Velcade® (bortezomib)
- Relapsed and Refractory Myeloma, Single Agent
- Relapsed and Refractory Myeloma, Combination Studies
- Newly-diagnosed Myeloma
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Based on the demonstrated efficacy of Velcade in relapsed and refractory disease, its effectiveness and safety when used earlier in the disease process is now being evaluated. Encouraging preliminary data from studies of Velcade alone or in combination with other commonly used agents as initial therapy for myeloma were reported at recent scientific meetings.
Velcade Monotherapy
A Phase II trial of single-agent Velcade was initiated to evaluate the activity and neurotoxicity of the agent in patients with symptomatic, previously untreated disease. (Anderson et al. J Clin Oncol. 2006 ASCO Annual Meeting Proceedings Part I. 2006; 24:18S. Abstract 7504.) In this study, patients received a standard Velcade dosing regimen (1.3 mg/m² on days 1, 4, 8, and 11 of a 21-day cycle) for 8 cycles. Dexamethasone was not permitted. Because peripheral neuropathy has been dose limiting in previous trials, neurologic evaluation was performed before and after treatment, and if significant neuropathy developed. If neuropathy occurred, early intervention with dose modification, medication, and/or dietary supplements was implemented.
Preliminary results from 65 patients evaluable for response (of 66 enrolled) show that Velcade therapy led to a CR rate of 10% and an partial response rate of 30%, for an overall response rate of 40%. The most common adverse events were neuropathy, fatigue, and rash, and were mild-to-moderate in most cases. Of the 65 evaluable patients, 36 (55%) reported neuropathy. Of these, 23 reported Grade 1 neuropathy, 12 reported Grade 2 neuropathy, and 1 developed Grade 3 neuropathy. Peripheral neuropathy resolved in 75% of cases when the Velcade dose was reduced or when the course of therapy was completed. Neurologic data show that underlying small-fiber neuropathy (neuropathy that primarily presents with pain or sensory problems) appears to be more common in myeloma than previously thought, being present in 52% of patients at baseline, and can also develop during Velcade therapy.
The high response rate seen with single-agent Velcade in newly diagnosed disease suggests that the agent may provide a strong foundation for combining with other agents for front-line therapy and underscores why some of the highest recorded response rates in the treatment of front-line myeloma have been seen with various combination therapies that include Velcade (see below).
Preliminary data presented at ASH 2005 suggest that Velcade monotherapy is also effective as front-line therapy in patients with high-risk disease, but further follow-up is required. (Dispenzieri et al, Blood. 2005;106(11). Abstract 2546.)
Combination Therapy
Preliminary results of several combination trials, such as those summarized below, include response rates of up to 95% using various combinations and dosing regimens. A number of studies have shown there is no compromise of stem cell harvest following various Velcade-based regimens and side effects have been similar to that seen in studies in relapsed/refractory disease. These data support the potential utility of Velcade as front-line therapy in patients who are candidates for autologous stem cell transplant as well as for those who are not.
Non-Transplant Candidates
Velcade/Melphalan/Prednisone (V-MP). The addition of Velcade to the standard melphalan-prednisone regimen was evaluated in elderly untreated myeloma patients to determine the optimum Velcade dose and efficacy. (Mateos et al. Blood. 2006. June 13;epub ahead of print.) In this open-label Phase I/II study, patients (median age, 75 yrs) received four 6-week cycles of V-MP (Velcade administered on days 1, 4, 8, 11, 22, 26, 29, and 32) followed by five 5-week cycles (Velcade administered on days 1, 8, 15, and 22). Patients in the first phase of the study received Velcade at 1.0 mg/m² (n=6) or 1.3 mg/m² (n=6) and the remainder (n=48) received Velcade at 1.3 mg/m², determined to be the maximum tolerated dose.
Results show an 89% response rate after a median of 5 cycles of therapy, with 32% of patients achieving a complete response and an additional 11% achieving a near-CR. (These rates are similar to those typically seen only in the transplant setting.) Responses were relatively rapid and likelihood of a response was not affected by cytogenetic abnormalities. Most grade 3/4 toxicities were hematologic in nature and included thrombocytopenia (52%), neutropenia (43%), infection (17%), diarrhea (17%), and anemia (10%).
This study provided the basis for the Phase III VISTA trial comparing V-MP to MP.
Transplant Candidates
Velcade is being evaluated in combination with a number of agents as primary therapy for patients who are candidates for autologous transplant. The table below summarizes key findings from select studies, some of which are described in greater detail below.
