Results from a recent Spanish study suggest that treatment with a combination of intravenous busulfan and melphalan is as effective as melphalan alone in preparing patients with multiple myeloma for stem cell transplantation.

Given that the busulfan (Busulfex)-melphalan (Alkeran) regimen uses a lower dose of melphalan (140 mg/m²) than the melphalan-only regimen (200 mg/m²), these findings may benefit patients who are unable to tolerate high doses of melphalan.

A previous study found that an oral busulfan-melphalan combination might be more effective but not as safe as melphalan alone in preparing patients for a stem cell transplant (see related Beacon news).

The study’s lead investigator Dr. Javier de la Rubia from the university hospital La Fe in Valencia, Spain, explained that the use of intravenous (IV) busulfan, as opposed to oral busulfan, avoids metabolization of the drug in the liver, thereby avoiding liver toxicity.

“In fact, our study clearly shows that IV busulfan maintains the anti-myeloma effect of the oral busulfan but without the liver toxicity of the oral formulation,” said Dr. de la Rubia.

Based on their findings, the Spanish researchers suggest that the combination be investigated further in prospective clinical trials versus melphalan alone.

However, according to Dr. Muneer Abidi, an associate professor of medical oncology at Wayne State University, who was not involved in the study, results from the current study are unlikely to lead to any changes in clinical practice. He explained that the busulfan-melphalan regimen does not offer an improvement in efficacy over melphalan therapy.

“This trial demonstrates no difference in response and overall or progression-free survival with the busulfan-melphalan preparative regimen,” said Dr. Abidi. “It is unclear if there is going to be a change in standard of care unless better efficacy is evident.”

Currently, many myeloma patients under the age of 65 undergo high-dose chemotherapy followed by stem cell transplantation as part of their initial myeloma treatment regimen.  The high dose chemotherapy, which is referred to as a conditioning regimen, is administered with the intention of eliminating cancerous cells from the patient’s bone marrow.

“The efficacy of auto-transplants [that is, transplants that use patients’ own stem cells] is based on the anti-tumor effect of the conditioning regimen,” explained de la Rubia.

Currently, high-dose melphalan (200 mg/m²) is the most commonly used conditioning regimen in multiple myeloma.

However, some researchers are working to find more effective alternative conditioning regimens.

“The possibility of developing more effective preparative regimens opens the alternative of improving the response rate in patients with multiple myeloma and therefore increasing progression-free survival and maybe overall survival,” said Dr. de la Rubia.

Dr. de la Rubia and his colleagues sought to compare the efficacy and safety of a combination of intravenous busulfan and melphalan against those of melphalan alone.

The researchers recruited 51 newly diagnosed myeloma patients to participate in the study between 2005 and 2009. In preparation for stem cell transplantation, the patients received a combination of intravenous busulfan (9.6 mg/kg over a period of three days) and melphalan (140 mg/m² as a single dose).

The researchers compared the results from these patients to those from 102 patients who had received conditioning with melphalan alone (200 mg/m² either over two days or as a single dose) between 2001 and 2005 as part of a previous study.

The median age of participants in both studies was 61 years. Participants in both studies had comparable disease severity at diagnosis.

All participants had received the same initial treatment, which did not include novel agents. Participants in both studies had responded similarly to the initial treatment.

The median time between diagnosis and stem cell transplantation was between 9.2 and 9.4 months. Median follow-up time was 4.2 years for the busulfan-melphalan group and 5.3 years for the melphalan-only group.

Results from the studies show that the overall and complete response rates after stem cell transplantation were similar for both groups. The overall response rate was 90 percent in the busulfan-melphalan group, compared to 91 percent in the melphalan-only group.

Although the progression-free survival time was longer in the busulfan-melphalan group (2.8 years) than the melphalan-only group (2 years), the researchers found that this difference was not statistically significant. The share of patients remaining progression free after six years was significantly higher in the busulfan-melphalan group (23 percent) than the melphalan-only group (17 percent).

Overall survival was not significantly different between the busulfan-melphalan (5.5 years) and melphalan-only (5.3 years) treatment groups. About 47 percent of patients in the busulfan-melphalan group had died at the time of analysis, as compared to 61 percent in the melphalan-only group.

The most common side effects of both treatment regimens were inflammation of the mucous membranes lining the digestive tract (88 percent in the busulfan-melphalan group and 46 percent in the melphalan-only group), and fever accompanied by an abnormal drop in white blood cell counts (84 percent in the busulfan-melphalan group and 61 percent in the melphalan-only group).

Previous studies have indicated that oral busulfan may be associated with an increased risk of sinusoidal obstructive syndrome (SOS) in the liver. In this condition, small veins in the liver become blocked leading to an enlargement of the liver.  The condition has also been associated with kidney failure.

Results from the current study showed that patients on intravenous busulfan and melphalan did not develop SOS. However, 14 percent of patients in the busulfan-melphalan group developed mild liver toxicity, compared to none in the melphalan group.

About 4 percent of patients died from transplant-related events in the busulfan- melphalan group, compared to 2 percent in the melphalan only group.

For more information, please see the study in Biology of Blood and Marrow Transplantation (abstract).