Results from a recent Italian Phase 1/2 clinical trial indicate that the combination of Pomalyst, cyclophosphamide, and prednisone is effective and safe in relapsed and refractory multiple myeloma patients.
Overall, 51 percent of patients in the trial responded to the treatment, and the median progression-free survival time was 10.4 months. The median overall survival had not been reached yet; however, 69 percent of patients were alive one year after starting treatment.
The study participants had previously been treated with a median of three prior therapies, and all had received prior treatment with Revlimid (lenalidomide), an agent in the same class of drugs as Pomalyst (pomalidomide, Imnovid). Patients who had relapsed after prior Revlimid treatment had better one-year progression-free survival (72 percent), compared to the overall study population (48 percent), and compared to those who were resistant (refractory) to Revlimid treatment (37 percent).
The response rates and survival outcomes seen in the current study are better than those seen in a recent trial testing the two-drug combination of Pomalyst plus dexamethasone (Decadron) in relapsed and refractory myeloma patients (see related Beacon news).
However, the response rates for the Pomalyst-cyclophosphamide (Cytoxan)-prednisone combination are not as high as those reported for other three-drug combinations that physicians might consider as alternatives, such as Kyprolis (carfilzomib)-Revlimid-dexamethasone and Pomalyst-Velcade (bortezomib)-dexamethasone.
Thus, the Pomalyst, cyclophosphamide, prednisone combination studied in the current trial may be more appropriate for older patients, or for patients whose general health is relatively fragile. Prednisone is often easier for patients to tolerate than dexamethasone, and the Pomalyst-cyclophosphamide-prednisone regimen in the current study did not have many severe side effects.
Indeed, the tolerability of the three-drug combination led the authors of the current study to suggest that, in future trials involving the combination, it may be advisable to use a higher dose of Pomalyst than they used in their trial. The authors also believe that future trials of the combination are warranted given the results of their study.
Background
Pomalyst belongs to the same class of drugs, known as immunomodulatory agents, as Revlimid and thalidomide (Thalomid). They all work by causing a patient’s immune system to attack and destroy cancerous cells.
Pomalyst was approved by the FDA in February for the treatment of myeloma patients who have received at least two prior therapies, including Revlimid and Velcade (bortezomib), and who were refractory to their last therapy. The FDA’s recommended dosing for Pomalyst is 4 mg daily for 21 days out of a 28-day treatment cycle.
Previous studies have shown that the addition of alkylating agents, such as melphalan (Alkeran) and cyclophosphamide, to treatment with novel agents, such as Revlimid or Velcade, increases response rates and, in some cases, prolongs progression-free survival.
The investigators of the current study therefore sought to assess if adding cyclophosphamide to a Pomalyst regimen improved responses in refractory patients.
Study Design
The investigators recruited 69 relapsed and refractory myeloma patients across 12 treatment centers in Italy between August 2010 and May 2012; 24 patients participated in the Phase 1 part of the trial, and 45 participated in the Phase 2 part of the trial. The median age of the patients was 69 years.
Patients had received a median of three prior therapies. All of the patients had previously received Revlimid, 84 percent had previously received Velcade, 20 percent had received thalidomide, and 33 percent had undergone stem cell transplantation.
In addition, 33 percent of patients had relapsed after treatment with Revlimid, 67 percent of the patients were refractory to Revlimid (had relapsed during, or soon after, treatment with Revlimid), and 32 percent were refractory to both Revlimid and Velcade.
Furthermore, 26 percent of the patients had high-risk chromosomal abnormalities.
Phase 1 of the trial was used to determine the maximum tolerated dose of Pomalyst; Phase 2 of the trial assessed the maximum tolerated dose in a larger group of patients.
Pomalyst was administered orally at doses ranging from 1 mg to 2.5 mg per day in the Phase 1 trial and at the maximum tolerated dose of 2.5 mg per day in the Phase 2 trial, in combination with 50 mg of cyclophosphamide and 50 mg of prednisone every other day, for a total of six 28-day treatment cycles.
Patients were then treated with maintenance therapy that consisted of 1 mg of Pomalyst daily and 25 mg of prednisone every other day until relapse or disease progression.
The median follow-up time was 15 months.
Study Results
In the Phase 1 portion of the trial, the investigators determined that the maximum tolerated dose for Pomalyst was 2.5 mg per day.
The results reported hereafter apply to the 55 patients who were treated with the maximum tolerated dose of Pomalyst.
Overall, 51 percent of patients responded to treatment, with 5 percent achieving a complete response, 19 percent a very good partial response, and 27 percent a partial response.
The median time to response was 1.8 months, and the median duration of response had not been reached yet at the last follow-up.
The median progression-free survival time was 10.4 months, and one-year progression-free survival was 48 percent.
One-year progression-free survival was significantly higher among patients who responded to treatment (68 percent), compared to those who did not (26 percent).
In addition, patients who had previously relapsed after Revlimid therapy had improved one-year progression-free survival (72 percent), compared to the overall group of study participants. However, patients who were refractory to prior Revlimid therapy had inferior progression-free survival (37 percent).
The study authors report that younger age also had a positive effect on progression-free survival, although they did not provide specific details on the issue.
The authors also note that high-risk chromosomal abnormalities did not have a statistically significant effect on one-year progression-free survival rate, although there was a trend to such abnormalities having an impact (47 percent one-year progression-free survival in standard-risk patients, versus 35 percent in high-risk patients).
The median overall survival time for all patients had not been reached yet. However, 69 percent of patients were alive one year after treatment initiation.
The investigators also state that the three-drug combination had an acceptable safety profile. The most common severe side effects were low white blood cell counts (42 percent), low platelet counts (11 percent), and low red blood cell counts (9 percent).
Two patients died during the study due to infections considered to be treatment-related.
Comparison Of Results With Other Three-Drug Combinations For Relapsed Myeloma
Several recent trials have investigated three-drug regimens for relapsed myeloma patients.
In a Phase 1 trial of the combination Pomalyst, Velcade, and dexamethasone (PVd), the overall response rate was 73 percent(see related Beacon news). All patients in this trial, however, had previously been treated with both Revlimid and Velcade at some point, and all had received a stem cell transplant. At the same time, the median number of previous therapies in the PVd trial was two, compared to three in the current study, and the median age of the patients in the PVd trial was 60, compared to 69.
In a Phase 2 trial of Kyprolis, Revlimid, and dexamethasone (CRd), the overall response rate was 77 percent (see related Beacon news). Like the patients in the current study, the patients in the CRd study had a median of three previous therapies, but the median age of the patients in the CRd study was 63.
For more information about the Pomalyst-cyclophosphamide-prednisone study, please refer to the article in the journal Blood (abstract) or a slide deck (PDF) with an early analysis of the study results. The slide deck was presented at last years American Society of Hematology annual meeting; it is provided as a courtesy to the Beacon’s readers by Dr. Antonio Palumbo, a co-author of the current study.
