The results of a recent Phase 3 study conducted throughout Europe show that treatment with a combination of Velcade, thalidomide, and dexamethasone leads to superior clinical benefits compared to treatment with thalidomide and dexamethasone alone in multiple myeloma patients who have relapsed or progressed after a stem cell transplant.

Specifically, more patients responded to the three-drug regimen.  In addition, the group of patients treated with the three-drug combination responded longer and did not progress as quickly as those treated with the two-drug combination. However, the three-drug combination led to a higher rate of severe side effects.

Dr. Laurent Garderet of Hopital Saint Antoine in Paris, France, and lead investigator of the study, said that more intensive three-drug therapy is clearly better than less intensive therapy in this patient population, but it needs to be given at the appropriate doses and for the appropriate duration.

“I would recommend VTD [Velcade-thalidomide-dexamethasone] but with the appropriate dosages and route,” said Dr. Garderet.

“When we initiated the trial in 2005, we didn't know what the best dosages were for Velcade and thalidomide in combination,” he explained. “We know now that thalidomide should be given at 100 mg per dose (and not 200 mg per dose as in the trial), Velcade should be given subcutaneously because it is associated with much less neurotoxicity, and [we should] quickly move from a biweekly to weekly [Velcade] schedule,” he added.

Based on these findings, the study investigators contend that the combination of Velcade (bortezomib), thalidomide (Thalomid), and dexamethasone (Decadron) may become a new standard course of treatment for relapsed and progressing myeloma patients after stem cell transplantation.

Results of recent clinical trials have shown that the combination of Velcade, thalidomide, and dexa­metha­sone (abbreviated as VTD) leads to better response rates than thalidomide and dexamethasone (abbreviated as TD) alone in newly diagnosed myeloma patients when used as planned additional (consolidation) therapy for all patients soon after stem cell transplantation (see related Beacon news).

However, the efficacy and safety of VTD in myeloma patients with progressing or relapsing disease after a stem cell transplant had not yet been evaluated, leading European researchers to conduct the current clinical trial.

Between 2006 and 2010, 269 multiple myeloma patients with relapsing or progressive disease after an autologous (own) stem cell transplant were enrolled in the study. Twenty percent of the patients had previously been treated with Velcade, and 8 percent had previously been treated with thalidomide.  Previous treatment with Revlimid (lenalidomide) apparently was negligible.

Patients were randomly assigned to receive the VTD regimen or the TD regimen.

For one year, patients in both groups received 200 mg of thalidomide every day and 40 mg of dexa­metha­sone per day for four days every three weeks. Patients in the VTD group received an additional 1.3 mg/m² of Velcade on days 1, 4, 8, and 11 for eight three-week cycles, followed by the same dose on days 1, 8, 15, and 22 for four six-week cycles.

The researchers found that the combined complete and near-complete response rate was higher for patients treated with VTD (45 percent) than those treated with TD (25 percent). Additionally, the median time to first response was significantly shorter in patients who received VTD (1.6 months) than in those who received TD (2.3 months).

Furthermore, the VTD group showed a longer median duration of response of 17.2 months, compared to 13.4 months in the TD group.

Patients receiving VTD also demonstrated a longer median time to disease progression (19.5 months) compared to those receiving TD (13.8 months).

At a median follow-up time of 30 months, the two-year overall survival rates were not statistically different between the two treatment groups (71 percent for VTD and 65 percent for TD).

Dr. Garderet explained that the follow-up time may have been too short to observe a difference in survival. However, he added, “We are actually updating the results with a longer follow-up (one year longer). Hopefully, overall survival will be superior [for patients treated with VTD].”

Severe to life-threatening treatment-related side effects occurred more frequently in the VTD group (71 percent) than in the TD group (57 percent). Severe peripheral neuropathy, a common side effect of both Velcade and thalidomide that is characterized by pain and tingling in the extremities, was significantly more common in the VTD group (29 percent) than in the TD group (12 percent).

Overall, 28 percent of patients in the VTD group and 9 percent in the TD group discontinued treatment before the end of the treatment period due to side effects.

In order to reduce the side effects resulting from the VTD regimen, in particular the rate of peripheral neuropathy, the investigators recommend adjusting the dosing or schedule of Velcade administration.

For more information, please see the study in the Journal of Clinical Oncology (abstract) and the editorial (full text) that accompanies the study.