Results of a recent small Australian study suggest that multiple myeloma patients who relapse within 12 months of their first transplant may benefit from a second transplant with melphalan plus Velcade as the intensive therapy immediately prior to their second transplant.

Based on these findings, the investigators propose that this regimen be further explored in the context of back-to-back stem cell transplants in patients who are at risk for an early relapse.

The study investigators note, however, that their study was small and retrospective in nature, and that a follow-up study with a larger patient group is needed to confirm these findings.

High-dose chemotherapy coupled with a stem cell transplant is a common therapeutic approach for multiple myeloma patients under the age of 65.

The approach typically uses melphalan (Alkeran) as the chemotherapy agent. It is administered at high doses with the goal of eliminating cancerous cells from the patient's bone marrow. However, because the high-dose melphalan also destroys most of the patient's healthy bone marrow cells, it is followed by a stem cell transplant, during which previously harvested stem cells are reinfused back into the patient.

Many patients who receive a stem cell transplant eventually relapse and require further treatment. According to the Australian researchers, myeloma patients with high-risk chromosomal abnormalities are especially prone to early relapse.

One of the treatment options for patients who relapse after their first stem cell transplant is a second transplant, also called a salvage transplant.

Previous studies have found that salvage transplants are well tolerated. In patients with one to two prior lines of therapy, the overall response rates are between 80 percent and 90 percent. For patients with three to six prior lines of therapy, the overall response rates fall to between 55 percent and 64 percent.

Attempts to increase the efficacy of melphalan by increasing the dosage have not led to any changes in overall survival. However, previous studies have found that combining Velcade (bortezomib) with the melphalan administered prior to stem cell transplants may have an additive anti-myeloma effect, leading to improved outcomes (see related Beacon news).

Preclinical studies suggest that myeloma cells exposed to Velcade may be less resistant to melphalan, meaning that a patient who may not respond to melphalan alone may respond to melphalan if it is given in combination with Velcade. In addition, a recent clinical trial showed that patients who received a dose of Velcade 24 hours after receiving high-dose melphalan experienced better response rates compared to those who received high-dose melphalan after Velcade (see related Beacon news).

In the current study, Australian investigators sought to compare the outcomes of patients who received melphalan and Velcade immediately prior to a stem cell transplant to those who received melphalan alone.

The researchers retrospectively analyzed records for three groups of myeloma patients.

The first group included 23 patients with a median age of 57 who were treated with the combination of melphalan and Velcade immediately prior to a stem cell transplant between 2008 and 2011. These patients had received a median of three prior lines of therapy. Within this group, 70 percent had undergone a prior transplant with high-dose melphalan alone. The remaining 30 percent of patients were recently diagnosed and had never undergone a stem cell transplant, but were considered high-risk due to chromosomal abnormalities or kidney impairment.

The second group included 16 patients with a median age of 58 years who all had a second, salvage, transplant involving only high-dose melphalan. These patients had a median of two prior lines of therapy.

The third and final group consisted of 131 patients who had received an initial stem cell transplant with only high-dose melphalan. They had a median age of 58 years and received their transplants between 2005 and 2011.

Patients in all three groups received 200 mg/m² of melphalan two days prior to their stem cell infusion. Patients with kidney impairment received a reduced dose of 140 mg/m² of melphalan.

The patients who received the melphalan-Velcade combination were given between 1.3 mg/m² and 1.6 mg/m² of Velcade 24 hours after receiving melphalan (or one day prior to their transplant).

The study investigators measured response rates three months after transplantation. Of the patients who received melphalan-Velcade, 65 percent responded to the treatment. Those who received melphalan-Velcade with their transplant demonstrated deeper responses (38 percent with a very good partial response or better), compared to patients who received melphalan alone with their transplant (13 percent); however, the results were not considered statistically significant.

Patients who achieved at least a minimal response after the melphalan-Velcade regimen as part of their transplant demonstrated longer progression-free survival (11 months) and overall survival (32 months), compared to those who did not respond at all (2 months and 3 months, respectively).

The progression-free survival times were similar among patients who received melphalan-Velcade and those who received melphalan alone. However, the median overall survival time was longer for patients who received melphalan-Velcade (24 months), compared to those who received melphalan alone as part of their transplant (13 months).

Among the patients who received a salvage transplant, fewer patients receiving melphalan-Velcade prior to the transplant responded (63 percent), compared to patients receiving melphalan alone (88 percent); however, the difference was not considered statistically significant.

In addition, the median progression-free survival and overall survival times were not significantly different between patients who received melphalan-Velcade prior to a salvage transplant and those who received melphalan alone prior to the salvage transplant.

The study also confirmed that patients who relapsed more than 12 months after their first stem cell transplant experienced longer overall survival compared to those who relapsed earlier (29 months versus 11 months, respectively).

A key result of the study, however, involved the patients in the study who relapsed within 12 months of their first transplant. Among these patients, those who received melphalan-Velcade as part of their transplant had superior overall survival after receiving melphalan-Velcade as part of their second transplant compared to those who received melphalan alone with their second transplant (14.5 months versus 8 months, respectively).

For more information, please see the study in Leukemia and Lymphoma (abstract).