Summary of Recent Combination Velcade Trials in Patients with Newly-Diagnosed Myeloma who are Candidates for Transplant |
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*Response rates shown are prior to stem cell transplant (SCT). Following SCT, 57% achieved a CR or near CR and 95% achieved a CR or PR.
†Response rates shown are prior to stem cell transplant (SCT). Following SCT, 33% achieved a CR and 90% achieved a CR or PR.
NR = Not reported
†Response rates shown are prior to stem cell transplant (SCT). Following SCT, 33% achieved a CR and 90% achieved a CR or PR.
NR = Not reported
Velcade +/- Dexamethasone. Preliminary results of a multicenter Phase II trial of Velcade with or without dexamethasone in patients with previously untreated myeloma show that the combination is active as first-line therapy. (Jagannath et al. Blood. 2005;106(11). Abstract 783.) In this study, newly diagnosed patients received Velcade (1.3 mg/m² on days 1, 4, 8, and 11 of a 21-day cycle) for up to 6 cycles and dexamethasone was added if less than a partial response was achieved after 2 cycles or less than a complete response after 4 cycles.
Data from 48 evaluable patients show a response rate of 90% (CR + PR) and a CR/nCR rate of 18% with the combination. Addition of dexamethasone was required in 36 of 48 patients (75%), and 64% of these patients achieved additional responses with the added therapy. Stem cell harvest proceeded without difficulty in 23 of 23 patients attempted and all 23 patients underwent autologous stem cell transplant with complete hematologic recovery.
Side effects in the study were similar to those seen in other Velcade trials and included neuropathy/neuropathic pain (36%), fatigue (20%), constipation (16%), nausea (12%), anorexia (8%), abdominal pain/cramping (6%), neutropenia (12%), thrombocytopenia (4%), diarrhea (8%), and muscle pain (4%), including 2% of patients each experiencing grade 4 thrombocytopenia or neutropenia.
Results from the first 32 patients enrolled in the study were published in June 2005. (Jagannath et al. Br J Haematol. 2005;129(6):776-783.)
Velcade/Thalidomide/Dexamethasone. Velcade has also been found to be highly effective in combination with thal-dex (VTD) prior to transplant. (Wang et al. Blood. 2005;106(11). Abstract 784.) In a small study (n=38), only two cycles of this combination were necessary to achieve remission in 92% of patients with previously untreated myeloma, thus minimizing exposure and toxicity to these novel agents. Overall, toxicity was minor and reversible, with a low incidence of Grade 3/4 adverse events (DVT/pulmonary embolism, 5%; myelosuppression, infection, and neuropathy, 8%). BTD was followed by autologous stem cell transplant, which resulted in all patients responding (PR=66%, CR=34%).
Velcade (PS-341)/Adriamycin/Dexamethasone (PAD). The combination of Velcade, Adriamycin (doxorubicin) and dexamethasone is being evaluated as front-line therapy in a study being conducted in the UK. (Oakervee et al. Br J Haematol. 2005;129(6):755-762.) The rationale to using this regimen is that dexamethasone adds to the efficacy of Velcade, and in the lab, adding a cytotoxic agent such as doxorubicin has a synergistic effect.
In this study, patients receive Velcade at the standard dose (1.3 mg/m² on days 1, 4, 8, and 11 of each 21-day cycle), Adriamycin (0, 4.5, or 9 mg/m² during days 1-4 of each cycle) and dexamethasone (40 mg on days 1-4, 8-11, and 15-18 during cycle 1 and days 1-4 during subsequent cycles). Patients receive 4 cycles of induction therapy prior to stem cell harvest, high-dose melphalan chemotherapy (200 mg/m²), and transplant.
Following PAD, 95% of patients achieved a complete or partial response and 29% achieved a complete or near complete response (CR or nCR, see table below). All but one of the 21 patients treated underwent successful stem cell harvest. Following transplant, the CR/nCR rate increased to 57%. This response rate is similar to the CR rate reported for tandem (double) autologous transplants.
Data from 48 evaluable patients show a response rate of 90% (CR + PR) and a CR/nCR rate of 18% with the combination. Addition of dexamethasone was required in 36 of 48 patients (75%), and 64% of these patients achieved additional responses with the added therapy. Stem cell harvest proceeded without difficulty in 23 of 23 patients attempted and all 23 patients underwent autologous stem cell transplant with complete hematologic recovery.
Side effects in the study were similar to those seen in other Velcade trials and included neuropathy/neuropathic pain (36%), fatigue (20%), constipation (16%), nausea (12%), anorexia (8%), abdominal pain/cramping (6%), neutropenia (12%), thrombocytopenia (4%), diarrhea (8%), and muscle pain (4%), including 2% of patients each experiencing grade 4 thrombocytopenia or neutropenia.
