Pomalidomide continues to show promise as a treatment for relapsed or refractory multiple myeloma patients, according to updated results from two recent Phase 2 clinical trials.

Findings from the two trials were presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago earlier this month.

“Pomalidomide has been tested in multiple clinical trials … and responses were between 30 percent to up to 65 percent when patients had one to three prior lines of therapy. Most interestingly, this agent is showing responses even in patients who are [resistant to] Velcade or Revlimid,” said Dr. Irene Ghobrial from the Dana Farber Cancer Institute in Boston, who presented a review of some of the pomalidomide results at ASCO.

“Now we have a new immunomodulatory agent that will be added to [our available treatments] for myeloma. This is important for patients who are Velcade and Revlimid refractory. As myeloma patients live longer and longer... they need new agents of therapy, and pomalidomide may be one of those agents,” added Dr. Ghobrial.

Pomalidomide ^[3] (Pomalyst ^[1]) is an immunomodulatory agent, meaning that it works by inducing a patient’s immune system to attack and destroy myeloma cells. It belongs to the same class of drugs as thalidomide ^[4] (Thalomid) and Revlimid ^[5] (lenalidomide).

Pomalidomide is being developed by Celgene Corporation (NASDAQ: CELG), the same company that markets Revlimid and thalidomide in the United States and internationally.

Several studies presented at the 2011 annual meeting of the American Society of Hematology last December showed that pomalidomide may be effective in treating relapsed myeloma patients, including those who are refractory (resistant) to Revlimid or Velcade ^[6] (bortezomib) (see related Beacon ^[7] news).

In April, Celgene submitted an application to the U.S. Food and Drug Administration (FDA) for the approval of pomalidomide as a treatment for relapsed or refractory myeloma (see related Beacon ^[8] news). Celgene announced last week that it also has submitted an application to have pomalidomide approved in Europe, and that the FDA has granted standard review designation to pomalidomide’s application for approval in the U.S.

These developments mean that pomalidomide could be available as a new myeloma treatment in both Europe and the United States by early next year (see related Beacon ^[9] news).

Details of two key ASCO presentations about pomalidomide are summarized below.

Pomalidomide Plus Dexamethasone In Myeloma Patients Resistant To Revlimid Or Velcade

Dr. Ravi Vij of the Washington University School of Medicine in St. Louis presented updated results of a Phase 2 study investigating the efficacy of pomalidomide plus low-dose dexamethasone ^[10] (Decadron) in myeloma patients resistant to Revlimid, Velcade, or both.

Results of the study indicate that pomalidomide plus low-dose dexamethasone may induce a response in heavily pre-treated myeloma patients, including patients who have received a prior stem cell transplant.

“Pomalidomide in combination with low-dose dexamethasone has shown a 30 percent response rate in a population of patients who are heavily pre-treated. The response rate was similar regardless of prior resistance to Revlimid, Velcade, or both, suggesting the lack of cross-resistance between pomalidomide and Revlimid,” said Dr. Vij.

According to Dr. Vij, survival outcomes currently are poor for myeloma patients who relapse after receiving treatment with Revlimid or Velcade.

“Relapsed and refractory multiple myeloma patients refractory to Velcade and immunomodulatory drugs have an overall survival of approximately nine months, and only three months if they receive no therapy following relapse, thus reflecting the poor outcome among these patients,” said Dr. Vij.

“Effective new treatments are urgently needed to improve the outcome of these patients,” he added.

The study discussed by Dr. Vij included a total of 221 relapsed or refractory myeloma patients who had received a median of five prior lines of therapy.

Thirty-nine percent of patients were resistant to Revlimid, 37 percent were resistant to Velcade, 31 percent were resistant to both Revlimid and Velcade, and 21 percent were resistant to both Revlimid and Velcade and had also received a prior stem cell transplant.

In the study, patients were randomized into two treatment groups.

Patients in the pomalidomide plus dexamethasone treatment group received upfront treatment with both pomalidomide (4 mg per day on days 1 to 21 of each 28-day treatment cycle) and dexamethasone (40 mg per week).

Patients in the pomalidomide treatment group received the same schedule of pomalidomide upfront, but did not receive dexamethasone. However, 56 percent of patients in this group began receiving 40 mg of dexamethasone weekly once their disease had progressed.

Patients received a median of five treatment cycles.

Across all patients, the overall response rate was 20 percent. The median time to response was two months. Patients in the pomalidomide plus dexamethasone treatment group had a higher overall response rate than patients in the pomalidomide treatment group (30 percent versus 9 percent).

“Single-agent pomalidomide may not have as much activity, but when combined with dexamethasone, we start seeing higher activity,” said Dr. Ghobrial.

The median progression-free survival was 3.5 months across all patients. Patients in the pomalidomide plus dexamethasone treatment group had a longer median progression-free survival time than patients in the pomalidomide treatment group (3.8 months versus 2.5 months).

The one-year overall survival rate was 59 percent across all patients.

