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In addition to being a treatment target in myeloma, proteasome inhibition with Velcade may also provide a means of sensitizing resistant myeloma cells to chemotherapeutic agents. Thus, combining Velcade with other agents is a rational approach to treatment.
Velcade is being evaluated in combination with a wide variety of agents for the treatment of relapsed or refractory disease. These agents include:
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Summary of Recent Combination Velcade Trials in Relapsed/Refractory Myeloma
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Velcade/Melphalan. Velcade is being evaluated in combination with melphalan in relapsed or refractory myeloma in a Phase I/II study, based on the synergistic activity of this combination in the laboratory. (Berenson et al. J Clin Oncol. 2006;24(6):937-44.) Patients received reduced-dose Velcade (0.7 or 1.0 mg/m² on days 1, 4, 8, and 11 of each 28-day cycle) plus melphalan at various escalating doses (0.025-0.25 mg/kg on days 1-4).
Thirty-five patients were enrolled and 34 were evaluable for response. Two patients achieved a CR (6%), 3 achieved a near CR (9%), and 11 patients achieved a PR (32%). The maximum-tolerated dose was determined to be 1.0 mg/m² of Velcade and 0.10 mg/kg of melphalan, and responses were observed in 5 of 6 evaluable patients (83%) at this dose. Median progression-free survival for all patients was 8 months. Grade 3 or higher toxicities were mainly related to myelosuppression.
Velcade/Doxil. Velcade is being evaluated in combination with Doxil (liposomal doxorubicin, Ortho-Biotech) in patients with refractory hematologic malignancies, including myeloma. Results of a Phase I study indicate that Velcade may enhance sensitivity to anthracyclines (doxorubicin or related compounds) and overcome anthracycline resistance. (Orlowski et al. Blood. 2005;105(8):3058-65.)
The Phase I study included 24 patients with relapsed and refractory myeloma, about half of whom had disease that did not respond to previous therapy with anthracyclines. Patients received Velcade doses of 0.9 to 1.5 mg/m² in addition to 30 mg/m² of Doxil. The maximum tolerated dose as defined from the first cycle of treatment was 1.5 mg/m² of Velcade and 30 mg/m² of Doxil. Therefore, the investigators recommend that the Velcade dose to be tested in combination with Doxil in future studies be 1.3 mg/m².
This combination appears to have significant activity in refractory myeloma. Sixteen of the 22 evaluable myeloma patients (73%) achieved a partial or complete response (PR or CR), including 5 CRs and 3 near CRs. Responses were seen in 9 of 13 patients who had previously not responded to or progressed on anthracycline therapy. Additional data presented at ASCO in 2006 show a median time-to-progression of 9.3 months with the combination of Velcade and Doxil, compared with 3.8 months on the patients’ prior therapy. (Biehn et al. J Clin Oncol. 2006 ASCO Annual Meeting Proceedings Part I. 2006; 24:18S. Abstract 7617.) Median overall survival was 38.3 months.
Toxicities observed with the combination were similar to those observed with either drug alone. The most common side effects included fatigue, nausea, vomiting, constipation, diarrhea, neutropenia, thrombocytopenia, and neuropathy, and were generally manageable. Grade 3 or 4 dose-limiting toxicities seen during the first cycle of therapy included constipation, diarrhea, low blood pressure, fainting, low sodium levels in the blood, neuropathy, neutropenia, and thrombocytopenia. Grade 3 or 4 toxicities seen in later cycles included gastrointestinal events, fatigue, neuropathy, neutropenia, palmar plantar erythrodysesthesia (PPE), fainting, thrombocytopenia, and weight loss. These toxicities led to dose reductions in patients receiving Velcade at the 1.4 or 1.5 mg/m² dose level.
Velcade/Thalidomide (VT). The combination of Velcade and thalidomide was shown to have notable activity in a study of heavily pretreated, relapsed or refractory myeloma patients. (Zangari et al. Blood. 2005;106(11). Abstract 2552.) In this study, patients receive Velcade (1.0 or 1.3 mg/m² on days 1, 4, 8, and 11 of each 21-day cycle) for 8 cycles and daily oral thalidomide (50-200 mg/day) is added at the second cycle. Dexamethasone is added if there is a suboptimal response (stable or progressive disease) after 3 cycles.
