Талидомид+дексаметазон в лечении миеломы

[Dr.Vad]

The combination of thalidomide and dexamethasone (thal/dex) is an effective induction therapy in patients with newly diagnosed multiple myeloma, according to investigators in a phase III trial coordinated by the Eastern Cooperative Oncology Group (ECOG). They reported their findings here at the 46th annual meeting of the American Society of Hematology (ASH).

In a phase 3 randomized trial, response rates to the combination were superior to those of dexamethasone alone, but at the cost of added toxicities and the risk of deep venous thrombosis requiring antithrombotic prophylaxis, according to lead investigator S. Vincent Rajkumar, MD, associate professor of medicine and consultant in the Division of Hematology at the Mayo Clinic in Rochester, Minnesota.

"This is amazing, because now we're using a drug that goes back to the '50s as the first-line therapy for a devastating cancer," Dr. Rajkumar said during a press briefing.

The study, called E1A00, compared thal/dex to dexamethasone alone as first-line therapy in patients with newly diagnosed multiple myeloma. The rationale for the combination, Dr. Rajkumar said during his oral presentation, came from studies showing that dexamethasone can evoke a 45% response rate in patients with multiple myeloma, and a 25% response rate in patients with relapsed disease. In addition, preclinical studies have shown a synergy between thalidomide and dexamethasone with evidence that thal/dex is effective in patients with relapsed multiple myeloma.

A total of 207 patients were randomized to receive either thal/dex or dexamethasone alone as first-line therapy. Each group received the designated therapy in four cycles, although treatment beyond four cycles was permitted at the discretion of individual physicians. Thalidomide was given in a 200 mg oral dose, and dexamethasone was given in doses of 40 mg on days 1-4, 9-12, and 17-20. All patients also received a bisphosphonate, either pamidronate or zoledronic acid, monthly.

Patients who achieved a complete or partial remission or stable disease after four or more cycles discontinued treatment to undergo stem cell transplantation. Patients who had disease progression at any time point also discontinued treatment. Response was defined as either a 50% reduction in serum and urine M protein or a 90% reduction in urine M protein.

Using study criteria, best response within four cycles occurred in 72 (73%) of 99 patients receiving thal/dex, and 50 (50%) of 100 patients receiving dexamethasone alone. The median time to response was identical in each group at 1.1 months.

In all, four (4%) of 99 patients receiving thal/dex had a complete response compared with none of the patients receiving dexamethasone alone. Disease progression within four cycles occurred in 2% of patients receiving thal/dex and in 4% of those receiving dexamethasone alone.

Toxicities occurring within 4 cycles of treatment included grade 3 or 4 deep venous thrombosis in 17 thal/dex patients (17%) and three dexamethasone patients (3%). Total toxicities of any type were 34% in the combination group and 18% in the monotherapy group.

In an interview with Medscape, Dr. Rajkumar was asked why his group compared thal/dex with dexamethasone alone, and not against the VAD induction regimen (vincristine, adriamycin, and dexamethasone) used in some centers, he maintained that the other agents add a great deal of toxicity with little proven additional therapeutic benefit.

"This is an oral regimen. [Patients are] going to go for a transplant anyway — why do you want to intensify the induction therapy when they've just been told they have myeloma," Dr. Rajkumar asked rhetorically. "So I think a better option than to intensify at that stage is to give them a good oral induction regimen that may get them into a minimal residual state in three to four cycles, and then we can talk about dose intensification," he said.

Along those lines, Dr. Rajkumar is currently conducting a new trial with lenalidomide, a more potent analog of thalidomide in clinical development. The investigators plan to look at lenalidomide in combination with two different dexamethasone doses: 12 vs four days per month.

"My hypothesis is that with these new drugs we don't need that much steroids, and you can greatly minimize the side effects even more by using a lower dose of dex," Dr. Rajkumar said. The new study will also include a group comparing lenalidomide/dex with thal/dex in patients who fail the former therapy.

Kanti Rai, MD, vice president of ASH and a professor of medicine at the Albert Einstein College of Medicine in New York City, who was not involved in the study, told Medscape that the combination of dexamethasone with either thalidomide or, potentially, lenalidomide, offers promise as a bridge to stem cell transplantation in patients with multiple myeloma.

"I am very impressed by thalidomide in multiple myeloma. Many people are using dexamethasone as a single agent in front-line treatment. High doses of dexamethasone are quite comfortable, and they like it only because it doesn't involve chemotherapy that carries myelotoxicities and other problems," Dr. Rai said.

"In today's day and age virtually every multiple myeloma patient with no comorbidity goes for transplant, so that if we can achieve a reasonably low tumor burden with any nonchemotherapy based treatment, and then go with transplant, then those patients ought to do better. And combining the two, the initial data are extremely promising that it can achieve the same kind of thing faster and [more durably], and prepare patients for transplant," Dr. Rai said.