V-H gene analysis of IgM-secreting myeloma indicates an origin from a memory cell undergoing isotype switch events

IgM-secreting plasma cell tumors are rare variants of typical isotype switc hed multiple myeloma with a similar disease outcome. To probe the origin an d clonal history of these tumors, we have analyzed V-H gene sequences in 6 cases. Potentially functional tumor-derived V-H genes were all derived from V(H)3, with the V-3.7 gene segment being used by 4 of 6. All were somatica lly mutated, with a mean deviation from germline sequence of 5.2% (range, 3 .1% to 7.1%). The distribution of replacement mutations was consistent with antigen selection in 4 of 6 cases, and no intraclonal heterogeneity was ob served. Clonally related switched isotype transcripts were sought in 4 case s, and Cy transcripts with tumor-derived CDR3 sequence were identified in 2 of 4. These findings indicate that IgM-secreting myelomas are arrested at a postfollicular stage at which somatic mutation has been silenced. Isotype switch variants show the cell of origin to be at the IgM to IgG switch poi nt. These features indicate that the final neoplastic event has occurred at a stage immediately before that of typical isotype-switched myeloma. One p ossibility is that IgM myeloma involves the previously identified precursor cell of typical myeloma. (C) 1999 by The American Society of Hematology.