APEX trial. Final results of the Phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial in relapsed and refractory myeloma were published in the New England Journal of Medicine in June 2005. (Richardson et al. N Engl J Med. 2005;352(24):2487-2498.) Velcade exhibited superior efficacy compared with high-dose dexamethasone, a recognized standard of care in this setting. Patients receiving Velcade had significantly greater time to progression, higher response rates, and improved survival.

The APEX trial enrolled 669 patients whose disease had progressed despite one to three previous therapies. The trial was being conducted in 93 sites in the United States, Canada, and Europe. Velcade (1.3 mg/m²) was administered as an injection for eight 3-week cycles followed by three 5-week cycles. Patients receiving high-dose dexamethasone who experienced progressive disease were eligible to receive Velcade as part of a companion study being conducted at each site.

In December 2003, an independent data monitoring committee recommended an early end to the APEX trial. This was because the findings of a pre-specified interim analysis found a statistically significant improvement in time to disease progression?the primary endpoint of the trial?in patients receiving Velcade compared to patients receiving high-dose dexamethasone. Based on the recommendation of the committee and the notification of regulatory authorities, Millennium halted the control arm of the study. This allowed patients who were currently receiving dexamethasone the option to immediately crossover to Velcade treatment.

Results of the trial show that, compared with high-dose dexamethasone, Velcade resulted in an improved response rate (see table below) and a 78% increase in time to disease progression. Treatment with Velcade was associated with significant improvement in 1-year survival and overall survival versus dexamethasone and was associated with a 41% reduction in risk of death. This is the first and largest randomized study demonstrating a survival advantage in relapsed/refractory myeloma.

A subset analysis was performed on the 251 patients in the study who had earlier-stage disease (ie, they had received only one prior therapy). In this analysis of Velcade as second-line treatment, Velcade was also found to be superior to high-dose dexamethasone in terms of time to progression, overall response rate, and 1-year survival (see table below). Approximately 13% of patients receiving Velcade achieved a complete or near-complete response (6.25% each). The probability of death with dexamethasone was 2.56 times that of Velcade therapy.

Adverse events seen in the APEX trial were predominantly grades 1 or 2, generally resembled those previously reported in the Phase II trials, and were manageable. The most common side effects reported with Velcade or dexamethasone are presented in the table below.

The incidence of serious adverse events was similar in both groups (44% for patients receiving Velcade and 43% for those receiving dexamethasone). The incidence of adverse events of grade 3 or higher was 75% in the Velcade group and 60% in the dexamethasone group. Fourteen percent of patients receiving Velcade experienced a grade 4 adverse event, the most common of which were low platelet or neutrophil counts or elevated calcium levels. Sixteen percent of dexamethasone-treated patients experienced a grade 4 adverse event, the most common of which was high blood sugar.

As in the Phase II studies, thrombocytopenia was transient and characterized by a cyclic decrease in platelet counts followed by recovery. In patients developing grade 2 or higher neuropathy, symptoms improved or resolved in 51% of patients with a median of 3.5 months from first onset.

In summary, this study confirmed the efficacy of Velcade in early relapse, as well as in more advanced disease.

Additional APEX analyses. Data continue to be reported from the APEX trial. Additional analyses of data reported at the American Society of Clinical Oncology meeting in 2005 showed significantly improved outcomes and quality of life in relapsed patients receiving Velcade. In summary:

• Velcade therapy appears to overcome the adverse impact of chromosome 13 deletion on survival or response rates. (Jagannath et al. ASCO 2005. Abstract 6501.) Whereas deletion of chromosome 13 was associated with markedly decreased survival in the dexamethasone arm, it was not associated with a difference in survival or response rate in the Velcade arm. These data are consistent with the findings of the SUMMIT trial, and represent the first time a therapy has overcome this poor prognostic indicator.
  
  
• Velcade was found to be significantly more effective than high-dose dexamethasone in elderly and other high-risk patients with relapsed myeloma (ie, patients with >1 prior therapy, beta–2 microglobulin >2.5 mg/L, and/or refractory to prior treatment). (Richardson et al. ASCO 2005. Abstract 6533.) Median time to disease progression was significantly improved and response rates were significantly higher in these patient populations. Rates of Grade 3/4 adverse events were only slightly higher with Velcade as compared with dexamethasone and rates of serious adverse events were similar in these patient populations.
  
  
• Velcade therapy was associated with better health-related quality of life compared with high-dose dexamethasone therapy. (Lee et al. ASCO 2005. Abstract 6535.) Significantly better outcomes were demonstrated in global health and physical role, cognitive and emotional functioning, and symptoms of neurotoxicity, nausea, shortness of breath, sleep, diarrhea, and financial impact.

