The results of a recent Phase 3 clinical trial indicate that treatment with high-dose melphalan (Alkeran) prior to a stem cell transplant results in a longer period of remission for myeloma patients than treatment with reduced-intensity melphalan. The differences in remission duration were larger for patients younger than 60 years old.

Based on the significant difference in progression-free survival between the two treatment groups, the researchers concluded that high-dose (200 mg/m²) melphalan is more effective in preparing younger, medically fit multiple myeloma patients for stem cell transplants. However, reduced-intensity (100 mg/m²) melphalan may be safer in patients with other health-related complications.

The study investigators recommended further comparison of high- and reduced-intensity melphalan when used in combination with newer agents such as Velcade (bortezomib) or Revlimid (lenalidomide).

Although high-dose melphalan is the most common chemotherapy regimen used to kill residual myeloma cells just before stem cell transplantation, it often causes side effects such as diminished production of blood cells, gastrointestinal problems, and increased risk of infection. In the elderly and those suffering from other serious conditions, these effects are accented and may even be life-threatening.

The results of a prior, retrospective study comparing high-dose and reduced-intensity melphalan suggest that reduced-intensity melphalan may be as effective as high-dose melphalan in treating multiple myeloma while leading to fewer and less severe side effects.

Retrospective studies, which look back at the data of patients already treated, cannot control the execution of the trial and, therefore, may have more sources of bias than prospective studies that select a variable to investigate before treating patients accordingly.

In this prospective Phase 3 study, researchers compared the effectiveness and safety of high-dose and reduced-intensity melphalan regimens in patients with newly diagnosed myeloma.

Doctors randomly assigned 298 patients less than 65 years old to two treatment groups of 149 each, the high intensity group receiving 200 mg/m² melphalan and the reduced-intensity group receiving 100 mg/m² melphalan. Aside from the two different dosages of melphalan, both groups received the same induction treatment – two 28-day cycles of 1 mg/m² vincristine on day 1, 50 mg/m² doxorubin (Adriamycin) on day 1, and 40 mg dexamethasone (Decadron) on days 1 to 4.

Stem cells were collected from the blood stream after one or two cycles of cyclophosphamide and granulocyte colony-stimulating factor (G-CSF), which stimulates stem cell production.

At least one month after stem cell collection and two days before the transplant, patients received a melphalan dose of either 100 mg/m² (reduced intensity) or 200 mg/m² (high intensity).

Patients were given G-CSF to increase their white blood cell counts as well as medications to prevent infection.

The median follow-up time was 44.6 months. Researchers focused primarily on overall survival, and secondarily on progression-free survival and side effects.

Out of the 149 participants who received high-intensity melphalan, 117 (78 percent) achieved at least a partial response, 55 (37 percent) experienced at least a very good partial response, and 22 (15 percent) achieved a complete response. Twenty-seven patients (18 percent) remained stable, and one patient (1 percent) experienced disease progression.

In the reduced-intensity group, 107 patients (72 percent) reached at least a partial response, 32 (21 percent) achieved at least a very good partial response, and 12 (8 percent) achieved a complete response. Thirty-four participants (23 percent) had stable disease, and five (3 percent) progressed.

Overall survival was not significantly different for the two groups. The median overall survival for the reduced-intensity group of patients was 60 months. Based on the number of patients who were still living by the end of the follow-up, researchers could not determine a median overall survival in the high-intensity group. Doctors estimated that at five years, the survival rates would be 62 percent and 48 percent for patients receiving high- and reduced-intensity melphalan, respectively.

Participants in the high-intensity group experienced a significantly greater remission duration than those in the reduced-intensity group (31.4 months versus 26.2 months). The remission duration gap between the two doses was more pronounced in patients under 60 years old.

Patients receiving high-intensity melphalan were more likely to experience at least one serious or life-threatening side effect (45 percent versus 30 percent). Side effects included low white blood cell count (77 percent versus 67 percent), low platelet count (76 percent versus 49 percent), infection (40 percent versus 30 percent), inflammation of the digestive tract (17 percent versus 3 percent), and gastrointestinal problems (11 percent versus 1 percent).

In addition, more patients receiving high-intensity melphalan required platelet transfusions (56 percent versus 38 percent) and antibiotics (41 percent versus 29 percent). In each treatment group, three patients died of complications, including pneumonia, stroke, cardiac failure, brain hemorrhaging, and septic shock.

For more information, please see the study in the journal Blood (abstract) and the clinical trial description (NCT00950768).