Results from a recent small Phase 3 clinical trial show that the use of Velcade in preparation for donor stem cell transplantation as well as its use soon after transplantation and as maintenance therapy may be effective in high-risk multiple myeloma patients.

The results also indicate that the use of Velcade (bortezomib) soon after donor trans­­plan­­ta­­tion reduces the risk of developing a life-threatening donor trans­plant-related complication known as graft-versus-host disease.

The researchers note that, similar to other donor transplant protocols, the relapse rate was high. Thus, they recommend study of other novel agents in combination with Velcade to increase the duration of response and lower the risk of relapse.  Since the procedure was well tolerated, they also suggest that their approach should be studied in less heavily pretreated myeloma patients.

Background

Donor (allogeneic) stem cell transplantation has the potential to be a curative therapy for multiple myeloma. During the procedure, the patient receives chemotherapy and/or radiation treatment, which destroy the patient’s diseased stem cells as well as their healthy ones. The patient’s cells are then replaced by stem cells from a healthy donor.

However, donor stem cell transplants are associated with life-threatening side effects, such as graft-versus-host disease (GVHD), a condition in which immune cells from the donor attack the recipient’s cells.

There are two main types of conditioning regimens that can be used prior to stem cell transplantation. The first is known as “high-intensity conditioning” and is designed to destroy as many myeloma cells as possible. These regimens tend to be very toxic, which limits their effectiveness in older patients.

The other type of regimen, known as “reduced-intensity conditioning,” is less intense and less toxic than high-intensity treatments. Due to its lower toxicity, these regimens are particularly useful for older patients and patients who are not as fit.

However, the researchers of the current study point out that patients are more likely to relapse following donor transplants that use reduced-intensity conditioning regimens.  In addition, they state that although reduced-intensity conditioning regimens are less toxic, they have not yet been shown to reduce the risk of GVHD.

Following transplantation, maintenance therapy, a prolonged and often low-dose form of treatment, can be used to prevent disease progression.

Velcade has been shown to enhance the efficacy of melphalan (Alkeran), and the combination has been shown to be safe when used in preparation for autologous stem cell transplantation (using the patient’s own stem cells).  Previous studies also indicate that Velcade may reduce the risk of GVHD.

Thus, the researchers decided to investigate if a reduced-intensity conditioning regimen of Velcade, melphalan, and fludarabine (Fludara) and post-transplantation treatment with Velcade could improve response rates and reduce the risk of GVHD following donor stem cell transplantation.

Study Design

Between November 2007 and February 2010, Spanish researchers enrolled 16 patients who had high-risk multiple myeloma and who were eligible for donor stem cell transplantation. The median age of the patients was 51 years.

Patients were considered “high risk” if they had one or more of the chromosomal abnormalities t(4;14), t(14;16), or del(17p); three or more chromosomal abnormalities; refractory (treatment resistant) myeloma; or myeloma that relapsed after an autologous stem cell transplant.

The patients had received a median of three prior therapies. All had relapsed after a prior autologous stem cell transplant, and 81 percent had previously received Velcade.

Prior to the conditioning regimen, all the patients received two cycles of Velcade and dexamethasone (Decadron). The patients subsequently received a third cycle of only Velcade.

Then, the patients received a reduced-intensity conditioning regimen that consisted of 30 mg/m² of fludarabine daily for five days followed by 70 mg/m² of melphalan daily for two days, and finally one dose of 1.3 mg/m² of Velcade two days prior to stem cell transplantation.

All patients received cyclosporin (Sandimmune) and methotrexate to prevent GVHD.  In addition, 44 percent of the patients received Velcade on days 3 and 7 following transplantation to further reduce the risk of developing GVHD.

All patients also received Velcade maintenance therapy on days 1, 8, 15 of a 28-day cycle for the first two cycles and then on the same days of a 56-day cycle for five additional cycles.  Maintenance therapy was started on day 50 for the first half of the patients and then modified to start on day 78 for the remaining patients to reduce side effects.

The median follow-up time was 2.3 years.

Study Results

The overall response rate 100 days after the allogeneic transplant was 87 percent, with 56 percent achieving a complete response and 31 percent achieving a partial response. An additional 6 percent of the patients remained stable after transplantation.

The researchers state that these results compare favorably to previous donor stem cell transplant protocols, which have shown response rates of up to 73 percent when utilizing back-to-back autologous and donor stem cell transplants.  These prior studies have also included a mixture of newly diagnosed and pretreated myeloma patients.

However, the researchers reported that 63 percent of the patients in their study relapsed a median of 8 months following transplantation, despite the use of Velcade maintenance therapy.

The three-year overall survival rate was 41 percent.  At the time of analysis, 63 percent of the patients had died, either due to relapse (38 percent) or infections (25 percent).

The investigators state that the procedure they used was safe, particularly when Velcade was administered soon after donor stem cell transplantation.

The most common severe side effects of Velcade maintenance therapy were low platelet counts (31 per­cent), peripheral neuropathy (pain, tingling, or loss of sensation in the extremities, 13 percent), and liver damage (13 percent).

Overall, 25 percent of the patients developed severe acute GVHD, which occurs within 100 days of trans­­plan­­ta­­tion, while 19 percent developed moderate acute GVHD. The researchers found, however, that patients who received Velcade soon after transplantation were less likely to develop acute GVHD (28 percent developed moderate GVHD) compared to patients who did not receive Velcade soon after transplantation (44 percent developed severe GVHD and 11 percent developed moderate GVHD).

The rate of treatment-related death at three years was 25 percent. The researchers note that there were no GVHD-related deaths.

For more information, please refer to the study in the British Journal of Haematology (abstract).