The results of a small Phase 2 study indicate that sequential mainte­nance therapy involving six months of Velcade followed by six months of thalidomide is both effective and tolerable in multiple myeloma patients who have received a stem cell transplant.

The Phase 2 trial was carried out recently at the City of Hope National Medical Center in Duarte, California.

Many patients in the trial experienced peripheral neuropathy (nerve damage that causes pain and tingling in the extremities).

However, the City of Hope researchers believe a key result of their study is that no severe cases of periph­eral neuropathy occurred during the trial.

Severe peripheral neuropathy has been an issue in previous trials of Velcade ^[1] (bortezomib) and thalidomide ^[2] (Thalomid) as maintenance therapy, particularly when the drugs have been given in combination with one another, rather than sequentially.

Given the results of their study, the City of Hope researchers recommend larger studies to further investigate the impact of their sequential maintenance regimen on response depth and duration.

Many patients who undergo stem cell transplantation eventually relapse. The purpose of maintenance therapy following transplantation is to prolong the remission period and extend survival.  The International Myeloma Working Group recently published a consensus statement on maintenance therapy (see related Beacon ^[3] news).

The novel anti-myeloma agents thalidomide, Velcade, and Revlimid ^[4] (lenalidomide) all have been investi­gated as potential maintenance therapies.

Revlimid and thalidomide, however, are the two agents most commonly used for maintenance treatment, in part because they are orally administered, making them more convenient to use over extended periods of time.

Prior studies assessing thalidomide as maintenance therapy have demonstrated improved progression-free survival and, to a lesser degree, overall survival, but thalidomide-based maintenance regimens also have been associated with significant side effects.

Revlimid has demonstrated efficacy as a maintenance therapy, including a clear survival benefit in one of the three major trials investigating the drug as maintenance treatment.  Nevertheless, there are concerns about Revlimid maintenance therapy because it is associated with an increased risk of secondary cancer (see related Beacon ^[5] news).

Velcade controls myeloma cell death via a different pathway than thalidomide and Revlimid. It has also been investigated as maintenance therapy in multiple myeloma, although not as extensively as thalidomide and Revlimid.

According to the City of Hope researchers, Velcade as a maintenance therapy has led to complete response rates of 30 percent to 57 percent in previously untreated patients when used in combination with thalidomide or Revlimid. However, the combination therapies are associated with substantial side effects.

The researchers therefore sought to investigate the feasibility of sequentially administering Velcade-dexamethasone ^[6] (Decadron) and thalidomide-dexamethasone as maintenance therapy following stem cell transplantation. By administering these two drug combinations separately, one after the other, the researchers hypothesized that they could take advantage of the combined anti-myeloma effect of Velcade and thalidomide while reducing the occurrence of severe side effects.

The study included 45 myeloma patients with a median age of 55 years, who were enrolled between March 2008 and June 2010. All 45 patients received a stem cell transplant, and 40 subsequently started maintenance therapy.

Within six to eight weeks of the transplant, patients received 1.3 mg/m² of Velcade on a weekly basis -- that is, days 1, 8, and 15 of a 28-day cycle -- plus 40 mg of oral dexamethasone on days 1 through 4, for a total of six cycles.

Upon completion of Velcade therapy, the patients immediately received six 28-day cycles of daily thalidomide (starting at 50 mg and escalating to a maximum of 200 mg) plus 40 mg of dexamethasone on days 1 through 4. After completing six cycles of the thalidomide-dexamethasone combination, patients continued thalidomide alone until either disease progression or the appearance of intolerable side effects.

The median follow-up time was 13.5 months.

After the transplant, 33 percent of patients achieved a complete response, 30 percent reached a very good partial response, and 38 percent achieved a partial response.

Following Velcade maintenance therapy alone, 53 percent reached a complete response, 18 reached a very good partial response, and 20 percent reached a partial response.

The median tolerated thalidomide dose was 50 mg, and the median duration of thalidomide therapy was 23.3 months.

At one year post-transplant and six months after the start of thalidomide therapy, 50 percent of the patients maintained a complete response, 5 percent a very good partial response, and 8 percent a partial response.  The authors described the complete response rate achieved during the study as "impressive."

The one-year progression-free survival rate was 88 percent, and the one-year overall survival rate was 95 percent.  These results appear comparable to those observed at a similar point in time in the CALGB 100104 trial, which is a much larger U.S. trial testing Revlimid maintenance therapy after stem cell transplanta­tion (see related Beacon ^[7] news).

Following Velcade maintenance therapy, 53 percent experienced severe blood-related side effects including low white blood cell counts (50 percent), and low platelet counts (3 percent).  Additionally, 84 percent of patients experienced mild to moderate peripheral neuropathy; no cases of severe peripheral neuropathy were reported.

Following thalidomide therapy, 16 percent experienced severe side effects including swelling (4 percent), constipation (4 percent), blood clotting (4 percent), and low white blood cell counts (4 percent). The rate of mild to moderate peripheral neuropathy decreased to 64 percent six months after the start of thalidomide therapy; there continued to be no cases of severe peripheral neuropathy.

According to the study investigators, their results are similar to those from recent studies that investigated the use of weekly Velcade in combination with melphalan ^[8] (Alkeran) and thalidomide in patients who were not eligible for transplants. This combination also resulted in a significant reduction of peripheral neuropathy without negatively impacting outcomes.

For more information, please see the study in the journal Biology of Blood and Marrow Transplantation ^[9] (abstract).