Velcade is approved by the FDA for the treatment of patients who have received one prior therapy. Velcade, alone (sometimes called "monotherapy" or "single-agent") and in combination with other commonly used treatments, has been studied in patients who have previously received therapy.

Data from a number of clinical trials have demonstrated Velcade's efficacy in delaying disease progression, achieving high response rates, and improving survival in patients with relapsed and refractory myeloma. Velcade has also been shown to be highly effective in heavily-pretreated patients, in retreating patients, and at a lower dose of 1.0 mg/m² (versus 1.3 mg/m²).

• Results from the Phase III APEX clinical trial comparing Velcade with high-dose dexamethasone in 669 people with relapsed/refractory myeloma showed that Velcade was more effective than dexamethasone, a known standard of care.^1,2 In this study, patients treated with Velcade had a significantly longer time-to-disease progression (TTP), higher response rates, and improved survival compared with patients treated with high-dose dexamethasone. This trial was ended early due to a significant improvement in time-to-disease progression in patients treated with Velcade and patients treated with dexamethasone were allowed to immediately begin treatment with Velcade.
  
  
  • Improved time-to-disease progression: There was a 78% improvement in the median time-to-disease progression (approximately 3 months) in patients treated with Velcade compared with patients treated with dexamethasone.
  
  
  • Higher response rates: An updated analysis of patients treated with Velcade showed that 9% had a complete response, 7% had a near complete response, and 34% had a partial response. In the initial analysis a complete response was seen in 6% of Velcade treated patients compared with less than 1 percent of patients treated with dexamethasone; 7% of patients treated with Velcade had a near complete response, compared with <1% treated with dexamethasone; and 32% of patients treated with Velcade had a partial response, compared with 17% of patients treated with dexamethasone.
  
  
  • Improved overall survival: Eighty percent of patients treated with Velcade were alive 1 year after Velcade treatment, compared with 67% of patients treated with dexamethasone. These data include patients treated with dexamethasone who later crossed over into the Velcade group, suggesting that the improvements in overall survival may have been greater.


• Results from the Phase II SUMMIT trial of 202 patients with relapsed and refractory myeloma who had already been treated with a median of six prior therapies showed that 35% of patients responded to Velcade with a partial response or better.³ Eighteen percent of patients who did not respond to Velcade alone improved their response with the addition of dexamethasone. The median overall survival was approximately 16 months, compared to a historically expected survival of 6 to 9 months for these patients.


• Results from the Phase II CREST clinical trial of 54 myeloma patients who had previously relapsed during or following upfront therapy showed that 4% of patients treated with a lower dose of Velcade (1.0 mg/m² compared with 1.3 mg/m²) still achieved a complete or near complete response and 19% had a partial response.⁴ When dexamethasone was added, 37% of patients treated with the lower dose of Velcade had a partial or complete response. At the higher dose, patients achieved higher response rates (12% achieved a complete or near complete response, 35% achieved a partial response, and 50% of patients achieved a partial response or better when dexamethasone was added). Notably, patients treated with the lower dose of Velcade had less frequent neuropathy and gastrointestinal side effects.


• Preliminary data from the Phase IV EVEREST trial of myeloma patients who had previously received Velcade (1.0 or 1.3 mg/m²) alone or in combination with dexamethasone suggest that Velcade is effective in retreating patients who have already been treated with Velcade.⁵ Thirty-nine percent of 23 evaluable patients treated with Velcade after having previously been treated with Velcade alone or in combination with dexamethasone had at least a partial response.

Velcade has been shown to be effective in various patient populations.

Elderly and "High-Risk" Patients: Data from the large Phase III APEX clinical trial show that the length of time before myeloma worsened was significantly longer, response rates were better, and one-year survival rates were higher in elderly and other high-risk patients treated with Velcade compared with patients treated with dexamethasone.⁶ High risk patients included patients who had been treated with more than one prior therapy, patients with beta-2 microglobulin higher than 2.5 mg/dL, and/or patients who did not respond to the last prior treatment.

