In a recent study, Spanish researchers found that oral busulfan increased progression-free survival following stem cell transplant in newly diagnosed multiple myeloma patients compared to melphalan. However, there was no difference in overall survival between the two treatments.  Furthermore, oral busulfan treatment was associated with an increased risk of death due to the drug’s side effects.

The current standard of care for multiple myeloma patients under the age of 65 is treatment with high dose chemotherapy followed by stem cell transplant.  High dose chemotherapy prior to stem cell transplant, often called a conditioning regimen, is administered with the intention of eliminating cancerous cells from the patient’s bone marrow.

Melphalan (Alkeran), administered as a single dose of 200 mg/m² (MEL200), is currently the most widely accepted conditioning regimen for multiple myeloma.

However, little research has focused on improving the efficacy of the conditioning regimen, which may result in better responses following stem cell transplant.

“I think this study will stimulate the investigation of more efficient conditioning regimens for multiple myeloma, since very little has been done in this field in the past,” said Dr. Juan Jose Lahuerta, principal investigator of the study, in an email to The Myeloma Beacon.

The goal of this study was to compare a conditioning regimen that included busulfan (Myleran) to the standard MEL200 regimen.

Of the 767 newly diagnosed multiple myeloma patients under the age of 70 enrolled in the study, 225 received oral busulfan (12 mg/kg) followed by a single dose of melphalan 140 mg/m² (BUMEL). The remaining 542 patients received a MEL200 conditioning regimen.

At the time of the transplant, no statistical differences were seen between the BUMEL and MEL200 conditioned groups.  The average time to stem cell collection and platelet engraftment, meaning that the stem cells began producing platelets again, was similar.  Furthermore, the hospitalization time averaged 20 days for both groups.

Responses to treatment were similar between both groups.  Partial response or better after the stem cell transplant was seen in 90 percent of BUMEL-conditioned patients compared to 92 percent of MEL200 patients.

Time to disease progression was significantly improved in the BUMEL conditioned group. Five years after the transplant, 39 percent of patients in the BUMEL-conditioned group remained progression free compared to 21 percent of MEL200 conditioned patients.

At the time of follow up, the median progression-free survival for BUMEL-conditioned patients was 41 months, compared to 31 months for those who received MEL200.

Despite the improved progression-free survival of BUMEL-treated patients, the overall survival between the two groups was similar.

The median time of survival was 79 months for BUMEL-conditioned patients and 71 months for those who received MEL200. The five-year overall survival rates for BUMEL and MEL200 patients were 55 percent and 57 percent, respectively.

Patients who received the BUMEL conditioning regimen were at a significantly increased risk of developing veno-occlusive disease compared to those who received MEL200.

Veno-occlusive disease is a complication of high-dose chemotherapy in which some of the small veins of the liver are blocked. Patients with veno-occlusive disease often experience weight gain due to fluid retention and increased liver size.  The condition is also associated with kidney failure.

Of those patients who received BUMEL conditioning, 8 percent were diagnosed with veno-occlusive disease, compared to less than 1 percent of patients who received MEL200.  In 3 percent of BUMEL patients, death was directly attributed to veno-occlusive disease, compared to less than 1 percent of patients in the MEL200 group.

Furthermore, a higher percentage of patients in the BUMEL group died within 100 days of transplant from causes other than multiple myeloma, including stroke and infection in the blood stream.  Of those treated with BUMEL, 5 percent died from such complications, compared to 3 percent treated with MEL200.

The researchers concluded, “Our analysis suggests that BUMEL may have greater anti-myeloma activity than MEL200; however, this should be balanced against its higher toxicity profile and treatment related mortality.”

They suggested that the study be extended using the intravenous formulation of busulfan, which other studies have demonstrated to reduce or eliminate the risk of veno-occlusive disease.

For more information, please see the full article in Haematologica.