Final results from a Phase 3 study show that Pomalyst in combination with low-dose dexamethasone is effective for relapsed and refractory multiple myeloma patients not responding to treatment with Revlimid and Velcade.

Specifically, the results show that patients receiving Pomalyst (pomalidomide, Imnovid) in combination with low-dose dexamethasone (Decadron) had higher response rates and longer progression-free and overall survival than patients who received high-dose dexamethasone alone.

High-dose dexamethasone was chosen as the comparator in this study because, according to the study investigators, it was a common rescue treatment for heavily pretreated patients at the time the study was started.

Pomalyst plus dexamethasone improved survival by four to five months, with median overall survival being 12.7 months for patients treated with the combination and 8.1 months for those treated with dexamethasone alone.

The investigators note the significance of this difference given that half of the patients initially treated with high-dose dexamethasone later received Pomalyst during the study after an interim analysis demonstrated the efficacy of the combination.

The researchers state that the side effects of the combination were similar to those of other drugs in the same class as Pomalyst – Revlimid (lenalidomide) and thalidomide (Thalomid).

The most common severe to life-threatening side effects were low blood cell counts and infection, with almost half of the patients developing severely low white blood cell counts.

However, the investigators consider the combination to be well tolerated because the discontinuation rate due to side effects was low (4 percent).

Based on the results of this study, the European Commission recently approved pomalidomide, which is expected to be marketed in Europe under the brand name Imnovid, for the treatment of multiple myeloma patients who have received at least two prior therapies, including Revlimid and Velcade (bor­tezomib), and have demon­strat­ed disease progression on their last therapy (see related Beacon news).

Background

Until recently, there were very few treatment options available for myeloma patients once Revlimid and Velcade failed to work for them. Treatment for these patients was limited to treatment with dexamethasone alone or in combination with other drugs, reuse of a previous treatment regimen, use of older chemotherapies and drugs, or enrollment in a clinical trial.

In February of this year and July of last year, Pomalyst and Kyprolis (carfilzomib), respectively, were approved for refractory myeloma patients previously treated with Revlimid and Velcade.

Pomalyst is an immunomodulatory agent in the same class of drugs as Revlimid and thalidomide. It fights myeloma by inducing a patient’s immune system to target and destroy the cancerous cells.

Pomalyst’s approval in the United States was based on a Phase 2 clinical trial of Pomalyst plus low-dose dexamethasone in refractory myeloma patients (see related Beacon news).

The current study is the first Phase 3 trial to investigate the combination.

Pomalyst is also being studied at various dosage levels and in combination with other anti-myeloma drugs in patients with relapsed and refractory multiple myeloma.

Study Design

The Phase 3 study, known as “MM-003,” was conducted at various locations in Australia, Canada, Europe, Russia, and the United States. Patient enrollment began in March 2011, and data collection was completed in March 2013.

The study included 455 relapsed and refractory myeloma patients with a median age of 64 years. They had received a median of five prior therapies.  All patients had been previously treated with Revlimid and Velcade.  In addition, all patients were refractory (resistant) to or could not tolerate at least one of these drugs, and 74 percent of the patients were refractory to both.

Two-thirds of the study participants were treated with 4 mg of Pomalyst on days 1 to 21 and 40 mg of dexa­methasone once per week of a 28-day treatment cycle. The remaining third were treated with high-dose dexamethasone, 40 mg per day on days 1 to 4, 9 to 12, and 17 to 20 of a 28-day cycle.

Patients were treated until their myeloma progressed or they were unable to tolerate their treatment.

An interim analysis conducted in September 2012 showed that patients receiving Pomalyst plus low-dose dexamethasone had superior progression-free and overall survival compared to those receiving high-dose dexamethasone alone.  Therefore, an independent review board recommended that all patients originally assigned to receive dexamethasone alone should be allowed to switch to Pomalyst treatment with or with­out dexamethasone.  Half of those patients began to receive Pomalyst by the time of the final analysis.

The median follow-up time was 10 months.

Results

Overall, 31 percent of the patients responded to treatment with Pomalyst plus low-dose dexamethasone, with 1 percent achieving a complete response, 5 percent a very good partial response, and 26 percent a partial response. In comparison, 10 percent of patients treated with high-dose dexamethasone responded, with less than 1 percent achieving a very good partial response and 9 percent a partial response.

The median duration of response was 7.0 months in patients receiving Pomalyst plus low-dose dexametha­sone and 6.1 months in patients receiving high-dose dexamethasone.

Patients who received Pomalyst plus low-dose dexamethasone had significantly longer median progres­sion-free survival than those who received high-dose dexamethasone alone (4 months versus 1.9 months, respectively).

A subgroup analysis showed that, irrespective of previous treatment, progression-free survival was longer for patients receiving Pomalyst plus low-dose dexamethasone.

The median overall survival was also significantly longer for patients treated with Pomalyst plus low-dose dexamethasone (12.7 months), compared to those treated with high-dose dexamethasone (8.1 months).

A subgroup analysis showed that patients refractory to Revlimid and patients whose last treatment was Revlimid had superior survival when treated with Pomalyst plus low-dose dexamethasone.

However, the investigators note that patients who were refractory to both Revlimid and Velcade, patients who were intolerant to Velcade, and patients whose last treatment was Velcade had similar survival regardless of whether they were treated with Pomalyst plus dexamethasone or dexamethasone alone.

According to the investigators, age did not affect efficacy of the combination. The overall response rates, progression-free survival, and overall survival were similar for patients up to and including 65 years and those older than 65 years.

The most common severe and life-threatening side effects included low white blood cell counts (48 percent of patients receiving Pomalyst plus low-dose dexamethasone versus 16 percent of patients receiving high-dose dexamethasone alone), anemia (33 percent versus 37 percent), infections (30 percent versus 24 per­cent), and low platelet counts (22 percent versus 26 percent).

Few patients discontinued treatment because of treatment-related side effects (4 percent of patients on Pomalyst plus low-dose dexamethasone versus 6 percent of patients on high-dose dexamethasone).

Among the patients treated with Pomalyst plus low-dose dexamethasone, 4 percent of patients died due to treatment-related side effects, compared to 5 percent of patients in the high-dose dexamethasone group. Most deaths were the result of infections, although there were two cases of multiorgan failure and one case of a nervous system disorder in the Pomalyst plus low-dose dexamethasone group.

For more information, please refer to the study in the journal The Lancet (abstract). To learn more about all current Pomalyst trials for multiple myeloma, please see the U.S. Clinical Trials Registry.