Two phase II studies with Bortezomib ( Velcade ) showed very high response rates in front-line multiple myeloma.
Overall response rates ranged from 88 to 95 percent with complete and near complete responses ranging from 25 to 29 percent.
Use of Bortezomib in the front-line setting allowed for successful stem cell transplants for these patients.

A complete and near complete response rate of 57 percent was reported following single stem cell transplant preceded by induction with Bortezomib, Doxorubicin and Dexamethasone ( PAD ).
This response rate was similar to the complete and very good partial response rates previously published for tandem transplants.

Bortezomib, the first of a new class of medicines called proteasome inhibitors, is the first treatment in more than a decade to be approved for patients with multiple myeloma and is currently approved for the treatment of patients who have received at least one prior therapy.

" These data indicate that earlier use of Bortezomib may improve overall response outcomes for multiple myeloma patients," said James Cavenagh, principal investigator of the PAD study at St. Bartholomew's Hospital, West Smithfield, London.

Bortezomib for injection alone and in combination with Dexamethasone

The multicenter phase II study, led by Sundar Jagannath, assessed the efficacy and safety of Bortezomib as a single agent and in combination with standard therapy dexamethasone in patients with previously untreated, symptomatic multiple myeloma.

Patients were treated for up to six cycles with Bortezomib.
Dexamethasone was administered the day of and the day after Bortezomib if less than a partial response ( PR ) after cycle two or less than a complete response ( CR ) after cycle four was achieved.
Patients received a median of six cycles. Response was assessed according to the European Group for Blood and Marrow Transplantation ( EBMT ) criteria. Results from 32 evaluable patients included:

- Overall response rate ( CR+PR ) for Bortezomib alone or in combination with Dexamethasone was 88 percent with a complete and near complete response rate of 25 percent;

- After two cycles of therapy, single agent Bortezomib achieved a response rate of 40 percent;

- Six of eight patients who achieved complete or near complete responses did so on Bortezomib alone;

- Survival at one year was 87 percent with a median follow-up of 5.5 months; and

- Improved response after the addition of dexamethasone was observed in 68 percent of patients who received Dexamethasone.

Stem cell harvesting and engraftment was successful for all transplant patients in this study. Adverse events were reported to be manageable and included gastrointestinal events, neuropathy, myalgia, fatigue, and hematologic toxicities.

PAD induction therapy prior to Stem Cell Transplant

The multicenter phase I/II study, led by Cavenagh, assessed Bortezomib in combination with Doxorubicin and Dexamethasone ( PAD ) as induction therapy prior to stem cell transplant in previously untreated multiple myeloma patients.
Four cycles of PAD therapy were administered to patients. Thereafter, patients underwent stem cell mobilization, and the ability to adequately harvest peripheral blood stem cells was evaluated. High-dose Melphalan was administered, peripheral blood stem cells were infused, and the rate of hematologic recovery was assessed. Response, based on EBMT criteria, was measured after each cycle of PAD and three months after transplantation. Results from the 21 patients included:

- Overall response rate ( CR+PR ) was 95 percent with a complete and near complete response rate of 29 percent;

- Stem cell collection was adequate in 20 of 21 patients;

- Eighteen of 20 patients were successfully transplanted as two patients declined transplant;

- Post-transplantation, the overall response rate at three months was 95 percent with a 57 percent complete and near complete response rate; and

- No dose limiting toxicities occurred and adverse events included infections, hyperglycemia, peripheral neuropathy, postural hypotension, gastrointestinal events and atrial fibrillation.

The works have been published in the British Journal of Haematology.

Bortezomib is contraindicated in patients with hypersensitivity to Bortezomib, boron, or mannitol.
Risks associated with Bortezomib therapy include new or worsening peripheral neuropathy, hypotension, cardiac disorders, gastrointestinal adverse events, thrombocytopenia and tumor lysis syndrome. Women of childbearing potential should avoid becoming pregnant while being treated with Bortezomib.

In 331 patients who were treated with Bortezomib in a phase III study, the most commonly reported adverse events were asthenic conditions ( 61% ), diarrhea ( 57% ), nausea ( 57% ), constipation ( 42% ), peripheral neuropathy ( 36% ), vomiting ( 35% ), pyrexia ( 35% ), thrombocytopenia ( 35% ), psychiatric disorders ( 35% ), anorexia and appetite decreased ( 34% ), parasthesia ( 27% ), dysesthesia ( 27% ), anemia and headache ( 26% ), and cough ( 21% ). 14% of patients reported at least one episode of grade 4 toxicity; the most common grade 4 toxicities were thrombocytopenia ( 4% ), neutropenia ( 2% ), and hypercalcemia ( 2% ). A total of 144 patients on Bortezomib ( 44% ) reported serious adverse events ( SAEs ) during the study. The most commonly reported SAEs were pyrexia ( 6% ), diarrhea ( 5% ), dyspnea and pneumonia ( 4% ), and vomiting ( 3% ).

Source: Millennium, 2005


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