Results from the first 32 patients enrolled in the study were published in June 2005. (Jagannath et al. Br J Haematol. 2005;129(6):776-783.)
Velcade/Thalidomide/Dexamethasone. Velcade has also been found to be highly effective in combination with thal-dex (VTD) prior to transplant. (Wang et al. Blood. 2005;106(11). Abstract 784.) In a small study (n=38), only two cycles of this combination were necessary to achieve remission in 92% of patients with previously untreated myeloma, thus minimizing exposure and toxicity to these novel agents. Overall, toxicity was minor and reversible, with a low incidence of Grade 3/4 adverse events (DVT/pulmonary embolism, 5%; myelosuppression, infection, and neuropathy, 8%). BTD was followed by autologous stem cell transplant, which resulted in all patients responding (PR=66%, CR=34%).
Velcade (PS-341)/Adriamycin/Dexamethasone (PAD). The combination of Velcade, Adriamycin (doxorubicin) and dexamethasone is being evaluated as front-line therapy in a study being conducted in the UK. (Oakervee et al. Br J Haematol. 2005;129(6):755-762.) The rationale to using this regimen is that dexamethasone adds to the efficacy of Velcade, and in the lab, adding a cytotoxic agent such as doxorubicin has a synergistic effect.
In this study, patients receive Velcade at the standard dose (1.3 mg/m² on days 1, 4, 8, and 11 of each 21-day cycle), Adriamycin (0, 4.5, or 9 mg/m² during days 1-4 of each cycle) and dexamethasone (40 mg on days 1-4, 8-11, and 15-18 during cycle 1 and days 1-4 during subsequent cycles). Patients receive 4 cycles of induction therapy prior to stem cell harvest, high-dose melphalan chemotherapy (200 mg/m²), and transplant.
Following PAD, 95% of patients achieved a complete or partial response and 29% achieved a complete or near complete response (CR or nCR, see table below). All but one of the 21 patients treated underwent successful stem cell harvest. Following transplant, the CR/nCR rate increased to 57%. This response rate is similar to the CR rate reported for tandem (double) autologous transplants.
Responses to PAD (Velcade, Adriamycin, and dexamethasone) and Subsequent Stem Cell Transplant (n=21)* |
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CR = complete response; nCR = near complete response; VGPR = very good partial response; PR = partial response
*18 of 21 patients received a stem cell transplant; stem cell harvest was unsuccessful in 1 patient and 2 patients declined transplant.
*18 of 21 patients received a stem cell transplant; stem cell harvest was unsuccessful in 1 patient and 2 patients declined transplant.
The major toxicities seen were peripheral neuropathy and neuropathic pain, which were seen in 48% of patients overall, were primarily grade 1 in severity, generally appeared during cycle 3 or 4, and were improving after completion of therapy. Serious adverse events that were thought to be possibly drug-related included neuropathy, low blood pressure upon standing, and nausea/vomiting, (1 patient each), and shingles (3 patients). Other severe adverse events not thought to be drug-related included line infections (3 patients), other infections (4 patients), and irregular heartbeat (1 patient).
Additional patients enrolled in the study received a reduced dose of Velcade (1.0 mg/m²) as part of the regimen to see if the frequency of neuropathy could be reduced while preserving efficacy. (Popat et al. Blood. 2005;106(11). Abstract 2554.) Seventeen percent of the patients enrolled at this dose (n=18) achieved a CR following PAD therapy. No patients receiving the reduced dose experienced neuropathy greater than grade 1 or 2.
Velcade plus Dexamethasone. The combination of Velcade and high-dose dexamethasone is being evaluated as induction treatment in newly diagnosed patients who are eligible for autologous stem cell transplant. (Harousseau et al. ASCO 2005. Abstract 6653.) In this Phase II IFM study, patients receive standard Velcade dosing for 4 cycles (1.3 mg/m² on days 1, 4, 8, and 11) in addition to high-dose dexamethasone (40 mg on days 1-4 and 9-12 for cycles 1 and 2 and days 1-4 for cycles 3 and 4). Stem cell collection is performed prior to the fourth cycle.
