Results of a recent, small German study show that donor stem cell trans­plan­tation followed by Revlimid maintenance therapy may be feasible in heavily pretreated relapsed or refractory multiple myeloma patients.

“For younger and fit patients, [donor] stem cell transplantation followed by maintenance therapy with [Revlimid] is a reasonable treatment option for patients who have already relapsed [after an autologous stem cell transplant],” said Dr. Nicolaus Kröger of the University Hospital Hamburg-Eppendorf in Germany and lead investigator of the study.

Dr. Philip McCarthy of the Roswell Park Cancer Institute in Buffalo, New York, who was not involved in the study, agreed that this treatment regimen may be feasible in younger, high-risk patients, but suggested that further studies are needed to support these findings.

“For a younger, high-risk patient population, the majority of whom have responded to salvage therapy after a failed autologous stem cell transplant, this may be an approach that would need to be confirmed,” said Dr. McCarthy.

Although the study did not directly compare donor transplantation with and without Revlimid maintenance, Dr. Kröger and his colleagues point out that the progression-free survival in this study is higher than in similar studies that have tested donor transplantation without the use of Revlimid maintenance.

At the same time, the researchers note that Revlimid may increase the risk of developing the life-threatening complication graft-versus-host disease.

“There is likely a risk of graft-versus-host disease with Revlimid maintenance following allotransplantation. So, [Revlimid maintenance] after allotransplant should be considered only for progressing disease,” said Dr. McCarthy.

However, Dr. Kröger stated that the “major step forward” in the study is the relatively low rate of treatment-related mortality (6 percent) among the study participants.

Although advances have been made in recent years to lower the treatment-related mortality rate associated with donor transplants, rates in previous studies with similarly heavily pretreated patients have often been around 20 percent.

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 taken 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. A certain type of these immune cells, called T-cells, can 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.

Although a donor stem cell transplant offers a greater potential for a cure than an autologous stem cell transplant, due to the graft-versus-myeloma effect, it also places patients at a greater risk of developing graft-versus-host disease (GVHD).

GVHD is similar to the graft-versus-myeloma effect in that the donor T-cells recognize the patient’s cells as foreign and attack them.  However, with GVHD, the T-cells attack the patient’s healthy cells.

“Graft-versus-host disease is a major side effect of [donor] stem cell transplantation because the new T-cells from the donor attack normal cells from the patient,” said Dr. Kröger.

“However, the T-cells also attack myeloma cells and can reduce the risk of relapse. Therefore, most [cases of] graft-versus-host disease can be controlled by medication, such as steroids,” he added.

Elderly patients or patients with concurrent illnesses also often cannot tolerate the toxicity of conditioning regimens (high-dose chemotherapy) leading up to traditional donor stem cell transplants.

Therefore, in recent years the introduction of reduced-intensity and toxicity-reduced conditioning regimens has enabled more myeloma patients to receive donor stem cell transplants, particularly when prior therapies have failed.

Reduced-intensity conditioning regimens carry a lower risk of death, but also a higher risk of relapse, compared to standard conditioning regimens. Toxicity-reduced conditioning regimens are high-intensity but use drugs that have a lower risk of death.

Previous studies have also suggested that maintenance therapy with Revlimid (lenalidomide) reduces the risk of relapse following an autologous stem cell transplant (see related Beacon news).

However, data on Revlimid maintenance following a donor stem cell transplant are more limited.

In the current study, researchers assessed the effectiveness of a toxicity-reduced donor stem cell transplant – followed by Revlimid maintenance – in reducing the risk of relapse in heavily pretreated myeloma patients.

The study included a total of 33 relapsed or refractory multiple myeloma patients, who were enrolled between July 2006 and November 2010. Patients had a median age of 50 years.

All patients had either relapsed after receiving an autologous stem cell transplant or could not collect enough stem cells for a transplant. Forty-eight percent of patients had relapsed after receiving one prior autologous stem cell transplant, 45 percent after two prior transplants, and 3 percent after three prior transplants.

In addition, 15 percent of patients had received no further treatment after they had relapsed following their most recent autologous stem cell transplant.

