Consider High-Dose Melphalan as Standard Conditioning for Multiple Myeloma

NANTES, France—As the conditioning regimen for autologous transplantation in multiple myeloma, high-dose melphalan (Alkeran) 200 mg/m² is as effective as, but less toxic than, melphalan 140 mg/m² plus total body irradiation. This approach should be considered as the standard conditioning regimen, French investigators contended at the ASH meeting.

Jean-Luc Harousseau, MD, of the University Hospital Hotel-Dieu, Nantes, France, presented preliminary results from a 42-center study of 442 patients age 65 and younger with newly diagnosed multiple myeloma. The patients were randomized to high-dose melphalan 140 mg/m² plus total body irradiation (TBI) with 8 Gy, or higher-dose melphalan 200 mg/m² alone (HDM200).

Patients first received three cycles of vincristine, Adriamycin , and dexamethasone (VAD), then underwent collection of peripheral blood progenitor cells (PBPC) after priming with G-CSF alone or with cyclophosphamide (Cytoxan, Neosar) plus growth factors. At the time of PBPC harvest, patients were randomly assigned to one of the two conditioning regimens, followed by PBPC autologous transplantation.

Hematologic Toxicity

The analysis included 221 evaluable patients. The two treatment groups were well balanced for initial characteristics, response to VAD, type of PBPC mobilization, and growth factors. Median number of CD34+ cells in the graft was slightly higher in the TBI group.

Hematologic toxicity for the HDM200 group was significantly less than for the TBI group (see Table 1). For extra-hematologic toxicity, the only significant difference was the incidence of grade 3 or higher mucositis (51.5% after TBI versus 29.5% after HDM200; P = .003). There was also more pulmonary and cardiac toxicity with TBI.

There were no toxic deaths with HDM200, but, perhaps because of higher toxicity, four toxic deaths occurred with TBI. The difference was not statistically significant. Clinical outcomes were not significantly different for the two regimens, including percentage of complete remissions (30% for TBI and 33% for HDM200) or complete remissions plus very good partial remissions (41% for TBI and 53% for HDM200).

Median Survival

At a median follow-up of 26 months, median event-free survival was 22 months for TBI and 18 months for HDM200 (not significant). There were no significant differences in 2-year event-free survival (20 months for HDM200 and 30 months for TBI) or overall survival at 26 months (70% for HDM200 and 80% for TBI), Dr. Harousseau reported.

“We concluded there is no significant difference in outcome between these regimens, but the hematologic and extrahematologic toxicities are lower with high-dose melphalan 200. We feel that high-dose melphalan alone should be the standard conditioning regimen for autologous transplantation in patients with newly diagnosed multiple myeloma, and in future protocols we will abandon total body irradiation.”

Since high-dose melphalan 200 is well-tolerated, the investigators have explored higher doses and have shown that 220 mg/m² is feasible, the only adverse event being a high incidence of severe mucositis. A new strategy that combines high-dose melphalan 220 mg/m² with anti-interleukin-6 and dexamethasone, has had “very encouraging results” in 18 relapsed patients, Dr. Harousseau reported.