Data on 48 evaluable patients of the 53 patients enrolled were presented at the Myeloma Workshop. An overall response rate of 67% (CR and PR) and a CR rate of 21% was seen after 4 cycles of therapy. Stem cell harvest was successful in all patients who proceeded to transplant (45 patients). After transplant, the overall response rate increased to 90% and the CR rate increased to 31%. A total of 83% of patients received all 16 planned doses of Velcade. Adverse events reported (n=18 patients) were mainly grade 1/2 and included gastrointestinal events (50%), neuropathy (29%), fatigue (29%), skin toxicity (19%), infection (19%), and hematologic toxicities (17%). Grade 3 events included gastrointestinal events (2%), neuropathy (6%), fatigue (2%), skin toxicity (2%), infection (2%), and liver toxicity (4%). Grade 4 gastrointestinal events were seen in 2% of patients.
The data from this study are the basis for a planned randomized Phase III IFM trial that will compare Velcade plus high-dose dexamethasone with VAD (vincristine, Adriamycin, and dexamethasone), a standard induction regimen, in patients up to the age of 65.
Velcade as part of Total Therapy 3. The Total Therapy concept incorporates the use of intensive chemotherapy before and after tandem (double) autologous transplants. Based on the promising results with combination Velcade, thalidomide, and dexamethasone (VTD) in endstage myeloma, investigators at the University of Arkansas are utilizing this combination as part of their Total Therapy 3 regimen for newly diagnosed myeloma. (Barlogie et al. J Clin Oncol. ASCO Annual Meeting Proceedings Part I. 2006;24(18S). Abstract 7519.)
In Total Therapy 3, the combination of VTD and PACE (cisplatin, Adriamycin, cyclophosphamide, and etoposide) is used for induction and stem cell mobilization prior to the transplants, consolidation, and maintenance. Early results on the 247 patients enrolled suggest that VTD-PACE has promising activity as an induction regimen and allows robust stem cell collection, particularly after the first cycle of treatment. An estimated CR/nCR response rate of 80% was seen at 18 months. Grade 3/4 toxicities were mainly hematologic (suppressed blood cell counts), while non-hematologic toxicities were similar to those seen previously with DT-PACE. There was one treatment-related death in the setting of renal failure at diagnosis.
Velcade after previous therapy. The effect of Velcade therapy on stem cell collection in patients who have received prior therapy is being evaluated in a pilot study. (Uy et al. Blood. 2004;104(11). Abstract 541.) Preliminary results indicate that treatment with two cycles of Velcade does not adversely affect stem cell yield or time to engraftment in patients undergoing autologous stem cell transplant who had previously received anthracycline - (eg, doxorubicin) or thalidomide-based therapies.
To be eligible for the study, patients could have received up to five cycles of VAD, DVd (Doxil, vincristine, reduced-dose dexamethasone), or thal-dex and/or up to one cycle of an alkylating agent-based regimen (eg, cyclophosphamide or melphalan). They received two 21-day cycles of Velcade therapy (1.3 mg/m² on days 1, 4, 8, and 11) prior to mobilization and transplant. Following the transplant, patients continued to receive six 35-day cycles of Velcade (1.3 mg/m² on days 1, 8, 15, and 22).
At the time of the meeting, 34 of 40 planned patients were enrolled and 25/25 patients had adequate numbers of stem cells collected within one or two collections. Twenty-three of 23 patients had successfully engrafted and 18 patients were eligible for response between 90 and 120 days post-transplant. Eighty-nine percent of the patients had achieved a CR or PR and 33% had achieved a CR or near CR during that time.
Velcade/Doxil. Combination therapy with Velcade and Doxil was previously shown to be effective and well tolerated in a Phase I trial in patients with relapsed and/or refractory myeloma, which led to its investigation in previously untreated patients. Preliminary results of a Phase II study of this combination as initial therapy that is being conducted by the Cancer and Leukemia Group B (CALGB) were reported at the 10th International Myeloma Workshop in April 2005. (Orlowski et al. Haematologica. 2005;90(suppl. 1):151. Abstract PO.730.) Complete or partial responses were seen in 12 of 15 patients and no patients had progressed at that time. Thus far, the toxicities seen in this study were similar to those seen in the Phase I study.
Additional patients enrolled in the study received a reduced dose of Velcade (1.0 mg/m²) as part of the regimen to see if the frequency of neuropathy could be reduced while preserving efficacy. (Popat et al. Blood. 2005;106(11). Abstract 2554.) Seventeen percent of the patients enrolled at this dose (n=18) achieved a CR following PAD therapy. No patients receiving the reduced dose experienced neuropathy greater than grade 1 or 2.
