Human primary myeloma cells as well as myeloma cell lines lack the expression of Pax-5 gene and CD19 expression on their surface, and myeloma cells are well known to be heterogeneous with regard to their morphology and surface phenotype. The expression of translineage markers, such as CD33, CD7, CD56, CD4 or CD86, has been reported to be observed in most cases of multiple myeloma, although their positive % in the bone marrow mononuclear cells are variable case by case. We found that the expression of CD33 in Liu01, a subclone fromU266 cells and vitamin D3-treated ILKM3 cells, correlated to the monocytoid morphology with convoluted nuclei and the increased expression of C/EBPα. The expression of CD56 in myeloma cells is also well known, but its meaning remains to be clarified. We examined whether CD56(+) myeloma cells also express either CD7, the NK lineage marker, or neuron-specific enolase (NSE), the neuronal cell marker. The expression of NSE was found in CD56(+) myeloma cell lines (NOP-2 and Liu01 cells) as well as primary myeloma cells both by RT-PCR and immunostaining. The expression of CD7 in Liu01 and forskolin-stimulated U266 cells was observed and compatible with large granules in the cytoplasm, and showed an increase expression of perforin mRNA. However, these findings were not observed in Pax-5(+) B cell lines. Interestingly, IL-6 could downregulate the expression of CD33, CD7 or CD56 in primary myeloma cells as well as Liu01 cells. Therefore, these data suggest that Pax-5(−) myeloma cells, but not Pax-5(+) B cells, are capable of multi-lineage differentiation, and IL-6 can induce their dedifferentiation. We propose here that the myeloma cells dropping out of their lineage (B cell linage) can become stem cell-like cells; we call them “stone cells”(stem cell-like cells dropping out of the lineage).