The median overall survival time was similar between patients in the pomalidomide plus dexamethasone treatment group and patients in the pomalidomide treatment group (14.4 months versus 13.6 months).

Patients who had relapsed after receiving Revlimid, Velcade, both, or both along with a stem cell transplant had similar response rates (25 percent, 29 percent, 28 percent, and 34 percent, respectively).

“Overall, whether [patients] were refractory to Revlimid, refractory to Velcade, or refractory to both and had a prior stem cell transplant, the response ranged between 30 and 35 percent, showing again and again that [pomalidomide] is very active in this patient population,” commented Dr. Ghobrial.

Furthermore, patients who had relapsed after receiving Revlimid, Velcade, both, or both along with a stem cell transplant also had comparable median progression-free survival times (3.8 months, 3.8 months, 3.8 months, and 4.6 months, respectively) and one-year survival rates (65 percent, 60 percent, 61 percent, and 67 percent, respectively).

The most common blood-related side effects included a low number of neutrophils (a type of white blood cell) in 38 percent of patients, low red blood cell counts (19 percent), low platelet counts (19 percent), and a low number of leukocytes (another type of white blood cell) in 7 percent of patients.

“As far as the tolerability of [pomalidomide] goes, in the overall population the toxicities were mainly [blood-related],” said Dr. Vij.

The most common non-blood-related side effects included pneumonia (15 percent of patients), back pain (10 percent), shortness of breath (10 percent), and fatigue (9 percent).

There were no severe cases of peripheral neuropathy, a condition characterized by pain and tingling in the hands and feet.

Eighty percent of patients in both treatment groups discontinued treatment during the study, mainly because of disease progression.

Pomalidomide, Clarithromycin, And Dexamethasone In Myeloma Patients Resistant To Revlimid

According to updated results of a separate Phase 2 trial, the combination of pomalidomide, clarithromycin (Biaxin), and dexamethasone – known as ClaPD – is effective in heavily pre-treated relapsed or refractory myeloma patients.

The results of the trial were presented during an ASCO poster session.

Clarithromycin, an antibiotic used to treat bacterial infections, has been shown to improve the anti-myeloma activity of Revlimid and dexamethasone in a combination frontline regimen known as BiRD (see related article in the journal Blood ^[11]).

In the current study, researchers sought to determine whether clarithromycin may also enhance the anti-myeloma activity of pomalidomide plus dexamethasone when used to treat relapsed or refractory disease.

The study included 73 myeloma patients. The median patient age was 63 years. All patients had relapsed after receiving at least three prior lines of therapy, one of which included Revlimid.  The median number of previous therapies was five.

All patients received 4 mg of pomalidomide on days 1 to 21 of each 28-day treatment cycle. In addition, they received 500 mg of clarithromycin twice per day and 40 mg of dexamethasone weekly during each cycle. Treatment continued until disease progression occurred.

Patients received a median of six cycles of therapy.

The overall response rate was 56 percent, with 5 percent of patients achieving a stringent complete response, 18 percent a very good partial response, and 33 percent a partial response.

Patients who were resistant to both Revlimid and Velcade achieved similar overall response rates (58 percent).

The median progression-free survival time was 7.5 months.

After a median follow-up of 12 months, 85 percent of patients are alive and 42 percent remain progression-free.

The most common severe to life-threatening side effects included low white blood cell counts (43 percent of patients), low platelet counts (23 percent), and low red blood cell counts (16 percent).

Future Directions

According to Dr. Ghobrial, several clinical trials have shown that combinations involving pomalidomide can provide high responses in relapsed or refractory myeloma patients. However, several questions about the use of pomalidomide for the treatment of myeloma still need to be addressed going forward.

“We now need to see whether [pomalidomide] can be used in upfront therapy and whether we should replace Revlimid with pomalidomide in upfront therapy for myeloma. And should we also think of pomalidomide maintenance, knowing that Revlimid is used now in maintenance therapy?” said Dr. Ghobrial.

“Should we start thinking of using pomalidomide in high-risk smoldering myeloma? [A previous study] has shown that Revlimid, when used in high risk smoldering myeloma, can improve progression-free survival in these patients. Could we potentially use an active agent like pomalidomide in these patients?” she added (see related Beacon news article ^[12] and interview ^[13]).

Phase 3 clinical trials are currently underway to further investigate the combination of pomalidomide and dexamethasone for the treatment of relapsed and refractory myeloma.

One Phase 3 study comparing pomalidomide in combination with either low-dose or high-dose dexamethasone is currently enrolling patients in Europe, Australia, and Canada.

Another Phase 3 study comparing the combination of pomalidomide, Velcade, and dexamethasone versus Velcade plus dexamethasone is currently being planned in the United States.

For more information, please see abstracts 8016 ^[14] and 8036 ^[15] on the ASCO ^[16] meeting website.  In addition, Dr. Vij has made a copy of his presentation ^[17] (PDF) available for download and viewing as a courtesy to the Beacon's readers.