Velcade plus Dexamethasone. The combination of Velcade and high-dose dexamethasone is being evaluated as induction treatment in newly diagnosed patients who are eligible for autologous stem cell transplant. (Harousseau et al. ASCO 2005. Abstract 6653.) In this Phase II IFM study, patients receive standard Velcade dosing for 4 cycles (1.3 mg/m² on days 1, 4, 8, and 11) in addition to high-dose dexamethasone (40 mg on days 1-4 and 9-12 for cycles 1 and 2 and days 1-4 for cycles 3 and 4). Stem cell collection is performed prior to the fourth cycle.
Data on 48 evaluable patients of the 53 patients enrolled were presented at the Myeloma Workshop. An overall response rate of 67% (CR and PR) and a CR rate of 21% was seen after 4 cycles of therapy. Stem cell harvest was successful in all patients who proceeded to transplant (45 patients). After transplant, the overall response rate increased to 90% and the CR rate increased to 31%. A total of 83% of patients received all 16 planned doses of Velcade. Adverse events reported (n=18 patients) were mainly grade 1/2 and included gastrointestinal events (50%), neuropathy (29%), fatigue (29%), skin toxicity (19%), infection (19%), and hematologic toxicities (17%). Grade 3 events included gastrointestinal events (2%), neuropathy (6%), fatigue (2%), skin toxicity (2%), infection (2%), and liver toxicity (4%). Grade 4 gastrointestinal events were seen in 2% of patients.
The data from this study are the basis for a planned randomized Phase III IFM trial that will compare Velcade plus high-dose dexamethasone with VAD (vincristine, Adriamycin, and dexamethasone), a standard induction regimen, in patients up to the age of 65.
Velcade as part of Total Therapy 3. The Total Therapy concept incorporates the use of intensive chemotherapy before and after tandem (double) autologous transplants. Based on the promising results with combination Velcade, thalidomide, and dexamethasone (VTD) in endstage myeloma, investigators at the University of Arkansas are utilizing this combination as part of their Total Therapy 3 regimen for newly diagnosed myeloma. (Barlogie et al. J Clin Oncol. ASCO Annual Meeting Proceedings Part I. 2006;24(18S). Abstract 7519.)
In Total Therapy 3, the combination of VTD and PACE (cisplatin, Adriamycin, cyclophosphamide, and etoposide) is used for induction and stem cell mobilization prior to the transplants, consolidation, and maintenance. Early results on the 247 patients enrolled suggest that VTD-PACE has promising activity as an induction regimen and allows robust stem cell collection, particularly after the first cycle of treatment. An estimated CR/nCR response rate of 80% was seen at 18 months. Grade 3/4 toxicities were mainly hematologic (suppressed blood cell counts), while non-hematologic toxicities were similar to those seen previously with DT-PACE. There was one treatment-related death in the setting of renal failure at diagnosis.
Velcade after previous therapy. The effect of Velcade therapy on stem cell collection in patients who have received prior therapy is being evaluated in a pilot study. (Uy et al. Blood. 2004;104(11). Abstract 541.) Preliminary results indicate that treatment with two cycles of Velcade does not adversely affect stem cell yield or time to engraftment in patients undergoing autologous stem cell transplant who had previously received anthracycline - (eg, doxorubicin) or thalidomide-based therapies.
To be eligible for the study, patients could have received up to five cycles of VAD, DVd (Doxil, vincristine, reduced-dose dexamethasone), or thal-dex and/or up to one cycle of an alkylating agent-based regimen (eg, cyclophosphamide or melphalan). They received two 21-day cycles of Velcade therapy (1.3 mg/m² on days 1, 4, 8, and 11) prior to mobilization and transplant. Following the transplant, patients continued to receive six 35-day cycles of Velcade (1.3 mg/m² on days 1, 8, 15, and 22).
At the time of the meeting, 34 of 40 planned patients were enrolled and 25/25 patients had adequate numbers of stem cells collected within one or two collections. Twenty-three of 23 patients had successfully engrafted and 18 patients were eligible for response between 90 and 120 days post-transplant. Eighty-nine percent of the patients had achieved a CR or PR and 33% had achieved a CR or near CR during that time.
Velcade/Doxil. Combination therapy with Velcade and Doxil was previously shown to be effective and well tolerated in a Phase I trial in patients with relapsed and/or refractory myeloma, which led to its investigation in previously untreated patients. Preliminary results of a Phase II study of this combination as initial therapy that is being conducted by the Cancer and Leukemia Group B (CALGB) were reported at the 10th International Myeloma Workshop in April 2005. (Orlowski et al. Haematologica. 2005;90(suppl. 1):151. Abstract PO.730.) Complete or partial responses were seen in 12 of 15 patients and no patients had progressed at that time. Thus far, the toxicities seen in this study were similar to those seen in the Phase I study.