Results of a recent international Phase 3 study demonstrate that the addi­tion of Zolinza to Velcade increases response rates and slightly im­proves progression-free survival in relapsed and refractory myeloma patients compared to treatment with Velcade alone.

Specifically, 56 percent of patients responded to treatment with Zolinza ^[1] (vorin­o­stat) plus Velcade ^[2] (bortezomib) compared to 41 percent of patients treated with Velcade plus placebo.

However, despite improvements in responses, the difference in pro­gres­sion-free survival between the two treatment groups was small. Treat­ment with Zolinza plus Velcade was associated with a 25-day increase in progression-free survival compared to treatment with Velcade plus pla­cebo (from 6.8 months to 7.6 months), which according to the investigators suggests that the observed re­sponses were not durable.

The investigators also note that although the difference in these time spans was statistically significant, it is not clear that it is clinically significant.

The share of patients who experienced severe to life-threatening side effects was similar in both treatment groups, although patients treated with Zolinza plus Velcade had more blood-related side effects. Patients in the Zolinza plus Velcade group also experienced two times as much severe diarrhea and nausea and three times as much fatigue as patients in the Velcade plus placebo group.

Nevertheless the investigators describe the side effects as manageable because patients could tolerate the combination regimen for a prolonged time with the appropriate dose modifications. They suggest that dif­fer­ent treatment schedules for Zolinza and Velcade may decrease the side effects of the combination and, therefore, increase its efficacy.

However, Dr. Ravi Vij from Washington University School of Medicine, who was not involved in the study, doubts that an alternative schedule will be explored in clinical trials.

“At this time, I think very few physicians are prescribing Zolinza for patients with myeloma,” said Dr. Vij. “Also, Merck [the company that markets Zolinza], I believe, has decided not to file for FDA approval despite the trial being reported as positive. I think the toxicity of the combination makes it unappealing.”

According to Dr. Vij, the future of the class of drugs that Zolinza belongs to, called histone deacetylase (HDAC) inhibitors, in multiple myeloma depends to a large extent on the results of the so-called PANO­RAMA-1 study ^[3], a Phase 3 trial that investigates the efficacy and safety of another HDAC inhibitor, pano­bino­stat ^[4], in combination with Velcade and dexamethasone ^[5] (Decadron) in relapsed multiple myeloma pa­tients.

Preliminary results from the current study were presented at the 2011 American Society of Hematology annual meeting (see related Beacon ^[6] news).

Background

Zolinza, which is marketed by the U.S. pharmaceutical company Merck, is an oral drug already approved in the United States for a certain type of lymphoma. It also is approved for a similar use in Canada and Aus­tralia, but not in Europe.

Zolinza is a HDAC inhibitor, which works by increasing the production of proteins that slow cell division and cause cell death. Two other drugs that have been investigated as potential myeloma treatments – pano­bino­stat and Istodax ^[7] (romidep­sin) – belong to the same class of drugs.

Results from previous trials suggest that the addition of HDAC inhibitors may help Velcade kill myeloma cells.

Two Phase 1 clinical studies previously demonstrated the activity of the combination of Zolinza and Velcade, with a generally well-tolerated safety profile.

These results, along with the need for additional therapies to treat patients with relapsed or refractory mye­loma, motivated the investigators to conduct this trial.

Study Design

The Phase 3 study included 637 relapsed and refractory multiple myeloma patients who were treated at 174 treatment centers across 31 countries from January 2009 through September 2011.

The median patient age was 62 years.

Patients in the study had received a median of two prior therapies. The three most common prior treatments were dexamethasone (85 percent of patients in the Zolinza plus Velcade group and 83 percent of patients in the Velcade plus placebo group), melphalan ^[8] (Alkeran) (63 percent and 69 percent, respectively), and tha­lid­o­mide ^[9] (Thalomid) (52 percent and 60 percent, respectively).

In addition, 36 percent of all patients had previously received a stem cell transplant. About one quarter (24 percent) of all patients were previously treated with Velcade, but none were resistant (refractory) to the drug.

Half of the participants in this study received 400 mg of Zolinza on days 1 to 14 and 1.3 mg/m² of Velcade on days 1, 4, 8, and 11 of a 21-day treatment cycle. The other half received Velcade plus placebo.

The median follow-up time was 14.2 months.

Results

More patients receiving the Zolinza plus Velcade combination responded to treatment (56 percent) than patients receiving Velcade alone (41 percent).

More specifically, 8 percent of patients in the Zolinza plus Velcade group achieved a complete response and 48 percent a partial response, while 5 percent of patients in the Velcade only group achieved a complete response and 35 percent a partial response. In addition, 15 percent of the Zolinza plus Velcade group and 13 percent of the Velcade only group achieved a minimum response.

Patients treated with Zolinza and Velcade responded more quickly to treatment (36 days) than those treated with Velcade alone (43 days).

In addition, progression-free survival time was longer in patients who received Zolinza plus Velcade (7.6 months) than in patients treated with Velcade alone (6.8 months).

The study investigators note significant treatment-dependent differences in progression-free survival in favor of Zolinza plus Velcade treatment for patients without previous Velcade or Kyprolis ^[10] (carfilzomib) treatment, patients with previous thalidomide or Revlimid ^[11] (lenalidomide) treatment, patients with non-refractory dis­ease, patients younger than 65 years, women, patients with less advanced myeloma, and patients with only one previous treatment regimen.

^[12]
Click on image to view a larger version of it.

Overall survival was similar for the two groups, with a median overall survival time of 28 months for patients in the Velcade only group and the median overall survival not yet being reached for the Zolinza plus Velcade treatment group.

(Click here ^[12] or on the image to the right to see a larger graph of the overall survival results.)

The share of patients who experienced severe to live-threatening side effects was similar for both treatment groups (41 percent of patients in the Zolinza plus Velcade group and 43 percent in the Velcade only group).

However, more patients in the Zolinza plus Velcade group than in the Velcade group experienced blood-related side effects. The most common of these were low platelet counts (45 percent versus 24 percent), low white blood cell counts (29 percent versus 25 percent), and anemia (17 percent versus 13 percent).

The investigators also note increases in severe fatigue (17 percent versus 5 percent), diarrhea (16 percent versus 8 percent), nausea (8 percent versus 4 percent), and vomiting (7 percent versus. 4 percent) among patients in the Zolinza plus Velcade group.

Half (50 percent) of the patients in the Zolinza plus Velcade group required at least one dose reduction, compared with 25 percent of patients in the Velcade group. Overall, more patients needed Velcade dose reductions than Zolinza or placebo reductions. More patients (63 percent) in the Zolinza plus Velcade group needed at least one Velcade dose reduction than did patients in the Velcade only group (49 percent).

The share of patients who discontinued treatment due to side effects was almost the same in both treat­ment groups (21 percent of the Zolinza plus Velcade group and 22 percent of the Velcade only group). Also similar was the proportion of patients who died due to complications of side effects (3 percent of the Zolinza plus Velcade group and 5 percent of the Velcade group).

When the data was collected in September 2011 for the analysis, 7 percent of patients remained on treat­ment and 93 percent had discontinued treatment.

For more information, please refer to the study in The Lancet Oncology ^[13] (abstract).