A highly efficient cloning system for in vitro myeloma colony growth could be valuable for screening antineoplastic agents in resistant patients and for testing the effects of purging methods in the context of autologous bone marrow transplantation. In this paper we report the results of experiments intended to improve the myeloma cloning system in plasma clot originally described by Ludwig et al. We tested the effects of the addition of phytohemagglutinin (PHA), coupled with a transformation of the original plasma clot method into a liquid culture system. A statistically higher number of myeloma colonies was observed in the liquid system in the presence of PHA (20 cases, median 84.5 vs. 9.5; p = 0.005), whereas a single variant (either PHA alone or liquid system alone) did not determine any significant growth variation. The increase in the cloning efficiency was evident even in the cases characterized by low bone marrow plasma cell infiltration, suggesting that this method is suitable for the described purposes.