Updated data reported at American Society of Hematology meeting in December 2005, including time-to-progression, response rates, survival, time-to-response, and duration of response, continue to support the findings of the original analysis. (Richardson et al. Blood. 2005;106(11). Abstract 2547.) Extended survival data show a 6-month survival advantage in the Velcade arm compared with the dexamethasone arm (median overall survival, 30 vs. 24 mos.), even though 62% of patients in the dexamethasone arm crossed over to Velcade at some point. One-year survival was 80% in the Velcade arm versus 67% in the dexamethasone arm. Data from 333 evaluable patients in the Velcade arm showed an overall response rate of 43% (CR, 9%; nCR, 7%; PR, 34%). Among patients who had received only one prior therapy, the response rate was 51% and median survival was >35 months at the time of the meeting (median not reached).

Additional data from the trial are helping determine optimal usage of Velcade (see box below).

Major Findings From Subanalyses of the APEX Trial Reported at ASH 2005 Sixty-six percent of patients achieved maximum disease reduction during or after their fourth cycle of treatment. (Richardson et al. Blood. 2005;106(11). Abstract 2547.) When they occur, thrombocytopenia and neutropenia typically resolve prior to the next cycle of therapy. As a patient responds to therapy, the severity of thrombocytopenia improves, so early platelet support, rather than dose reduction, might be warranted to maximize the effect of Velcade. (Lonial et al. Blood. 2005;106(11). Abstract 3474.) Patients who respond to Velcade have improvements in their serum alkaline phosphatase levels, suggesting that this may help predict response to therapy. (Zangari et al. Blood. 2005;106(11). Abstract 510.) Dosing modification guidelines were helpful in reducing the incidence of severe peripheral neuropathy with Velcade therapy. In addition, neuropathy was reversible in most patients. (San Miguel et al. Blood. 2005;106(11). Abstract 366.)

Results of an analysis aimed to evaluate the impact of prior autologous stem cell transplant on the APEX results were reported at ASCO in 2006. (Vogl et al. J Clin Oncol. ASCO Annual Meeting Proceedings Part I. 2006;24(18S). Abstract 7546.) The data show that Velcade is consistently superior to dexamethasone in overall response rate, CR rate, and time-to-progression, regardless of prior transplant status. In addition, overall survival is superior in patients who had received a prior autologous stem cell transplant.

Results of a subset analysis of the APEX trial reported at the European Hematology Association meeting in June 2006 indicate that the hematologic adverse events seen with Velcade are both predictable and manageable and are not affected by age and renal function. (Lonial et al. Presented at EHA 2006. Abstract 0492.)

In the study, the average number of cycles of treatment received was six. The median (midpoint) time to response was 38 days (range, 30 to 127 days) and the median duration of response to Velcade alone was 12.7 months (Richardson et al. Data presented at the European Hematology Association [EHA] meeting, 2004. Abstract 304.) The median overall survival was approximately 17 months, compared with a historically expected survival of 6 to 9 months in this patient population. Median time to progression with Velcade alone was about 7 months.

In this study, complete and partial response rates were independent of the number or type of prior treatments. There was a relatively decreased likelihood of response in patients with either greater than 50% plasma cells or abnormal cytogenetics in the bone marrow, and in patients over 65 years of age. Responses were seen in patients with chromosome 13 abnormalities, normally considered a negative prognostic factor.

Certain prognostic factors that indicated high tumor burden were associated with decreased duration of response, time to progression, and overall survival. These prognostic factors included factors such as low albumin level, poor performance status, >50% plasma cells in the bone marrow, elevated C-reactive protein, and lower platelet counts. However, factors such as older age, chromosome 13 deletion, beta-2 microglobulin level, and type or number of prior therapies were not predictive of these time to event parameters. (Richardson et al. Blood. 2005;106(9):2977-81.)

In the SUMMIT trial, adverse events were generally predictable and manageable with medications, increased fluid intake, dose reductions or by stopping treatment temporarily, and/or other supportive care measures as needed. The most commonly reported events are indicated in the table below.

CREST trial. A smaller, open-label Phase II dose-ranging trial that was similar to SUMMIT in design was also conducted. (Jagannath S, et al. Br J Haematol. 2004;127:165-172.) Known as the CREST study, it involved 54 patients who had either progressed on front-line therapy or relapsed at any time after front-line therapy. The patients' median number of prior therapies was 3 (range, 1-7), thus overall they had earlier stage disease than patients in the SUMMIT trial.

Patients received one of two doses of Velcade (1.0 or 1.3 mg/m²) intravenously on days 1, 4, 8, and 11 of a 21-day cycle. The cycle could be repeated up to eight times and dexamethasone could be added if there was low response. Responses were assessed using the same modified Bladé criteria (EBMT/IBMTR/ABMTR criteria) used in the SUMMIT trial.

