Findings from a small, retrospective French study show that an autolo­gous stem cell transplant followed by a reduced-intensity donor stem cell transplant may lead to long-term control of multiple myeloma.

With a median follow-up time of seven years, the five-year progression-free and overall survival rates were 26 percent and 52 percent, re­spec­tively.

The results of the current study also show that myeloma patients who receive a donor transplant as part of their first-line of treatment appear to benefit more from the procedure than patients who receive the transplant after relapsing. These findings demonstrate the benefits of early donor transplantation compared to waiting until relapse.

The researchers point out that prolonged follow-up times after donor transplantation seem to be necessary to see the survival benefit of the procedure. They state that the positive impact of donor transplantation in their study did not emerge until two to three years after the procedure.

These findings are in line with another recent European study that showed during long-term follow-up that an autologous stem cell transplant followed by a reduced-intensity donor transplant provided a survival benefit compared to a single or two back-to-back autologous transplants (see related Beacon ^[1] news).

However, an important caveat to these as well as the European results is that many of the patients in both of the analyses did not receive novel agents, such as thalidomide ^[2] (Thalomid), Velcade ^[3] (bortezomib), or Rev­limid ^[4] (lenalidomide), as part of their treatment.

These novel agents have significantly improved the life expectancies of multiple myeloma patients and, in turn, have raised questions about the appropriate role of stem cell transplantation in the treatment of myeloma.

In addition, donor transplants in both studies frequently involved serious complications.  In the current study, for example, 17 percent of the patients died within a year of their donor transplant due to transplant-related complications.

The French researchers therefore recommend that the autologous-donor transplantation approach be investigated further in combination with novel agents, and that such investigation be primarily in high-risk myeloma patients, since high-risk patients are particularly in need of better treatments.

Background

Multiple myeloma continues to be incurable for the majority of patients, despite recent advances in the treatment of the disease.

Donor (allogeneic) stem cell transplantation, however, has the potential to be a curative therapy for myeloma.

As part of the transplantation procedure, a patient is first treated with a “conditioning” regimen, consisting of radiation and/or chemo­therapy, which kills off many of the patient’s myeloma cells.  The conditioning regi­men, however, also kills off many of the patient’s healthy stem cells and blood cells.

Thus, after the conditioning regimen, the patient receives an infusion of stem cells to replenish the cells destroyed during the pre-transplant conditioning regimen.  The stem cells can be ones collected from the patient prior to conditioning therapy, which is known as an autologous transplant, or the cells can be collected from a healthy donor, which is known as an allogeneic transplant.

There are two different kinds of conditioning regimens that can be used as part of the donor transplantation process:  The first includes high-intensity regimens, which are designed to destroy as many myeloma cells as possible. While very effective, these treatments are quite toxic. The second option includes so-called “reduced-intensity” regimens, which are both less intense and less toxic than the high-intensity treatments. Due to their lower toxicity, the reduced-intensity regimens are particularly useful for older patients and patients with other diseases.

Study Design

In the current study, researchers from the Institut Paoli-Calmette in Marseille, France, sought to assess the long-term outcomes of multiple myeloma patients who received an autologous stem cell transplant followed by a reduced-intensity donor transplant.

They retrospectively analyzed the records of 53 multiple myeloma patients who underwent an autologous stem cell transplant followed by a reduced-intensity donor stem cell transplant at their institution between 1999 and 2007.

The median patient age was 50 years. At the time of diagnosis, 87 percent of patients had stage 3 multiple myeloma.

All patients had received initial treatment with a combina­tion of vincristine ^[5] (Oncovin), doxorubicin ^[6] (Adria­mycin), and dexamethasone ^[7] (Decadron) (VAD) or another similar regimen.

Overall, 42 percent of patients were classified as having high-risk disease at the time of diagnosis. These patients received the reduced-intensity donor transplant as part of their first line of treatment, immediately following the autol­o­gous stem cell transplant, which is also known as tandem transplantation.

The remaining 58 percent of patients were classified as having low- and intermediate-risk disease at diagnosis. These patients received the reduced-intensity donor transplant after they had relapsed following at least one autologous transplant.

No patients in the study had initial treatment that included a novel agent, but 38 percent were treated with novel agents after their first relapse and prior to donor transplantation.

The conditioning regimen used prior to autologous transplant was high-dose melphalan (Alkeran).

For the donor transplants, there were two different conditioning regimens used

The median time between diagnosis and the reduced-intensity donor transplant was 34 months, and the median time between the autologous and donor transplants were 10 months.

Following donor transplantation, 21 percent of patients received a median of two donor lymphocyte infusions, a process in which white blood cells from the stem cell donor are infused into the myeloma patient.

The median follow-up time was seven years.

Study Results

The progression-free survival rate for all patients included in the analysis was 26 percent at five years and 24 percent at 10 years.  The researchers found that progression-free survival plateaued after six years.

The patients who received the donor transplant as part of their first-line therapy, however, had a significantly higher five-year progression-free survival rate compared to patients who received the donor transplant after relapsing (41 percent versus 16 percent).

The researchers made a similar observation with regard to the overall survival rate.  Among all of the patients included in the study, the overall survival rate was 52 percent at five years and 32 percent at 10 years.  However, the five-year overall survival rate was 67 percent for those who received the donor transplant as part of their first-line therapy versus 42 percent for those who received it after relapsing.

These results are particularly notable given that the patients who received a donor transplant as part of their front-line therapy were patients who had been classified as having high-risk disease.  The remaining patients, who received a donor transplant at relapse – and who had poorer overall survival outcomes – had been classified as having low- or medium-risk disease.

Graft-versus-host disease (GVHD) was a common side effect among the patients in this study. GVHD is a serious donor transplant-related complication, in which the donor cells recognize the patient cells as foreign and attack them.

Overall, 38 percent of patients experienced acute GVHD, which occurs within 100 days of the transplant. In addition, 59 percent of patients experienced chronic GVHD, which occurs 100 or more days after the transplant.

The researchers found that the development of chronic GHVD had a positive effect on progression-free survival.

Within the first year of donor transplantation, 17 percent of patients died due to transplant-related compli­ca­tions.  Patients who developed acute GVHD were at higher risk of dying from transplant-related com­pli­ca­tions.

Despite the risk of such complications, the authors of the current study believe that the autologous-donor transplantation approach deserves further investigation -- particularly in high-risk myeloma patients, for whom current treatment approaches still are often not very effective, and in combination with novel anti-myeloma therapies.

For more information, please refer to the study in the American Journal of Hematology ^[8] (abstract).