Results from a Spanish Phase 3 clinical trial suggest that initial treatment with a combination of Velcade, thalidomide, and dexamethasone may lead to better responses before and after stem cell transplantation, as compared to treatment with thalidomide and dexamethasone alone. In addition, treatment with the three-drug combination increases progression-free survival time.

The study investigators concluded that their findings support the use of a combination of Velcade ^[1] (bortezomib), thalidomide ^[2] (Thalomid), and dexamethasone ^[3] (Decadron), often referred to as VTD, as initial treatment in newly diagnosed myeloma patients who are eligible for stem cell transplantation.

A myeloma patient’s initial treatment regimen is called induction therapy.

Previous studies have found that patients who respond well to induction therapy and then undergo stem cell transplantation show less residual disease and longer progression-free survival after transplantation. According to the Spanish researchers, successful induction therapy is therefore thought to be critical for long-term survival after stem cell transplantation.

The Spanish researchers noted that induction regimens that include one novel agent such as Velcade or thalidomide have only led to modest improvements in response rates and survival after stem cell transplantation. Various three-drug combinations that include two novel agents are therefore being investigated as potential induction therapies.

For instance, a previous study has shown that induction therapy with Velcade, Revlimid ^[4] (lenalidomide), and dexamethasone is highly effective (see related Beacon ^[5] news); all patients responded to the combination therapy.

Revlimid, however, is not approved for newly diagnosed myeloma patients.  In Europe, in particular, physicians have limited ability to prescribe drugs other than for their approved uses.  So thalidomide, a chemical analogue of Revlimid that is approved for newly diagnosed myeloma patients, is frequently used in Europe.

In the current study, the Spanish researchers investigated if induction with the combination of Velcade, thalidomide, and dexamethasone (VTD) could improve outcomes.

They recruited 386 newly diagnosed myeloma patients between April 2006 and August 2009. All participants were 65 years old or younger, with a median age of 56 years. The researchers categorized 21 percent of participants as ‘high-risk’ based on chromosomal abnormalities in their myeloma cells.

Patients were randomly assigned to one of three treatment groups.

The first group received induction therapy with thalidomide and dexamethasone, abbreviated as TD.  Specifically, patients in this group received 200 mg of thalidomide daily and 40 mg of dexamethasone on days 1 to 4 and 9 to 12 for six 28-day treatment cycles.

The second group of participants received induction therapy with VTD.  They received thalidomide and dexamethasone using the same dosing schedule as patients in the TD group. In addition, they received 1.3 mg/m² of Velcade on days 1, 4, 8 and 11 of each cycle.

Study participants in the third group received four cycles of induction treatment, alternating between two regimens that were used in previous transplantation trials in Spain. The first regimen was a combination of vincristine ^[6] (Oncovin), BCNU (carmustine), melphalan ^[7] (Alkeran), cyclophosphamide ^[8] (Cytoxan), and prednisone ^[9] (abbreviated as VBMCP), and the second was a combination of vincristine, BCNU, doxorubicin ^[10] (Adriamycin), and dexamethasone (called VBAD). The alternating regimen was followed by two cycles of Velcade treatment.

After 24 weeks of induction therapy, patients were scheduled to receive an autologous stem cell transplant. Three months after transplantation, they were randomly assigned to receive maintenance therapy with interferon alpha-2b, thalidomide, or thalidomide and Velcade.

The median follow-up time was 35.2 months.

The researchers first examined responses at the end of the induction phase. Results from the study showed that more patients who received VTD induction achieved a complete response (35 percent) than patients receiving TD (14 percent) or alternating therapy (21 percent).

The scientists then separately analyzed the subset of patients with high-risk multiple myeloma. In this subset of patients, VTD also increased the likelihood of a complete response. About 35 percent of high-risk patients showed a complete response after VTD induction, compared to none in the TD induction arm and 22 percent in the alternating therapy arm.

About 73 percent of participants received a stem cell transplant at the end of the induction phase.

The researchers found that the share of patients who achieved a complete response increased from 35 percent to 57 percent in the VTD arm after transplantation. This share also increased from 14 percent to 40 percent in the TD arm, and from 21 percent to 48 percent in the alternating therapy arm.

The median progression-free survival time with VTD was 56.2 months, compared to 28.2 months and 35.3 months with TD and alternating therapy, respectively.

Patients with high-risk chromosomal abnormalities had shorter progression-free survival times in all treatment groups. In the VTD arm, patients with chromosomal abnormalities had a median progression-free survival time of 23.5 months, whereas this time was not reached for patients without chromosomal abnormalities. Median progression-free survival was 8.9 months for patients with chromosomal abnormalities and 29.4 months for patients without chromosomal abnormalities in the TD treatment, and 18 months and 35.3 months, respectively, in the alternating therapy arm.

In addition, survival after disease progression was significantly shorter in patients with high-risk chromosomal abnormalities (12.3 months) as compared to those without (not yet reached).

The four-year overall survival was not significantly different among the three treatment arms (74 percent for VTD induction, 65 percent for TD, and 70 percent for alternating therapy).

The most common severe side effects of VTD treatment were infections, seen in 21 percent of patients. In comparison, 16 percent of patients developed infections in the TD arm and 15 percent in the alternating therapy arm.

Peripheral neuropathy was also significantly higher with VTD (14 percent) than with TD (5 percent) or alternating therapy (9 percent). Severely low white blood cell counts occurred more frequently with alternating therapy (22 percent) than with VTD (10 percent) or TD (14 percent).

For more information, please see the study in Blood ^[11] (abstract).