The median time between the last autologous stem cell transplant and the donor stem cell transplant was 20 months.

In preparation for the donor stem cell transplant, patients received a toxicity-reduced conditioning regimen consisting of 11.2 mg/kg of busulfan and 120 mg/kg of cyclophosphamide (Cytoxan), both administered intravenously.

To prevent graft-versus-host disease, patients received antithymocyte globulin (ATG) for three days leading up to the donor stem cell transplant as well as CellCept (mycophenolate mofetil) for 28 days and cyclosporine A for up to 180 days after the donor stem cell transplant.

Prior to receiving the donor stem cell transplant, 67 percent of patients were in remission (3 percent complete response and 64 percent partial response), while an additional 9 percent of patients had stable disease.

Following the donor stem cell transplant – but prior to Revlimid maintenance – 83 percent of patients achieved remission (29 percent complete response and 54 percent partial response), while an additional 17 percent had stable disease.

The majority of the patients developed graft-versus-host disease, with 25 percent experiencing mild, 28 percent moderate, and 6 percent severe graft-versus-host disease.

Almost three-quarters (73 percent) of the patients then began Revlimid maintenance at a median of 168 days following the donor stem cell transplant. The remaining patients did not receive Revlimid maintenance because of ongoing graft-versus-host disease, low blood cell counts, or patient request.

Patients who received Revlimid maintenance started with a median dose of 5 mg daily for 21 days, followed by a one-week rest, and repeated this cycle four times. If they did not experience severe side effects after four cycles, patients received additional cycles with increased Revlimid doses. In total, patients received a median of six cycles of Revlimid maintenance.

Following Revlimid maintenance, 94 percent of patients achieved remission (46 percent complete response, 21 percent very good partial response, and 27 percent partial response), while an additional 3 percent had stable disease.

After a median follow-up of 19 months, 42 percent of patients relapsed.  Compared to a 55 percent relapse rate in a previous study of donor transplantation (without Revlimid maintenance therapy), Dr. Kröger said, “A 13 percent reduction in relapse rate at three years is a significant step forward.”

However, Dr. McCarthy said, “There is still a fairly high relapse rate [among the study participants], so a different approach such as maintenance therapy with a proteasome inhibitor alone or in combination with low-dose Revlimid may be worth investigating.”

The estimated three-year progression-free survival rate and overall survival rate were 52 percent and 79 percent, respectively.

According to the study investigators, the increase in the complete response rate following Revlimid maintenance as well as the relatively long three-year progression-free survival rate supports the efficacy of Revlimid maintenance.

However, while referring to Revlimid maintenance, Dr. Kröger commented that there are “two sides of a coin.” Although Revlimid maintenance may reduce the risk of relapse, it may also increase the risk of graft-versus-host disease in myeloma patients following a donor stem cell transplant.

“Revlimid activates [donor] T-cells, and therefore [patients have] a higher risk of [developing] graft-versus-host disease. In contrast, these T-cells also attack myeloma cells, which reduces the risk of relapse,” said Dr. Kröger.

In order to decrease the risk of graft-versus-host disease associated with Revlimid maintenance, Dr. McCarthy suggested using Revlimid in combination with other agents following the donor stem cell transplant.

“[Revlimid] will need to be combined with other agents [such as proteasome inhibitors] that might attenuate the graft-versus-host disease risk and improve the anti-myeloma effect,” said Dr. McCarthy.

The main side effects experienced during  Revlimid maintenance included moderate to severe graft-versus host disease (28 percent of patients), viral infection (16 percent), low platelet counts (16 percent), peripheral neuropathy (16 percent), low white blood cell counts (8 percent), and other infections (8 percent).

During follow-up, 54 percent of patients discontinued Revlimid maintenance due to progressive disease, graft-versus-host disease, low platelet counts, or fatigue.

Within one year of their donor stem cell transplant, 6 percent of patients died from treatment-related com­pli­cations, either from infection or organ failure.

For more information, please see the article in the journal Bone Marrow Transplantation (abstract).