Pomalidomide has demonstrated efficacy in heavily pre-treated multiple myeloma patients who have been treated with – or are even refractory to – Revlimid and Velcade.

Three studies of the use of pomalidomide (Pomalyst) in relapsed and refractory multiple myeloma patients were presented yesterday at the American Society of Hematology annual meeting in Orlando.

Pomalidomide, which is being developed by the pharmaceutical company Celgene, is an immunomodulatory agent that induces the immune system to destroy myeloma cells. It belongs to the same class of drugs as Revlimid (lenalidomide) and thalidomide (Thalomid).

Comparison Of Two Dose Schedules For Pomalidomide Plus Low-Dose Dexamethasone In Relapsed Multiple Myeloma Patients

This Phase 2 study investigated the efficacy of two different dosing schedules of pomalidomide plus low-dose dexamethasone (Decadron) in heavily pre-treated multiple myeloma patients.

Both combinations were found to be effective and well tolerated by this particular patient group.

Given these results, Dr. Xavier Leleu, lead investigator of the study, suggested going forward with the less frequent dosing since efficacy was the same for both dosing schedules, but less frequent dosing would cause fewer side effects and be more convenient.

The study included 92 heavily pre-treated myeloma patients who had received a median of four prior therapies.  All patients were resistant to Revlimid and Velcade (bortezomib) therapy, and about 50 percent had previously received thalidomide.

The patients were divided in two different treatment groups. The first group received 4 mg pomalidomide on days 1 through 21 of a 28-day cycle. The second group received 4 mg pomalidomide on each day of a 28-day cycle. Both groups received the same low-dose schedule of dexamethasone, and treatment was administered until disease progression. Patients in both treatment groups received a median of five treatment cycles.

In the first treatment group, 42 percent of patients responded to treatment compared to 39 percent of patients in the second treatment group. Dr. Leleu mentioned that most responses were partial responses. He and his colleagues did not observe any stringent complete responses and only very few complete responses.

Time to best response was very similar between the two treatment groups at 2 and 1.7 months, respectively.

Time to disease progression was also similar between the two treatment groups. At a median follow-up of 6.5 months, time to disease progression was predicted to be 7 months for the patients on the 21 out of 28 day regimen, and 9.7 months for the patients on the continuous regimen.

The 6 month overall survival was 88 percent for the first group and 85 percent for the second group, which Dr. Leleu described as “absolutely remarkable in these advanced patients.”

Severe side effects were low. The most common severe side effect that the researchers observed was low white blood cell counts, which occurred in 34 percent and 33 percent of the two treatment groups, respectively.

The rate of severe side effects that were not blood-related was very low in both arms, which Dr. Leleu said is important because it allows the patients to stay on therapy longer. No patients experienced worsening of peripheral neuropathy, and no patient showed signs of blood clots.

Patients in both treatment groups required dose reductions (49 percent in the first group and 41 percent in the second group). Dr. Leleu pointed out, however, that many patients were able to go back to higher doses. Twelve patients in the first group and 7 patients in second group had to discontinue therapy.

Comparison Of Two Dosage Strategies Of Pomalidomide And Dexamethasone In Revlimid And Velcade Resistant Multiple Myeloma Patients

Researchers from the Mayo Clinic conducted two sequential Phase 2 trials to investigate the efficacy of two different doses of pomalidomide – 2 mg daily and 4 mg daily – with low-dose dexamethasone in multiple myeloma patients who were resistant to both Revlimid and Velcade.

Pomalidomide and dexamethasone were demonstrated to be effective in both trials, but the results of the studies did not confirm an advantage of 4 mg over 2 mg pomalidomide.

“We found no evidence of a dose response,” said Dr. Martha Lacy, lead investigator of the studies. “The overall remission rate is similar with both dose levels.”

“We are cautiously optimistic that the regimen is effective in high-risk patients,” she added.

Thirty-five patients were enrolled in each study. Participants had received a median of six prior therapies, and almost 60 percent of the patients were considered high risk.

Of the patients who received 2 mg pomalidomide, 14 percent achieved very good partial response, 11 percent a partial response, and 24 percent a minor response for an overall response rate of 49 percent.

