The results of an Italian Phase 3 study show that consolidation therapy with a combination of Velcade, thalidomide, and dexamethasone is more effective in newly diagnosed multiple myeloma patients than treatment with thalidomide and dexamethasone alone.

Specifically, the three-drug regimen led to higher rates of complete responses, as well as longer progression-free survival, compared to the two-drug regimen.

“Analyses performed in our study demonstrate that VTD [Velcade-thalidomide-dexamethasone] consolidation therapy significantly contributed to improved clinical outcomes,” said lead study investigator Dr. Michele Cavo from the Seragnoli Institute of Hematology in Bologna, Italy.

Preliminary results from this study were presented at the European Hematology Association meeting in June 2011 (see related Beacon news). 

According to the study investigators, previous studies have shown that reaching a complete response or at least a very good partial response before and after stem cell transplantation is a strong indicator of long-term outcomes.

Novel agents including thalidomide (Thalomid), Revlimid (lenalidomide), and Velcade (bortezomib) have been incorporated into myeloma therapy before (induction) and after (consolidation) stem cell transplantation.

The goal of consolidation therapy is to deepen a patient’s response to previous treatments. It usually involves a short course of treatment, often using the same drugs used in the patient’s induction regimen. Consolidation therapy differs from maintenance therapy, which usually involves a longer course of treatment with the goal of preventing disease progression for as long as possible while maintaining a favorable quality of life.

Study Design

In the current study, Italian researchers investigated the efficacy of Velcade in combination with thalidomide and dexamethasone (Decadron) as both induction and consolidation therapies.

They recruited 474 newly diagnosed multiple myeloma patients between May 2006 and April 2008 and randomly divided them into two treatment groups. Participants either received Velcade, thalidomide, and dexamethasone (abbreviated as VTD) or thalidomide and dexamethasone alone (abbreviated as TD) as induction therapy prior to double stem cell transplantation. Following the transplant, patients received the same corresponding drug combination as consolidation therapy.

Before the first stem cell transplant, patients in the VTD group received three 21-day cycles of 1.3 mg/m² of Velcade on days 1, 4, 8, and 11, 100 mg of thalidomide daily for the first 14 days and 200 mg of thalidomide daily thereafter, and 40 mg of dexamethasone on the day of and the day after each Velcade administration. Those in the TD group received the same dosage of thalidomide plus 40 mg of dexamethasone on days 1 through 4 and 9 through 12 of three 21-day cycles.

Patients then received two consecutive stem cell transplants, spaced three to six months apart. Three months following the second transplant, all patients underwent two 35-day cycles of consolidation therapy. Patients in the VTD group received 1.3 mg/m² of Velcade on days 1, 8, 15, and 22, 100 mg of thalidomide daily, and 40 mg of dexamethasone on the day of and the day after Velcade administration. Patients in the TD group received 100 mg of thalidomide daily and 40 mg of dexamethasone on days 1 through 4 and 20 through 23.

After the completion of consolidation therapy, patients received maintenance therapy, which consisted of 40 mg of dexamethasone on days 1 through 4 every 28 days until disease progression, relapse, or excessive toxicity.

Overall, 320 patients who completed the entire treatment regimen were included in the evaluation. Patients were evaluated after a median follow-up of 30 months from the start of consolidation therapy.

Study Results

After the second transplant, more VTD-treated patients achieved at least a near complete response (63 percent) than TD-treated patients (55 percent); however, the difference was not considered statistically significant.

Following consolidation therapy, patients who were treated with VTD demonstrated a significant improvement in complete response and near complete response rates compared to those treated with TD. Of those in the VTD group, 73 percent achieved a complete response or near-complete response, compared to 61 percent of TD-treated patients.

The probability of improving from less than a complete response to a complete response after consolidation therapy was significantly higher in VTD-treated patients (31 percent) than in those treated with TD (17 percent). 

Furthermore, the researchers found that progression-free survival was significantly longer in the VTD group (median has not yet been reached) compared to the TD group (32 months). The estimated 3-year progression-free survival rate was 60 percent in VTD-treated patients versus 48 percent in TD-treated patients.

The researchers pointed out that patients who did not achieve a complete response prior to consolidation therapy benefited the most from the VTD regimen. Of these patients, the rate of disease progression or death was significantly higher in the TD group (47 percent) compared to the VTD group (29 percent).

There was no significant difference in overall survival between the treatment groups. The estimated 3-year overall survival rate was 90 percent in the VTD group versus 88 percent in the TD group.

“The short follow-up time did not allow us to appreciate different survival distributions,” said Dr. Cavo.  He also added, “The study was not designed with the statistical power to demonstrate a survival benefit with VTD versus TD consolidation after double autologous stem cell transplantation. Proving an overall survival benefit at this time is likely to be difficult, due to the rapidly increasing availability of effective salvage therapies at the time of relapse, which might favorably influence the course of the disease.”

During consolidation therapy, peripheral neuropathy (pain or tingling in the extremities), which is commonly associated with both Velcade and thalidomide, occurred in 16 percent of VTD-treated patients, compared to 5 percent of TD-treated patients.  However, only 1 percent of patients receiving VTD consolidation experienced severe neuropathy.

For more information, please see the study in the journal Blood (abstract).