The results of a recent French Phase 2 study investigating two Pomalyst (poma­lido­mide) dosing schedules have been published.

The response, survival, and safety data from the study are in line with the results of other Pomalyst trials that have been made public over the past year or two.

In particular, the trial results indicate that the combination of Pomalyst plus low-dose dexamethasone is effective in multiple myeloma patients who have re­lapsed from, or are resistant to treatment with, Revlimid and Velcade.

Based on the data from this study and as well as other Pomalyst clinical trials, the study authors rec­om­mend a Pomalyst dosing regimen that is in agreement with the one recently approved by the U.S. Food and Drug Administration (FDA).

More specifically, the authors find that 4 mg of Pomalyst administered for 21 days of a 28-day cycle with low-dose dexamethasone (Decadron) is advan­tageous as compared to administering Pomalyst all 28 days together with low-dose dexamethasone.

Also based on the results of their study, the French researchers recommend that patients with advanced myeloma who do not respond rapidly to a two-drug Pomalyst regimen, such as Pomalyst plus dexametha­sone, should be switched to a three-drug Pomalyst regimen, such as Pomalyst plus cyclophosphamide (Cytoxan) and prednisone, or Pomalyst plus clarithromycin (Biaxin) and dexa­metha­sone.

Background And Study Design

Pomalyst belongs to the same class of drugs, known as immunomodulatory agents, as Revlimid (lenalidomide) and thalidomide (Thalomid).  They all work by causing a patient's immune system to attack and destroy cancerous cells.

Earlier this month, Pomalyst was approved by FDA for the treatment of relapsed and refractory multiple myeloma (see related Beacon news).

The FDA's recommended dosing for Pomalyst is 4 mg daily for 21 days out of a 28 day cycle, which is the same dosing the French researchers eventually recommend in their study.

The FDA's approval of Pomalyst is based on results from the Phase 2 "MM-002" trial of Pomalyst plus dexa­methasone versus Pomalyst alone in myeloma patients who had a median of five prior lines of therapy. Patients who received the combination regimen had a significantly higher overall response rate (29 percent) compared to those who received only Pomalyst (7 percent).  Preliminary survival results from the trial indi­cate that the median progression-free survival was 4.6 months and the median overall survival was 16.5 months for Pomalyst plus dexamethasone.

Furthermore, interim results from the Phase 3 "MM-003" trial of Pomalyst in heavily pretreated patients showed that a combination of Pomalyst plus low-dose dexamethasone was more effective than high-dose dexamethasone alone. Patients treated with the combination regimen had a significantly higher overall response rate (21 percent) compared to those who received only high-dose dexamethasone (3 percent). In addition, patients who received the combination had a median progression-free survival of 3.6 months, and the median overall survival has not yet been reached but appears to be approximately 15 months.

As the French researchers were planning their Pomalyst trial, the results of the MM-002 and MM-003 trials were not yet available.  Moreover, although early trials had shown that Pomalyst could be effective in re­lapsed myeloma patients, one important issue was still unresolved: the drug's dosing regimen.

The French researchers therefore decided to investigate Pomalyst's dosing in their trial, while also col­lect­ing additional information about the drug's effectiveness.

Between October 2009 and August 2010, 84 relapsed or refractory multiple myeloma patients were enrolled in the French study, which took place at multiple research centers. The study participants had a median age of 60 years and were diagnosed a median of 5.9 years prior to the study.

Overall, study participants had received a median of five prior lines of therapy. Every patient had received prior treatment with Velcade and Revlimid, and 76 percent of patients were refractory to both agents.

Patients were randomly divided into two treatment groups. Half of the patients received 4 mg of Pomalyst on days 1 to 21 of each 28-day treatment cycle along with 40 mg of dexa­metha­sone once per week. The other half of the patients received 4 mg of Pomalyst all 28 days of the treatment cycle along with 40 mg of dexa­methasone once per week. Dosages of both Pomalyst and dexamethasone were decreased for patients who experienced treatment-related side effects.