Of the patients who received 4 mg pomalidomide, 9 percent achieved a very good partial response, 20 percent a partial response, and 12 percent a minor response for an overall response rate of 40 percent.

Of the patients considered high-risk, 33 percent achieved at least a minor response.

Dr. Lacy mentioned that response to treatment was rapid. The median time to response was 1 and 1.7 months for the two groups, respectively. The median duration of response was 12 months for the 2 mg group; it has not been reached yet for the 4 mg group.

At the time of analysis, 71 percent of patients were still alive, and 17 percent and 29 percent of the two study groups are still being treated. Treatment discontinuation was mostly due to disease progression. Some patients in the 4 mg group stopped treatment due to side effects.

Overall survival at 6 months was 78 percent for patients who received 2 mg of pomalidomide and 69 percent for patients who received 4 mg.

Low white blood cell counts were the most common blood-related side effects (49 percent for the 2 mg treatment group and 66 percent for the 4 mg treatment group).

Among the side effects that were not blood-related, the most common were fatigue, nerve damage to the limbs (peripheral neuropathy), and infection complications.

Seventy percent of participants had neuropathy prior to the study. Neuropathy that may possibly be linked to pomalidomide occurred in 20 percent of patients in the 2 mg treatment group and 29 percent of patients in the 4 mg treatment group.

Results for the patients who had been treated with 2 mg pomalidomide were presented at the annual meeting of the American Society of Clinical Oncology this summer (see related Beacon news).

Phase 1/2 Study Of Pomalidomide Alone Or In Combination With Low-Dose Dexamethasone In Relapsed And Resistant Multiple Myeloma Patients

The Phase 1 portion of this study investigated the maximum tolerated dose of pomalidomide while the Phase 2 portion, which is still ongoing and enrolling, is comparing pomalidomide alone with pomalidomide plus low-dose dexamethasone in relapsed myeloma patients who are also resistant to Revlimid and Velcade.

The results of the Phase 1 portion of the study showed that single agent pomalidomide is effective and safe in this patient population and the addition of dexamethasone can induce a response in patients who were unresponsive to pomalidomide alone.

“The activity of this drug is promising, and we have been impressed with the safety of this drug,” said Dr. Paul Richardson, a myeloma expert from the Dana-Farber Cancer Institute in Boston and lead investigator of this trial.

Four doses of pomalidomide (2, 3, 4 and 5 mg) were tested in 39 relapsed and refractory (resistant) myeloma patients. Participants had received a median of six prior therapies.

Patients received pomalidomide daily for 21 days of a 28 day cycle. Low-dose dexamethasone was added to the treatment regimen if patients did not respond to treatment or if they experienced disease progression. Dexamethasone was added to 20 of the patients’ regimens.

Twenty-five percent of patients achieved a partial response or better, and 50 percent achieved at least a minimal response. Dr. Richardson pointed out that he and his colleagues found that higher doses caused better responses.

The most commonly reported side effects were low blood cell counts.  Dr. Richardson added that the rate of peripheral neuropathy was relatively low.

Based on the findings, the researchers selected 4 mg of pomalidomide as the maximum tolerated dose and to be used in the Phase 2 study.

In Phase 2 of the trial, half of the participants received 4 mg pomalidomide plus dexamethasone, and the other half received 4 mg pomalidomide alone. Patients who received pomalidomide alone could add dexamethasone if they did not respond to the treatment.

As in the Phase 1 trial, patients had to be relapsed/refractory and must have received both Revlimid and Velcade before. Patients had received a median of five prior therapies. About 75 percent had received prior thalidomide, and 75 percent had also received a stem cell transplant.

The researchers have recruited 221 patients for the trial so far. They reported results based on data from the first 120 patients.

Overall, 25 percent of patients achieved at least a partial response.

As in the Phase 1 part of the trial, the main side effect was low blood cell counts, but Dr. Richardson pointed out that they were manageable. The rate of peripheral neuropathy was also low. The researchers did not record any cases of severe neuropathy.

For more information about the three pomalidomide studies, please refer to abstract 859, abstract 863, and abstract 864 on the American Society of Hematology annual meeting website.