patients with these high-risk variants were expected to have sustained complete remission, compared to a staggering 91 percent of the low-risk group. Additionally, the MMSET/FGFR3-type, a genetic profile that had fared poorly under TT2, responded so well to TT3 that it no longer indicates poor prognosis.

The results of the Total Therapy trials, which are still ongoing, reveal continued advances in treating myeloma as new drugs enter the market.

Study researchers optimistically explain, “Extrapolating from TT1 and TT2 survival observations, we predict 10-year estimates of sustained complete remission with TT3 in excess of 65%, most of which should be durable beyond this landmark and thus boding well for cure.”

For more information about the International Congress and the research presented, please see the Turkish Society of Hematology Web site.