Double autologous stem cell transplantation is the standard treatment in newly diagnosed multiple myeloma (MM) patients younger than 65 years; therefore, optimization of leukapheresis is crucial. We performed a retrospective analysis of 297 leukaphereses comparing semiautomated (V4.7 in 20% of collections) versus automated (V6.0 in 80%) Caridian (COBE) Spectra versions and analyzing the influence of M-protein on the outcome. Both methods gave comparable collection efficiencies (CE%) (53.4% vs. 55.7% in V6.0 and V4.7, respectively) with similar leukapheresis time and processed volume. Harvest volume was higher in V4.7 (P < 0.0001) with similar contamination of red blood cells (RBCs) (P = 0.77) and platelets (P = 0.09) when compared with V6.0. In patients with higher peripheral white blood cells (WBCs), V6.0 with adjusted harvest volume (<700 mL), achieved similar CD34(+) CE% (P = 0.39) and better enrichment of nucleated cells (P < 0.0,002) but higher RBCs (P < 0.0,001) and platelets contamination (P = 0.001), when compared with a larger cycle volume in patients with lower WBCs. In hard to mobilize patients, CD34(+) CE% was significantly more efficient with V4.7 than V6.0 (P < 0.0,001). CD34(+) CE% was unaffected by serologic M-protein, but platelet CE% was higher in the absence of M-protein (P = 0.0,003), without any reduction in peripheral patients platelets. We, therefore, conclude that in the setting of MM patients with a high WBCs count and/or low percentage of peripheral CD34(+) cells, collections with V4.7 or adjusted cycle volume V6.0 gave comparable result in CD34(+) CE%. RBCs and platelets contamination is higher if low cycle volume is chosen. In hard to mobilize patients, V4.7 is advisable.