Results from a small Italian Phase 2 clinical trial indicate that Velcade plus dexamethasone, followed by donor lymphocyte infusions, may be an important treatment option for patients who relapse after donor stem cell transplantation.

The findings show that almost two-thirds of the patients responded to the Velcade ^[1] (bortezomib)-dexamethasone ^[2] (Decadron) combination, and that donor lymphocyte infusions deepened the responses achieved with Velcade-dexamethasone.

The study investigators also note that side effects associated with the treatment were manageable and expected, considering the high likelihood of these patients developing transplant-related complications.

The Italian study is important.  Donor stem cell transplants are often viewed as a last line of defense against myeloma.  Indeed, in the Italian study, the donor transplant was the second transplant the patients had received.  All of them had previously received a stem cell transplant using their own stem cells.

The current study, however, confirms previous research showing that, even if a myeloma patient relapses after a donor stem cell transplant, there are still treatment options that can improve patient survival.

As important as the Italian study is, it also leaves unanswered a key question: For patients like the ones who participated in the study, is Velcade the best option to use with donor lymphocyte infusions, or is it better to use a different anti-myeloma drug, such as thalidomide ^[3] (Thalomid) or Revlimid ^[4] (lenalidomide)?

Donor, or allogeneic, stem cell transplantation is a procedure in which a patient receives high-dose chemotherapy followed by an infusion of stem cells from a matched donor in order to replace the cells that were destroyed by the chemotherapy. These stem cells can be from either a related donor, such as a sibling or other relative, or from an unrelated donor.

Once transfused into the patient, the donor stem cells eventually mature into immune cells that hopefully recognize the patient’s myeloma cells as abnormal cells and destroy them. This phenomenon is known as the graft-versus-myeloma effect.

A donor stem cell transplant is different from an autologous stem cell transplant, in which a patient’s own stem cells are collected and returned to the patient following chemotherapy.

Despite its curative potential for multiple myeloma, there is still a high risk of relapse after a donor stem cell transplant. Additionally, donor transplantation is a risky procedure due to the potential for life-threatening complications, such as graft-versus-host-disease (GVHD).

GVHD is similar to the graft-versus-myeloma effect in that the immune cells recognize the patient’s cells as foreign and attack them.  However, with GVHD, the immune cells attack the patient’s healthy cells.

Previous research has shown that donor lymphocyte infusions may be an effective therapy for patients who relapse after donor stem cell transplantation. The procedure involves collecting lymphocytes, a type of white blood cell, from the stem cell donor and infusing them into the patient after the stem cell transplant. The lymphocytes are associated with the same graft-versus-myeloma effect as the donor transplant.

According to the Italian researchers, donor lymphocyte infusions induce a response rate of approximately 30 percent. Previous studies have shown that increasing doses of donor lymphocyte infusions had the highest anti-myeloma activity and were associated with a low rate of GVHD.

In an effort to increase the response rate in patients relapsing after donor transplantation, the Italian researchers combined donor lymphocyte infusions with Velcade-based therapy. They argued that Velcade has shown good response rates in patients relapsing after autologous stem cell transplants and that its side effect profile does not overlap with the common donor transplant-related complications.

The Phase 2 study included 19 multiple myeloma patients with a median age of 57 years who had relapsed after donor stem cell transplantation.

Patients had received a median of two prior lines of therapy.  All had previously received an autologous stem cell transplant.

The median time between the donor transplant and enrollment in the trial was 55 months.

Between 2007 and 2010, patients received three cycles of Velcade plus dexamethasone, followed by a maximum of four increasing doses of donor lymphocyte infusions.

The median follow-up time was 40 months.

The researchers found that 62 percent of patients responded to the Velcade-dexamethasone combination, with 5 percent of patients achieving a complete response, 31 percent a very good partial response, and 26 percent a partial response.

The overall response rate increased to 68 percent after the donor lymphocyte infusions. The researchers point out that many patients were able to deepen their responses with donor lymphocyte infusions. After donor lymphocyte infusions, 19 percent of patients achieved a stringent complete response, 13 percent a complete response, 31 percent a very good partial response, and 6 percent a partial response.

Patients responded for a median of 17 months. The researchers found that patients who developed chronic GVHD, which occurs after 100 days of the transplant, responded significantly longer (29 months) than patients who did not develop chronic GVHD (8 months).

After three years, the progression-free survival rate was 31 percent and the overall survival rate was 73 percent.

Chronic GVHD also had a positive effect on progression-free survival: patients who developed chronic GVHD had a significantly longer three-year progression-free survival (37 months) than patients who did not develop chronic GVHD (8 months). However, overall survival did not differ between the two groups.

According to the researchers, the safety profile of the treatment was acceptable.

The most common side effects included infections (63 percent), peripheral neuropathy (pain, tingling, or loss of feeling in the extremities due to nerve damage) (59 percent), and weakness (32 percent).

In addition, 31 percent of patients developed GVHD. However, the researchers point out that no patients developed extensive chronic GVHD.

The authors of the current study note that the response and survival rates seen in their trial are similar to those that were seen in a retrospective analysis by Dutch researchers.  The Dutch study ^[5] (full text), which was retrospective, also looked at the impact of Velcade-dexamethasone treatment combined with donor lymphocyte infusions in patients who relapsed after a donor stem cell transplant.

The authors of the Dutch study, however, concluded from their findings that treating patients with Velcade and dexamethasone prior to donor lymphocyte infusions "did not result in durable remissions."  Instead, the Dutch researchers suggest that other anti-myeloma drugs, particularly thalidomide, may be a better option for combining with donor lymphocyte infusions.

This is an issue the Italian investigators do not address in their study.  It therefore is one that myeloma specialists will need to investigate further in future research.

For more information on the Italian study, please see the related journal article in Biology of Blood and Marrow Transplantation ^[6] (abstract).