POMALIDOMIDE PROMISING FOR MM

STOCKHOLM — A combination of pomalidomide (Pomalyst) and low-dose dexamethasone in double-refractory multiple myeloma has shown "highly significant" survival in a phase 3 trial.

The results even surprised lead investigator Jesús San Miguel, MD, from University Hospital in Salamanca, Spain. He explained that he did not expect to see such a large improvement in overall survival with pomalidomide plus low-dose dexamethasone, compared with high-dose dexamethasone alone (12.7 vs 8.1 months; hazard ratio [HR], 0.74; P = .28).

Dr. San Miguel presented results from the large multicenter phase 3 study, known as the MM-003 trial, here at the 18th Congress of the European Hematology Association.

It was difficult to demonstrate overall survival because if patients receiving high-dose dexamethasone progressed, "they entered a companion study to receive pomalidomide. But to our surprise, in this study we saw a significant survival advantage in patients on pomalidomide," he told Medscape Medical News.

"We can now conclude that we have a new standard of care for heavily pretreated multiple myeloma patients who have failed on bortezomib [Velcade] and lenalidomide [Revlimid]," he noted.

"What pomalidomide brings to the table is that for our worst group of patients — the double-refractory ones — this offers treatment hope," said Sagar Lonial, MD, from Emory University in Atlanta, who spoke at an educational session on multiple myeloma.

Pomalidomide is already available in the United States; it was approved by the US Food and Drug Administration for use in multiple myeloma in February. It will likely be available in Europe soon. In May, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP)recommended marketing authorization for pomalidomide to treat patients with multiple myeloma. A final decision is usually made 2 to 3 months after the decision by CHMP.

Details of the Study

The MM-003 trial involved 455 patients with refractory multiple myeloma, 72% of whom had failed both bortezomib and lenalidomide. "These patients had no other options," said Dr. San Miguel.

Patients were randomized to 1 of 2 groups: 302 patients received pomalidomide 4 mg/day on days 1 to 21 plus once-weekly low-dose dexamethasone (40 mg for patients 75 years and younger and 20 mg for those older than 75 years); and 153 patients received high-dose dexamethasone (40 mg for patients 75 years and younger and 20 mg for those older than 75 years) on days 1 to 4, 9 to 12, and 17 to 20. Median follow-up was 10 months.

Progression-free survival, the primary end point, was better with the pomalidomide combination than with high-dose dexamethasone (4.0 vs 1.9 months; HR, 0.48; P = .001).

Overall survival was also better with the pomalidomide combination than with high-dose dexamethasone (12.7 vs 8.1 months; HR, 0.74; P = .28), as were the overall response rate (31% vs 10%) and the molecular response rate (39% vs 16%).

Pomalidomide is similar to both thalidomide (Thalomid) and lenalidomide, although it has small molecular differences that translate into clear differences in the mechanism of action. "Both lenalidomide and pomalidomide have greater immunomodulatory activity than thalidomide, show a stronger activation of natural killer and natural killer T-cells, and have a more pronounced anti-inflammatory effect," explained Dr. San Miguel.

It was clear that pomalidomide would work in multiple myeloma because "several phase 1 and 2 trials showed clear activity in this respect," he said.

Adverse Events

"Toxicity is particularly important because we are dealing with end-stage disease," Dr. San Miguel explained. "The only difference between the experimental and the control arm is in the incidence of neutropenia.... In fact, the rate of discontinuation in this trial has been very low."

Table. Number of Adverse Events in the MM-003 Study

Adverse Events	Pomalidomide and Low-Dose Dexamethasone (n = 300)	High-Dose Dexamethasone (n = 150)
Grade 3/4 neutropenia	48	16
Grade 3/4 infection	30	24
Related Discontinuation	9	11

Dr. Lonial added it is impressive that pomalidomide has activity in patients who are resistant to lenalidomide and bortezomib. "Roughly 1 in 3 patients will achieve a partial response or better, and almost half achieve molecular response or better that translates into remission duration and improved survival. This is a really important step for patients."

Dr. San Miguel reports that he sits on advisory boards for Millennium, Celgene, Janssen, Novartis, Onyx, among others. Dr. Lonial reports that he has relationships with Millennium, Celgene, Novartis, and Sanofi.

18th Congress of the European Hematology Association (EHA): Abstract S1151. Presented June 16, 2013.