Patients with Chromosome 13 Deletion: Patients with chromosome 13 deletion are understood to have a particularly aggressive form of myeloma that is difficult to treat and has a poor prognosis. Data from the Phase III APEX trial and the Phase II SUMMIT trial show that patients with the chromosome 13 deletion who were treated with Velcade survived as long and had similar response rates to patients who do not have the chromosome 13 deletion.⁷

Patient with Renal Impairment: Renal (kidney) impairment is linked to poor prognosis in patients with multiple myeloma. Data from the Phase III APEX trial show response rates, the length of time before the disease progresses, and the length of time patients survive following treatment were similar among patients with varying degrees of renal impairment who were treated with Velcade.⁸

Based on the success of Velcade alone in treating patients with relapsed and refractory multiple myeloma, several combination treatments are now being used or studied in clinical trials. Data from these studies show that treatment with Velcade combinations have resulted in high response rates and improved disease-free survival.

• Velcade and Doxil: Doxil® (doxorubicin HCl liposome injection, Ortho Biotech) is approved for use in combination with Velcade to treat relapsed and refractory myeloma patients who have not previously received Velcade and who have received at least one prior therapy. Results from a Phase III clinical trial show that patients treated with Velcade and Doxil were disease-free significantly longer (a median time of 6.5 months) than patients treated with Velcade alone (a median time of 9.3 months).⁹


• Velcade and Revlimid with or without Dexamethasone: Preliminary data from a Phase II trial studying the safety and efficacy of Velcade in combination with Revlimid® (lenalidomide, Celgene) and with or without dexamethasone show that the overall response rate (≥ partial response) was 55%.¹⁰ Out of 33 patients evaluated, 36% have achieved a complete response, near-complete response, or very good partial response. Enrollment is ongoing.


• Velcade and Melphalan: Data from a Phase I/II study of 35 patients with relapsed and refractory myeloma found that 47% of patients treated with Velcade and melphalan had a complete response, a near-complete response, or a partial response.¹¹ Median progression-free survival was 8 months for these patients. Please note that melphalan-based combinations are not appropriate for patients considering a stem cell transplant.


• Velcade, Melphalan, Prednisone, and Thalomid: The addition of Thalomid® (thalidomide, Celgene) and Velcade to the standard melphalan/prednisone combination significantly increases patients' response rates and the length of time patients' remain disease-free following treatment when used in the relapsed setting.¹² Of the 30 patients in this Phase I/II study who received this combination, 17% had a complete response and 27% had a very good partial response. Please note that melphalan-based combinations are not appropriate for patients considering a stem cell transplant.

For more information about additional clinical trials evaluating Velcade in relapsed and refractory myeloma, click here.

References

1. Richardson PG, Sonneveld P, Schuster M, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487-2498.
2. Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110(10):3557-60.
3. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609-2617.
4. Jagannath S, Barlogie B, Berenson J, et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004;127:165-172.
5. Sood R, Carloss H, Kerr R, et al. Retreatment with bortezomib alone or in combination for patients with multiple myeloma (MM) following an initial response to bortezomib: a phase IV, open-label trial. J Clin Oncol. 2006;17(9):ix205. Abstract 679P.
6. Richardson PG, Sonneveld P, Schuster MW, et al. Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myeloma. Br J Haematol. 2007;137(5):429-435.
7. Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007;21(1):151-7.)
8. San-Miguel JF, Richardson PG, Sonneveld P, et al. Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study. Leukemia. 2008;22(4):842-849.
9. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25(25):3892-3901.
10. Anderson KC, Jagannath S, Jakubowiak A, et al. Phase II study of lenalidomide (len), bortezomib (Bz), and dexamethasone (Dex) in patients (pts) with relapsed or relapsed and refractory multiple myeloma (MM). J Clin Oncol. 2008(May 20 suppl). Abstract 8545.
11. Berenson JR, Yang HH, Sadler K, et al. Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2006;24(6):937-44.
12. Palumbo A, Ambrosini MT, Benevolo, G, et al. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. Blood. 2007;109(7):2767-2772.