Results from a small British Phase 2 study suggest that therapy with a combi­nation of cyclophosphamide, thalidomide, and dexamethasone may deepen multiple myeloma patients’ responses after stem cell transplantation. In addition, the combination therapy was well tolerated.

However, the British scientists note that larger randomized trials are required to confirm these results.

“The results suggest that post-transplant consolidation therapy with a multi-drug regimen such as cyclophosphamide-thalidomide-dexamethasone may improve the depth of response in the aftermath of autologous transplantation,” said Dr. Jacob Laubach from the Dana-Farber Cancer Center in Boston, who was not involved in the study.

Consolidation therapy refers to a short course of treatment given to myeloma patients after their initial therapy. The goal of consolidation therapy is to deepen patients’ responses after the initial therapy. Consoli­dation therapy is different from maintenance therapy, which involves a prolonged, and often low-dose, form of treatment with the goal to prevent disease progression for as long as possible while maintaining a favorable quality of life.

According to Dr. Neil Rabin of the University College Hospital in London and lead author of the study, thalidomide ^[1] (Thalomid) maintenance therapy improves response rates and progression-free survival in multiple myeloma patients. However, he said, “The duration of thalidomide [therapy] is limited by toxicity, with most patients stopping this treatment after about 12 months.”

He explained that if thalidomide is given in combination with cyclophosphamide ^[2] (Cytoxan) and dexa­metha­sone ^[3] (Decadron) in the form of consolidation therapy, it allows a short course of thalidomide treatment to be given without significant long-term side effects.

Previous studies have shown that the combination of cyclophosphamide, thalidomide, and dexamethasone, commonly referred to as CTD, is effective in newly diagnosed multiple myeloma patients who are ineligible for stem cell transplantation (see related Beacon news ^[4]).

In the current study, Dr. Rabin and his colleagues sought to determine whether three to six months of consolidation therapy with CTD is safe and able to improve response rates following autologous stem cell transplantation.

The study included 45 multiple myeloma patients, who were enrolled between September 2004 and August 2008. All participants had at least stable disease at three months after stem cell transplantation.

Patients who had received thalidomide or other novel agents as a part of their initial therapy were not eligible to participate in the study.

The median patient age was 60 years.

Patients started on CTD consolidation therapy at a median time of 17 weeks after stem cell transplantation.

They received 400mg/m² of cyclophosphamide administered orally once a week, 50 mg to 200 mg of thalidomide daily, and 40 mg of dexamethasone on days 1 through 4 of a 28-day treatment cycle.

The median duration of consolidation therapy was 16 weeks.

The researchers found that the share of patients who achieved a very good partial or complete response increased from 44 percent at three months post transplantation to 63 percent at six months and 72 percent at twelve months.

Two percent of patients deepened their response from a very good partial response to a complete response, 30 percent from a partial response to a very good partial response, and 2 percent from stable disease to a partial response.

When the researchers retrospectively analyzed data from patients with similar characteristics who under­went stem cell transplantation at their institution but did not receive consolidation therapy, they found that the share of patients who achieved a very good partial or complete response remained the same at around 50 percent between three and twelve months post transplant.

The median progression-free survival time was 26 months for the patients who received CTD consolidation, compared to 21 months for patients included in the retrospective analysis who did not receive consolidation therapy. However, this difference was not considered statistically significant.

The researchers did not observe any differences in overall survival between the two patient groups. “The follow-up is too short, and numbers too small to show any difference in overall survival,” explained Dr. Rabin.

After a median follow-up period of 49 months, 80 percent of patients showed disease progression. How­ever, according to the British researchers, CTD consolidation did not adversely affect response to subse­quent therapy at relapse. Approximately two-thirds of patients (61 percent) received Velcade ^[5] (bortezomib) at relapse, and 82 percent of these patients achieved a partial response or better.

The researchers also stated that the treatment regimen was well tolerated.

The most common severe side effect seen during CTD consolidation was low white blood cell counts, which was observed in 36 percent of patients.

All other common side effects were mild to moderate in nature and included fatigue (49 percent), consti­pation (45 percent), low red blood cell counts (45 percent), and peripheral neuropathy (pain and tingling or numbness in the hands and feet) (33 percent).

The researchers pointed out that side effects resolved when treatment was stopped and that only 4 percent of participants withdrew from the study due to side effects.

When asked whether a thalidomide-based consolidation regimen had any particular advantages or disadvantages compared to Revlimid ^[6] (lenalidomide)-based consolidation regimens, Dr. Laubach pointed out that that question cannot be conclusively answered without a randomized study comparing a Revlimid- versus a thalidomide-containing regimen for consolidation and/or maintenance. However, he said, “It is safe to say that Revlimid is generally better tolerated than thalidomide over the long term, as Revlimid is much less likely to induce nerve injury and sedation.” Revlimid and thalidomide are in the same class of drugs called immunomodulatory agents.

However, Dr. Rabin pointed out that the potential advantage of CTD consolidation may be its lower cost, particularly in countries that do not have access to Revlimid consolidation/maintenance. “In addition, a brief block of treatment limits the time on treatment compared to maintenance strategies, allowing a good quality of life in first remission,” he said.

For more information, please see the study in the British Journal of Hematology ^[7] (abstract).