The majority of the 85 patients enrolled in this study to date (84%) had received a stem cell transplant; 66% had received two transplants. Fifty-five percent responded with a partial or complete response and responses were seen in patients who had received prior thalidomide and dexamethasone. For all patients, median event-free survival was 9 months and median overall survival was 22 months. However, event-free survival and overall survival was superior in patients who had not received prior thalidomide and in patients with normal cytogenetics. The combination was tolerable in this heavily pretreated population. The most common Grade 3 or 4 toxicity was myelosuppression (thrombocytopenia and neutropenia).
Thirty-five patients were enrolled and 34 were evaluable for response. Two patients achieved a CR (6%), 3 achieved a near CR (9%), and 11 patients achieved a PR (32%). The maximum-tolerated dose was determined to be 1.0 mg/m² of Velcade and 0.10 mg/kg of melphalan, and responses were observed in 5 of 6 evaluable patients (83%) at this dose. Median progression-free survival for all patients was 8 months. Grade 3 or higher toxicities were mainly related to myelosuppression.
Velcade/Doxil. Velcade is being evaluated in combination with Doxil (liposomal doxorubicin, Ortho-Biotech) in patients with refractory hematologic malignancies, including myeloma. Results of a Phase I study indicate that Velcade may enhance sensitivity to anthracyclines (doxorubicin or related compounds) and overcome anthracycline resistance. (Orlowski et al. Blood. 2005;105(8):3058-65.)
The Phase I study included 24 patients with relapsed and refractory myeloma, about half of whom had disease that did not respond to previous therapy with anthracyclines. Patients received Velcade doses of 0.9 to 1.5 mg/m² in addition to 30 mg/m² of Doxil. The maximum tolerated dose as defined from the first cycle of treatment was 1.5 mg/m² of Velcade and 30 mg/m² of Doxil. Therefore, the investigators recommend that the Velcade dose to be tested in combination with Doxil in future studies be 1.3 mg/m².
This combination appears to have significant activity in refractory myeloma. Sixteen of the 22 evaluable myeloma patients (73%) achieved a partial or complete response (PR or CR), including 5 CRs and 3 near CRs. Responses were seen in 9 of 13 patients who had previously not responded to or progressed on anthracycline therapy. Additional data presented at ASCO in 2006 show a median time-to-progression of 9.3 months with the combination of Velcade and Doxil, compared with 3.8 months on the patients’ prior therapy. (Biehn et al. J Clin Oncol. 2006 ASCO Annual Meeting Proceedings Part I. 2006; 24:18S. Abstract 7617.) Median overall survival was 38.3 months.
Toxicities observed with the combination were similar to those observed with either drug alone. The most common side effects included fatigue, nausea, vomiting, constipation, diarrhea, neutropenia, thrombocytopenia, and neuropathy, and were generally manageable. Grade 3 or 4 dose-limiting toxicities seen during the first cycle of therapy included constipation, diarrhea, low blood pressure, fainting, low sodium levels in the blood, neuropathy, neutropenia, and thrombocytopenia. Grade 3 or 4 toxicities seen in later cycles included gastrointestinal events, fatigue, neuropathy, neutropenia, palmar plantar erythrodysesthesia (PPE), fainting, thrombocytopenia, and weight loss. These toxicities led to dose reductions in patients receiving Velcade at the 1.4 or 1.5 mg/m² dose level.
Velcade/Thalidomide (VT). The combination of Velcade and thalidomide was shown to have notable activity in a study of heavily pretreated, relapsed or refractory myeloma patients. (Zangari et al. Blood. 2005;106(11). Abstract 2552.) In this study, patients receive Velcade (1.0 or 1.3 mg/m² on days 1, 4, 8, and 11 of each 21-day cycle) for 8 cycles and daily oral thalidomide (50-200 mg/day) is added at the second cycle. Dexamethasone is added if there is a suboptimal response (stable or progressive disease) after 3 cycles.
The majority of the 85 patients enrolled in this study to date (84%) had received a stem cell transplant; 66% had received two transplants. Fifty-five percent responded with a partial or complete response and responses were seen in patients who had received prior thalidomide and dexamethasone. For all patients, median event-free survival was 9 months and median overall survival was 22 months. However, event-free survival and overall survival was superior in patients who had not received prior thalidomide and in patients with normal cytogenetics. The combination was tolerable in this heavily pretreated population. The most common Grade 3 or 4 toxicity was myelosuppression (thrombocytopenia and neutropenia).