Response And Survival Results - All Patients

Patients responded similarly to both dosing regimens.

In particular, 35 percent of patients treated with Pomalyst for 21 out of 28 days responded to treatment, with 2 percent achieving a complete response, 2 percent a very good partial response, and 30 percent a partial response.

Among those treated with Pomalyst all 28 days of each treatment cycle. 34 percent responded, with 5 percent achieving a complete response, 2 percent a very good partial response, and 27 percent a partial response.

An additional 44 percent of those treated for 21 days and 51 percent of those treated all 28 days had stable disease.

Patients responded for a median of 6.4 months if treated for 21 days and a median of 8.3 months if treated all 28 days of each treatment cycle.

After a median follow-up of 23 months, the median progression-free survival was 5.4 months for those treated 21 days and 4.4 months for those treated all 28 days of each treatment cycle.

The median overall survival was 14.9 months for the 21-day dosing group and 14.8 months for the 28-day group.  At 18 months, 49 percent of the patients treated for 21 days and 39 percent of those treated all 28 days were still alive.  One death in the 28-day dosing group was considered to be treatment related.

These response and survival results are comparable to the results from both the MM-002 and MM-003 clinical trials.

Response And Survival Results - Specific Patient Groups

The study investigators then analyzed how certain groups of patients responded to treatment with Pomalyst plus dexamethasone.

Although the investigators found that the number and types of prior treatment regimens did not significantly affect response to Pomalyst treatment, more than six prior lines of therapy appeared to negatively affect response.  For this group of patients, the overall response rate was 21 percent (compared to 35 percent overall), the median progression-free survival was 3.2 months (compared to 4.6 months), and the median overall survival was 9.2 months (compared to 14.9 months).

Being refractory to previous treatment with Revlimid or Velcade had less of an impact on response.  The study investigators state that these results demonstrate that Pomalyst plus dexamethasone may benefit myeloma patients who have failed previous therapy, including Revlimid and Velcade.

In particular, the overall response rate was 36 percent for patients refractory to Revlimid, 29 percent for those refractory to Velcade, and 20 percent for those refractory to both Revlimid and Velcade (compared to 35 percent overall).

Furthermore, the median progression-free survival times were 4.2 months, 3.8 months, and 3.8 months, respectively (compared to 4.6 months overall); and the median overall survival times were 13.9 months, 13.8 months, and 13.8 months, respectively (compared to 14.9 months overall).

Among the 31 percent of study participants who were at least 65 years of age, the overall response rate (27 percent), median progression-free survival (3.8 months), and 18-month survival rate (31 percent) all appeared to be lower than the overall population (35 percent, 4.6 months, and 44 percent, respectively), although none of the differences were statistically significant.

Patients who responded to treatment experienced better survival outcomes than those who did not. Responders had a median progression-free survival of 11.3 months compared to 3.8 months for non-responders and an 18-month overall survival rate of 69 percent compared to 36 percent for non-responders.

The researchers found that patients were able to remain on treatment longer when Pomalyst was administered for 21 days each treatment cycle.  Specifically, the median duration of treatment was 8 cycles for patients receiving Pomalyst for 21 days per cycle, compared to 6 cycles for patients treated with Pomalyst all 28 days.

Twelve percent of patients continued treatment for at least 30 months.  Most patients discontinued treatment due to disease progression.

Safety-Related Results

Serious and life-threatening side effects were common; 93 percent of patients treated with Pomalyst for 21 days per treatment cycle experienced at least one severe side effect and 85 percent of those treated for 28 days per treatment cycle experienced at least one.

Overall, the most common severe side effects included low white blood cell counts (62 percent), low red blood cell counts (36 percent), low platelet counts (27 percent), pneumonia (13 percent), shortness of breath (12 percent), bone pain (11 percent), and kidney failure (11 percent).

For more information, please see this study in the journal Blood (abstract).