High-dose therapy for refractory multiple myeloma: Improved prognosis with better supportive care and double transplants

One hundred and thirty-five patients with advanced and refractory myeloma received one of three high-dose therapy regimens: melphalan at doses of 90 to 100 mg/m² (MEL 100; 47 patients) without autotransplant; total body irradiation (TBI; 850 cGy) with either melphalan 140 mg/m² or thiotepa 750 mg/m² and autologous bone marrow transplant (ABMT) (≤30% plasma cells; 21 patients); melphalan 200 mg/m² (MEL 200) supported by both peripheral blood stem cells (PBSC) and ABMT plus GM-CSF intended as a double-transplant program (67 patients; 42 have completed and 3 are still awaiting a second autotransplant; 5 additional patients received an allograft for their second transplant). Mortality within 2 months of therapy was 20% to 25% with MEL 100 and TBI regimens, but less than 1% with MEL 200, mainly because severe neutropenia (<500/μL) was shortened to less than 1 week due to infusion of PBSC and use of growth factor therapy. Low β2-microglobulin (β2M) levels ≤2.5 mg/L and MEL 200 therapy were identified as the two most important independent favorable variables associated with prolonged event-free survival (EFS) and overall survival (OS). On the basis of these two parameters, three risk groups were defined: 29 good-risk patients with low β2M receiving MEL 200 had the best outcome, with median durations of EFS of 37 months and projected OS of ≥43 months; 54 intermediate-risk patients displaying one of the two favorable parameters had EFS and OS durations of 16 and 36 months, respectively; and 52 poor-risk patients with high β2M not receiving MEL 200 had a dismal prognosis, with EFS of 3 months and OS of 5 months (all P < .0001). Further analysis that excluded treatment as a variable identified high β2M and resistant relapse as the two major adverse prognostic factors, one of which was present in 80% of the 135 patients. Among these 108 high- risk patients, prognosis was improved markedly with MEL 200 because of both better supportive care (PBSC and hematopoietic growth factors) and more intensive therapy using the double-transplant approach. This study supports the concept that safer and potentially more-effective therapies can be developed in the setting of advanced and resistant disease.