Results of a recent Italian study show that a four-drug combination regimen of Velcade, Doxil, dexamethasone, and thalidomide may be more effective than two- or three-drug combinations for multiple myeloma patients who have relapsed or are resistant to prior treatment.

“This study clearly reinforced the idea that aggressive therapy, even in the second-line relapse setting, is of great value,” said Dr. Mario Curti, a hematologist at Los Alamitos Medical Center in Los Alamitos, California, who was not involved in the study. “It allows another treatment option to be considered in the relapse setting, especially for those [patients] who are not transplant candidates.”

The study authors indicated, however, that because patients achieved a complete response with the four-drug combination therapy only when their disease was not too far advanced, this combination may be effective only when used in the initial stages of relapsed or resistant disease.

“We reported that patients treated in third or subsequent relapse [did not] obtain a complete response,” explained the study’s lead author Dr. Massimo Offidani from the Ospedali Riuniti in Ancona, Italy. “These are the data which other [researchers] have also found.”

Because of the side effects associated with the four-drug combination therapy, the study authors suggested that less intensive therapies may benefit patients in the later stages of disease, when quality of life and disease control are more important than quality of remission.

Recent research has shown that four-drug combination treatments may be more effective in newly diagnosed multiple myeloma patients than two- or three drug combinations (see related Beacon ^[1] news). According to Dr. Offidani and his colleagues, there is currently no data available about the use of four-drug combinations in relapsed or refractory myeloma patients.

“There has been a historical bias against three- and four-drug regimens for patients with multiple myeloma, as it was felt to be too toxic in a population that already was substantially compromised due to their illness,” Dr. Curti told the Myeloma Beacon.

Preclinical studies have shown that thalidomide ^[2] (Thalomid) enhances the activity of Velcade ^[3] (bortezomib) and dexamethasone ^[4] (Decadron).  Additionally, they have shown that Doxil ^[5] (doxorubicin liposomal) enhances the activity of thalidomide and Velcade-dexamethasone against myeloma cells.

Based on these findings, Dr. Offidani and his colleagues sought to determine whether or not a four-drug combination of Velcade, Doxil, dexamethasone, and thalidomide would be an effective treatment for relapsed or refractory myeloma patients.

They also assessed whether outcome could be improved by further treating the patients with alternating cycles of Velcade-dexamethasone and thalidomide-dexamethasone followed by thalidomide treatment during remission.

The study included 46 relapsed and refractory patients with a median age of 64 years. Participants had received a median of one prior therapy.

Patients received six 28-day cycles of 1.3 mg/m² Velcade on days 1, 4, 8, and 11; 30 mg/m² Doxil on day 4; 20 mg oral dexamethasone on days 1 to 2, 4 to 5, 8 to 9, and 11 to 12; and 100 mg oral thalidomide daily.

Because nine of the first 20 patients receiving treatment experienced pain and tingling sensations from nerve damage to the extremities, the study authors amended the regimen in all therapeutic phases to 1.3 mg/m² Velcade on days 1, 4, and 11, and 50 mg thalidomide daily.

Among the participants, 76 percent responded to the four-drug combination.  Specifically, 35 percent achieved a complete response, 33 percent achieved a very good partial response, and 9 percent achieved a partial response.

The study authors found that the rate of complete responses was higher in patients who had received two or fewer prior therapies than in patients with more prior therapies (41 percent versus 0 percent).  Other factors including age, prior autologous stem cell transplant, and refractory disease did not affect the quality of response.

The most common side effect associated with the four-drug combination treatment was pain and tingling sensations from nerve damage to the extremities (30 percent). Additionally, 15 percent developed infections, 28 percent experienced low blood cell counts, and 4 percent developed blood clots in the veins.

Of the patients who completed the four-drug regimen, 57 percent went on to receive six alternating 28-day cycles of 1.3 mg/m² Velcade on days 1, 4, and 11 plus 20 mg oral dexamethasone on days 1 to 4, and 50 mg thalidomide daily plus 20 mg oral dexamethasone on days 1 to 4.

After receiving this second therapy, 37 percent achieved a complete response, 35 percent achieved a very good partial response, and 4 percent achieved a partial response. According to Dr. Offidani and his colleagues, these response rates are much better than the 20 percent complete response rates that have been reported with two-drug combinations recently.

Of the patients who completed this second therapy, 44 percent went on to receive 50 mg thalidomide daily during remission until they relapsed or experienced intolerable side effects. Dr. Offidani and his colleagues found that thalidomide did not improve patient response during remission.

After a median follow-up of 31 months, 61 percent of participants relapsed, and 44 percent died.

The median overall survival was 40 months, and the median time to disease progression was 18.5 months.

The study authors found that patients who completed the treatment protocol had a significantly longer time to disease progression than patients who did not complete the protocol (not reached versus seven months).

“I don’t know what will be the impact [of this four-drug regimen] in the near future of myeloma therapy,” Dr. Offidani told The Myeloma Beacon, “but we can state that [it] represents a new, effective rescue possibility for patients with relapsed-refractory multiple myeloma.”

The study authors recommended further investigation of the four-drug combination therapy in larger Phase 2 and Phase 3 trials.

“I suspect a larger Phase 3 study would prove beneficial in solidifying this combination as a new standard of care in relapsed myeloma,” said Dr. Curti.

For more information, please see the article in the Annals of Hematology ^[6] (abstract).