Response rates are shown in the table below. Eight of 27 patients (30%) receiving Velcade at 1.0 mg/m² achieved a complete or partial response (CR or PR) and 10 of 26 patients (38%) receiving Velcade at 1.3 mg/m² achieved a CR or PR. When dexamethasone was added, the response rate (CR or PR) improved to 37% in the 1.0–mg/m² group and 50% in the 1.3 mg/m² group.

In this study, toxicities were manageable and consistent with those observed in other trials. The most commonly reported side effects included fatigue (70%), diarrhea (44%), fever (41%), constipation (37%), peripheral neuropathy (41%), joint pain (35%), insomnia (35%), headache (31%), limb pain (31%), low platelet counts (30%), and upper respiratory tract infection (30%). There was a trend toward a lower incidence of neuropathy and gastrointestinal events at the 1.0–mg/m² dose compared with the 1.3–mg/m² dose.

This trial provides valuable information to the treating physician who may need to reduce the standard Velcade dose because of side effects because it demonstrated meaningful clinical benefit at the lower 1.0 mg/m² dose.

Combined Phase II analyses. A number of additional safety and efficacy analyses were conducted on data from the Phase II Velcade trials in relapsed/refractory disease. Data on patients in the Phase II trials who received high-dose dexamethasone after they had not responded to, or relapsed after, treatment with Velcade alone show that the addition of dexamethasone was associated with improvement in responses without substantial toxicity. (Jagannath et al. Haematologica. 2006;91(7):929-34.) Of the total 101 evaluable patients who had dexamethasone added to their Velcade regimen, 22% had an improved response. Responses to combination therapy were seen in patients who were refractory to both Velcade and dexamethasone as single agents. Side effects with the combination were similar to those seen with Velcade alone.

A follow-up analysis of the Phase II safety data provided important information regarding neuropathy. (Richardson et al. J Clin Oncol. 2006;24(19):3113-20.) Overall, about 35% of patients experienced peripheral neuropathy, which was mostly Grade 1 (mild) or Grade 2 (moderate). However, 81% of patients entered these trials with some evidence of peripheral neuropathy based upon patient questionnaire. The incidence of severe (Grade 3) neuropathy during treatment was lower in patients without neuropathy at the start of the study than in patients with evidence of neuropathy at that time (4% vs. 14%, respectively). Importantly, severe peripheral neuropathy was reversible in 71% of patients after dose reduction or discontinuation.

Because of the rate of thrombocytopenia seen in the phase II trials, data from the trials and other studies were further analyzed to determine the relationship between therapy and platelet counts. (Lonial et al. Blood. 2005;106(12):3777-84.) The data suggest that Velcade temporarily suppresses the formation of platelets rather than being directly toxic to bone marrow cells. The lowest platelet counts seen during therapy were consistent and averaged about 40% of the platelet counts at baseline. Decreases were dose-related and counts typically returned to baseline during the rest period. The development of severe thrombocytopenia with Velcade therapy appears to be related to a patient's platelet count prior to starting therapy; it was uncommon for a patient to develop severe Grade 4 thrombocytopenia unless his or her initial platelet count was already low (less than 70,000). A normal platelet count in adults is 150,000 to 400,000.

An analysis of limited data on myeloma patients with renal disease in the phase II trials suggests that Velcade can be given safely in patients with severe renal impairment, with response rates and toxicity comparable to those seen in patients with less severe renal impairment. (Jagannath, et al. Blood. 2003;102(11). Abstract 828.)

Open-label extension trial. An open-label extension trial (Study 029) involving patients who had previously received Velcade in a company-sponsored clinical trial was conducted to collect long-term safety and survival data. (Berenson et al. Cancer. 2005;104(10):2141-8.) The 71 patients, whom the investigators' thought would benefit from additional Velcade therapy, included 63 patients who had participated in SUMMIT or CREST and had achieved clinical benefit.

In the extension trial, patients continued to receive Velcade at the dose and schedule used in the original trial. The dose could be increased if there was less than optimal response or modified for toxicity or maintenance. The majority of patients had completed ≥7 cycles of therapy in the original trial and went on to receive a median of 7 cycles (range, 1-24 cycles) of additional therapy in the extension study at the same or a higher dose.

In patients treated with Velcade with or without dexamethasone for almost a year (retreatment or continuation), tolerability was similar to that seen in the original 6-month studies and there was no evidence of cumulative or permanent long-term toxicity. Adverse events were similar to those reported in the Phase II trials in incidence and grade. The primary reasons for discontinuation were lack of efficacy at the time of discontinuation (44%), adverse events (21%), and study closure due to commercial availability of Velcade (22%).